Published Ahead of Print on June 17, 2015 as 10.1212/WNL.0000000000001737
Development of excessive daytime sleepiness in early Parkinson disease
Lena K. Tholfsen, MD Jan P. Larsen, MD, PhD Jörn Schulz, PhD Ole-Bjorn Tysnes, MD, PhD Michaela D. Gjerstad, MD, PhD
Correspondence to Dr. Gjerstad: [email protected]
ABSTRACT
Objective: To examine the frequency, development, and risk factors of excessive daytime sleepiness (EDS) in a cohort of originally drug-naive patients with incident Parkinson disease (PD) during the first 5 years after diagnosis.
Methods: One hundred fifty-three drug-naive patients with early PD derived from a populationbased incident cohort and 169 control participants were assessed for EDS and reevaluated after 1, 3, and 5 years on medication. EDS was diagnosed according to the Epworth Sleepiness Scale. Cutoff score above 10 was applied. Generalized estimating equation models for correlated data were used to examine associated and risk factors for EDS. Results: Patients reported EDS more often than control participants at the time of diagnosis and during follow-up. The frequency of EDS in PD increased from 11.8% at baseline to 23.4% after 5 years. Associated factors were male sex, the use of dopamine agonists, and higher Montgomery-Åsberg Depression Rating Scale and Unified Parkinson’s Disease Rating Scale–activities of daily living scores. Main risk factor for developing EDS was an increased Epworth Sleepiness Scale score at baseline.
Conclusion: EDS is more frequent in PD even before treatment initiation compared with control participants and increases in occurrence with disease progression. The main risk factor for developing EDS with time is an early predisposition for sleepiness. In addition, the use of dopamine agonists was associated with the development of EDS. These findings necessitate caution in patients with PD and early increased sleep propensity and when using dopamine agonists. Neurology® 2015;85:1–7 GLOSSARY ADL 5 activities of daily living; EDS 5 excessive daytime sleepiness; ESS 5 Epworth Sleepiness Scale; MADRS 5 MontgomeryÅsberg Depression Rating Scale; MMSE 5 Mini-Mental State Examination; PD 5 Parkinson disease; UPDRS 5 Unified Parkinson’s Disease Rating Scale.
Lesions of the brainstem and mesencephalon affecting the sleep/wake regulation are one of the possible mechanisms for the development of excessive daytime sleepiness (EDS).1 According to the Braak hypothesis, structural changes in these areas are found in the premotor stages of Parkinson disease (PD), raising the assumption that different sleep disorders may already emerge in an early disease state.2 Previously conducted studies of EDS in PD are mainly cross-sectional or in patients with more advanced disease and show an association with advanced motor impairment,3 the use of dopamine agonists,4 and male sex.5 The same features have been proposed as possible risk factors. The frequency and implications of EDS in early PD are, however, only partially assessed, and more research is needed to further explore whether EDS emerges mainly as a consequence of disease-related pathology at early stages or whether it is a symptom caused by other factors that could benefit from different types of interventions. The aims of this study were therefore to examine the frequency, development, associated covariates, and risk factors of EDS in a cohort of originally drug-naive patients with incident PD and during the first 5 years on medication. From The Norwegian Centre for Movement Disorders (L.K.T., J.P.L., J.S., M.D.G.), Stavanger; Department of Neurology (L.K.T., M.D.G.), Stavanger University Hospital; and Department of Neurology (O-B.T.), Haukeland University Hospital, Bergen, Norway. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2015 American Academy of Neurology
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METHODS Study design. The purpose of this study was to examine sleepiness in newly diagnosed and originally untreated patients with PD and thereafter on medication during 5 years of follow-up. The study is part of the Norwegian ParkWest Study, which is a prospective controlled longitudinal cohort study of incident PD. The patients included in this substudy were nondemented and nondepressed, and had complete data regarding sleepiness. The baseline examinations were conducted before treatment initiation and the patients were then followed with 6-month intervals by study neurologists experienced in movement disorders. Trained study nurses conducted interviews at baseline, 1 year, and then biannually. The patients who were unable to attend the hospital were offered examinations at their homes or nursing homes to minimize attrition bias.
Rating Scale (UPDRS)7 in the patients’ on-state, diagnostic criteria for dementia (Movement Disorders Society Task Force),8 Montgomery-Åsberg Depression Rating Scale (MADRS),9 and Mini-Mental State Examination (MMSE).10 PD phenotype was classified as tremor-dominant, intermediate type, or postural instability–gait disorder as described in previous studies.11 Insomnia was recorded if the patient reported nocturnal sleep problems. For the evaluation of excessive daytime somnolence, the Epworth Sleepiness Scale (ESS)12 was conducted as an interview by a trained study nurse. According to the international standard, a cutoff ESS score of $11 was applied. The ESS has been well validated in PD and has good psychometric properties.13 The dopaminergic medication given was categorized into 2 groups: patients using dopamine agonists and those who were not.
Standard protocol approvals, registrations, and patient consents. The study was approved by the Regional Committee
Statistical analysis. All statistical analyses were performed in
for Medical Research Ethics, Western Norway. Signed written informed consent was obtained from all participants.
