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Keywords Narcolepsy · Quality of life · Cataplexy · Excessive daytime sleepiness Introduction Narcolepsy is a neurological sleep disorder characterized by excessive daytime sleepiness (EDS) caused by loss of hypo- cretin (orexin) in postero-lateral hypothalamus. Narcolepsy is classied as narcolepsy with cataplexy (type 1, NT1), or without cataplexy (type 2, NT2) [1 ]. The prevalence of type 2 and type 1 narcolepsy lies between 0.16–0.66% and 0.025–0.05%, respectively [2 ]. While there is no reported prevalence for narcolepsy in the Korean adult population, in a study of 20,407 Korean adolescents the prevalence of narcolepsy with cataplexy in the younger age groups was determined as 0.015% [3 ].

Narcoleptics often experience more di culties in their social, vocational, and personal lives. Patients with narco- lepsy report higher rates of comorbid medical and/or psychi- atric problems, and often present with additional sleep disor - ders [4 , 5 ]. Thus, it can be understood that narcolepsy has a negative inuence on quality of life (QoL) [6 , 7 ]. However, the exact factors that adversely aect QoL in these patients are not well known. Excessive daytime sleepiness, a major symptom of narcolepsy with considerable effects on QoL, has been reported in 91% of narcoleptics [8 ]. In obstructive sleep apnea (OSA), EDS/somnolence is also commonly reported [ 9 ] with a negative inuence on QoL [10]. A previous study reported that the QoL in narcolepsy patients was lower than in OSA patients [11]; however, it did not exactly dierenti- ate between narcolepsy and OSA with somnolence (OSA- som), and to our knowledge no other study has compared QoL between narcolepsy and OSA-som (Korean version of Epworth sleepiness scale, K-ESS ≥ 10). Therefore, it would * Yong Won Cho [email protected] 1 College of Nursing, Daegu Health College, Daegu, South Korea 2 Department of Neurology, Dongsan Medical Center, Keimyung University School of Medicine, 56 Dalseong-ro, Jung-gu, Daegu 41931, South Korea 3 Department of Neurology, Georgetown University Hospital, Washington, DC, USA Vol.:(0123456789) 1 3 448 Sleep and Biological Rhythms (2019) 17:447–454 be valuable to compare QoL between narcolepsy and OSA- som, in addition to investigating the impact of EDS on QoL.

Fatigue, poor memory, social or vocational dysfunction, and mood disturbances are common complaints in chronic insomnia, which are recognized to have a negative inuence on QoL [12, 13]. Despite di culty sleeping at night, insom- niacs do not exhibit heightened levels of EDS [14]. On the other hand, comparing dierent sleep-related symptoms in narcolepsy and insomnia, EDS has been established as the predominant symptom of narcolepsy. Therefore, given the eects of sleep disturbance on daytime activity and wors- ening the QoL, to compare narcolepsy and insomnia, we investigated the degree of sleep disturbance and its inuence on QoL. Cataplexy often happens without notice and can be harm- ful to patients. It commonly interferes with the patients’ social life. The lack of hypocretin is reported to be associ- ated with more EDS and wake intruding sleep in NT1 [15].

In fact, some studies have indicated the involvement of hypocretinergic system in emotional and psychiatric symp- toms such as anxiety [16] and depression [17]. In addition, cataplexy often happens in with the setting of emotional behaviors such as laughter. Despite some dierences in day - time functioning between NT1 and NT2, they both present with EDS. The purpose of this study was to investigate QoL in nar - colepsy focusing on its inuential factors. In particular, to control for sleep-related factors especially EDS, we com- pared QoL in patients with narcolepsy (both NT1 and NT2), OSA-som, and insomnia.

