1
Impaired Vigilance Is Associated with Erectile Dysfunction in Patients with Sleep Apnea Roland Popp, PhD,* Yannick Kleemann, MD,† Maximilian Burger, MD,‡ Michael Pfeifer, MD,†§ Michael Arzt, MD,†1 and Stephan Budweiser, MD¶1 *Department of Psychiatry and Psychotherapy, Center of Sleep Medicine, University of Regensburg, Regensburg, Germany; †Department of Internal Medicine II, University of Regensburg, Regensburg, Germany; ‡Department of Urology, Caritas St. Josef Medical Center, University of Regensburg, Regensburg, Germany; §Center for Pneumology, Donaustauf Hospital, Donaustauf, Germany; ¶Department of Internal Medicine III, Division of Pulmonary and Respiratory Medicine, RoMed Clinical Center Rosenheim, Rosenheim, Germany DOI: 10.1111/jsm.12789
ABSTRACT
Introduction. Erectile dysfunction (ED) is frequent in patients with obstructive sleep apnea (OSA) and may act as a surrogate of endothelial dysfunction. Furthermore, impairments of vigilance and sustained attention are also commonly associated with OSA. Aim. The purpose of this study was to evaluate whether there is an association between ED and sustained attention deficits. Methods. A prospective cross-sectional cohort of 401 male in-patients undergoing diagnostic polysomnography for suspected OSA and a 25-minute sustained attention test was analyzed. ED was assessed using the 15-item International Index of Erectile Function (IIEF-15) questionnaire. The Epworth Sleepiness Scale (ESS) served as a measure of daytime sleepiness. Main Outcome Measure. Severity of impaired erectile function (EF) assessed by the IIEF-15, core task parameters of the sustained attention test (i.e., CR: correct reactions; V-CR: variation of correct reactions, CE: commission errors, RT: reaction time; V-RT: variation of reaction times). Results. Three hundred eighty-one consecutive patients presenting for in-lab polysomnography were included in the analysis. Impaired EF was diagnosed in 246 patients (65%). With increasing impairment of EF, patients scored significantly worse in all vigilance test parameters and demonstrated more severely diminished vigilance (normal EF: 11.9%, moderately impaired EF: 24.1%, and severely impaired EF: 34.9%). Multivariate regression analyses including established risk factors for ED, OSA, or sleepiness revealed a significant independent association between lower scores for EF and impairments on the following vigilance test variables: odds ratio (95% confidence interval) for V-CR: 0.52 (0.34–0.81), CE: 0.87 (0.80–0.95), and V-RT: 0.91 (0.87–0.96). The ESS was independently associated with both measures of performance instability: odds ratio for V-CR: 6.94 (2.97–16.23) and V-RT: 1.28 (1.14–1.44). Conclusions. In OSA patients, the severity of impaired EF was associated with impaired vigilance performance, independent of other known risk factors for ED or OSA and not mediated by sleepiness. Potentially, the findings suggest a direct relationship between vascular or endothelial dysfunction and impairments in both EF and neurobehavioral cognitive function. Popp R, Kleemann Y, Burger M, Pfeifer M, Arzt M, and Budweiser S. Impaired vigilance is associated with erectile dysfunction in patients with sleep apnea. J Sex Med **;**:**–**. Key Words. Erectile Function; Erectile Dysfunction, Sexual Dysfunction; Endothelial Dysfunction; Vigilance Performance; Sustained Attention; Daytime Sleepiness
1
Contributed equally.
