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High incidence of obstructive sleep apnea syndrome in patients with late-onset epilepsy
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High incidence of obstructive sleep apnea syndrome in patients with late-onset epilepsy Incidence élevée du syndrome d’apnées obstructives du sommeil chez les patients avec épilepsie de survenue tardive Aude Maurousset ∗, Bertrand De Toffol , Julien Praline , Julien Biberon , Nadège Limousin Department of neurology, Inserm U930, university hospital Bretonneau, 2, boulevard Tonnellé, 37044 Tours cedex 9, France Received 21 May 2016; accepted 23 November 2016
KEYWORDS Late-onset epilepsy; Leukoaraiosis; Obstructive sleep apnea syndrome; Polysomnography
∗
Summary Objectives. — The objective of the present study was to evaluate the prevalence of obstructive sleep apnea (OSA) in patients with late-onset epilepsy (LOE) who were considered at higher risk of cardiovascular disease. Methods. — Polysomnography was performed on 27 patients with LOE. Berlin questionnaires and Epworth sleepiness score were performed on all patients. We compared clinical, demographic and anthropometric characteristics, questionnaire scores on the patients with no or mild OSA (group 1) and the patients with moderate or severe OSA (group 2). Patients eligible for continuous positive airway pressure (CPAP) therapy were reviewed in consultation. Results. — Twenty-four patients (88.9%) had OSA and 55.6% had moderate or severe OSA. Patients in group 2 (n = 15) were older than patients in group 1 (n = 12). The two groups were similar in terms of body mass index (BMI), neck circumference, nocturnal seizure frequency, vascular cardiovascular risk factors and excessive daytime sleepiness. Leukoaraiosis in MRI was highly prevalent in our patients (40.7%), especially in group 2 patients. Eighty percent of the patients who had begun CPAP therapy experienced decreased seizure frequency. Conclusion. — Patients with LOE should be screened for the presence of OSA and treated accordingly. © 2016 Elsevier Masson SAS. All rights reserved.
Corresponding author. E-mail address: [email protected] (A. Maurousset).
http://dx.doi.org/10.1016/j.neucli.2016.11.002 0987-7053/© 2016 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Maurousset A, et al. High incidence of obstructive sleep apnea syndrome in patients with late-onset epilepsy. Neurophysiologie Clinique/Clinical Neurophysiology (2016), http://dx.doi.org/10.1016/j.neucli.2016.11.002
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MOTS CLÉS Épilepsie débutant à un âge tardif ; Leuco-araïose ; Polysomnographie ; Syndrome d’apnées obstructives du sommeil
Résumé Objectif. — L’objectif de cette étude était d’évaluer la prévalence du syndrome d’apnées obstructives du sommeil (SAOS) chez les patients débutant une épilepsie à un âge tardif et qui sont donc considérés à haut risque cardiovasculaire. Méthodes. — Une polysomnographie a été réalisée chez 27 patients ayant débuté une épilepsie à un âge tardif. Un questionnaire de Berlin et une échelle de somnolence d’Epworth ont été réalisés chez tous les patients. Nous avons comparé les caractéristiques cliniques, démographiques et anthropométriques ainsi que les questionnaires de sommeil chez les patients n’ayant pas ou ayant un léger SAOS et les patients en ayant un modéré ou sévère. Les patients éligibles à un traitement par continuous positive airway pressure (CPAP) ont été revus en consultation. Résultats. — Vingt-quatre patients (88,9 %) avaient un SAOS et 55,6 % avaient un SAOS modéré ou sévère. Les patients du groupe 2 (n = 15) étaient plus vieux que ceux du groupe 1 (n = 12). Les deux groupes étaient similaires en termes d’index de masse corporelle (IMC), de circonférence cervicale, de fréquence des crises nocturnes, de facteurs de risque cardiovasculaire et de somnolence diurne excessive. La leuco-araïose sur l’IRM était fréquente chez nos patients (40,7 %), surtout chez ceux du groupe 2. Parmi les patients qui ont débuté un traitement par CPAP, 80 % ont eu une diminution de la fréquence des crises. Conclusion. — Le SAOS doit être recherché chez les patients débutant une épilepsie à un âge tardif et traité s’il est présent. © 2016 Elsevier Masson SAS. Tous droits r´ eserv´ es.
Introduction
Methods
Studies have shown that epilepsy affects approximately 1 to 2% of the elderly population, and increases progressively with age. Late-onset seizures are conventionally defined as epileptic seizures, which occur in subjects over 50 years. They are often attributed to underlying occult cerebrovascular disease when the main cause has not been found after usual testing [9]. Establishing the diagnosis of epilepsy in old age can be more difficult than in younger patients, due to the extensive range of differential diagnoses and a higher prevalence of concomitant disease [17]. Cardiovascular risk factors such as dyslipidemia [16] and hypertension [27] have already been reported as independent risk factors for late-onset epilepsy (LOE). Some authors suggested that patients with LOE and without clinically overt cerebrovascular disease should be considered as having an increased risk of stroke [3,5,35]. Consequently, these patients should be screened for the presence of vascular risk factors and treated accordingly. Obstructive sleep apnea syndrome (OSA) is a common disorder associated with an increased risk of cardiovascular disease and stroke. Polysomnography (PSG) provides the opportunity to diagnose the presence and severity of sleepdisordered breathing as well as the occurrence of seizures or paroxysmal activities. Therefore, the objective of the present study was to evaluate the prevalence of OSA. We also sought to determine the prevalence of patients with paroxysmal activity during polysomnography. We examined these patients for variables related to OSA using the common tools for recognizing the presence of sleep disturbances including sleep apnea: the Berlin questionnaire and the Epworth Sleepiness Scale (ESS).
Patients The study participants were patients admitted to the department of Neurology in Tours, between 1st February 2013 and 20 March 2015; were over 50 years old, and met the study criteria. A board-certified epileptologist diagnosed the epilepsy on the base of clinical history, scalp-recorded electroencephalography, physical findings, brain 3.0-T magnetic resonance imaging. Patients were excluded if they had provoked epileptic seizures (e.g., seizures induced by medications or metabolic abnormalities), or symptomatic seizures (e.g., seizures closely related to neurological or systemic insults). Patients were also excluded if they were unable to give informed consent for polysomnography, were medically unstable, or had a prior history of OSA. Anthropometric measures including body mass index (BMI), waist and neck circumference as well as gender were documented for all patients. Medical records were utilized to obtain information on the type of seizures (partial or generalised tonic clonic seizure), antiepileptic drugs used and seizure patterns (diurnal or nocturnal). Brain MRI and EEG were performed on all patients. Cardiovascular risk factors such as dyslipidemia, diabetes mellitus and hypertension were also collected. The study was approved by the hospital ethics committee.
