Insomnia, Sleep Quality, and Quality of Life in Mild to ... - ATS Journals

ORIGINAL RESEARCH Insomnia, Sleep Quality, and Quality of Life in Mild to Moderate Parkinson’s Disease Shirin Shafazand1, Douglas M. Wallace2,3, Kristopher L. Arheart4, Silvia Vargas1,2, Corneliu C. Luca2, Henry Moore2, Heather Katzen2, Bonnie Levin2, and Carlos Singer2 1

Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Miller School of Medicine, 2Department of Neurology, Miller School of Medicine, and 4Division of Biostatistics, Department of Public Health Sciences, University of Miami, Miami, Florida; and 3Neurology Service, Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, Florida

Abstract Rationale: Sleep disorders are prevalent in Parkinson’s disease but underreported in clinical settings. The contribution of sleep disorders to health-related quality of life (HRQOL) for patients with this degenerative neurological disease are not well known. Objectives: To evaluate the impact of insomnia symptoms, obstructive sleep apnea (OSA), and poor sleep quality on HRQOL in a cohort of patients with idiopathic Parkinson’s disease. Methods: We enrolled a convenience sample of 66 adults seen in the University of Miami Movement Disorders Clinic between July 2011 and June 2013. Participants completed validated questionnaires to determine insomnia symptoms, OSA risk, depression, anxiety, and HRQOL. All patients underwent unattended polysomnography to confirm OSA. Results were compared for those with and without insomnia symptoms. Principal component and regression analyses were performed to evaluate determinants of HRQOL. Measurements and Main Results: Participants were predominately Hispanic males with mild to moderate Parkinson’s disease. Insomnia symptoms were reported

for 46% of the study subjects. OSA (apnea–hypopnea index, >5) was noted in 47%, with a mean apnea–hypopnea index of 8.3 6 11.0. Fairly bad to very bad sleep quality was reported by 21% of the participants. Insomnia (r = 0.71; P , 0.001), daytime sleepiness (r = 0.36; P = 0.003), depression symptoms (r = 0.44; P , 0.001), and anxiety symptoms (r = 0.33; P = 0.006) were significant correlates of poor sleep quality. OSA, severity of Parkinson’s disease, and dopaminergic therapy were not. In the principal component analysis, sleep quality was a significant component of the “psychological factor” that in turn was a significant determinant of overall HRQOL. Conclusions: Insomnia symptoms, OSA, and subsequent poor sleep quality are prevalent in Parkinson’s disease. In this singlecenter, exploratory study, we found that insomnia and poor sleep quality, but not OSA, play important roles in determining overall quality of life for patients with this disease. Clinical trial registered with www.clinicaltrials.gov (NCT02034357). Keywords: sleep–wake disorders; sleep initiation and maintenance disorders; health-related quality of life; Parkinson’s disease; idiopathic

(Received in original form August 23, 2016; accepted in final form December 29, 2016 ) Supported by a grant from the National Parkinson Foundation (S.S., C.S.). Author Contributions: All authors had access to the data and contributed substantially to the design, acquisition, and analysis of data, as well as to the writing of the manuscript. Correspondence and requests for reprints should be addressed to Shirin Shafazand, M.D., M.S., Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Miller School of Medicine, University of Miami, P.O. Box 016960 (D60), Miami, FL 33101. E-mail: [email protected] Ann Am Thorac Soc Vol 14, No 3, pp 412–419, Mar 2017 Copyright © 2017 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201608-625OC Internet address: www.atsjournals.org

Nonmotor symptoms are increasingly recognized as important causes of morbidity and disability in patients with in Parkinson’s disease (1). In a multicenter study of 1,072 consecutive patients with treatment-naive or treated stable Parkinson’s disease, 98.6%

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of patients reported nonmotor symptoms. One-third of all participants surveyed reported sleep disturbances (1). Emerging evidence suggests that nonmotor symptoms have a negative impact on health-related quality of life (HRQOL)

and may be even more disruptive than the motor manifestations of Parkinson’s disease (1). Despite their prevalence and impact, healthcare providers frequently fail to identify or do not fully address major nonmotor symptoms such as sleep