© 2014 International Society for Sexual Medicine
J Sex Med **;**:**–**
2 Introduction
E
rectile dysfunction (ED) is a frequent symptom affecting about 20% of the male population [1]. ED is also a particularly common condition in men with obstructive sleep apnea (OSA). The incidence of ED among this population is in a range between 40% and 64% [2–4], and male patients with OSA experience more sexual dissatisfaction and sexual dysfunction compared with age-matched controls [5]. However, decreased libido or sexual dysfunction may be underrecognized in these patients, as not all of them address these problems voluntarily. While there appears to be a direct link between OSA and the development of ED, the common overlapping risk factors (i.e., age, hypertension, diabetes, and psychological factors such as depression) make it somewhat difficult to confirm a clear causal relationship [6]. However, a few studies could detect that OSA and the related intermittent nocturnal hypoxemia were an independent risk factor and correlate with ED and overall sexual function [3,7]. ED is a surrogate of endothelial and vascular dysfunction. Due to altered vasodilating and vasoconstricting processes, endothelial dysfunction can cause both ED and cardiovascular diseases [8,9]. ED may even be an initial symptom of an early stage of endothelial dysfunction leading to arteriosclerosis and cardiovascular disease [10,11]. There is converging evidence that OSA produces (cerebro)vascular microlesions as well as sympathetic activation and enhances endothelial dysfunction [6]. These dysfunctions evoke changes in microvascular perfusion that favor the rise of ED. Specifically, repetitive nocturnal hypoxemia due to OSA induces oxidative stress, hormonal alterations, and increased inflammatory stimuli. Finally, OSA-related intermittent hypoxia can result in an amplified risk of hypertension and cardio- and cerebrovascular disease (e.g., myocardial infarction and strokes) [12,13]. Sleepiness may further augment the risk for vascular events. Thus, in patients with OSA, sleepiness is an independent risk factor for vascular events [14,15]. In addition, OSA can produce psychological alterations and neural dysfunction such as impaired vigilance or alertness [16]. Remarkably, an early finding of Bédard and colleagues specifically related nocturnal hypoxemia to vigilance impairments in OSA [17]. As a basic pathophysiological mechanism, the authors assumed a hypoxia-induced vascular damage of the brain.
J Sex Med **;**:**–**
Popp et al. In contrast to sexual dysfunction, vigilance problems are much more apparent neurobehavioral complaints in OSA patients seeking treatment in a sleep laboratory. These patients frequently report difficulties staying awake and alert especially in boring or tedious situations, which results in increased daytime sleepiness, vigilance impairments, and unintended lapses of sustained attention. In general, vigilance or sustained attention (most researchers use both terms synonymously [18,19]) refers to the basic ability of the organisms to maintain their attention and remain alert to stimuli over prolonged periods of time, even if the monitoring task is monotonous [20]. On vigilance tasks, patients with severe OSA demonstrated impaired performance compared with healthy controls [21,22]. Recently, a meta-review underscored the negative effects of OSA on cognition, most likely in the domain of attention/vigilance [23]. To date, no study has evaluated the association of impaired vigilance performance with sexual dysfunction in patients with OSA. Based on these considerations and on the assumption that ED and vigilance in these patients may be due to a common underlying mechanism of endothelial or vascular dysfunction, we would expect a statistical association between those different domains of performance. Thus, the aim of this analysis was to examine a possible link between ED and neurobehavioral impairments of sustained attention in the presence of other risk factors for ED and OSA. Specifically, since sustained attention deficits are sensitive to sleepiness, we considered subjective daytime sleepiness as a possible confounding or mediating factor of vigilance performance in patients with OSA. Methods
Study Population A subgroup from a prospective study sample comprising 401 consecutive male in-patients with supposed OSA who were referred to diagnostic in-lab polysomnography between June 2006 and June 2007 entered the present analysis [7,24]. As described previously, only patients with neurological or psychiatric dysfunctions (e.g., depression), hypogonadism, current treatment with phosphodiesterase-5-inhibitors, or severe lung diseases had not been included into the study [7]. For the present analysis, we only included patients who underwent a full record of valid data in a 25-minute sustained attention task (N = 381). Nineteen patients refused to perform the complete
Impaired Vigilance and ED in Patients with Sleep Apnea test, and one subject obviously misunderstood the test instruction resulting in 498 commission errors. The full study protocol was approved by the university ethics committee. All patients gave written informed consent prior to the start of the study.