Sleep interview Participants completed a survey prior to their sleep study, which included the Berlin questionnaire and the ESS. The
Please cite this article in press as: Maurousset A, et al. High incidence of obstructive sleep apnea syndrome in patients with late-onset epilepsy. Neurophysiologie Clinique/Clinical Neurophysiology (2016), http://dx.doi.org/10.1016/j.neucli.2016.11.002
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OSA and LOE Berlin score indicated a high probability of OSA if 2 or more categories were positive. An ESS ≥ 11 indicated excessive daytime sleepiness. We also investigated the presence of insomnia and restless legs syndrome.
Polysomnography The participants stayed overnight in the neurology unit. The PSG involved digital video, 13-channels electroencephalogram (EEG) (Fp1, Fp2, T3, T4, O1, O2, C3, C4, F7, F8, Cz and two referenced to linked mastoid A1 and A2), 4 electro-oculogram channels and 3 submental electromyogram channels, snore microphone, airflow thermistor and nasal pressure transducer, thoracic and abdomen respiratory effort belts, pulse oximetry and electrocardiography. The entire sleep period was monitored by a trained sleep technologist who studied each PSG according to standard criteria [12]. Apneas were scored if there was a ≥ 90% decrement in airflow for 10 seconds. Hypopneas were scored if there was a ≥ 50% decrement in the nasal pressure transducer channel for 10 seconds with associated 3% oxygen desaturation or a 3 second EEG arousal [12]. The average number of apneas and hypopneas per hour of sleep (apnea-hypopnea index [AHI]) was calculated. The PSGs were reviewed by a sleep specialist in order to confirm the accuracy of the staging and respiratory scoring. Data collected included: total sleep time, apnea-hypopnea index, percentage of sleep time spent in saturation ≤ 90%, arousal index, index of periodic limb movements, the time the patient retired to bed, the time he rose after sleep, estimated total sleep time, presence of paroxysmal inter-critical activities and nocturnal seizures. Medical records were reviewed and the subjects were followed up to determine the long-term outcomes of epilepsy and OSA on the subjects diagnosed with OSA. Patients who did not return for their hospital follow-up were telephoned.
Statistical analysis The participants were classified into two groups as follows: group 1 patients with no or a mild level of AHI (less than 15) and group 2 patients, those with moderate or severe level of AHI (equal or greater than 15). A P-value of 0.05 was considered significant. The continuous variables of age, neck circumference, body mass index were compared between the 2 groups using a MannWhitney non-parametric test. Categorical variables such as diabetes mellitus, hypertension, dyslipidemia, sex, ESS and Berlin scores were compared between the 2 groups by using Chi2 -tests or by using Fisher’s exact tests when one of the expected values was < 5.
Results Demographic and clinical characteristics of the study population Of the 39 patients screened, 12 (30.8%) were excluded due to at least one of the exclusion criteria. Eight patients had provoked or symptomatic seizures: 2 acute alcohol
3 intoxications, 1 intracerebral hematoma, 1 cavernoma, 3 strokes and 1 tumor lesion. One patient had psychogenic non-epileptic seizures. Three other patients had known apnea syndrome. Of the 27 patients, 16 (59.3%) were men and the mean age was 67.8 ± 8.6 years. Demographic and clinical details of patients are summarized in Table 1. Seventeen patients (62.9%) had received antiepileptic drug before polysomnography [lamotrigine (n = 4), levetiracetam (n = 9), sodium valproate (n = 2), lacosamide (n = 2), eslicarbazepine (n = 2), gabapentin (n = 1), zonisamide (n = 1), clobazam (n = 2)]. Three patients had received hypnotic drugs before polysomnography: two patients received clobazam (their AHI were 5 and 7/hour) and one received lorazepam at a dosage of 1 mg/day (AHI 72/hour). This last patient had no hypoxemia (time spent with an oxygen saturation ≤ 90% was 0.42%). Brain MRI showed leukoaraiosis in 11 patients (40.7%). Among those patients, 8 (72.7%) had hypertension. Epileptiform activity in the EEG was found in 5 patients (17.9%).
Sleep interview Ten patients (37.0%) obtained Berlin scores with two or more positive categories, indicating a high probability of OSA. Three patients (11.1%) complained of excessive daytime sleepiness with an ESS ≥ 11. Of the 24 patients with OSA, 8 patients (33.3%) obtained Berlin scores indicating a high risk of OSA and 3 patients (12.5%) complained of excessive daytime sleepiness with an ESS ≥ 11. Ten patients (41.7%) with OSA complained of severe and daily snoring. Thirteen patients (48.1%) met the criteria for insomnia. Restless leg syndrome was present in 13 patients (48.1%).
Polysomnography The median time between the diagnosis of epilepsy and PSG was 38.39 ± 51.76 months. PSG revealed paroxysmal activities in 6 patients (22.2%). Details of these paroxysmal activities are summarized in Table 2. Among these patients, 4 had normal waking EEG and 3 had nocturnal seizures. Among the 14 patients with nocturnal seizures, only four (28.6%) had paroxysmal activities during sleep. Overall, 88.9% of our sample had OSA (AHI ≥ 5), 7 patients (25.9%) had moderate OSA (between 15 and 29), and 8 patients (29.6%) had severe OSA (AHI ≥ 30). Twelve patients with SAOS had nocturnal seizures. No patients had central sleep apnea (CSA).
Comparison between patients with AHI ≥ 15/hour and < 15/hour The 27 patients were divided into two groups: 12 patients had an IAH < 15 (group 1) and 15 patients with an IAH ≥ 15 (group 2). Group 2 were significantly older. The two groups were similar in neck circumference, BMI, cardiovascular factor risks, type of seizures. The two groups exhibited a similar rate of insomnia, restless leg syndrome, and similar ESS and Berlin scores. The results are summarized in Table 1.