AnnalsATS Volume 14 Number 3 | March 2017

ORIGINAL RESEARCH disorders, depression, anxiety, and fatigue in more than 50% of patients (2). This is an important oversight because sleep disturbances, mood, fatigue, and apathy appear to be key determinants of HRQOL in Parkinson’s disease, and the totality of nonmotor symptoms increases the cost of care and caregiver burden. Much of the literature on sleep disturbances in Parkinson’s disease is focused on REM sleep behavior disorder (RBD) as a prevalent sleep disorder that may predate motor symptoms of Parkinson’s disease and provoke sleeprelated injury (3). However, insomnia, excessive daytime sleepiness (EDS), and obstructive sleep apnea (OSA) are also reported in Parkinson’s disease and likely affect overall sleep quality (4). Not much is known about the relative interaction of these sleep disorders and their impact on HRQOL in Parkinson’s disease. In a chronic disease where curative therapies have remained elusive, identifying and treating sleep disorders with subsequent improvements in quality of life are important therapeutic goals. Also, much of the current literature suffers from methodological limitations, including lack of objective polysomnography (PSG) and use of nonvalidated questionnaires to diagnose specific sleep disorders (5). We hypothesize that insomnia symptoms play an important role in sleep quality and HRQOL in Parkinson’s disease, even after controlling for OSA, mood, Parkinson’s disease severity, and use of dopamine agonists. Our present study adds to the body of evidence regarding the importance of sleep disorders in Parkinson’s disease and addresses prior limitations by using overnight PSG and validated questionnaires to describe sleep in a clinical cohort of predominately Hispanic patients living in South Florida with idiopathic Parkinson’s disease.

Participants had a Hoehn and Yahr stage less than or equal to 3 and were medically stable with no medication changes in the month prior to enrollment. PSG was performed within 2 weeks of study enrollment. Participants were excluded if they (1) were unable to read English or Spanish at a fifth-grade level, (2) were already treated for OSA with positive airway pressure or surgery, (3) had a prior history of neurosurgical procedures for Parkinson’s disease, (4) had significant cognitive impairment as defined by Mini Mental State Examination score less than 26, (5) had a history of major uncontrolled psychiatric illness or drug or alcohol abuse/ dependence, or (6) had a history of head injury or other neurological disorders. The University of Miami Panel on Human Subjects in Medical Research approved the protocol, and all participants signed a written informed consent form prior to enrollment (IRB number UM 20110265). Study Variables

Methods

Demographic characteristics and medical history, including comorbidities and medication use, were obtained by patient interview and a review of medical records. Dopaminergic drug dosages were converted to levodopa dosage equivalents (LDE) using a previously published formula (6). Participants underwent a full neurological examination, including completion of the Unified Parkinson’s Disease Rating Scale and determination of Parkinson’s disease severity using the modified Hoehn and Yahr stage (7). Anthropometric measurements (height and weight) were obtained on the day of enrollment. Participants completed validated questionnaires (available in both English and Spanish) to determine risk for various sleep and mood symptoms. All subjects underwent an unattended level II PSG at home to objectively diagnose OSA. The technician who scored the PSG and the interpreting physician were blinded to study group assignment.

Subjects

Sleep Questionnaires

We enrolled a convenience sample of 66 adults (age, >18 yr) referred to the University of Miami Movement Disorders Clinic between July 2011 and June 2013. A movement disorder neurologist diagnosed participants with idiopathic Parkinson’s disease using the UK Parkinson’s Disease Society Brain Bank criteria.

Sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI) (8) and the Parkinson’s Disease Sleep Scale (PDSS) (9). A global PSQI score greater than 5 yields a diagnostic sensitivity of 89.6% and specificity of 86.5% (k = 0.75; P , 0.001) in distinguishing “poor” and “good” sleepers (10).

Shafazand, Wallace, Arheart, et al.: Sleep and Quality of Life in Parkinson’s Disease

The PDSS is a validated visual analogue scale designed to measure sleep complaints over the previous week in patients with Parkinson’s disease. The PDSS addresses 15 symptoms commonly associated with sleep disturbance in Parkinson’s disease in eight main areas, including overall sleep quality, sleep onset and maintenance insomnia, nocturnal restlessness, nocturnal psychosis, nocturia, nocturnal motor symptoms, refreshing sleep, and daytime sleepiness. A mean score is obtained, ranging from 0 (most severe) to 150 (free of symptoms) (11). It has been suggested that patients with Parkinson’s disease with an overall score less than 82 or a score under 5 on any subitem on the PDSS have a significant sleep disturbance and would benefit from a formal sleep evaluation (12). The Athens Insomnia Scale (AIS) was used to evaluate insomnia symptoms. It consists of eight items: The first five pertain to sleep induction, awakenings during the night, final awakening, total sleep duration, and sleep quality, and the last three items refer to well-being, functional capacity, and sleepiness during the day (13). The Berlin Questionnaire (14) was used to determine increased risk of OSA. Results were correlated with actual OSA diagnosis (via PSG) to determine the clinical usefulness of this screening questionnaire in patients with Parkinson’s disease. Subjective daytime sleepiness was measured using the Epworth Sleepiness Scale (ESS) (15). Total scores range from 0 to 24, with higher scores indicating a greater propensity to fall asleep in different situations. Depression, Anxiety, and HRQOL Questionnaires