Assessments Erectile Function To assess ED the 15-item International Index of Erectile Function (IIEF-15) questionnaire [25] was used, which includes 15 questions referring to different sexual domains including “erectile function” (EF). Overall sexual function is described by the IIEF-15 summary score (range 5–75 points). In our study, we focused on ED as defined by ≤25 points of the EF subdomain, with values of 11–25 indicating “mild to moderately” and ≤10 “severely” impaired EF. Sleepiness Daytime sleepiness was measured by the German version of the Epworth Sleepiness Scale (ESS) assessing sleep propensity in activities of daily life [26]. Scores >10 (range 0–24) are considered as clinically suspicious for increased daytime sleepiness [26,27]. Sustained Attention The test “Vigil-Vigilance” (VIGIL-S1 test form of the Vienna Test System, Schuhfried GmbH, Mödling, Austria) is based on the Mackworth clock, an established assessment method on sustained attention under monotonous conditions [28,29]. On a black screen, 32 small white circles are arranged to form a larger circle that looks like a clock face. A white dot moves clockwise along the large circle in small jumps at a rate of 1.5 seconds per move (test duration: 25 minutes). Patients had to press a reaction key whenever a target stimulus (total number of 100) occurred, i.e., a double jump skipping one of the small circles. The vigilance test was administered in the course of the morning after the first diagnostic polysomnography night. The computerized task automatically records a number of test variables: the number of correct reactions (maximum 100), the number of commission errors, the mean reaction time (in 1/100 seconds), the variance of correct reactions (V-CR), and the variance of reaction times (V-RT). For each of the five test variables, vigilance decrements of an individual are defined by a test parameter
3
value ≤16 percentile (based on a normative sample of adults provided by the Vienna Test System). Severely diminished vigilance (SDV) was present when a patient revealed vigilance decrements on at least two of all five test parameters.
Polysomnography As described previously [7,24] in more detail, the patients underwent diagnostic in-lab polysomnography (MEPAL-System, Martinsried, Germany). According to the American Academy of Sleep Medicine [30] the severity of sleep-disordered breathing was quantified by the apnea–hypopnea index (AHI), defined as the number of apneas and hypopneas per hour of sleep. To account for the diagnosis of periodic limb movements in sleep (PLMS) and to avoid contamination by apneainduced motoric arousals, we mainly used the last titration night for positive airway pressure therapy to assess the PLMS Index (the diagnostic polysomnography was used in 14 patients, since no subsequent titration night was performed). Valid data of periodic limb movements were able to be obtained in 377 patients and were analyzed automatically (REMbrandt-PSG-Software, Embla, Ontario, Canada). Statistical Analysis Continuous variables are presented as mean and standard deviation. Differences between baseline characteristics of patients with and without impaired EF were compared using the t-test for quantitative variables and using the chi-square test for binary variables. To compare groups with different severity of ED, one-way analysis of variance (anova) was applied for continuous variables. To evaluate whether various classes of ED severity (i.e., normal EF, moderately impaired EF, and severely impaired EF) are associated with altered performance on various vigilance task parameters, we used Jonckheere’s trend test for ordered differences. The association of EF as an independent variable with multiple dependent variables (i.e., every five vigilance parameters) was evaluated by univariate and multivariate regression analyses. For all multivariate regression models, we considered confounding variables and established risk factors for impaired EF, sleep-disordered breathing, and daytime sleepiness. That included age, obesity (body mass index), smoking history, hyperlipidemia, chronic obstructive pulmonary disease (COPD), atherosclerosis, heart failure, coronary J Sex Med **;**:**–**