Please cite this article in press as: Maurousset A, et al. High incidence of obstructive sleep apnea syndrome in patients with late-onset epilepsy. Neurophysiologie Clinique/Clinical Neurophysiology (2016), http://dx.doi.org/10.1016/j.neucli.2016.11.002
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A. Maurousset et al. Table 1
Demographic and clinical differences between group 1 and group 2. All patients
Demographic characteristics and cardiovascular factor risks Men, n (%) 16 (59.3) Age, years ± SD 67.8 ± 8.6 Neck circumference, cm 39.2 ± 3.2 Abdominal circumference, cm 97.8 ± 16.3 Hypertension, n (%) 15 (55.6) Dyslipidemia, n (%) 12 (44.4) Diabetes mellitus, n (%) 5 (18.5) BMI, kg/m2 ± SD 26 ± 4.9 Epilepsy Type of seizure Partial seizure, n (%) 14 (51.9) Generalized seizure, n (%) 16 (59.3) Nocturnal seizure, n (%) 14 (52) Leukoaraiosis, n (%) 11 (40.7) Epileptiform activity in EEG, n (%) 5 (17.9) Antiepileptic drug, n (%) 17 (62.9) Hypnotics use, n (%) 3 (11.1) Sleep interview ESS ≥ 11, n (%) 3 (11.1) Berlin score: high risk of OSA, n (%) 10 (37) Insomnia, n (%) 13 (48.1) Restless legs syndrome, n (%) 13 (48.1)
Group 1 AHI < 15 n = 12
Group 2 AHI > 15 n = 15
P
8 (66.7) 62.4 38.3 93.1 5 (41.7) 4 (33.3) 1 (8.3) 24.0
8 (46.7) 72.0 40.0 102.0 10 (66.7) 8 (53.3) 4 (26.7) 27.9
0.70 0.007 0.19 0.11 0.26 0.44 0.34 0.07
6 7 6 3 3 6 2
8 (53.3) 9 (60) 8 (53.3) 8 (53.3) 2 (13.3) 11 (73.3) 1 (6.7)
1 1 1 0.24 0.63 0.26 0.57
3 6 8 5
0.23 1 0.7 0.44
(50) (58.3) (50) (25) (25) (50) (16.7)
0 4 (33.3) 5 (41.7) 8 (66.7)
(20) (40) (53.3) (33.3)
AHI: apnea-hypopnea index; SD: standard deviations; BMI: body mass index; ESS: Epworth sleepiness scale; OSA: obstructive syndrome apnea.
Table 2
Characteristics of patients with paroxysmal activities in PSG.
Sex
Age, years
AHI
Type of paroxysmal activity
Sleep stage Where the activity occurs
AED
F M F
67 62 72
1 9 11
Focal sharp waves Focal spikes Focal spikes
Lamotrigine Lamotrigine Levetiracetam
F F F
69 64 81
19 38 44
Generalized polyspikes and polyspike-waves 2 focal seizures Focal spikes
Sleep-wake transition Slow wave sleep Transition from stage 2 to stage 3 All stages Slow wave sleep Slow wave sleep
Zonisamide No No
PSG: polysomnography; AHI: apnea-hypopnea index; AED: antiepileptic drugs; F: female; M: male.
In France, CPAP is reimbursed for patients with AHI ≥ 30 events/h or for those with high levels of sleep fragmentation (AHI ≥ 15 and respiratory arousal index ≥ 10 per hour). The percentage of patients who met the diagnostic criteria was 37.0%. Long-term outcomes for the subjects diagnosed with OSA and requiring CPAP are summarized in Table 3. Half of the patients refused CPAP treatment. Of the 5 subjects who began treatment with CPAP, all were able to continue on CPAP. Only one noted no improvement. All other patients noted improvements in seizure control and two became seizure free. Two patients experienced decreased excessive daytime sleepiness. Long-term outcomes for the subjects with no or mild OSA (12 patients) was: 8 patients were not followed up in
hospital, 2 had no change in seizure frequency and 2 were seizure free. Long-term outcomes for the subjects with moderate or severe OSA who did not undergo CPAP was: 7 patients were not followed up in hospital, 1 patient became seizure free with sodium valproate and carbamazepine, 1 patient was seizure free with zonisamide, and 1 patient had no change in seizure frequency with lamotrigine. No comparison was made due to insufficient data.
Discussion We found a high prevalence of OSA (88.9%) among patients with late-onset epilepsy, and furthermore approximately
Please cite this article in press as: Maurousset A, et al. High incidence of obstructive sleep apnea syndrome in patients with late-onset epilepsy. Neurophysiologie Clinique/Clinical Neurophysiology (2016), http://dx.doi.org/10.1016/j.neucli.2016.11.002
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OSA and LOE Table 3
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Long-term outcomes of subjects with OSA requiring CPAP therapy.
Subjects
Age, years
Gender
AHI
Outcome
AED
1 2 3
72 75 66
F M M
24 28 30
Lamotrigine Lamotrigine Sodium valproate And eslicarbazepine
4
68
M
32
5 6
72 64
M F
35 38
7
81
F
44
8
63
M
45
Declined treatment with CPAP Declined treatment with CPAP Continuing to use CPAP 6 months after titration with good adherence (6 hours per night) and with improvement in Epworth scores Seizure improved with only one seizure in 6 months Continuing to use CPAP 2 months after titration with good adherence (7 hours per night) and with improvement in Epworth scores. Became seizure free Declined treatment with CPAP Continuing to use CPAP 23 months after titration with good adherence (7 hours per night). Became seizure free Continuing to use CPAP 12 months after titration with moderate adherence (4 hours per night). No change in seizures Declined treatment with CPAP
9
79
F
46
10
81
F
72
Continuing to use CPAP 6 months after titration with good adherence (12 hours per night). Seizure improved with only one seizure in 6 months Declined treatment with CPAP
Lamotrigine
Lamotrigine Lamotrigine
Lamotrigine
Sodium valproate And carbamazepine Levetiracetam
Levetiracetam
OSA: obstructive syndrome apnea; CPAP: continuous positive airway pressure; AHI: apnea-hypopnea index; AED: antiepileptic drug; F: female; M: male.