The Beck Depression Inventory-II (16) and the Beck Anxiety Inventory (17) were used as brief psychological screening tools to assess depression and anxiety symptomatology, respectively (18, 19). We used the 39-item Parkinson’s Disease Questionnaire (PDQ39) to determine disease-specific HRQOL in Parkinson’s disease. The PDQ39 is a self-administered questionnaire that comprises 39 items addressing eight domains of health in Parkinson’s disease, including mobility, activities of daily living, emotional wellbeing, stigma, social support, cognition, communication, and bodily discomfort. A higher score on this scale indicates worse perceived quality of life (20). 413

ORIGINAL RESEARCH Polysomnography

We used in-home level II PSG with the Embletta X100 portable recording unit (Natus Medical, Pleasanton, CA) in accordance with standards established by the American Academy of Sleep Medicine (21). Level II PSG includes an EEG montage for sleep stage scoring, in addition to respiratory channels. The Embletta X100 unit has been validated against a standard in laboratory-attended PSG with good performance characteristics and accuracy in detecting OSA (22). Apneas were scored in accordance with American Academy of Sleep Medicine scoring rules as a greater

than 90% reduction in airflow from preevent baseline breathing lasting 10 seconds or longer. Central apneas were scored when apnea occurred in the absence of respiratory effort. Hypopneas were scored using greater than 30% reduction in airflow with 4% desaturation. An apnea– hypopnea index (AHI) of five or more events per hour, defined as the number of apneas and hypopneas per hour of sleep, was used to diagnose OSA. Data Analysis

We report mean and SD, median and interquartile ranges, and frequency data.

Participants were divided into two groups (insomnia and no insomnia) based on AIS score greater than or equal to 6, indicating presence of insomnia. Differences in study variables were compared using the chi-square test, Fisher’s exact test, or Student’s t test. The frequency of poor sleep quality was calculated as the proportion of individuals with a PSQI greater than or equal to 5. High risk for OSA was calculated as the proportion of individuals with a Berlin Questionnaire score greater than or equal to 2. EDS was defined as the proportion of participants with ESS scores greater than or equal to 10.

Table 1. Characteristics of study participants Characteristic

Age,* yr Male sex, n (%) BMI,* kg/m2 Marital status, n (%) Married/partner Other (single, divorced, widow) Ethnicity, Hispanic or Latino, n (%) Race, white, n (%) Education,† n (%) Grade 8 education level or less Some high school or high school diploma Some college or college degree Professional degree Employment, n (%) Employed Unemployed Other (retired, disability, housewife) Comorbidities, n (%) Myocardial infarction Stroke Hypertension Diabetes Chronic kidney disease Anxiety and/or depression Previous history of malignancy Beck Depression Inventory*† Beck Anxiety Inventory*† LDE dose,* mg UPDRS* Mentation, behavior, mood Activities of daily living Motor examination Total score Modified Hoehn and Yahr staging, n (%) Stage 0 Stage 1 Stage 1.5 Stage 2 Stage 2.5 Stage 3

All Participants (n = 66)

Participants with Insomnia (n = 32)

Participants with No Insomnia (n = 34)

64 6 10 49 (74) 27 6 4

63 6 9 22 (69) 27 6 4

65 6 11 27 (79) 26 6 4

56 10 43 64

(85) (15) (65) (97)

27 5 20 31

(84) (16) (63) (97)

29 5 23 33

(85) (15) (68) (97)

2 12 30 22

(3) (18) (45) (33)

1 4 10 17

(3) (13) (31) (24)

1 8 20 5

(3) (24) (59) (15)

P Value

0.46 0.40 0.29 0.91 0.79 0.37 0.01

0.15 15 (23) 1 (2) 50 (76)

6 (19) 1 (0) 25 (78)