Methods We retrospectively screened 148 patients with possible narcolepsy who had visited a tertiary sleep center between August 2011 and August 2016. All subjects had been eval- uated by a sleep specialist and had completed a series of standard sleep-related questionnaires. According to the International Classication of Sleep Disorders (ICSD) 3rd edition [1 ], narcolepsy was dened by a mean sleep onset latency of less than 8 min and two or more sleep onset REM periods (SOREMPs) during a standard multiple sleep latency test (MSLT). In the right clinical setting with cor - roborative ndings on the sleep studies, we do not routinely check the cerebrospinal uid hypocretin level. During the screening process, we excluded 48 patients who did not meet the diagnostic criteria for narcolepsy (13 patients with mean sleep onset latency of more than 8 min, and 35 patients with less than 2 SOREMs), 28 patients who did not provide data for QoL, and 9 patients with other comorbid medical diseases (Fig. 1). We successfully enrolled 63 narcoleptics. All of the patients were diagnosed with narcolepsy for the rst time and the data were collected before starting the treatment.

The controls included 87 patients with insomnia, and 49 patients with OSA-som out of 165 total OSA patients. Of that total, 116 were OSA patients without somnolence. All subjects completed a PSG. Insomnia was diagnosed accord- ing to the ICSD 3 [1 ], and patients with OSA had respiratory disturbance index (RDI) score of 5 or higher [1 ]. Patients were categorized as OSA-som if their Korean version of Epworth Sleepiness Scale (K-ESS) score was ≥ 10 [ 18]. We excluded patients younger than 18 years, who did not do quality of life questionnaires, and who were comorbid with medical diseases, psychiatric disorders, or other sleep disor - ders such as restless legs syndrome and parasomnia. This study was approved by the institutional ethics com- mittee of the regional hospital. Measurements Quality of life was assessed using the Korean version of the Short-Form 36-Item Health Survey (K-SF36) [19]. K-SF36 is a common measure of health that is often used to deter - mine the cost-eectiveness of treatment. All of the subjects completed sleep- and psychiatric-related questionnaires including Korean versions of the Insomnia Severity Index (K-ISI) [20], the K-ESS [18], and the Hospital Anxiety and Depression Scale (HAS, HDS) [21].

Statistics analysis Data analysis was performed using SPSS version 25.0, and p < 0.05 was considered statistically signicant. We com - pared narcolepsy with OSA-som, and insomnia patients. The Chi-square test was used for dierences in gender, ANOVA was used to analyze age and BMI (Body Mass Index) data, Fig. 1 Narcolepsy patient screening ow chart 1 3 449 Sleep and Biological Rhythms (2019) 17:447–454 and Schee test for post hoc testing. ANCOVA was used to analyze K-ISI, K-ESS, and K-SF36 scores after adjusting for age and gender, and pair-wise comparisons were used for dierences found between the groups. Pearson correlation was used for analyzing the correlation between age, gender, BMI, K-SF36, K-ISI, K-ESS, HAS, HDS, and MSLT/RDI.

Multiple linear regression was used to investigate the predic- tors of QoL.

Results Demographic and clinical characteristics among narcoleptics, OSA‑som patients, and insomniacs We studied 63 narcoleptics (33 NT1 and 30 NT2), 49 OSA- som patients, and 87 insomniacs. Narcoleptics were signi- cantly younger than both OSA-som patients and insomniacs.

Narcoleptics were more likely to be female than OSA-som patients (31.7% vs. 12.2%, respectively), but less likely to be female compared to insomniacs (31.7% vs. 63.2%, respectively). There was no signicant dierence in BMI among the groups (Table 1).