Patients and controls. The patients and control participants were recruited from multiple sources in the community in the time period between November 1, 2004, and August 31, 2006.6 Among the 212 patients originally included, 30 patients were excluded because of dementia at baseline or dopaminergic treatment at baseline, or because they were rediagnosed as not having PD during follow-up. Twenty-nine other patients were excluded because of death or they were lost to follow-up before the 5-year visit. Thus, a total of 153 patients were included. After matching for age and sex, 169 control participants were eligible for evaluation of EDS during the first 5 years of the study. Examinations. The same standardized examinations and questionnaires were used throughout the study. Patients were evaluated with a clinical examination, Unified Parkinson’s Disease
Table 1
SPSS 22 (IBM Corp., Armonk, NY). The Mann–Whitney test was used to compare the means of continuous variables and the Pearson x2 test was used to compare proportions of categorical variables of patients with or without EDS. Population-averaged regressions models, using generalized estimating equations, were applied to investigate factors associated with ESS (model 1) and risk factors for the development of EDS (model 2). Model 1 was based on all patients in the cohort and included all consecutive examinations during the follow-up time. The independent variables included were age, sex, follow-up time in years, PD phenotype, insomnia, UPDRS-II (activities of daily living [ADL]) and UPDRS-III (motor function), MMSE score, MADRS score, levodopa equivalent dose, and the use of agonists. The dependent variable, the ESS, was used as a continuous scale in this model. Model 2, risk-factor analysis, included patients without EDS at baseline. Predictor variables were age, sex, follow-up time in years, PD phenotype, insomnia, UPDRS-II (ADL) and UPDRS-III (motor function), MMSE
Clinical and demographic features of patients in early PD Baseline
No. (%)
5y
no EDS
EDS
no EDS
EDS
135 (88.2)
18 (11.8)
111 (77.6)
34 (23.4)
a
BL total ESS score, mean (SD)
4.9 (2.6)
13.0 (2.3)
4.9 (3.1)
8.9 (4.0)a
Age, y, mean (SD)
66.5 (8.9)
64.8 (10.1)
71.3 (9.4)
70.2 (8.1)
Male sex, n (%)
82 (60.7)
12 (66.7)
61 (55.0)
26 (76.5)b
MMSE score, mean (SD)
28.1 (2.3)
27.9 (2.0)
27.1 (3.5)
25.9 (4.8)
MADRS score, mean (SD)
4.2 (4.5)
4.8 (5.6)
4.0 (4.6)
5.2 (5.8)
UPDRS-II (ADL) score, mean (SD)
8.0 (4.4)
8.7 (4.2)
10.9 (5.3)
14.5 (6.8)a
UPDRS-III (motor) score, mean (SD)
21.4 (9.4)
20.6 (10.2)
23.3 (11.2)
30.7 (13.9)b
PIGD phenotype, n (%)
48 (35.6)
9 (50.0)
69 (62.2)
20 (58.9)
Daily levodopa equivalent dose, mg, mean (SD)
0
0
596 (334)
587 (364)
Dopamine agonists monotherapy or in combination, n (%)
0
0
61 (55.9)
20 (58.9)
Insomnia, n (%)
46 (34.1)
3 (16.7)
40 (36.0)
12 (35.3)
Abbreviations: ADL 5 activities of daily living; BL 5 baseline values; EDS 5 excessive daytime sleepiness; ESS 5 Epworth Sleepiness Scale; MADRS 5 Montgomery-Åsberg Depression Rating Scale; MMSE 5 Mini-Mental State Examination; PD 5 Parkinson disease; PIGD 5 postural instability–gait disorder; UPDRS 5 Unified Parkinson’s Disease Rating Scale. Data are presented as means for continuous data and as proportions for categorical data. Pearson x2 and Student t test were used for statistical analysis. a p # 0.005. b p # 0.05. 2
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Table 2
Factors associated with higher Epworth Sleepiness Scale scores in patients with early PD Unadjusted modela
Adjusted modelb
95% CI Measure
B
Lower
Final modelc
95% CI Upper
p
B
Lower
d
1.920
0.828
95% CI B
Lower
Upper
p
3.012
d
0.001
1.871
0.775
2.967
0.001d
0.980
0.320
1.641
0.004d
Upper
p
Male sex
2.049
0.926
3.172
0.000
Use of dopamine agonist
1.07
0.448
1.693
0.001d
0.882
0.150
1.614
0.018d
1.304
0.026
d
0.273
20.353
0.900
0.393
PIGD phenotype
0.693
0.082
Insomnia
20.302
20.963
0.359
0.370
20.544
21.191
0.103
0.099
20.549
21.191
0.094
0.094
Age
20.057
20.110
20.004
0.035d
20.047
20.099
0.005
0.075
20.047
20.098
0.005
0.075
UPDRS-ADL score
0.109
0.043
0.176
0.001d
0.115
0.026
0.205
0.012d
0.087
0.017
0.158
0.015d
UPDRS-motor score
0.025
20.006
0.056
0.111
20.023
20.065
0.019
0.280
MADRS score
0.059
0.000
0.118
0.049d
0.079
0.014
0.144
0.017d
0.078
0.012
0.143
0.020d
20.113
20.255
0.030
0.121
0.164
0.016
0.311
0.030d
MMSE score
20.065
20.196
0.066
0.330
d
0.001
20.001
0.002
0.453
0.068
20.161
0.298
0.560
LED
0.002
0.001
0.003
0.001
Follow-up time in years
0.326
0.189
0.464
0.000d
Abbreviations: CI 5 confidence interval; LED 5 levodopa equivalent dose; MADRS 5 Montgomery-Åsberg Depression Rating Scale; MMSE 5 Mini-Mental State Examination; PD 5 Parkinson disease; PIGD 5 postural instability–gait disorder; UPDRS-ADL 5 Unified Parkinson’s Disease Rating Scale–activities of daily living. a The unadjusted relationship between ESS and the covariates were analyzed including only one covariate at a time. b The adjusted relationship includes all main effects. c The finally adjusted relationship includes selected main effects by stepwise exclusion based on the significance value. d Significant values.
score, and MADRS score. Patients were drug-naive at baseline and in order to evaluate the effect of dopamine agonists, model 2 was repeated in the patients without EDS at the 1-year follow-up and adding the use of dopamine agonists at this visit as an independent variable. The response variable EDS for model 2 was binary. The statistical analyses were conducted with all variables separately evaluated (unadjusted model), estimating interrelation of all the variables (adjusted model), and finally including only with variables of significance from the adjusted analysis (final model) (tables 1 and 2). RESULTS The population in this study consisted of 153 patients with PD who were drug-naive at inclusion and 169 control participants. The average age of the patients was 66 years (SD 9.0) at baseline and 61% were men. The patients were nondemented and nondepressed. The average UPDRS-ADL score was 8.0 (SD 4.4) and UPDRS-motor score 21.3 (SD 9.5) at baseline. Fifty-seven patients (37.3%) presented with a postural instability–gait disorder phenotype. The average ESS score was 5.8 (SD 3.7) and median score 5.0. The control participants were an average age of 66 years at baseline (SD 9.1), 52% were men, and the average ESS score was 5.0 (SD 2.9). No significant differences were found between patients and controls regarding mean age, sex, or ESS scores at baseline.
compared with 8 (4.7%) control participants. During follow-up, the frequency increased in patients to 21 (13.7%) after 1 year and 24 (15.9%) after 3 years, and to 6 (3.6%) and 12 (7.2%) in control participants. After 5 years, 34 patients (23.4%) and 13 (8.0%) control participants reported EDS. Persistence of EDS during the 5-year follow-up period.