9 (26) 0 (0) 25 (74)

5 (8) 5 (8) 27 (41) 8 (12) 7 (11) 26 (39) 13 (20) 9.2 6 7.3 9.1 6 8.6 363.2 6 255.3

2 (6) 2 (6) 13 (41) 6 (19) 5 (16) 15 (47) 6 (19) 11.5 6 8.0 12.0 6 10.0 412.0 6 255.9

3 (9) 3 (9) 14 (41) 2 (6) 2 (6) 11 (32) 7 (21) 7.3 6 6.4 6.6 6 6.7 315.2 6 251.8

1.0 1.0 1.0 0.14 0.25 0.31 1.0 0.02 0.01 0.13

1.5 6 1.3 10.9 6 5.2 16.1 6 7.4 30.4 6 13.3

1.4 6 1.2 11.5 6 4.4 15.8 6 7.3 30.7 6 11.3

1.5 6 1.4 11.0 6 6.0 16.7 6 7.4 31.0 6 15.2

0.77 0.73 0.64 0.96 0.25

0 1 4 35 3 4

(0) (2) (6) (53) (5) (6)

0 0 2 13 3 2

(0) (0) (10) (65) (15) (10)

0 1 2 22 0 2

(0) (0) (7) (82) (0) (7)

Definition of abbreviations: BMI = body mass index; LDE = levodopa dosage equivalents; UPDRS = Unified Parkinson’s Disease Rating Scale. Numbers are rounded and may not add to 100%. Hoehn and Yahr staging was missing for 20 participants and is not included in the analysis. UPDRS was missing for 10 participants and is not included in the analysis; for UPDRS, the higher the score, the worse the impairment. *Mean 6 SD. † P , 0.05 for the comparison between insomnia and no insomnia groups.

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ORIGINAL RESEARCH Table 2. Polysomnographic data Metric*

Total sleep time, min Wake after sleep onset, min Latency to REM,† min ODI Lowest O2 saturation, % Average O2 saturation, % Stage N1, % Stage N2, % Stage N3, % Stage R, % AHI

All



309 6 102 162 6 94 115 6 121 4.3 6 7.3 89.9 6 4.3 93.7 6 10.9 11.7 6 13.1 68.1 6 24.1 9.7 6 15.5 9.6 6 10.2 8.3 6 11.0

297 6 106 158 6 102 77 6 82 6.0 6 9.1 89.5 6 4.1 92.3 6 16.1 12.1 6 13.4 70.5 6 21.7 5.7 6 10.7 9.9 6 10.2 10.5 6 14.0

313 6 103 172 6 88 143 6 144 3.0 6 5.2 90.1 6 4.7 94.9 6 1.9 11.1 6 13.4 68.5 6 26.1 11.6 6 18.0 8.4 6 10.5 6.8 6 7.7

P Value

0.54 0.56 0.03 0.12 0.56 0.36 0.76 0.74 0.11 0.56 0.20

Definition of abbreviations: AHI = apnea–hypopnea Index; ODI = oxygen desaturation index. *Mean 6 SD. † P , 0.05 for the comparison between insomnia and no insomnia groups.

We initially used multivariable linear regression to evaluate the relationship between disease-specific quality of life in Parkinson’s disease and a set of predictors that were selected on the basis of their clinical significance or statistical significance in bivariable analyses. The predictors included were insomnia, OSA, sleep quality, Parkinson’s disease severity, dopaminergic medications, depression, and anxiety. The multivariable regression analysis proved to be untenable because of significant correlations among the independent variables (collinearity) and the small sample size’s limiting the number of independent variables that could be entered into the model. We therefore used a

principal component analysis to obtain factor scores that represent the underlying dimensions of the collection of predictors. A varimax rotation was used to form orthogonal (uncorrelated or independent) factor scores from the set of predictors. These factor scores were then used as predictors of quality of life in a multivariable regression analysis. Because this was an exploratory study, no a priori power calculations were done. Post hoc power calculations show that the present study with 66 subjects has 90% power to detect an R2 value as small as 0.19 at the 0.05 a-level. The R2 detected in this study was 0.64. To detect a moderate R2 of 0.30 at the 0.05 a-level with 90% power, we

needed a sample size of only 38. Our sample size exceeds this at 66. We accepted a two-tailed P value less than 0.05 as statistically significant for all analyses. We analyzed data using SPSS for Windows version 17.0 (SPSS, Chicago, IL) and SAS 9.3 (SAS Institute, Inc., Cary, NC) software.