Severity of insomnia was worse in narcoleptics compared to OSA-som patients; however, this dierence did not reach statistical signicance. Narcoleptics had signicantly less severe insomnia compared to insomniacs. The severity of EDS was signicantly higher in narcoleptics than OSA-som patients and insomniacs. The mean of RDI from narcolepsy patients and insomniacs was signicantly less than OSA- som patients, and the RDI score from all narcolepsy patients and insomniacs was less than 5. In terms of anxiety and depression, there were no signi- cant dierences among the three groups (Table 1). Comparing QoL of narcoleptics, OSA‑som patients, and insomniacs There were no signicant dierences in QoL between the three groups. However, the mental component of QoL and total QoL were signicantly higher in OSA patients than in insomniacs (Table 1). Table 1 Demographic and clinical characteristics between groups Adjusted age and gender ANCOVA were used for analysis K-ISI, K-ESS, HAS, HDS, K-SF36 K-ISI Korean version of Insomnia Severity Index, K-ESS Korean version of Epworth Sleepiness Scale, RDI Respiratory Disturbance Index, HAS Hospital Anxiety scale, HDS Hospital Depressive Scale, K-SF36 Korean version of 36-item short-form health survey, PCS physical component summary, MCS mental component summery a Narcolepsy patientsb OSA with somnolence patientsc Insomniacs Narcolepsy a (N = 63) OSA with somnolence b (N = 49) Insomnia c (N = 87) F/x 2 pSchee/pairwise Age (years) 27.03 ± 9.2939.20 ± 11.8347.25 ± 13.05 54.81< 0.001 a < b < c Gender (% female) 20 (31.7)6 (12.2)55 (63.2) 36.80< 0.001 BMI (kg/m 2) 24.80 ± 3.90 25.33 ± 2.4823.85 ± 12.46 0.510.600 Narcolepsy (% Type 1) 33 (52.4)–– –– Sleep measure K-ISI 12.75 ± 6.107511.27 ± 4.8919.39 ± 5.74 21.05< 0.001 a < c, b < c K-ESS 15.17 ± 4.2613.43 ± 2.575.06 ± 4.50 82.69< 0.001 a > b > c RDI 1.55 ± 2.5836.97 ± 26.400.50 ± 1.02 136.67< 0.001 b > a, b > c 5 ≤ RDI < 15 (%) 12 (24.5) 15 ≤ RDI < 30 (%) 14 (28.6) RDI ≥ 30 (%) 23 (46.9) HAS 6.78 ± 3.215.98 ± 3.887.43 ± 4.70 2.760.065 HDS 8.73 ± 3.707.90 ± 3.358.54 ± 4.09 0.700.497 K-SF36 PCS 66.83 ± 16.5670.12 ± 13.9262.24 ± 17.90 2.820.062 MCS 61.25 ± 15.9967.65 ± 15.6556.91 ± 20.39 4.040.019 b > c SF36 total 67.41 ± 15.7872.84 ± 14.1762.69 ± 19.27 4.520.012 b > c 1 3 450 Sleep and Biological Rhythms (2019) 17:447–454 Correlation among severity of insomnia, EDS, anxiety, depression and QoL in each group of narcoleptics, OSA‑som, and insomniacs In narcoleptic patients, EDS showed significant posi- tive correlation with severity of insomnia (r = 0.366), age (r = 0.359), BMI (r = 0.353), and anxiety (r = 0.316).

Severity of insomnia showed signicant positive corre- lation with anxiety (r = 0.285), depression(r = 0.336), and age (r = 0.446). The QoL showed signicant nega- tive correlation with anxiety (r = − 0.631) and depression ( r = − 0.501), however QoL showed no signicant correla- tion with EDS and severity of insomnia (Table 2; Fig. 2).

Table 2 Correlation among severity of insomnia, EDS, anxiety, depression and QoL in each group of narcoleptics, OSA with somnolence, and insomniacs BMI Body Mass Index, RDI Respiratory Disturbance Index, K-SF36 Korean version of 36-item short-form health survey, K-ISI Korean version of Insomnia Severity Index, K-ESS Korean version of Epworth Sleepiness Scale, HAS Hospital Anxiety Scale, HDS Hospital Depression Scale, MSLT multiple sleep latency test *Correlation is signicant at the 0.05 level (two-tailed) **Correlation is signicant at the 0.01 level (two-tailed) Age GenderBMIK-ISI K-ESSHAS HDSMSLT/RDI SF36 total Narcoleptics Age 1 Gender − 0.1171 BMI 0.256*− 0.472**1 K-ISI 0.446**− 0.1630.2441 K-ESS 0.359**− 0.0780.353**0.366** 1 HAS − 0.0830.0800.0930.285* 0.316*1 HDS 0.158− 0.0710.2250.336** 0.1690.408** 1 MSLT − 0.0700.140− 0.165− 0.039 − 0.126− 0.077 − 0.0721 K-SF36 total 0.113− 0.038− 0.107− 0.226 − 0.122− 0.631** − 0.501**0.108 1 OSA with somnolence Age 1 Gender 0.557**1 BMI − 0.054− 0.0401 K-ISI 0.0110.275− 0.0651 K-ESS 0.0960.1330.0880.270 1 HAS 0.0200.067− 0.131− 0.131 − 0.1471 HDS − 0.1240.1140.069− 0.114 0.0180.601** 1 RDI − 0.056− 0.007− 0.0240.106 0.1340.103 0.2641 K-SF36 total 0.041− 0.0580.075− 0.255 0.003− 0.445** − 0.571**− 0.185 1 Insomniacs Age 1 Gender 0.1271 BMI − 0.0370.0321 K-ISI 0.1400.1610.1231 K-ESS − 0.317**− 0.264*− 0.110− 0.090 1 HAS − 0.167− 0.124− 0.1400.310** 0.1581 HDS − 0.013− 0.033− 0.0110.253* 0.0720.646** 1 K-SF36 total 0.171− 0.129− 0.126− 0.540** − 0.030− 0.530** − 0.542** 1 Fig. 2 Correlation in narcoleptics 1 3 451 Sleep and Biological Rhythms (2019) 17:447–454 In OSA-som patients, there were significant positive correlation between anxiety and depression (r = 0.601).