EDS was not reported as persisting from one visit to the next in all patients during the 5-year study period, but became more persistent as the disease developed
Figure 1
Development of excessive daytime sleepiness (EDS) in early Parkinson disease
Frequency of EDS at baseline and during follow-up.
Figure 1 shows the observed frequencies of EDS in patients and control participants at baseline, and at 1, 3, and 5 years of follow-up. Eighteen patients (11.8%) were diagnosed with EDS at baseline Neurology 85
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(figure 2). Forty-four percent of the patients with EDS at baseline had EDS 1 year later, while 79.2% of the patients with EDS at the 3-year visit were also affected after 5 years. Clinical and demographic features of the patients with and without EDS. The patients with EDS did not differ
from the patients without EDS according to age, sex, cognitive impairment, depression, insomnia complaints, severity of parkinsonism, or PD phenotype during the first 3 years of follow-up. After 5 years, the patients with EDS had higher UPDRS-ADL and UPDRSmotor scores. There was a male predominance in the EDS group at the 5-year visit (table 1). Associations and risk factors of EDS in early PD. The ESS was used as a continuous scale in the generalized estimating equation model to identify factors associated with experienced EDS. Male sex, increased UPDRS-ADL score, higher MADRS scores, and the use of dopamine agonists were found to be associated with a higher ESS score (table 2). Only patients without EDS at baseline were included in the analysis for the detection of risk factors. Higher ESS scores at baseline were the major risk factor for developing EDS. Sixty-five percent of patients with EDS at the 5-year follow-up had a score above 5 on the ESS at baseline (table 3). The analyses were repeated for the 1-year followup visit in order to include dopaminergic treatments
Figure 2
4
as possible risk factor. Findings were similar to the baseline evaluation, showing that an increased ESS score indicated risk of developing EDS with time. The use of dopamine agonists at the 1-year visit did not increase the risk for later EDS (data not shown). DISCUSSION This study shows an increased frequency of EDS in patients with untreated PD compared with sex- and age-matched controls. The occurrence of EDS increased further with disease progression. EDS could be reversed during the first years with the disease, but the diagnosis became more persistent and robust as the disease developed. The main risk factor for developing EDS in early PD was more symptoms of sleepiness before treatment initiation. Our results may have implications for management because increased sleep propensity at the time of diagnosis may indicate cautiousness when using dopamine agonists in patients with early PD. The frequency of EDS in early PD has not been established. Two smaller studies found no increased frequency of EDS in drug-naive patients with PD compared with controls,14,15 while a recent report described that 49% of patients with PD had EDS 3.5 years after their diagnosis.16 In our study, the frequency of EDS was more than 2-fold increased in drug-naive patients with PD compared with the control participants. Five years after PD diagnosis,
Frequency and persistence of excessive daytime sleepiness (EDS) in patients with early Parkinson disease
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Table 3
Risk-factor analysis of the development of EDS in newly diagnosed patients with PD Unadjusted modela
Adjusted modelb
95% CI for OR Measure
OR
Lower
Upper
Final modelc
95% CI for OR p d
95% CI for OR
OR
Lower
Upper
p
OR
Lower
Upper
p
2.092
0.913
4.791
0.081
Male sex
2.750
1.184
6.390
0.019
2.019
0.755
5.399
0.161
PIGD phenotype
1.002
0.447
2.246
0.996
1.025
0.431
2.439
0.955
20.962
2.230
0.415
0.927
Insomnia
20.533
1.514
.187
0.237
d
Age
0.956
0.924
0.990
0.011
0.967
0.925
1.011
0.140
0.972
0.935
1.010
0.145
ESS score
1.487
1.232
1.795
0.000d
1.532
1.238
1.894
0.000d
1.435
1.182
1.743
0.000d
UPDRS-ADL score
1.025
0.916
1.148
0.665
1.048
0.904
1.216
0.533
UPDRS-motor score
1.006
0.970
1.044
0.731
1.015
0.958
1.076
0.608
MADRS score
1.020
0.927
1.124
0.681
0.998
0.895
1.113
0.972
MMSE score
1.045
0.911
1.200
0.527
0.950
0.796
1.135
0.574
1.264
1.039
1.537
0.019d
1.256
1.039
1.517
0.018d
Follow-up time in years
1.213
1.030
1.430
d
0.021
Abbreviations: ADL 5 activities of daily living; CI 5 confidence interval; EDS 5 excessive daytime sleepiness; ESS 5 Epworth Sleepiness Scale; MADRS 5 Montgomery-Åsberg Depression Rating Scale; MMSE 5 Mini-Mental State Examination; OR 5 odds ratio; PD 5 Parkinson disease; PIGD 5 postural instability–gait disorder; UPDRS 5 Unified Parkinson’s Disease Rating Scale. a The unadjusted relationship between ESS and the covariates was analyzed including only one covariate at a time. b The adjusted relationship includes all main effects. c The finally adjusted relationship includes selected main effects by stepwise exclusion based on the significance value. d Significant values.