half of our patients had moderate or severe OSA. This prevalence is higher than in the general population. Peppard et al. estimated that currently, among adults 30—70 years of age, approximately 13% of men and 6% of women have moderate to severe OSA (AHI ≥ 15) [28]. The coexistence of OSA with epilepsy has already been described in several series. It appears to affect over 30% of patients with intractable seizures and OSA may be a contributing factor to worsening seizure control [21]. OSA was more likely to be found by PSG in adults with epilepsy who were male, older, suffering from somnolence, were heavier and who had experienced their first seizure at an older age [24]. In our study, patients with an AHI ≥ 15 were older than patients with an AHI < 15, however they were not more male patients, nor were they heavier. No patients had central sleep apnea. The largest community based study of CSA estimated that the prevalence of CSA is quite low (0.9%) compared to the prevalence of OSA [7]. This low prevalence explains the absence of CSA in our study. Some AEDs can aggravate sleep-related breathing disorders, in particular benzodiazepines and barbiturates [1,13,30]. In our study, no patient received barbiturates. Only three patients received benzodiazepines: two patients received clobazam (their AHI was 5 and 7/hour) and one
received lorazepam at low dosage (AHI 72/hour). None had hypoxemia. The low dose of benzodiazepine and the lack of hypoxemia contribute to our opinion that there is no link between hypnotic drug and OSA in our study. Excessive daytime sleepiness, measured with the ESS, was observed in only 3 of our patients (12.5%) with OSA. Similarly, only 8 of the patients with OSA (33.3%) were categorized as being at high risk for OSA on the Berlin Questionnaire. A prospective study compared, the prevalence of OSA by PSG in 11 adults with late-onset or worsening seizures, to 10 subjects, who were seizure free or had improving seizure control after the age of 50. Unlike our patients, the group with late-onset or worsening seizures had higher ESS scores on than the group with bettercontrolled epilepsy [4]. This discrepancy with our study can be explained by the fact that our patients were older than Chihorek’s patients (67.8 years versus 58.9). A large epidemiological study of 5407 patients with OSA, showed that OSA symptoms are less frequently reported in older patients [32]. Our results suggest that clinical screening of OSA, using self-report measures such as the Epworth scale or Berlin score will fail to identify many affected patients. The apparent association between sleep apnea syndrome and epilepsy may be due to several etiologies. Disorders of
Please cite this article in press as: Maurousset A, et al. High incidence of obstructive sleep apnea syndrome in patients with late-onset epilepsy. Neurophysiologie Clinique/Clinical Neurophysiology (2016), http://dx.doi.org/10.1016/j.neucli.2016.11.002
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the central nervous system may affect the regulation of respiration during sleep and increase the risk of sleep apnea. Disruption of sleep by obstructive respiratory events, and the accompanying chronic hypoxia, has been postulated as factors, which can lead to epileptic seizure via increased neuronal excitability [6,20,33]. Paroxysmal activities on the polysomnography were found in only 6 patients (22.2%). This could be explained by the limited number of EEG channels used during routine nocturnal polysomnography. On the other hand, 4 of these patients had no abnormalities during the waking EEG and two seizures were recorded in 1 patient. Non-REM sleep potentiates interictal epileptiform discharges and seizures [18,22] and over one-third of partial seizures arose during sleep [10]. The longer the duration of long-term videoelectroencephalography the higher the chances of detecting epileptiform discharges [26]. While video-PSG can be a tool for detecting paroxysmal interictal activities and nocturnal seizures in patients, the diagnosis of epilepsy remains essentially a clinical diagnosis. In addition, there is insufficient data on paroxysmal activity in older patients without epilepsy. Lack of relevant data can occur due to the limited number of EEG channels and insufficient information about the timing records of previous epileptic seizures. Of the five patients who accepted CPAP treatment, four demonstrated improved seizure control. Several uncontrolled series suggest that treatment of OSA in patients with epilepsy may improve seizure control [2,4,11,14,23,33] and a reduction in spike rate during sleep [31]. However, no large randomized placebo-controlled trial with significant outcomes has yet been published. In 2008, Malow et al. published a pilot study with 35 epileptic patients randomized to therapeutic CPAP (22 patients) or sham CPAP (13 patients). There was a significant reduction in the AHI during the second night of CPAP titration, in the therapeutic group compared to the sham group (P < 0.001). A 50% reduction in seizures was observed in 28% of the therapeutic group subjects compared to 15% of those in the sham group; although this result was not significant (P = 0.40) [19]. In addition, Vendrame et al. compared patients who were CPAP compliant (28 patients) with those who were not CPAP compliant (control group: 13 patients). Patients CPAP compliant demonstrated better seizure control than those who were noncompliant with its use [34]. The design of our study did not allow us to confirm if CPAP treatment improved seizure control; however, the results were encouraging. Leukoaraiosis was highly prevalent in our patients, especially in patients with moderate to severe OSA, suggesting a possible epileptogenic role for small vessel disease [26]. Previous studies have demonstrated that severe OSA is associated with the development of endothelial dysfunction, hypertension, atherosclerosis, stroke and myocardial infarction [15,25,29,36]. Arterial hypertension is associated with an increased risk of epileptic seizures [27]. The reason for this observation is most probably a link between epileptogenesis and cerebrovascular disease, causing structural or functional disruption of corticocortical or subcorticocortical circuits, or because such abnormalities may be below the resolution of current conventional neuroimaging techniques (e.g. microinfarcts, microhaemorrhages or disrupted white matter integrity) [8,26].
This study has several limitations, such as the low number of patients and the single-tertiary care center design. This limits the ability to draw a general conclusion. Subjects with sleep disorder symptoms or an understanding about the relationship between sleep and epilepsy may have been more likely to participate. A further limitation of our study was that long-term adherence to CPAP and benefits of CPAP treatment on seizure frequency were not evaluated. Larger prospective studies would appear necessary in order to confirm our findings and also to determine if treatment of OSA improves seizure control in older adults with lateonset epilepsy. A multicentre study is currently ongoing in France evaluating the efficacy of CPAP for seizure control in patients with drug-resistant epilepsy.
Conclusion Bidirectional associations seem to exist between LOE and cerebrovascular disease. OSA has been increasingly recognized as a significant comorbid condition in both, LOE and cerebrovascular disease. Our study suggests that there is a high prevalence of OSA in patients with LOE. Older adults were shown to have a higher prevalence of AHI ≥ 15 than the young. The prevalence of OSA was not significantly different in patients who were overweight, or had cardiovascular risk factors. Gender also did not affect the prevalence of OSA. Additionally, our results suggest that clinical screening of OSA using self-report measures (Epworth scale or Berlin score) will fail to identify many affected patients with LOE. Patients with late-onset epilepsy should be systematically screened for the presence of OSA and treated accordingly. Larger prospective studies would appear necessary in order to confirm our findings and also to determine if treatment of OSA improves seizure control in older adults with late-onset epilepsy. Controlled studies are also necessary to determine the efficiency of PSG in detecting paroxysmal activities in patients with LOE.