There was a negative correlation between QoL and anxiety ( r = − 0.445), and depression (r = − 0.571). There was no signicant correlation between EDS and anxiety, depression, severity of insomnia. Severity of insomnia also showed no signicant correlation with anxiety and depression (Table 2, Fig. 3).

In insomniacs, there was signicant positive correlation between severity of insomnia and anxiety (r = 0.310) and depression (r = 0.253). There was a signicant negative cor - relation between severity of insomnia and QoL (r = − 0.540).

There were signicant negative correlation between QoL and anxiety (r = − 0.530), depression (r = − 0.542). There was no signicant correlation between EDS and any of other variables (Table 2, Fig. 4). Predictors of QoL in narcolepsy, OSA‑som, and insomnia There was no signicant dierence between NT1 and NT2 in on the total score of the K-SF36. In order to analyze the predictors of QoL in each group, we considered age, gen - der, BMI, severity of insomnia, EDS, anxiety, and depressed mood as independent variables. In narcoleptics, anxiety and depressive mood signi- cantly aected QoL, however, anxiety (β = − 0.51) had a greater impact on the total QoL than depressive mood did ( β = − 0.29) (Table 3). Fig. 3 Correlation in OSA with somnolence Fig. 4 Correlation in insomniacs Table 3 Predictors of total QoL in narcoleptics, OSA with somnolence, and insomniacs Age, gender, BMI, K-ISI, K-ESS, HAS, and HDS as independent variables, for narcolepsy patients added MSLT, for OSA patients added RDI as independent variable Stepwise method was used for analysis BMI Body Mass Index, QoL quality of life, K-SF36 Korean version of 36-item short-form health survey, PCS physical component summary, MCS mental component summery, K-ISI Korean version of Insomnia Severity Index, K-ESS Korean version of Epworth Sleepiness Scale, HAS Hospital Anxiety Scale, HDS Hospital Depression Scale, MSLT multiple sleep latency test, RDI Respiratory Disturbance Index BS.Eβ R 2 change tp VIF Narcoleptics Constant 95.334.22 22.54< 0.001 HAS − 2.510.50− 0.51 0.399 − 4.97< 0.001 1.20 HDS − 1.240.43− 0.29 0.071 − 2.830.006 1.20 R 2 = 0.470, F = 26.58, p < 0.001 OSA with somnolence Constant 102.005.51 18.50< 0.001 HDS − 2.350.43− 0.60 0.326 − 5.420.001 1.20 K-ISI − 0.930.32− 0.32 0.104 − 2.890.006 1.20 R 2 = 0.430, F = 17.32, p < 0.001 Insomniacs Constant 107.265.66 18.94< 0.001 HDS − 1.440.48− 0.30 0.294 − 2.990.004 1.72 K-ISI − 1.330.27− 0.39 0.174 − 4.82< 0.001 1.11 Age 0.350.110.23 0.052 0.2990.004 1.02 R 2 = 0.519, F = 29.91, p < 0.001 1 3 452 Sleep and Biological Rhythms (2019) 17:447–454 In OSA-som patients, QoL was signicantly aected by depressive mood and severity of insomnia, and the depres- sive mood ( β = − 0.60) had greater impact on QoL than insomnia (β = − 0.32) did (Table 3).