4 Table 1
Popp et al. Characteristics and sleep parameters of patients with normal and impaired erectile function (EF)
Variables General measures (dimension) Age (years) Body mass index (BMI) (kg/m2) IIEF-15 (score) Epworth Sleepiness Scale (ESS) (score) Smoking history n (%) Nonsmokers Current smokers and ex-smokers Sleep measures (dimension) Sleep efficiency (%) REM sleep/sleep period time (%) Arousal index (/hour) PLMS index (/hour) [N = 377] AHI (/hour) AHI in REM sleep (/hour) Obstructive apnea (n) Mixed apnea (n) Central apnea (n) Hypopnea (n) SaO2 mean (%) SaO2 lowest (%)
Normal EF (N = 135)
Impaired EF (N = 246)
P value*
49.0 ± 9.4 31.9 ± 5.4 28.5 ± 1.3 7.4 ± 4.3
60.7 ± 11.2 33.4 ± 6.2 12.1 ± 8.2 7.8 ± 4.3
Impaired Vigilance Is Associated with Erectile Dysfunction in Patients with Sleep Apnea Roland Popp, PhD,* Yannick Kleemann, MD,† Maximilian Burger, MD,‡ Michael Pfeifer, MD,†§ Michael Arzt, MD,†1 and Stephan Budweiser, MD¶1 *Department of Psychiatry and Psychotherapy, Center of Sleep Medicine, University of Regensburg, Regensburg, Germany; †Department of Internal Medicine II, University of Regensburg, Regensburg, Germany; ‡Department of Urology, Caritas St. Josef Medical Center, University of Regensburg, Regensburg, Germany; §Center for Pneumology, Donaustauf Hospital, Donaustauf, Germany; ¶Department of Internal Medicine III, Division of Pulmonary and Respiratory Medicine, RoMed Clinical Center Rosenheim, Rosenheim, Germany DOI: 10.1111/jsm.12789
ABSTRACT
Introduction. Erectile dysfunction (ED) is frequent in patients with obstructive sleep apnea (OSA) and may act as a surrogate of endothelial dysfunction. Furthermore, impairments of vigilance and sustained attention are also commonly associated with OSA. Aim. The purpose of this study was to evaluate whether there is an association between ED and sustained attention deficits. Methods. A prospective cross-sectional cohort of 401 male in-patients undergoing diagnostic polysomnography for suspected OSA and a 25-minute sustained attention test was analyzed. ED was assessed using the 15-item International Index of Erectile Function (IIEF-15) questionnaire. The Epworth Sleepiness Scale (ESS) served as a measure of daytime sleepiness. Main Outcome Measure. Severity of impaired erectile function (EF) assessed by the IIEF-15, core task parameters of the sustained attention test (i.e., CR: correct reactions; V-CR: variation of correct reactions, CE: commission errors, RT: reaction time; V-RT: variation of reaction times). Results. Three hundred eighty-one consecutive patients presenting for in-lab polysomnography were included in the analysis. Impaired EF was diagnosed in 246 patients (65%). With increasing impairment of EF, patients scored significantly worse in all vigilance test parameters and demonstrated more severely diminished vigilance (normal EF: 11.9%, moderately impaired EF: 24.1%, and severely impaired EF: 34.9%). Multivariate regression analyses including established risk factors for ED, OSA, or sleepiness revealed a significant independent association between lower scores for EF and impairments on the following vigilance test variables: odds ratio (95% confidence interval) for V-CR: 0.52 (0.34–0.81), CE: 0.87 (0.80–0.95), and V-RT: 0.91 (0.87–0.96). The ESS was independently associated with both measures of performance instability: odds ratio for V-CR: 6.94 (2.97–16.23) and V-RT: 1.28 (1.14–1.44). Conclusions. In OSA patients, the severity of impaired EF was associated with impaired vigilance performance, independent of other known risk factors for ED or OSA and not mediated by sleepiness. Potentially, the findings suggest a direct relationship between vascular or endothelial dysfunction and impairments in both EF and neurobehavioral cognitive function. Popp R, Kleemann Y, Burger M, Pfeifer M, Arzt M, and Budweiser S. Impaired vigilance is associated with erectile dysfunction in patients with sleep apnea. J Sex Med **;**:**–**. Key Words. Erectile Function; Erectile Dysfunction, Sexual Dysfunction; Endothelial Dysfunction; Vigilance Performance; Sustained Attention; Daytime Sleepiness
1
Contributed equally.