we found a 3-fold increased frequency of EDS among patients. Although the frequency of EDS was rather low in early PD, we found that nearly every fourth patient experienced EDS after 5 years. Thus, our findings show that EDS is one of several major complaints that are experienced by patients with early PD. There is considerable information on EDS in more advanced PD and it is agreed that brain pathology of PD is one of the major causes.17–19 Understanding EDS in early or untreated PD is less examined and established. Two studies described EDS to be a consequence of treatment rather than of brain pathology in early PD.14,15 Other authors report that the ESS score is inversely correlated with the degree of dopaminergic degeneration in the striatum as an indication of early involvement of brain pathology.20 Furthermore, a prospective study of healthy elderly reports sleepiness to herald the diagnosis of PD, supporting the assumption that brain pathology is involved in these symptoms at early stages.21 Our results support both concepts of secondary and primary influence on EDS. Increased MADRS scores and the use of dopamine agonists were associated with higher ESS scores and may contribute to the development of EDS. Furthermore, symptoms of EDS were less persistent during the first 5 years of disease development in contrast to findings from studies of more advanced PD.3 These findings implicate that EDS is partly reversible at early stages
and possibly accessible for interventions. Drug-naive patients may have experienced secondary EDS caused by nocturnal motor problems and then were relieved by treatment initiation. In addition, dopaminergic agents, especially dopamine agonists, may have caused dose-dependent drowsiness,22 and transient depressive symptoms may have presented with EDS. With time and disease progression, the excessive sleepiness in patients in this study became more persistent, indicating that EDS converted to be more frequently caused by the presence of irreversible disease-related changes in brain areas involved in sleep–wake regulation. In addition to studying the occurrence of EDS and its associated factors in early PD, we have examined factors that at the time of diagnosis could predict the later development of EDS during the first 5 years of follow-up. We found that the major risk factor for EDS was a higher ESS score even before initiation of dopaminergic treatment. The same was found in a subsequent risk-factor analysis among medicated patients at the 1-year follow-up visit. Sixty-five percent of those with EDS after 5 years had ESS scores between 6 and 10 at baseline compared with 35% of the patients without EDS after 5 years. Obvious secondary causes for the higher ESS scores among those who developed EDS were not found. Taken together with the found association between dopamine agonists and EDS during follow-up, we believe that this information should be relevant for Neurology 85
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management of patients with early PD because it calls for increased awareness of EDS among those with early increased sleepiness and later treatment with dopamine agonists. Strengths of this study include the prospective and controlled study design of an unselected cohort of patients with untreated PD at baseline and very low attrition rates among patients and controls during the 5-year follow-up. It is, however, a limitation that relatively few patients developed EDS in early PD, leaving us with less strength in the statistical calculations. To investigate EDS in PD is a challenge because of the subjective nature of sleepiness and its multiple possible causes. It is the degree of subjectively experienced sleep problems and not the objective measures that leads to the diagnosis. This fact may cause both over- and underestimation of EDS. It is a limitation in this study that we did not have the multiple sleep latency test for objective assessment of EDS. Detailed information on different subtypes of insomnia was not available in this study, which poses another limitation. Nonetheless, we believe that our study provides new and important information on EDS in early PD. In this study, we found that the frequency of EDS was moderately increased in drug-naive patients with early PD compared with control participants and it increases with time. Increased sleepiness within the standard reference range of the ESS was the strongest risk factor for developing EDS during follow-up. Furthermore, pharmacologic effects, sex predisposition, depressive mood, and reduced function of daily living are associated with sleepiness even in early PD. Our findings have implications for the understanding of EDS in early PD and should increase clinicians’ awareness of EDS in patients with early increased sleepiness who are treated with dopamine agonists. These findings are new and should be confirmed in larger longitudinal cohort studies of patients with early PD. AUTHOR CONTRIBUTIONS Dr. Tholfsen and Dr. Gjerstad had full access to all the data in the study and take full responsibility for the integrity of the data and the accuracy of the data analyses. Larsen, Tysnes: study concept and design. Gjerstad, Tysnes: acquisition of data. Tholfsen, Gjerstad, Larsen, Schulz: analyses and interpretation of data. Tholfsen, Gjerstad, Larsen: drafting of the manuscript. All authors: critical revision of manuscript for important intellectual content. Tholfsen, Gjerstad, Schulz: statistical analyses. Larsen: obtained funding. Gjerstad and Larsen: study supervision.
STUDY FUNDING The Norwegian ParkWest Study was supported by grants 911218 and 911792 from the Western Norway Health Authority, grant 177966 from the Research Council of Norway, and the Norwegian Parkinson Disease Association.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures. 6
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Received November 25, 2014. Accepted in final form March 18, 2015. REFERENCES 1. Baumann CR. Traumatic brain injury and disturbed sleep and wakefulness. Neuromolecular Med 2012;14:205–212. 2. Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 2004;318: 121–134. 3. Gjerstad MD, Aarsland D, Larsen JP. Development of daytime somnolence over time in Parkinson’s disease. Neurology 2002;58:1544–1546. 4. Arnulf I. Excessive daytime sleepiness in parkinsonism. Sleep Med Rev 2005;9:185–200. 5. Martinez-Martin P, Falup Pecurariu C, Odin P, et al. Gender-related differences in the burden of non-motor symptoms in Parkinson’s disease. J Neurol 2012;259: 1639–1647. 6. Alves G, Muller B, Herlofson K, et al. Incidence of Parkinson’s disease in Norway: the Norwegian ParkWest Study. J Neurol Neurosurg Psychiatry 2009;80:851–857. 7. Fahn S, Elton RL; Members of the UPDRS Development Committee. Unified Parkinson’s Disease Rating Scale. In: Fahn S, Marsden CD, Calne DB, Lieberman A, editors. Recent Developments in Parkinson’s Disease. Florham Park, NJ: Macmillan Healthcare Information; 1987: 153–163. 8. Emre M, Aarsland D, Brown R, et al. Clinical diagnostic criteria for dementia associated with Parkinson’s disease. Mov Disord 2007;22:1689–1707. 9. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979;134: 382–389. 10. Folstein MF, Folstein SE, McHugh PR. “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198. 11. Jankovic J, McDermott M, Carter J, et al. Variable expression of Parkinson’s disease: a base-line analysis of the DATATOP cohort. The Parkinson Study Group. Neurology 1990;40:1529–1534. 12. Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep 1991;14: 540–545. 13. Hagell P, Broman JE. Measurement properties and hierarchical item structure of the Epworth Sleepiness Scale in Parkinson’s disease. J Sleep Res 2007;16:102–109. 14. Kaynak D, Kiziltan G, Kaynak H, Benbir G, Uysal O. Sleep and sleepiness in patients with Parkinson’s disease before and after dopaminergic treatment. Eur J Neurol 2005;12:199–207. 15. Fabbrini G, Barbanti P, Aurilia C, Vanacore N, Pauletti C, Meco G. Excessive daytime sleepiness in de novo and treated Parkinson’s disease. Mov Disord 2002;17:1026–1030. 16. Breen DP, Williams-Gray CH, Mason SL, Foltynie T, Barker RA. Excessive daytime sleepiness and its risk factors in incident Parkinson’s disease. J Neurol Neurosurg Psychiatry 2013;84:233–234. 17. Gjerstad MD, Alves G, Wentzel-Larsen T, Aarsland D, Larsen JP. Excessive daytime sleepiness in Parkinson disease: is it the drugs or the disease? Neurology 2006;67: 853–858. 18. Ondo WG, Dat Vuong K, Khan H, Atassi F, Kwak C, Jankovic J. Daytime sleepiness and other sleep disorders in Parkinson’s disease. Neurology 2001;57:1392–1396.