Results Characteristics of Study Participants

The study sample consisted of 66 participants (73% male, 53% Hispanic) with a mean age of 64 6 10 years and a mean body mass index (BMI) of 27 6 4 kg/m2

Table 3. Sleep questionnaires Metric

ESS*† High risk for OSA,† n (%) Global PSQI*† Sleep quality in the preceding month,† n (%) Very good Fairly good Fairly bad Very bad Self-reported sleep duration,*† h Total AIS*† Sleep induction, slight to very delayed,† n (%) Nighttime awakening, minor to serious problem,† n (%) Early morning awakening, a little earlier than desired to much earlier,† n (%) Total PDSS*†

P Value

All



7.6 6 5.2 31 (47) 6.6 6 4.3

9.4 6 5.9 19 (59) 9.1 6 4.4

6.1 6 4.1 12 (35) 4.3 6 2.7

16 (24) 36 (55) 9 (14) 5 (8) 6.6 6 1.5 5.9 6 4.3 27 (41) 45 (68) 33 (50)

2 (6) 16 (50) 9 (28) 5 (16) 6.0 6 1.5 9.7 6 2.9 20 (62) 27 (84) 28 (88)

14 (41) 20 (59) 0 (0) 0 (0) 7.2 6 1.2 2.5 6 1.7 7 (21) 18 (53) 5 (15)

0.01 0.05 0.000 0.000 — — — — 0.001 0.000 0.003 0.003 0.000

108 6 27

92 6 22

121 6 23

0.000

Definition of abbreviations: AIS = Athens Insomnia Scale; ESS = Epworth Sleepiness Score; OSA = Obstructive Sleep Apnea; PDSS = Parkinson Disease Sleep Scale; PSQI = Pittsburgh Sleep Quality Index. Numbers are rounded and may not add to 100%. *Mean 6 SD. † P , 0.05 for the comparison between insomnia and no insomnia groups.


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ORIGINAL RESEARCH (Table 1). Modified Hoehn and Yahr staging ranged from 1 to 3, and 74% were categorized as stage 2. The mean cumulative Unified Parkinson’s Disease Rating Scale score was 30 6 13, and the median Mini Mental State examination score was 29 (interquartile range, 4). There were no statistically significant differences in demographic characteristics, comorbidities, Parkinson’s disease severity, LDE medication use, and all other pharmacological therapies used in Parkinson’s disease between participants with insomnia symptoms and those without such symptoms, except that those in the insomnia group were more likely to have a professional degree. Participants with insomnia symptoms were more likely to report depression and anxiety (Table 1). Polysomnography Data

The mean total sleep time (TST) on the study night was 309 minutes (5 h, 9 min). Subjects spent the majority of time in N2 sleep (68% of TST), and REM sleep constituted only 9.6% of TST (Table 2). The mean oxygen desaturation index was 4.3, with the lowest mean oxygen saturation of 89.9%. There was no statistically significant difference in TST, percentage of time spent in each sleep stage, or wake after sleep onset between those with insomnia symptoms and those with no insomnia symptoms. The insomnia group had shorter latency to REM sleep (77 min vs. 143 min; P , 0.05). Risk of Obstructive Sleep Apnea and Its Prevalence on Polysomnography

An increased risk of OSA using the Berlin Questionnaire was noted in 44% of all participants (Table 3). Subjects with insomnia symptoms were more likely to have a positive score on the Berlin Questionnaire (59% vs. 35%; P , 0.05). Objective OSA (based on PSG; AHI, >5) was noted in 47% of the population, with mean AHI of 8.3 6 11.0 (Table 2). The association between Berlin Questionnaire risk category and actual OSA diagnosis was weak but statistically significant (Spearman’s rho = 0.24; P , 0.05). The insomnia group had a trend toward higher mean AHI (10.5 vs. 6.8; P = 0.2), but this did not reach statistical significance. Patients with Parkinson’s disease with OSA compared with those without OSA did not differ in symptoms of daytime sleepiness, Parkinson’s disease severity, and sex. Those with OSA compared with those 416

Table 4. Parkinson’s Disease Sleep Scale Mean 6 SD

Item

Percentage of Sample Scoring 6) were reported by 49% of all participants, with 41% reporting problems with sleep induction (early insomnia), 68% reporting middle insomnia, and 50% rising earlier than their desired hour. The mean AIS for all participants was 5.9 6 4.3 (Table 3), indicating overall subclinical insomnia in this population. Sleep Quality and Excessive Daytime Sleepiness