© 2014 International Society for Sexual Medicine
J Sex Med **;**:**–**
2 Introduction
E
rectile dysfunction (ED) is a frequent symptom affecting about 20% of the male population [1]. ED is also a particularly common condition in men with obstructive sleep apnea (OSA). The incidence of ED among this population is in a range between 40% and 64% [2–4], and male patients with OSA experience more sexual dissatisfaction and sexual dysfunction compared with age-matched controls [5]. However, decreased libido or sexual dysfunction may be underrecognized in these patients, as not all of them address these problems voluntarily. While there appears to be a direct link between OSA and the development of ED, the common overlapping risk factors (i.e., age, hypertension, diabetes, and psychological factors such as depression) make it somewhat difficult to confirm a clear causal relationship [6]. However, a few studies could detect that OSA and the related intermittent nocturnal hypoxemia were an independent risk factor and correlate with ED and overall sexual function [3,7]. ED is a surrogate of endothelial and vascular dysfunction. Due to altered vasodilating and vasoconstricting processes, endothelial dysfunction can cause both ED and cardiovascular diseases [8,9]. ED may even be an initial symptom of an early stage of endothelial dysfunction leading to arteriosclerosis and cardiovascular disease [10,11]. There is converging evidence that OSA produces (cerebro)vascular microlesions as well as sympathetic activation and enhances endothelial dysfunction [6]. These dysfunctions evoke changes in microvascular perfusion that favor the rise of ED. Specifically, repetitive nocturnal hypoxemia due to OSA induces oxidative stress, hormonal alterations, and increased inflammatory stimuli. Finally, OSA-related intermittent hypoxia can result in an amplified risk of hypertension and cardio- and cerebrovascular disease (e.g., myocardial infarction and strokes) [12,13]. Sleepiness may further augment the risk for vascular events. Thus, in patients with OSA, sleepiness is an independent risk factor for vascular events [14,15]. In addition, OSA can produce psychological alterations and neural dysfunction such as impaired vigilance or alertness [16]. Remarkably, an early finding of Bédard and colleagues specifically related nocturnal hypoxemia to vigilance impairments in OSA [17]. As a basic pathophysiological mechanism, the authors assumed a hypoxia-induced vascular damage of the brain.
J Sex Med **;**:**–**
Popp et al. In contrast to sexual dysfunction, vigilance problems are much more apparent neurobehavioral complaints in OSA patients seeking treatment in a sleep laboratory. These patients frequently report difficulties staying awake and alert especially in boring or tedious situations, which results in increased daytime sleepiness, vigilance impairments, and unintended lapses of sustained attention. In general, vigilance or sustained attention (most researchers use both terms synonymously [18,19]) refers to the basic ability of the organisms to maintain their attention and remain alert to stimuli over prolonged periods of time, even if the monitoring task is monotonous [20]. On vigilance tasks, patients with severe OSA demonstrated impaired performance compared with healthy controls [21,22]. Recently, a meta-review underscored the negative effects of OSA on cognition, most likely in the domain of attention/vigilance [23]. To date, no study has evaluated the association of impaired vigilance performance with sexual dysfunction in patients with OSA. Based on these considerations and on the assumption that ED and vigilance in these patients may be due to a common underlying mechanism of endothelial or vascular dysfunction, we would expect a statistical association between those different domains of performance. Thus, the aim of this analysis was to examine a possible link between ED and neurobehavioral impairments of sustained attention in the presence of other risk factors for ED and OSA. Specifically, since sustained attention deficits are sensitive to sleepiness, we considered subjective daytime sleepiness as a possible confounding or mediating factor of vigilance performance in patients with OSA. Methods
Study Population A subgroup from a prospective study sample comprising 401 consecutive male in-patients with supposed OSA who were referred to diagnostic in-lab polysomnography between June 2006 and June 2007 entered the present analysis [7,24]. As described previously, only patients with neurological or psychiatric dysfunctions (e.g., depression), hypogonadism, current treatment with phosphodiesterase-5-inhibitors, or severe lung diseases had not been included into the study [7]. For the present analysis, we only included patients who underwent a full record of valid data in a 25-minute sustained attention task (N = 381). Nineteen patients refused to perform the complete
Impaired Vigilance and ED in Patients with Sleep Apnea test, and one subject obviously misunderstood the test instruction resulting in 498 commission errors. The full study protocol was approved by the university ethics committee. All patients gave written informed consent prior to the start of the study.