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Development of excessive daytime sleepiness in early Parkinson disease Lena K. Tholfsen, Jan P. Larsen, Jörn Schulz, et al. Neurology published online June 17, 2015 DOI 10.1212/WNL.0000000000001737 This information is current as of June 17, 2015 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2015 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Development of excessive daytime sleepiness in early Parkinson disease
Lena K. Tholfsen, MD Jan P. Larsen, MD, PhD Jörn Schulz, PhD Ole-Bjorn Tysnes, MD, PhD Michaela D. Gjerstad, MD, PhD
Correspondence to Dr. Gjerstad: [email protected]
ABSTRACT
Objective: To examine the frequency, development, and risk factors of excessive daytime sleepiness (EDS) in a cohort of originally drug-naive patients with incident Parkinson disease (PD) during the first 5 years after diagnosis.
Methods: One hundred fifty-three drug-naive patients with early PD derived from a populationbased incident cohort and 169 control participants were assessed for EDS and reevaluated after 1, 3, and 5 years on medication. EDS was diagnosed according to the Epworth Sleepiness Scale. Cutoff score above 10 was applied. Generalized estimating equation models for correlated data were used to examine associated and risk factors for EDS. Results: Patients reported EDS more often than control participants at the time of diagnosis and during follow-up. The frequency of EDS in PD increased from 11.8% at baseline to 23.4% after 5 years. Associated factors were male sex, the use of dopamine agonists, and higher Montgomery-Åsberg Depression Rating Scale and Unified Parkinson’s Disease Rating Scale–activities of daily living scores. Main risk factor for developing EDS was an increased Epworth Sleepiness Scale score at baseline.
Conclusion: EDS is more frequent in PD even before treatment initiation compared with control participants and increases in occurrence with disease progression. The main risk factor for developing EDS with time is an early predisposition for sleepiness. In addition, the use of dopamine agonists was associated with the development of EDS. These findings necessitate caution in patients with PD and early increased sleep propensity and when using dopamine agonists. Neurology® 2015;85:1–7 GLOSSARY ADL 5 activities of daily living; EDS 5 excessive daytime sleepiness; ESS 5 Epworth Sleepiness Scale; MADRS 5 MontgomeryÅsberg Depression Rating Scale; MMSE 5 Mini-Mental State Examination; PD 5 Parkinson disease; UPDRS 5 Unified Parkinson’s Disease Rating Scale.
Lesions of the brainstem and mesencephalon affecting the sleep/wake regulation are one of the possible mechanisms for the development of excessive daytime sleepiness (EDS).1 According to the Braak hypothesis, structural changes in these areas are found in the premotor stages of Parkinson disease (PD), raising the assumption that different sleep disorders may already emerge in an early disease state.2 Previously conducted studies of EDS in PD are mainly cross-sectional or in patients with more advanced disease and show an association with advanced motor impairment,3 the use of dopamine agonists,4 and male sex.5 The same features have been proposed as possible risk factors. The frequency and implications of EDS in early PD are, however, only partially assessed, and more research is needed to further explore whether EDS emerges mainly as a consequence of disease-related pathology at early stages or whether it is a symptom caused by other factors that could benefit from different types of interventions. The aims of this study were therefore to examine the frequency, development, associated covariates, and risk factors of EDS in a cohort of originally drug-naive patients with incident PD and during the first 5 years on medication. From The Norwegian Centre for Movement Disorders (L.K.T., J.P.L., J.S., M.D.G.), Stavanger; Department of Neurology (L.K.T., M.D.G.), Stavanger University Hospital; and Department of Neurology (O-B.T.), Haukeland University Hospital, Bergen, Norway. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2015 American Academy of Neurology
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1
METHODS Study design. The purpose of this study was to examine sleepiness in newly diagnosed and originally untreated patients with PD and thereafter on medication during 5 years of follow-up. The study is part of the Norwegian ParkWest Study, which is a prospective controlled longitudinal cohort study of incident PD. The patients included in this substudy were nondemented and nondepressed, and had complete data regarding sleepiness. The baseline examinations were conducted before treatment initiation and the patients were then followed with 6-month intervals by study neurologists experienced in movement disorders. Trained study nurses conducted interviews at baseline, 1 year, and then biannually. The patients who were unable to attend the hospital were offered examinations at their homes or nursing homes to minimize attrition bias.
Rating Scale (UPDRS)7 in the patients’ on-state, diagnostic criteria for dementia (Movement Disorders Society Task Force),8 Montgomery-Åsberg Depression Rating Scale (MADRS),9 and Mini-Mental State Examination (MMSE).10 PD phenotype was classified as tremor-dominant, intermediate type, or postural instability–gait disorder as described in previous studies.11 Insomnia was recorded if the patient reported nocturnal sleep problems. For the evaluation of excessive daytime somnolence, the Epworth Sleepiness Scale (ESS)12 was conducted as an interview by a trained study nurse. According to the international standard, a cutoff ESS score of $11 was applied. The ESS has been well validated in PD and has good psychometric properties.13 The dopaminergic medication given was categorized into 2 groups: patients using dopamine agonists and those who were not.
Standard protocol approvals, registrations, and patient consents. The study was approved by the Regional Committee
Statistical analysis. All statistical analyses were performed in
for Medical Research Ethics, Western Norway. Signed written informed consent was obtained from all participants.