In insomniacs, QoL were signicantly aected by depres - sive mood, the severity of insomnia, and age but the sever - ity of insomnia ( β = − 0.39) had a greater impact on QoL than depressive mood (β = − 0.30) and age (β = 0.23) did (Table 3). Discussion The mean age of diagnosis for patients with narcolepsy was 27.03 (± 9.29) which was less than that of OSA patients, and insomniacs. This is consistent with the fact that narcolepsy starts at an early age [22– 24] while OSA and insomnia often start later in life. We found gender dierences in narcolepsy i.e., predominantly aecting the male. This is in contrast to most reports indicating no signicant gender dierence in narcolepsy [6 , 11, 25], however it is supported by a previous study reporting 78% male dominance in narcolepsy [26]. We found gender dierences in OSA and insomnia both consist- ent with previous studies reporting more than 70% of OSA patients being males [27, 28], and females being 1.6 times more likely than men to develop insomnia [28– 30].

Narcoleptics showed more severe insomnia than seen in OSA patients although this dierence did not reach statisti- cal signicance. Compared to insomniacs, both narcoleptics and OSA patients showed signicantly less severe insom- nia than insomniacs, however the mean score of severity of insomnia in narcoleptics (12.75) was higher than the cut o threshold (7) indicating subthreshold insomnia [20]. Previ- ous studies have reported that improving nocturnal sleep in narcolepsy would increase daytime alertness [31, 32]. There- fore, nocturnal sleep disturbance in patients with narcolepsy may well impact their QoL, although the eect may not be as severe as in insomniacs. This study showed that narcoleptics have signicantly more EDS than patients with OSA-som and insomniacs do.

Consistent with previous reports, we found EDS a common complaint in sleep disordered patients [33], however, we identied EDS as a symptom associated with poor QoL and worse psychological parameters in narcoleptics [34, 35].

For further investigation, we compared NT1 and NT2.

Fifty-two percent of narcoleptics in our study had NT1. We found that the type of narcolepsy did not have a signicant impact on QoL. It has been reported that narcolepsy symp- tomatology (narcolepsy with cataplexy-like symptoms, hyp- nagogic or hypnopompic hallucination, and sleep paralysis) is associated with poor QoL, symptoms of depression, and anxiety [34], yet our ndings indicated that cataplexy-like symptoms have no signicant eect on QoL. Previous studies have also associated QoL of narcoleptics with the degree of EDS and psychological variables such as depressive mood [7 , 26, 36]. We found that both anxiety and depression have a negative impact on QoL in narcolep- tics, but the total QoL were more aected by anxiety than depressive mood. The EDS did not have a signicant impact on QoL, contrary to other studies reporting a signicant association between EDS and psychiatric symptoms such as depression and anxiety [34, 37]. Although EDS did not impact QoL, it showed signicant correlation with anxiety.

Also, nocturnal sleep disturbance was not a factor impacting QoL, nocturnal sleep disturbance showed signicant correla- tion with anxiety, depression, and EDS. It is possible that QoL is indirectly aected by both EDS and nocturnal sleep disturbance through psychiatric factors as a downstream eect. Overall, we found anxiety the most impactful fac- tor in QoL of narcoleptics. A previous study reported more that anxiety than depressive mood in narcolepsy patients.