Disclosure of interest The authors declare that they have no competing interest.
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ORIGINAL ARTICLE/ARTICLE ORIGINAL
High incidence of obstructive sleep apnea syndrome in patients with late-onset epilepsy Incidence élevée du syndrome d’apnées obstructives du sommeil chez les patients avec épilepsie de survenue tardive Aude Maurousset ∗, Bertrand De Toffol , Julien Praline , Julien Biberon , Nadège Limousin Department of neurology, Inserm U930, university hospital Bretonneau, 2, boulevard Tonnellé, 37044 Tours cedex 9, France Received 21 May 2016; accepted 23 November 2016
KEYWORDS Late-onset epilepsy; Leukoaraiosis; Obstructive sleep apnea syndrome; Polysomnography
∗
Summary Objectives. — The objective of the present study was to evaluate the prevalence of obstructive sleep apnea (OSA) in patients with late-onset epilepsy (LOE) who were considered at higher risk of cardiovascular disease. Methods. — Polysomnography was performed on 27 patients with LOE. Berlin questionnaires and Epworth sleepiness score were performed on all patients. We compared clinical, demographic and anthropometric characteristics, questionnaire scores on the patients with no or mild OSA (group 1) and the patients with moderate or severe OSA (group 2). Patients eligible for continuous positive airway pressure (CPAP) therapy were reviewed in consultation. Results. — Twenty-four patients (88.9%) had OSA and 55.6% had moderate or severe OSA. Patients in group 2 (n = 15) were older than patients in group 1 (n = 12). The two groups were similar in terms of body mass index (BMI), neck circumference, nocturnal seizure frequency, vascular cardiovascular risk factors and excessive daytime sleepiness. Leukoaraiosis in MRI was highly prevalent in our patients (40.7%), especially in group 2 patients. Eighty percent of the patients who had begun CPAP therapy experienced decreased seizure frequency. Conclusion. — Patients with LOE should be screened for the presence of OSA and treated accordingly. © 2016 Elsevier Masson SAS. All rights reserved.
Corresponding author. E-mail address: [email protected] (A. Maurousset).
http://dx.doi.org/10.1016/j.neucli.2016.11.002 0987-7053/© 2016 Elsevier Masson SAS. All rights reserved.
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MOTS CLÉS Épilepsie débutant à un âge tardif ; Leuco-araïose ; Polysomnographie ; Syndrome d’apnées obstructives du sommeil
Résumé Objectif. — L’objectif de cette étude était d’évaluer la prévalence du syndrome d’apnées obstructives du sommeil (SAOS) chez les patients débutant une épilepsie à un âge tardif et qui sont donc considérés à haut risque cardiovasculaire. Méthodes. — Une polysomnographie a été réalisée chez 27 patients ayant débuté une épilepsie à un âge tardif. Un questionnaire de Berlin et une échelle de somnolence d’Epworth ont été réalisés chez tous les patients. Nous avons comparé les caractéristiques cliniques, démographiques et anthropométriques ainsi que les questionnaires de sommeil chez les patients n’ayant pas ou ayant un léger SAOS et les patients en ayant un modéré ou sévère. Les patients éligibles à un traitement par continuous positive airway pressure (CPAP) ont été revus en consultation. Résultats. — Vingt-quatre patients (88,9 %) avaient un SAOS et 55,6 % avaient un SAOS modéré ou sévère. Les patients du groupe 2 (n = 15) étaient plus vieux que ceux du groupe 1 (n = 12). Les deux groupes étaient similaires en termes d’index de masse corporelle (IMC), de circonférence cervicale, de fréquence des crises nocturnes, de facteurs de risque cardiovasculaire et de somnolence diurne excessive. La leuco-araïose sur l’IRM était fréquente chez nos patients (40,7 %), surtout chez ceux du groupe 2. Parmi les patients qui ont débuté un traitement par CPAP, 80 % ont eu une diminution de la fréquence des crises. Conclusion. — Le SAOS doit être recherché chez les patients débutant une épilepsie à un âge tardif et traité s’il est présent. © 2016 Elsevier Masson SAS. Tous droits r´ eserv´ es.
Introduction
Methods
Studies have shown that epilepsy affects approximately 1 to 2% of the elderly population, and increases progressively with age. Late-onset seizures are conventionally defined as epileptic seizures, which occur in subjects over 50 years. They are often attributed to underlying occult cerebrovascular disease when the main cause has not been found after usual testing [9]. Establishing the diagnosis of epilepsy in old age can be more difficult than in younger patients, due to the extensive range of differential diagnoses and a higher prevalence of concomitant disease [17]. Cardiovascular risk factors such as dyslipidemia [16] and hypertension [27] have already been reported as independent risk factors for late-onset epilepsy (LOE). Some authors suggested that patients with LOE and without clinically overt cerebrovascular disease should be considered as having an increased risk of stroke [3,5,35]. Consequently, these patients should be screened for the presence of vascular risk factors and treated accordingly. Obstructive sleep apnea syndrome (OSA) is a common disorder associated with an increased risk of cardiovascular disease and stroke. Polysomnography (PSG) provides the opportunity to diagnose the presence and severity of sleepdisordered breathing as well as the occurrence of seizures or paroxysmal activities. Therefore, the objective of the present study was to evaluate the prevalence of OSA. We also sought to determine the prevalence of patients with paroxysmal activity during polysomnography. We examined these patients for variables related to OSA using the common tools for recognizing the presence of sleep disturbances including sleep apnea: the Berlin questionnaire and the Epworth Sleepiness Scale (ESS).
Patients The study participants were patients admitted to the department of Neurology in Tours, between 1st February 2013 and 20 March 2015; were over 50 years old, and met the study criteria. A board-certified epileptologist diagnosed the epilepsy on the base of clinical history, scalp-recorded electroencephalography, physical findings, brain 3.0-T magnetic resonance imaging. Patients were excluded if they had provoked epileptic seizures (e.g., seizures induced by medications or metabolic abnormalities), or symptomatic seizures (e.g., seizures closely related to neurological or systemic insults). Patients were also excluded if they were unable to give informed consent for polysomnography, were medically unstable, or had a prior history of OSA. Anthropometric measures including body mass index (BMI), waist and neck circumference as well as gender were documented for all patients. Medical records were utilized to obtain information on the type of seizures (partial or generalised tonic clonic seizure), antiepileptic drugs used and seizure patterns (diurnal or nocturnal). Brain MRI and EEG were performed on all patients. Cardiovascular risk factors such as dyslipidemia, diabetes mellitus and hypertension were also collected. The study was approved by the hospital ethics committee.