Patients and controls. The patients and control participants were recruited from multiple sources in the community in the time period between November 1, 2004, and August 31, 2006.6 Among the 212 patients originally included, 30 patients were excluded because of dementia at baseline or dopaminergic treatment at baseline, or because they were rediagnosed as not having PD during follow-up. Twenty-nine other patients were excluded because of death or they were lost to follow-up before the 5-year visit. Thus, a total of 153 patients were included. After matching for age and sex, 169 control participants were eligible for evaluation of EDS during the first 5 years of the study. Examinations. The same standardized examinations and questionnaires were used throughout the study. Patients were evaluated with a clinical examination, Unified Parkinson’s Disease
Table 1
SPSS 22 (IBM Corp., Armonk, NY). The Mann–Whitney test was used to compare the means of continuous variables and the Pearson x2 test was used to compare proportions of categorical variables of patients with or without EDS. Population-averaged regressions models, using generalized estimating equations, were applied to investigate factors associated with ESS (model 1) and risk factors for the development of EDS (model 2). Model 1 was based on all patients in the cohort and included all consecutive examinations during the follow-up time. The independent variables included were age, sex, follow-up time in years, PD phenotype, insomnia, UPDRS-II (activities of daily living [ADL]) and UPDRS-III (motor function), MMSE score, MADRS score, levodopa equivalent dose, and the use of agonists. The dependent variable, the ESS, was used as a continuous scale in this model. Model 2, risk-factor analysis, included patients without EDS at baseline. Predictor variables were age, sex, follow-up time in years, PD phenotype, insomnia, UPDRS-II (ADL) and UPDRS-III (motor function), MMSE
Clinical and demographic features of patients in early PD Baseline
No. (%)
5y
no EDS
EDS
no EDS
EDS
135 (88.2)
18 (11.8)
111 (77.6)
34 (23.4)
a
BL total ESS score, mean (SD)
4.9 (2.6)
13.0 (2.3)
4.9 (3.1)
8.9 (4.0)a
Age, y, mean (SD)
66.5 (8.9)
64.8 (10.1)
71.3 (9.4)
70.2 (8.1)
Male sex, n (%)
82 (60.7)
12 (66.7)
61 (55.0)
26 (76.5)b
MMSE score, mean (SD)
28.1 (2.3)
27.9 (2.0)
27.1 (3.5)
25.9 (4.8)
MADRS score, mean (SD)
4.2 (4.5)
4.8 (5.6)
4.0 (4.6)
5.2 (5.8)
UPDRS-II (ADL) score, mean (SD)
8.0 (4.4)
8.7 (4.2)
10.9 (5.3)
14.5 (6.8)a
UPDRS-III (motor) score, mean (SD)
21.4 (9.4)
20.6 (10.2)
23.3 (11.2)
30.7 (13.9)b
PIGD phenotype, n (%)
48 (35.6)
9 (50.0)
69 (62.2)
20 (58.9)
Daily levodopa equivalent dose, mg, mean (SD)
0
0
596 (334)
587 (364)
Dopamine agonists monotherapy or in combination, n (%)
0
0
61 (55.9)
20 (58.9)
Insomnia, n (%)
46 (34.1)
3 (16.7)
40 (36.0)
12 (35.3)
Abbreviations: ADL 5 activities of daily living; BL 5 baseline values; EDS 5 excessive daytime sleepiness; ESS 5 Epworth Sleepiness Scale; MADRS 5 Montgomery-Åsberg Depression Rating Scale; MMSE 5 Mini-Mental State Examination; PD 5 Parkinson disease; PIGD 5 postural instability–gait disorder; UPDRS 5 Unified Parkinson’s Disease Rating Scale. Data are presented as means for continuous data and as proportions for categorical data. Pearson x2 and Student t test were used for statistical analysis. a p # 0.005. b p # 0.05. 2
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Table 2
Factors associated with higher Epworth Sleepiness Scale scores in patients with early PD Unadjusted modela
Adjusted modelb
95% CI Measure
B
Lower
Final modelc
95% CI Upper
p
B
Lower
d
1.920
0.828
95% CI B
Lower
Upper
p
3.012
d
0.001
1.871
0.775
2.967
0.001d
0.980
0.320
1.641
0.004d
Upper
p
Male sex
2.049
0.926
3.172
0.000
Use of dopamine agonist
1.07
0.448
1.693
0.001d
0.882
0.150
1.614
0.018d
1.304
0.026
d
0.273
20.353
0.900
0.393
PIGD phenotype
0.693
0.082
Insomnia
20.302
20.963
0.359
0.370
20.544
21.191
0.103
0.099
20.549
21.191
0.094
0.094
Age
20.057
20.110
20.004
0.035d
20.047
20.099
0.005
0.075
20.047
20.098
0.005
0.075
UPDRS-ADL score
0.109
0.043
0.176
0.001d
0.115
0.026
0.205
0.012d
0.087
0.017
0.158
0.015d
UPDRS-motor score
0.025
20.006
0.056
0.111
20.023
20.065
0.019
0.280
MADRS score
0.059
0.000
0.118
0.049d
0.079
0.014
0.144
0.017d
0.078
0.012
0.143
0.020d
20.113
20.255
0.030
0.121
0.164
0.016
0.311
0.030d
MMSE score
20.065
20.196
0.066
0.330
d
0.001
20.001
0.002
0.453
0.068
20.161
0.298
0.560
LED
0.002
0.001
0.003
0.001
Follow-up time in years
0.326
0.189
0.464
0.000d
Abbreviations: CI 5 confidence interval; LED 5 levodopa equivalent dose; MADRS 5 Montgomery-Åsberg Depression Rating Scale; MMSE 5 Mini-Mental State Examination; PD 5 Parkinson disease; PIGD 5 postural instability–gait disorder; UPDRS-ADL 5 Unified Parkinson’s Disease Rating Scale–activities of daily living. a The unadjusted relationship between ESS and the covariates were analyzed including only one covariate at a time. b The adjusted relationship includes all main effects. c The finally adjusted relationship includes selected main effects by stepwise exclusion based on the significance value. d Significant values.
score, and MADRS score. Patients were drug-naive at baseline and in order to evaluate the effect of dopamine agonists, model 2 was repeated in the patients without EDS at the 1-year follow-up and adding the use of dopamine agonists at this visit as an independent variable. The response variable EDS for model 2 was binary. The statistical analyses were conducted with all variables separately evaluated (unadjusted model), estimating interrelation of all the variables (adjusted model), and finally including only with variables of significance from the adjusted analysis (final model) (tables 1 and 2). RESULTS The population in this study consisted of 153 patients with PD who were drug-naive at inclusion and 169 control participants. The average age of the patients was 66 years (SD 9.0) at baseline and 61% were men. The patients were nondemented and nondepressed. The average UPDRS-ADL score was 8.0 (SD 4.4) and UPDRS-motor score 21.3 (SD 9.5) at baseline. Fifty-seven patients (37.3%) presented with a postural instability–gait disorder phenotype. The average ESS score was 5.8 (SD 3.7) and median score 5.0. The control participants were an average age of 66 years at baseline (SD 9.1), 52% were men, and the average ESS score was 5.0 (SD 2.9). No significant differences were found between patients and controls regarding mean age, sex, or ESS scores at baseline.
compared with 8 (4.7%) control participants. During follow-up, the frequency increased in patients to 21 (13.7%) after 1 year and 24 (15.9%) after 3 years, and to 6 (3.6%) and 12 (7.2%) in control participants. After 5 years, 34 patients (23.4%) and 13 (8.0%) control participants reported EDS. Persistence of EDS during the 5-year follow-up period.
EDS was not reported as persisting from one visit to the next in all patients during the 5-year study period, but became more persistent as the disease developed
Figure 1
Development of excessive daytime sleepiness (EDS) in early Parkinson disease
Frequency of EDS at baseline and during follow-up.