Additionally, many patients reported noticeable impairment in daily functioning due to anxiety and mood problems. We suggest that physicians consider this notion along with the sleep symptoms [38]. There were some dierences between narcolepsy patients and those with OSA-som, as well as between narcolepsy and insomnia patients. In both OSA-som and insomnia groups, the QoL was aected by severity of insomnia and depres- sive mood, however EDS did not correlate with severity of insomnia or any psychiatric factors. Some studies have reported coexisting with OSA as a contributing factor to EDS with negative inuence on QoL [39]. However, our ndings did not support these reports. In our results, the OSA-som was dened by K-ESS scale, so it should inuence the correlation between EDS and QoL. On the other hand, other study has reported a strong correlation between depres- sive mood and low QoL, although EDS might have a small eect on QoL [22]. That ndings may partially support our results. In OSA-som patients, the severity of insomnia did not show a signicant correlation with QoL, however in fac- tor analysis, controlling the eect of depression, severity of insomnia was included as one of the eect factors, and depressive mood seemed to aect QoL the most. Previous studies have reported that men with comorbid OSA and insomnia have greater prevalence and severity of depression, and lower QoL [40, 41] which is in line with our results. In addition, other studies reported that anxiety had strong cor - relation with depression, and was more common in female patients [42]. Our study only included six females, so we were unable to conrm these particular correlations. Further research is needed to determine the signicance of anxiety as an inuence on QoL. In current study the RDI did not show any correlation with QoL. This was supported by pre- vious studies which found no correlation between AHI and QoL and concluded that the eect of OSA on QoL cannot 1 3 453 Sleep and Biological Rhythms (2019) 17:447–454 be explored with PSG or by utilizing commonly used QoL questionnaires [10, 43].

In insomniacs, there were signicant correlations among severity of insomnia, depressive mood, anxiety, and QoL.

The factors impacting QoL were the severity of insomnia and depressive mood, with the severity of insomnia having the higher impact (β = − 0.39, vs β = − 0.30). In patients with insomnia, the severity of insomnia has been associated with psychiatric symptoms [13, 44], and QoL [45]. Our ndings could be supported by these data. In insomniacs, EDS did not show any correlation with severity of insomnia, psychi- atric factors, and QoL. In contrast to our results, some of previous studies have reported that EDS could be considered secondary to chronic insomnia and depression [46]. Also, EDS would correlate with lower QoL and depressive mood [ 47, 48].

The signicance of this study was to compare the factors inuencing the QoL of the narcolepsy group against the two groups each consisting of OSA-som and insomnia, in addi- tion to comparing NT1 and NT2 with each other. Thus, we investigated the dierence in the degrees of inuence fac- tors, such as EDS, sleep disturbance, cataplexy symptoms, and mood disturbance (depression and anxiety) on QoL. There were several limitations of our study. The rst is its retrospective design in addition to the data having been obtained from a pool of patients referred to a tertiary sleep center. We could not control nor include other variables that may have an eect on QoL. In addition, the diagno- ses of NT1 were merely based on patient reports with no CSF hypocretin (orexin) levels checked. Third, the OSA patients were rst diagnosed with OSA using PSG. A patient interview and sleep questionnaire were also given, which eliminated the need for further testing for comorbidities such as NT2, idiopathic hypersomnia, or insu cient sleep syndrome. Also, although this is a single center study, the results are not signicantly dierent from those reported by multicenter studies. In conclusion, the QoL of the total narcolepsy group was comparable to the OSA-som and insomnia groups. There are dierent inuential factors involved in QoL of narcolep- tics, OSA-som patients, and insomniacs. The EDS did not directly aect QoL, in fact, the most inuential factor in QoL in narcoleptics was anxiety while EDS showed a signicant correlation with anxiety. In OSA-som patients, the most sig- nicant factor impacting QoL was depressive mood, while for the insomniacs, it was severity of insomnia. Although, there were some dierences in the degree of eect, ulti- mately the QoL was aected most by psychiatric variables, directly or indirectly. Therefore, to improve the QoL in these patients, pharmacological or non-pharmacological psychiatric treatments should be considered. In particular, patients with narcolepsy, should prioritize anxiety manage- ment for the purpose of improving QoL. It should be noted that anxiety in narcolepsy patients may also be reduced as a result of narcolepsy treatment. Further research is needed to evaluate the eect of narcolepsy treatment on anxiety levels. Funding No funding was received in this study.

Compliance with ethical standards Conflict of interest None of the authors have potential conicts of in- terest to be disclosed.

Ethical standards This study was approved by the institutional review board of a regional university hospital and patient consent was exempt due to the retrospective nature of the study (#2017-02-009). All pro- cedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Animal rights This article does not contain any studies with animals performed by any of the authors.

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