Assessments Erectile Function To assess ED the 15-item International Index of Erectile Function (IIEF-15) questionnaire [25] was used, which includes 15 questions referring to different sexual domains including “erectile function” (EF). Overall sexual function is described by the IIEF-15 summary score (range 5–75 points). In our study, we focused on ED as defined by ≤25 points of the EF subdomain, with values of 11–25 indicating “mild to moderately” and ≤10 “severely” impaired EF. Sleepiness Daytime sleepiness was measured by the German version of the Epworth Sleepiness Scale (ESS) assessing sleep propensity in activities of daily life [26]. Scores >10 (range 0–24) are considered as clinically suspicious for increased daytime sleepiness [26,27]. Sustained Attention The test “Vigil-Vigilance” (VIGIL-S1 test form of the Vienna Test System, Schuhfried GmbH, Mödling, Austria) is based on the Mackworth clock, an established assessment method on sustained attention under monotonous conditions [28,29]. On a black screen, 32 small white circles are arranged to form a larger circle that looks like a clock face. A white dot moves clockwise along the large circle in small jumps at a rate of 1.5 seconds per move (test duration: 25 minutes). Patients had to press a reaction key whenever a target stimulus (total number of 100) occurred, i.e., a double jump skipping one of the small circles. The vigilance test was administered in the course of the morning after the first diagnostic polysomnography night. The computerized task automatically records a number of test variables: the number of correct reactions (maximum 100), the number of commission errors, the mean reaction time (in 1/100 seconds), the variance of correct reactions (V-CR), and the variance of reaction times (V-RT). For each of the five test variables, vigilance decrements of an individual are defined by a test parameter
3
value ≤16 percentile (based on a normative sample of adults provided by the Vienna Test System). Severely diminished vigilance (SDV) was present when a patient revealed vigilance decrements on at least two of all five test parameters.
Polysomnography As described previously [7,24] in more detail, the patients underwent diagnostic in-lab polysomnography (MEPAL-System, Martinsried, Germany). According to the American Academy of Sleep Medicine [30] the severity of sleep-disordered breathing was quantified by the apnea–hypopnea index (AHI), defined as the number of apneas and hypopneas per hour of sleep. To account for the diagnosis of periodic limb movements in sleep (PLMS) and to avoid contamination by apneainduced motoric arousals, we mainly used the last titration night for positive airway pressure therapy to assess the PLMS Index (the diagnostic polysomnography was used in 14 patients, since no subsequent titration night was performed). Valid data of periodic limb movements were able to be obtained in 377 patients and were analyzed automatically (REMbrandt-PSG-Software, Embla, Ontario, Canada). Statistical Analysis Continuous variables are presented as mean and standard deviation. Differences between baseline characteristics of patients with and without impaired EF were compared using the t-test for quantitative variables and using the chi-square test for binary variables. To compare groups with different severity of ED, one-way analysis of variance (anova) was applied for continuous variables. To evaluate whether various classes of ED severity (i.e., normal EF, moderately impaired EF, and severely impaired EF) are associated with altered performance on various vigilance task parameters, we used Jonckheere’s trend test for ordered differences. The association of EF as an independent variable with multiple dependent variables (i.e., every five vigilance parameters) was evaluated by univariate and multivariate regression analyses. For all multivariate regression models, we considered confounding variables and established risk factors for impaired EF, sleep-disordered breathing, and daytime sleepiness. That included age, obesity (body mass index), smoking history, hyperlipidemia, chronic obstructive pulmonary disease (COPD), atherosclerosis, heart failure, coronary J Sex Med **;**:**–**
4 Table 1
Popp et al. Characteristics and sleep parameters of patients with normal and impaired erectile function (EF)
Variables General measures (dimension) Age (years) Body mass index (BMI) (kg/m2) IIEF-15 (score) Epworth Sleepiness Scale (ESS) (score) Smoking history n (%) Nonsmokers Current smokers and ex-smokers Sleep measures (dimension) Sleep efficiency (%) REM sleep/sleep period time (%) Arousal index (/hour) PLMS index (/hour) [N = 377] AHI (/hour) AHI in REM sleep (/hour) Obstructive apnea (n) Mixed apnea (n) Central apnea (n) Hypopnea (n) SaO2 mean (%) SaO2 lowest (%)
Normal EF (N = 135)
Impaired EF (N = 246)
P value*
49.0 ± 9.4 31.9 ± 5.4 28.5 ± 1.3 7.4 ± 4.3
60.7 ± 11.2 33.4 ± 6.2 12.1 ± 8.2 7.8 ± 4.3