The mean PSQI for all participants was 6.6 6 4.3, indicating overall poor sleep quality. Only 26% of participants ranked their sleep quality as very good, whereas 21% reported fairly bad to very bad sleep quality, within the previous month. When queried about sleep during the previous month, 40% of all subjects reported having

20 20 14 9 17 14 29 11

nighttime arousals and 27% reported loud snoring or coughing during sleep three or more times per week. Fairly bad to very bad sleep quality was reported by 44% of participants with insomnia symptoms, whereas none of those without insomnia complaints reported poor sleep quality. Insomnia symptoms correlated strongly and significantly with overall sleep quality (r = 0.71; P , 0.001). Other significant correlates of poor sleep quality were daytime sleepiness (r = 0.36; P = 0.003), depression symptoms (r = 0.44; P , 0.001), and symptoms of anxiety (r = 0.33; P = 0.006). OSA, severity of Parkinson’s disease, and dopaminergic therapy were not significantly correlated with sleep quality. The PDSS score was less than 82 in 17% of the study population, indicating significant sleep disturbance in those patients. According to the PDSS results, poor nighttime sleep quality, sleep onset and maintenance insomnia, and nonrefreshing sleep were reported by 20%, 20%, and 29% of the study population, respectively (Table 4).

Table 5. Health-related quality of life: 39-idtem Parkinson’s Disease Questionnaire PDQ-39 Dimension*

Mobility Activities of daily living Emotional well-being Stigma† Social support Cognition Communication Pain† Overall score†

All

27.9 6 23.8 26.8 6 20.6 22.4 6 20.9 17.2 6 22.7 8.7 6 17.2 22.5 6 19.7 13.6 6 13.9 32.4 6 26.3 21.5 6 13.8

Participants with Participants with P Value Insomnia (n = 32) No Insomnia (n = 34) 33.2 6 27.2 28.8 6 21.6 25.9 6 22.9 24.0 6 27.3 12.2 6 21.3 26.9 6 20.9 15.3 6 15.9 43.3 6 27.3 26.7 6 15.4

24.4 6 20.3 26.6 6 19.9 19.9 6 19.5 11.9 6 16.0 4.6 6 10.9 18.6 6 18.6 12.2 6 11.5 22.5 6 21.9 17.6 6 11.1

0.15 0.67 0.25 0.03 0.08 0.09 0.37 0.001 0.000

Definition of abbreviation: PDQ-39 = 39-item Parkinson’s Disease Questionnaire. *Mean 6 SD. † P , 0.05 for the comparison between insomnia and no insomnia groups. The scores range from 0 (perfect health) to 100 (worse health).


ORIGINAL RESEARCH Overall, participants reported having a mean of 6.6 6 1.5 hours of sleep per night. There was a significant difference in sleep duration between groups, with the insomnia participants reporting shorter mean sleep duration (6.0 h vs. 7.2 h; P , 0.05). EDS was reported by 26% of all participants. A statistically significant difference in EDS was noted, with 41% of the insomnia group and 15% of the no insomnia group reporting EDS (P = 0.02). The mean ESS score for the entire study population was 7.6 6 5.2, with a statistically significant difference noted between groups (Table 3). Depression, Anxiety, and HRQOL

The mean Beck Depression Inventory-II score for all participants was 9.2 6 7.3, indicating minimal depressive symptoms in the study population. The insomnia group, although overall exhibiting mild depressive symptoms, had scores that were significantly higher than the no insomnia group (11.5 6 8.0 vs. 7.3 6 6.4; P , 0.05). The mean anxiety score for all participants was 9.1 6 8.6, indicating overall minimal anxiety symptoms in the study population, with the insomnia group having more anxiety symptoms than the no insomnia group (12.0 6 10.0 vs. 6.6 6 6.7; P , 0.05). The PDQ-39 score for the overall population was 21.5 6 13.8. Participants with insomnia reported worse overall PDQ-39 scores. There was a statistically significant difference between the two groups in the stigma and bodily pain dimensions, with the insomnia group reporting worse scores in these dimensions (Table 5). The PDQ-39 summary index and PSQI overall score were significantly correlated (r = 0.51; P , 0.001). Principal Component Analysis