Figure 1 shows the observed frequencies of EDS in patients and control participants at baseline, and at 1, 3, and 5 years of follow-up. Eighteen patients (11.8%) were diagnosed with EDS at baseline Neurology 85
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(figure 2). Forty-four percent of the patients with EDS at baseline had EDS 1 year later, while 79.2% of the patients with EDS at the 3-year visit were also affected after 5 years. Clinical and demographic features of the patients with and without EDS. The patients with EDS did not differ
from the patients without EDS according to age, sex, cognitive impairment, depression, insomnia complaints, severity of parkinsonism, or PD phenotype during the first 3 years of follow-up. After 5 years, the patients with EDS had higher UPDRS-ADL and UPDRSmotor scores. There was a male predominance in the EDS group at the 5-year visit (table 1). Associations and risk factors of EDS in early PD. The ESS was used as a continuous scale in the generalized estimating equation model to identify factors associated with experienced EDS. Male sex, increased UPDRS-ADL score, higher MADRS scores, and the use of dopamine agonists were found to be associated with a higher ESS score (table 2). Only patients without EDS at baseline were included in the analysis for the detection of risk factors. Higher ESS scores at baseline were the major risk factor for developing EDS. Sixty-five percent of patients with EDS at the 5-year follow-up had a score above 5 on the ESS at baseline (table 3). The analyses were repeated for the 1-year followup visit in order to include dopaminergic treatments
Figure 2
4
as possible risk factor. Findings were similar to the baseline evaluation, showing that an increased ESS score indicated risk of developing EDS with time. The use of dopamine agonists at the 1-year visit did not increase the risk for later EDS (data not shown). DISCUSSION This study shows an increased frequency of EDS in patients with untreated PD compared with sex- and age-matched controls. The occurrence of EDS increased further with disease progression. EDS could be reversed during the first years with the disease, but the diagnosis became more persistent and robust as the disease developed. The main risk factor for developing EDS in early PD was more symptoms of sleepiness before treatment initiation. Our results may have implications for management because increased sleep propensity at the time of diagnosis may indicate cautiousness when using dopamine agonists in patients with early PD. The frequency of EDS in early PD has not been established. Two smaller studies found no increased frequency of EDS in drug-naive patients with PD compared with controls,14,15 while a recent report described that 49% of patients with PD had EDS 3.5 years after their diagnosis.16 In our study, the frequency of EDS was more than 2-fold increased in drug-naive patients with PD compared with the control participants. Five years after PD diagnosis,
Frequency and persistence of excessive daytime sleepiness (EDS) in patients with early Parkinson disease
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Table 3
Risk-factor analysis of the development of EDS in newly diagnosed patients with PD Unadjusted modela
Adjusted modelb
95% CI for OR Measure
OR
Lower
Upper
Final modelc
95% CI for OR p d
95% CI for OR
OR
Lower
Upper
p
OR
Lower
Upper
p
2.092
0.913
4.791
0.081
Male sex
2.750
1.184
6.390
0.019
2.019
0.755
5.399
0.161
PIGD phenotype
1.002
0.447
2.246
0.996
1.025
0.431
2.439
0.955
20.962
2.230
0.415
0.927
Insomnia
20.533
1.514
.187
0.237
d
Age
0.956
0.924
0.990
0.011
0.967
0.925
1.011
0.140
0.972
0.935
1.010
0.145
ESS score
1.487
1.232
1.795
0.000d
1.532
1.238
1.894
0.000d
1.435
1.182
1.743
0.000d
UPDRS-ADL score
1.025
0.916
1.148
0.665
1.048
0.904
1.216
0.533
UPDRS-motor score
1.006
0.970
1.044
0.731
1.015
0.958
1.076
0.608
MADRS score
1.020
0.927
1.124
0.681
0.998
0.895
1.113
0.972
MMSE score
1.045
0.911
1.200
0.527
0.950
0.796
1.135
0.574
1.264
1.039
1.537
0.019d
1.256
1.039
1.517
0.018d
Follow-up time in years
1.213
1.030
1.430
d
0.021
Abbreviations: ADL 5 activities of daily living; CI 5 confidence interval; EDS 5 excessive daytime sleepiness; ESS 5 Epworth Sleepiness Scale; MADRS 5 Montgomery-Åsberg Depression Rating Scale; MMSE 5 Mini-Mental State Examination; OR 5 odds ratio; PD 5 Parkinson disease; PIGD 5 postural instability–gait disorder; UPDRS 5 Unified Parkinson’s Disease Rating Scale. a The unadjusted relationship between ESS and the covariates was analyzed including only one covariate at a time. b The adjusted relationship includes all main effects. c The finally adjusted relationship includes selected main effects by stepwise exclusion based on the significance value. d Significant values.