Sleep interview Participants completed a survey prior to their sleep study, which included the Berlin questionnaire and the ESS. The
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OSA and LOE Berlin score indicated a high probability of OSA if 2 or more categories were positive. An ESS ≥ 11 indicated excessive daytime sleepiness. We also investigated the presence of insomnia and restless legs syndrome.
Polysomnography The participants stayed overnight in the neurology unit. The PSG involved digital video, 13-channels electroencephalogram (EEG) (Fp1, Fp2, T3, T4, O1, O2, C3, C4, F7, F8, Cz and two referenced to linked mastoid A1 and A2), 4 electro-oculogram channels and 3 submental electromyogram channels, snore microphone, airflow thermistor and nasal pressure transducer, thoracic and abdomen respiratory effort belts, pulse oximetry and electrocardiography. The entire sleep period was monitored by a trained sleep technologist who studied each PSG according to standard criteria [12]. Apneas were scored if there was a ≥ 90% decrement in airflow for 10 seconds. Hypopneas were scored if there was a ≥ 50% decrement in the nasal pressure transducer channel for 10 seconds with associated 3% oxygen desaturation or a 3 second EEG arousal [12]. The average number of apneas and hypopneas per hour of sleep (apnea-hypopnea index [AHI]) was calculated. The PSGs were reviewed by a sleep specialist in order to confirm the accuracy of the staging and respiratory scoring. Data collected included: total sleep time, apnea-hypopnea index, percentage of sleep time spent in saturation ≤ 90%, arousal index, index of periodic limb movements, the time the patient retired to bed, the time he rose after sleep, estimated total sleep time, presence of paroxysmal inter-critical activities and nocturnal seizures. Medical records were reviewed and the subjects were followed up to determine the long-term outcomes of epilepsy and OSA on the subjects diagnosed with OSA. Patients who did not return for their hospital follow-up were telephoned.
Statistical analysis The participants were classified into two groups as follows: group 1 patients with no or a mild level of AHI (less than 15) and group 2 patients, those with moderate or severe level of AHI (equal or greater than 15). A P-value of 0.05 was considered significant. The continuous variables of age, neck circumference, body mass index were compared between the 2 groups using a MannWhitney non-parametric test. Categorical variables such as diabetes mellitus, hypertension, dyslipidemia, sex, ESS and Berlin scores were compared between the 2 groups by using Chi2 -tests or by using Fisher’s exact tests when one of the expected values was < 5.
Results Demographic and clinical characteristics of the study population Of the 39 patients screened, 12 (30.8%) were excluded due to at least one of the exclusion criteria. Eight patients had provoked or symptomatic seizures: 2 acute alcohol
3 intoxications, 1 intracerebral hematoma, 1 cavernoma, 3 strokes and 1 tumor lesion. One patient had psychogenic non-epileptic seizures. Three other patients had known apnea syndrome. Of the 27 patients, 16 (59.3%) were men and the mean age was 67.8 ± 8.6 years. Demographic and clinical details of patients are summarized in Table 1. Seventeen patients (62.9%) had received antiepileptic drug before polysomnography [lamotrigine (n = 4), levetiracetam (n = 9), sodium valproate (n = 2), lacosamide (n = 2), eslicarbazepine (n = 2), gabapentin (n = 1), zonisamide (n = 1), clobazam (n = 2)]. Three patients had received hypnotic drugs before polysomnography: two patients received clobazam (their AHI were 5 and 7/hour) and one received lorazepam at a dosage of 1 mg/day (AHI 72/hour). This last patient had no hypoxemia (time spent with an oxygen saturation ≤ 90% was 0.42%). Brain MRI showed leukoaraiosis in 11 patients (40.7%). Among those patients, 8 (72.7%) had hypertension. Epileptiform activity in the EEG was found in 5 patients (17.9%).
Sleep interview Ten patients (37.0%) obtained Berlin scores with two or more positive categories, indicating a high probability of OSA. Three patients (11.1%) complained of excessive daytime sleepiness with an ESS ≥ 11. Of the 24 patients with OSA, 8 patients (33.3%) obtained Berlin scores indicating a high risk of OSA and 3 patients (12.5%) complained of excessive daytime sleepiness with an ESS ≥ 11. Ten patients (41.7%) with OSA complained of severe and daily snoring. Thirteen patients (48.1%) met the criteria for insomnia. Restless leg syndrome was present in 13 patients (48.1%).
Polysomnography The median time between the diagnosis of epilepsy and PSG was 38.39 ± 51.76 months. PSG revealed paroxysmal activities in 6 patients (22.2%). Details of these paroxysmal activities are summarized in Table 2. Among these patients, 4 had normal waking EEG and 3 had nocturnal seizures. Among the 14 patients with nocturnal seizures, only four (28.6%) had paroxysmal activities during sleep. Overall, 88.9% of our sample had OSA (AHI ≥ 5), 7 patients (25.9%) had moderate OSA (between 15 and 29), and 8 patients (29.6%) had severe OSA (AHI ≥ 30). Twelve patients with SAOS had nocturnal seizures. No patients had central sleep apnea (CSA).
Comparison between patients with AHI ≥ 15/hour and < 15/hour The 27 patients were divided into two groups: 12 patients had an IAH < 15 (group 1) and 15 patients with an IAH ≥ 15 (group 2). Group 2 were significantly older. The two groups were similar in neck circumference, BMI, cardiovascular factor risks, type of seizures. The two groups exhibited a similar rate of insomnia, restless leg syndrome, and similar ESS and Berlin scores. The results are summarized in Table 1.