The principal component analysis with varimax rotation revealed two dimensions using the combination of predictor variables (OSA, sleep quality, Parkinson’s disease severity, dopaminergic medications, depression, and anxiety) (Table 6). These variables were chosen because of their clinical and statistical significance in bivariate analyses. The first factor represents the psychological dimension, consisting of anxiety, depression, sleep quality, and dopaminergic medications. The second factor represents the physical dimension and consists of Parkinson’s disease severity, dopaminergic medications, and sleep quality. Note that sleep quality

and dopaminergic medications are present in both factors because they likely have both psychological and physical impacts of living with Parkinson’s disease. Insomnia was highly correlated with the sleep quality variable and was not included in the factor analysis. The regression of PDQ-39 on the psychological and physical factors was significant (P , 0.001) and explained 64% of the variation. The psychological effect was positive and significant (P , 0.001), indicating that as psychological stress (poor sleep quality, anxiety, and depression) increased, HRQOL worsened. The physical effect was not significant (P = 0.061) but trended in the direction of HRQOL worsening as physical stress increased (Table 7).

Discussion HRQOL is a multidimensional construct that may be defined as a patient’s satisfaction or happiness with physical, emotional, and social domains of life that affect or are affected by health and wellbeing (23). It is an important health outcome to understand and address in chronic diseases such as Parkinson’s disease where there is no known cure. Our study adds to the existing sleep and Parkinson’s disease literature by uniquely evaluating many sleep complaints concurrently and determining the impact of sleep on quality of life in predominately male and Hispanic patients with mild to moderate Parkinson’s disease. Insomnia, OSA, and poor sleep quality were common in our patient population. Insomnia symptoms and poor sleep quality were highly correlated. In our principal component analysis, sleep quality was an important component of the psychological factor that in turn was a significant determinant of overall HRQOL in our patients with mild to moderate Parkinson’s disease. Symptoms of EDS were reported by slightly more than one-fourth of our study participants. EDS was significantly correlated with insomnia symptoms, with those participants reporting daytime sleepiness being more likely to report insomnia symptoms and poor sleep quality. Comorbid OSA may contribute to increased daytime sleepiness in those patients who also report symptoms of insomnia, particularly the subset of patients who have sleep maintenance insomnia (24).


Table 6. Varimax-rotated factor loading for psychological and physical components Variable

Psychological

Physical

0.86 0.86 0.54 20.20 0.15 0.37

20.01 0.10 0.48 0.69 0.63 0.58

Anxiety Depression Sleep quality Sleep apnea PD severity Dopaminergic medications

Definition of abbreviation: PD = Parkinson’s disease.

Additionally, daytime sleepiness has commonly been reported in patients with Parkinson’s disease (up to 75% of patients studied) (25). Although the exact etiology is unknown, it is believed to be related to neurodegenerative processes involving sleep regulatory centers, blunted melatonin response, dopamine agonist use, insomnia, restless legs syndrome (RLS), OSA, and depression (25). Traditionally, EDS has been defined by a score of 10 or higher on the ESS; however, a lower threshold of 7 on the ESS has been shown to have 75% sensitivity in predicting risk for driving accidents in patients with Parkinson’s disease (26). In our clinical sample, the mean ESS was 7.6, indicating a population sleepy enough to be at risk for driving accidents. Results reported on the prevalence and clinical correlates of OSA in Parkinson’s disease are mixed; some studies have shown a higher prevalence of OSA in patients with Parkinson’s disease (up to 60%) than in control subjects, whereas others have demonstrated no difference or even a lower prevalence of OSA in the Parkinson’s disease group (27). The prevalence of OSA in Parkinson’s disease (on average, a middle-aged to older population) is likely similar to age-matched control subjects in Table 7. Regression of 39-item Parkinson’s Disease Questionnaire on psychological and physical components Variable Intercept Psychological Physical

b-Value

SE

20.91 10.93 2.02

1.13 1.14 1.14

P Value ,0.001 ,0.001 0.061

R2 = 0.64; P , 0.001.