we found a 3-fold increased frequency of EDS among patients. Although the frequency of EDS was rather low in early PD, we found that nearly every fourth patient experienced EDS after 5 years. Thus, our findings show that EDS is one of several major complaints that are experienced by patients with early PD. There is considerable information on EDS in more advanced PD and it is agreed that brain pathology of PD is one of the major causes.17–19 Understanding EDS in early or untreated PD is less examined and established. Two studies described EDS to be a consequence of treatment rather than of brain pathology in early PD.14,15 Other authors report that the ESS score is inversely correlated with the degree of dopaminergic degeneration in the striatum as an indication of early involvement of brain pathology.20 Furthermore, a prospective study of healthy elderly reports sleepiness to herald the diagnosis of PD, supporting the assumption that brain pathology is involved in these symptoms at early stages.21 Our results support both concepts of secondary and primary influence on EDS. Increased MADRS scores and the use of dopamine agonists were associated with higher ESS scores and may contribute to the development of EDS. Furthermore, symptoms of EDS were less persistent during the first 5 years of disease development in contrast to findings from studies of more advanced PD.3 These findings implicate that EDS is partly reversible at early stages
and possibly accessible for interventions. Drug-naive patients may have experienced secondary EDS caused by nocturnal motor problems and then were relieved by treatment initiation. In addition, dopaminergic agents, especially dopamine agonists, may have caused dose-dependent drowsiness,22 and transient depressive symptoms may have presented with EDS. With time and disease progression, the excessive sleepiness in patients in this study became more persistent, indicating that EDS converted to be more frequently caused by the presence of irreversible disease-related changes in brain areas involved in sleep–wake regulation. In addition to studying the occurrence of EDS and its associated factors in early PD, we have examined factors that at the time of diagnosis could predict the later development of EDS during the first 5 years of follow-up. We found that the major risk factor for EDS was a higher ESS score even before initiation of dopaminergic treatment. The same was found in a subsequent risk-factor analysis among medicated patients at the 1-year follow-up visit. Sixty-five percent of those with EDS after 5 years had ESS scores between 6 and 10 at baseline compared with 35% of the patients without EDS after 5 years. Obvious secondary causes for the higher ESS scores among those who developed EDS were not found. Taken together with the found association between dopamine agonists and EDS during follow-up, we believe that this information should be relevant for Neurology 85
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management of patients with early PD because it calls for increased awareness of EDS among those with early increased sleepiness and later treatment with dopamine agonists. Strengths of this study include the prospective and controlled study design of an unselected cohort of patients with untreated PD at baseline and very low attrition rates among patients and controls during the 5-year follow-up. It is, however, a limitation that relatively few patients developed EDS in early PD, leaving us with less strength in the statistical calculations. To investigate EDS in PD is a challenge because of the subjective nature of sleepiness and its multiple possible causes. It is the degree of subjectively experienced sleep problems and not the objective measures that leads to the diagnosis. This fact may cause both over- and underestimation of EDS. It is a limitation in this study that we did not have the multiple sleep latency test for objective assessment of EDS. Detailed information on different subtypes of insomnia was not available in this study, which poses another limitation. Nonetheless, we believe that our study provides new and important information on EDS in early PD. In this study, we found that the frequency of EDS was moderately increased in drug-naive patients with early PD compared with control participants and it increases with time. Increased sleepiness within the standard reference range of the ESS was the strongest risk factor for developing EDS during follow-up. Furthermore, pharmacologic effects, sex predisposition, depressive mood, and reduced function of daily living are associated with sleepiness even in early PD. Our findings have implications for the understanding of EDS in early PD and should increase clinicians’ awareness of EDS in patients with early increased sleepiness who are treated with dopamine agonists. These findings are new and should be confirmed in larger longitudinal cohort studies of patients with early PD. AUTHOR CONTRIBUTIONS Dr. Tholfsen and Dr. Gjerstad had full access to all the data in the study and take full responsibility for the integrity of the data and the accuracy of the data analyses. Larsen, Tysnes: study concept and design. Gjerstad, Tysnes: acquisition of data. Tholfsen, Gjerstad, Larsen, Schulz: analyses and interpretation of data. Tholfsen, Gjerstad, Larsen: drafting of the manuscript. All authors: critical revision of manuscript for important intellectual content. Tholfsen, Gjerstad, Schulz: statistical analyses. Larsen: obtained funding. Gjerstad and Larsen: study supervision.
STUDY FUNDING The Norwegian ParkWest Study was supported by grants 911218 and 911792 from the Western Norway Health Authority, grant 177966 from the Research Council of Norway, and the Norwegian Parkinson Disease Association.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures. 6
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Received November 25, 2014. Accepted in final form March 18, 2015. REFERENCES 1. Baumann CR. Traumatic brain injury and disturbed sleep and wakefulness. Neuromolecular Med 2012;14:205–212. 2. Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 2004;318: 121–134. 3. Gjerstad MD, Aarsland D, Larsen JP. Development of daytime somnolence over time in Parkinson’s disease. Neurology 2002;58:1544–1546. 4. Arnulf I. Excessive daytime sleepiness in parkinsonism. Sleep Med Rev 2005;9:185–200. 5. Martinez-Martin P, Falup Pecurariu C, Odin P, et al. Gender-related differences in the burden of non-motor symptoms in Parkinson’s disease. J Neurol 2012;259: 1639–1647. 6. Alves G, Muller B, Herlofson K, et al. Incidence of Parkinson’s disease in Norway: the Norwegian ParkWest Study. J Neurol Neurosurg Psychiatry 2009;80:851–857. 7. Fahn S, Elton RL; Members of the UPDRS Development Committee. Unified Parkinson’s Disease Rating Scale. In: Fahn S, Marsden CD, Calne DB, Lieberman A, editors. Recent Developments in Parkinson’s Disease. Florham Park, NJ: Macmillan Healthcare Information; 1987: 153–163. 8. Emre M, Aarsland D, Brown R, et al. Clinical diagnostic criteria for dementia associated with Parkinson’s disease. Mov Disord 2007;22:1689–1707. 9. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979;134: 382–389. 10. Folstein MF, Folstein SE, McHugh PR. “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198. 11. Jankovic J, McDermott M, Carter J, et al. Variable expression of Parkinson’s disease: a base-line analysis of the DATATOP cohort. The Parkinson Study Group. Neurology 1990;40:1529–1534. 12. Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep 1991;14: 540–545. 13. Hagell P, Broman JE. Measurement properties and hierarchical item structure of the Epworth Sleepiness Scale in Parkinson’s disease. J Sleep Res 2007;16:102–109. 14. Kaynak D, Kiziltan G, Kaynak H, Benbir G, Uysal O. Sleep and sleepiness in patients with Parkinson’s disease before and after dopaminergic treatment. Eur J Neurol 2005;12:199–207. 15. Fabbrini G, Barbanti P, Aurilia C, Vanacore N, Pauletti C, Meco G. Excessive daytime sleepiness in de novo and treated Parkinson’s disease. Mov Disord 2002;17:1026–1030. 16. Breen DP, Williams-Gray CH, Mason SL, Foltynie T, Barker RA. Excessive daytime sleepiness and its risk factors in incident Parkinson’s disease. J Neurol Neurosurg Psychiatry 2013;84:233–234. 17. Gjerstad MD, Alves G, Wentzel-Larsen T, Aarsland D, Larsen JP. Excessive daytime sleepiness in Parkinson disease: is it the drugs or the disease? Neurology 2006;67: 853–858. 18. Ondo WG, Dat Vuong K, Khan H, Atassi F, Kwak C, Jankovic J. Daytime sleepiness and other sleep disorders in Parkinson’s disease. Neurology 2001;57:1392–1396.
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Development of excessive daytime sleepiness in early Parkinson disease Lena K. Tholfsen, Jan P. Larsen, Jörn Schulz, et al. Neurology published online June 17, 2015 DOI 10.1212/WNL.0000000000001737 This information is current as of June 17, 2015 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/early/2015/06/17/WNL.0000000000 001737.full.html
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