Please cite this article in press as: Maurousset A, et al. High incidence of obstructive sleep apnea syndrome in patients with late-onset epilepsy. Neurophysiologie Clinique/Clinical Neurophysiology (2016), http://dx.doi.org/10.1016/j.neucli.2016.11.002
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A. Maurousset et al. Table 1
Demographic and clinical differences between group 1 and group 2. All patients
Demographic characteristics and cardiovascular factor risks Men, n (%) 16 (59.3) Age, years ± SD 67.8 ± 8.6 Neck circumference, cm 39.2 ± 3.2 Abdominal circumference, cm 97.8 ± 16.3 Hypertension, n (%) 15 (55.6) Dyslipidemia, n (%) 12 (44.4) Diabetes mellitus, n (%) 5 (18.5) BMI, kg/m2 ± SD 26 ± 4.9 Epilepsy Type of seizure Partial seizure, n (%) 14 (51.9) Generalized seizure, n (%) 16 (59.3) Nocturnal seizure, n (%) 14 (52) Leukoaraiosis, n (%) 11 (40.7) Epileptiform activity in EEG, n (%) 5 (17.9) Antiepileptic drug, n (%) 17 (62.9) Hypnotics use, n (%) 3 (11.1) Sleep interview ESS ≥ 11, n (%) 3 (11.1) Berlin score: high risk of OSA, n (%) 10 (37) Insomnia, n (%) 13 (48.1) Restless legs syndrome, n (%) 13 (48.1)
Group 1 AHI < 15 n = 12
Group 2 AHI > 15 n = 15
P
8 (66.7) 62.4 38.3 93.1 5 (41.7) 4 (33.3) 1 (8.3) 24.0
8 (46.7) 72.0 40.0 102.0 10 (66.7) 8 (53.3) 4 (26.7) 27.9
0.70 0.007 0.19 0.11 0.26 0.44 0.34 0.07
6 7 6 3 3 6 2
8 (53.3) 9 (60) 8 (53.3) 8 (53.3) 2 (13.3) 11 (73.3) 1 (6.7)
1 1 1 0.24 0.63 0.26 0.57
3 6 8 5
0.23 1 0.7 0.44
(50) (58.3) (50) (25) (25) (50) (16.7)
0 4 (33.3) 5 (41.7) 8 (66.7)
(20) (40) (53.3) (33.3)
AHI: apnea-hypopnea index; SD: standard deviations; BMI: body mass index; ESS: Epworth sleepiness scale; OSA: obstructive syndrome apnea.
Table 2
Characteristics of patients with paroxysmal activities in PSG.
Sex
Age, years
AHI
Type of paroxysmal activity
Sleep stage Where the activity occurs
AED
F M F
67 62 72
1 9 11
Focal sharp waves Focal spikes Focal spikes
Lamotrigine Lamotrigine Levetiracetam
F F F
69 64 81
19 38 44
Generalized polyspikes and polyspike-waves 2 focal seizures Focal spikes
Sleep-wake transition Slow wave sleep Transition from stage 2 to stage 3 All stages Slow wave sleep Slow wave sleep
Zonisamide No No
PSG: polysomnography; AHI: apnea-hypopnea index; AED: antiepileptic drugs; F: female; M: male.
In France, CPAP is reimbursed for patients with AHI ≥ 30 events/h or for those with high levels of sleep fragmentation (AHI ≥ 15 and respiratory arousal index ≥ 10 per hour). The percentage of patients who met the diagnostic criteria was 37.0%. Long-term outcomes for the subjects diagnosed with OSA and requiring CPAP are summarized in Table 3. Half of the patients refused CPAP treatment. Of the 5 subjects who began treatment with CPAP, all were able to continue on CPAP. Only one noted no improvement. All other patients noted improvements in seizure control and two became seizure free. Two patients experienced decreased excessive daytime sleepiness. Long-term outcomes for the subjects with no or mild OSA (12 patients) was: 8 patients were not followed up in
hospital, 2 had no change in seizure frequency and 2 were seizure free. Long-term outcomes for the subjects with moderate or severe OSA who did not undergo CPAP was: 7 patients were not followed up in hospital, 1 patient became seizure free with sodium valproate and carbamazepine, 1 patient was seizure free with zonisamide, and 1 patient had no change in seizure frequency with lamotrigine. No comparison was made due to insufficient data.
Discussion We found a high prevalence of OSA (88.9%) among patients with late-onset epilepsy, and furthermore approximately
Please cite this article in press as: Maurousset A, et al. High incidence of obstructive sleep apnea syndrome in patients with late-onset epilepsy. Neurophysiologie Clinique/Clinical Neurophysiology (2016), http://dx.doi.org/10.1016/j.neucli.2016.11.002
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OSA and LOE Table 3
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Long-term outcomes of subjects with OSA requiring CPAP therapy.
Subjects
Age, years
Gender
AHI
Outcome
AED
1 2 3
72 75 66
F M M
24 28 30
Lamotrigine Lamotrigine Sodium valproate And eslicarbazepine
4
68
M
32
5 6
72 64
M F
35 38
7
81
F
44
8
63
M
45
Declined treatment with CPAP Declined treatment with CPAP Continuing to use CPAP 6 months after titration with good adherence (6 hours per night) and with improvement in Epworth scores Seizure improved with only one seizure in 6 months Continuing to use CPAP 2 months after titration with good adherence (7 hours per night) and with improvement in Epworth scores. Became seizure free Declined treatment with CPAP Continuing to use CPAP 23 months after titration with good adherence (7 hours per night). Became seizure free Continuing to use CPAP 12 months after titration with moderate adherence (4 hours per night). No change in seizures Declined treatment with CPAP
9
79
F
46
10
81
F
72
Continuing to use CPAP 6 months after titration with good adherence (12 hours per night). Seizure improved with only one seizure in 6 months Declined treatment with CPAP
Lamotrigine
Lamotrigine Lamotrigine
Lamotrigine
Sodium valproate And carbamazepine Levetiracetam
Levetiracetam
OSA: obstructive syndrome apnea; CPAP: continuous positive airway pressure; AHI: apnea-hypopnea index; AED: antiepileptic drug; F: female; M: male.