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ORIGINAL RESEARCH the general population (27). In keeping with a study by Neikrug and colleagues (28), 47% of the participants in our study were diagnosed with OSA with, on average, mild OSA severity. The severity of OSA may be underestimated when portable sleep study devices are used to measure AHI (29). REM sleep was also reduced in our sleep subjects, with only 10% of the time spent in REM sleep. This, too, may have contributed to the lower AHI noted in our subjects. Traditional OSA screening questionnaires, such as the Berlin Questionnaire, are useful, but as evidenced by our study, they are weakly correlated with objective PSG. Indeed, in our study, there were very few features distinguishing those with and without OSA. On average, patients with Parkinson’s disease with OSA were older and had higher BMI, although they were not obese. Until better screening tools are identified, a high index of clinical suspicion followed by definitive testing using PSG may be warranted. Insomnia symptoms were reported by nearly half of the participants. Insomnia was an important determinant of sleep quality even after we adjusted for depression, anxiety, Parkinson’s disease severity, and LDE. Using a validated insomnia questionnaire, we report a higher frequency of insomnia (46% vs. 37%) than that of a large, multicenter Italian study of 1,072 subjects with idiopathic Parkinson’s disease in which the researchers used a semistructured interview technique (1). Insomnia is more prevalent in patients with Parkinson’s disease than in age-matched control subjects and has been associated with increased depression, fatigue, and pain (30). The underlying etiology of insomnia in this population is thought to be multifactorial and due in part to neurodegenerative changes in the brainstem, thalamocortical pathways, and ventral tegmental areas in the midbrain leading to sleep–wake disturbances. Other important considerations are the effects of dopaminergic medications, particularly at

high doses, and autonomic dysfunction (nocturia, hypokinesia) occurring during sleep leading to disruptive nighttime sleep and insomnia symptoms (4). We used a Parkinson’s disease–specific measure (the PDSS) in addition to a more generic but widely used questionnaire (the PSQI) to measure sleep quality. Both questionnaires consistently reported poor sleep quality in about 20% of our study population. Insomnia, daytime sleepiness, depression symptoms, and anxiety symptoms were all significantly associated with poor sleep quality. Surprisingly, OSA severity (measured by AHI as well as oxygen desaturation index), Parkinson’s disease severity, and dopaminergic therapy were not significantly correlated with sleep quality. Similarly, Neikrug and colleagues (28) also found that OSA and Parkinson’s disease severity were not significant predictors of sleep quality. In our study, the regression model explains 64% of the variation observed in HRQOL, highlighting the importance of sleep quality in addition to depression and anxiety as predictors of HRQOL in Parkinson’s disease. Strengths and Limitations

The strength of our study is that, to our knowledge, it is the most comprehensive to date of sleep in Parkinson’s disease in terms of multiplicity of validated clinical assessment tools used in conjunction with ambulatory PSG. We recognize, however, that our study has several limitations, including a small study sample at a single center, which limited our ability to detect some potentially significant differences, and the provision of true population prevalence estimates. Under our study eligibility criteria, the patients were medically stable and had mild to moderate Parkinson’s disease, and all were taking dopaminergic medications. The results therefore cannot be generalized to patients with more severe Parkinson’s disease or to drug-naive patients. It is likely, however, that as Parkinson’s disease progresses, the prevalence of sleep complaints also

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increases, suggesting a need to address these problems early in the management of Parkinson’s disease (12). Our study was not designed to diagnose RBD; in the absence of video monitoring confirming movement during REM sleep, we could not make a definitive diagnosis of RBD. RBD has been shown to impair HRQOL in Parkinson’s disease (28), but its relative impact on HRQOL when controlling for other sleep disorders and depression is not well known. Additionally, owing to the portable nature of our PSG units, we did not evaluate the presence of periodic limb movements that may have an impact on sleep quality and subsequent HRQOL. On average, our study participants had mild OSA. The results cannot be generalized to patients with Parkinson’s disease with moderate to severe OSA who may indeed experience worsened sleep quality and HRQOL. Conclusions

This exploratory study increases the awareness that insomnia symptoms, OSA, poor sleep quality, and EDS are common in a clinical cohort of patients with mild to moderate Parkinson’s disease. Furthermore, in predominately Hispanic and male patients with Parkinson’s disease, the presence of poor sleep quality led to lower perceived HRQOL. Poor sleep quality contributed to poor quality of life even when we took into consideration the effects of depression, Parkinson’s disease severity, and dopaminergic medications. Our study highlights the need for increased awareness of and screening for sleep problems by healthcare providers taking care of patients with Parkinson’s disease. Much work remains to be done to determine whether a combination of pharmacological and nonpharmacological therapies aimed at improving insomnia, sleep quality, and other sleep disorders will improve HRQOL as well as cognitive and motor morbidities in patients with Parkinson’s disease. n

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