half of our patients had moderate or severe OSA. This prevalence is higher than in the general population. Peppard et al. estimated that currently, among adults 30—70 years of age, approximately 13% of men and 6% of women have moderate to severe OSA (AHI ≥ 15) [28]. The coexistence of OSA with epilepsy has already been described in several series. It appears to affect over 30% of patients with intractable seizures and OSA may be a contributing factor to worsening seizure control [21]. OSA was more likely to be found by PSG in adults with epilepsy who were male, older, suffering from somnolence, were heavier and who had experienced their first seizure at an older age [24]. In our study, patients with an AHI ≥ 15 were older than patients with an AHI < 15, however they were not more male patients, nor were they heavier. No patients had central sleep apnea. The largest community based study of CSA estimated that the prevalence of CSA is quite low (0.9%) compared to the prevalence of OSA [7]. This low prevalence explains the absence of CSA in our study. Some AEDs can aggravate sleep-related breathing disorders, in particular benzodiazepines and barbiturates [1,13,30]. In our study, no patient received barbiturates. Only three patients received benzodiazepines: two patients received clobazam (their AHI was 5 and 7/hour) and one
received lorazepam at low dosage (AHI 72/hour). None had hypoxemia. The low dose of benzodiazepine and the lack of hypoxemia contribute to our opinion that there is no link between hypnotic drug and OSA in our study. Excessive daytime sleepiness, measured with the ESS, was observed in only 3 of our patients (12.5%) with OSA. Similarly, only 8 of the patients with OSA (33.3%) were categorized as being at high risk for OSA on the Berlin Questionnaire. A prospective study compared, the prevalence of OSA by PSG in 11 adults with late-onset or worsening seizures, to 10 subjects, who were seizure free or had improving seizure control after the age of 50. Unlike our patients, the group with late-onset or worsening seizures had higher ESS scores on than the group with bettercontrolled epilepsy [4]. This discrepancy with our study can be explained by the fact that our patients were older than Chihorek’s patients (67.8 years versus 58.9). A large epidemiological study of 5407 patients with OSA, showed that OSA symptoms are less frequently reported in older patients [32]. Our results suggest that clinical screening of OSA, using self-report measures such as the Epworth scale or Berlin score will fail to identify many affected patients. The apparent association between sleep apnea syndrome and epilepsy may be due to several etiologies. Disorders of
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the central nervous system may affect the regulation of respiration during sleep and increase the risk of sleep apnea. Disruption of sleep by obstructive respiratory events, and the accompanying chronic hypoxia, has been postulated as factors, which can lead to epileptic seizure via increased neuronal excitability [6,20,33]. Paroxysmal activities on the polysomnography were found in only 6 patients (22.2%). This could be explained by the limited number of EEG channels used during routine nocturnal polysomnography. On the other hand, 4 of these patients had no abnormalities during the waking EEG and two seizures were recorded in 1 patient. Non-REM sleep potentiates interictal epileptiform discharges and seizures [18,22] and over one-third of partial seizures arose during sleep [10]. The longer the duration of long-term videoelectroencephalography the higher the chances of detecting epileptiform discharges [26]. While video-PSG can be a tool for detecting paroxysmal interictal activities and nocturnal seizures in patients, the diagnosis of epilepsy remains essentially a clinical diagnosis. In addition, there is insufficient data on paroxysmal activity in older patients without epilepsy. Lack of relevant data can occur due to the limited number of EEG channels and insufficient information about the timing records of previous epileptic seizures. Of the five patients who accepted CPAP treatment, four demonstrated improved seizure control. Several uncontrolled series suggest that treatment of OSA in patients with epilepsy may improve seizure control [2,4,11,14,23,33] and a reduction in spike rate during sleep [31]. However, no large randomized placebo-controlled trial with significant outcomes has yet been published. In 2008, Malow et al. published a pilot study with 35 epileptic patients randomized to therapeutic CPAP (22 patients) or sham CPAP (13 patients). There was a significant reduction in the AHI during the second night of CPAP titration, in the therapeutic group compared to the sham group (P < 0.001). A 50% reduction in seizures was observed in 28% of the therapeutic group subjects compared to 15% of those in the sham group; although this result was not significant (P = 0.40) [19]. In addition, Vendrame et al. compared patients who were CPAP compliant (28 patients) with those who were not CPAP compliant (control group: 13 patients). Patients CPAP compliant demonstrated better seizure control than those who were noncompliant with its use [34]. The design of our study did not allow us to confirm if CPAP treatment improved seizure control; however, the results were encouraging. Leukoaraiosis was highly prevalent in our patients, especially in patients with moderate to severe OSA, suggesting a possible epileptogenic role for small vessel disease [26]. Previous studies have demonstrated that severe OSA is associated with the development of endothelial dysfunction, hypertension, atherosclerosis, stroke and myocardial infarction [15,25,29,36]. Arterial hypertension is associated with an increased risk of epileptic seizures [27]. The reason for this observation is most probably a link between epileptogenesis and cerebrovascular disease, causing structural or functional disruption of corticocortical or subcorticocortical circuits, or because such abnormalities may be below the resolution of current conventional neuroimaging techniques (e.g. microinfarcts, microhaemorrhages or disrupted white matter integrity) [8,26].
This study has several limitations, such as the low number of patients and the single-tertiary care center design. This limits the ability to draw a general conclusion. Subjects with sleep disorder symptoms or an understanding about the relationship between sleep and epilepsy may have been more likely to participate. A further limitation of our study was that long-term adherence to CPAP and benefits of CPAP treatment on seizure frequency were not evaluated. Larger prospective studies would appear necessary in order to confirm our findings and also to determine if treatment of OSA improves seizure control in older adults with lateonset epilepsy. A multicentre study is currently ongoing in France evaluating the efficacy of CPAP for seizure control in patients with drug-resistant epilepsy.
Conclusion Bidirectional associations seem to exist between LOE and cerebrovascular disease. OSA has been increasingly recognized as a significant comorbid condition in both, LOE and cerebrovascular disease. Our study suggests that there is a high prevalence of OSA in patients with LOE. Older adults were shown to have a higher prevalence of AHI ≥ 15 than the young. The prevalence of OSA was not significantly different in patients who were overweight, or had cardiovascular risk factors. Gender also did not affect the prevalence of OSA. Additionally, our results suggest that clinical screening of OSA using self-report measures (Epworth scale or Berlin score) will fail to identify many affected patients with LOE. Patients with late-onset epilepsy should be systematically screened for the presence of OSA and treated accordingly. Larger prospective studies would appear necessary in order to confirm our findings and also to determine if treatment of OSA improves seizure control in older adults with late-onset epilepsy. Controlled studies are also necessary to determine the efficiency of PSG in detecting paroxysmal activities in patients with LOE.
Disclosure of interest The authors declare that they have no competing interest.
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Please cite this article in press as: Maurousset A, et al. High incidence of obstructive sleep apnea syndrome in patients with late-onset epilepsy. Neurophysiologie Clinique/Clinical Neurophysiology (2016), http://dx.doi.org/10.1016/j.neucli.2016.11.002
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Please cite this article in press as: Maurousset A, et al. High incidence of obstructive sleep apnea syndrome in patients with late-onset epilepsy. Neurophysiologie Clinique/Clinical Neurophysiology (2016), http://dx.doi.org/10.1016/j.neucli.2016.11.002