Abstract
Objective: To examine associated demographic and clinical correlates and the development of excessive daytime sleepiness (EDS) over 8 years in a community-based cohort of patients with Parkinson disease (PD).
Methods: A total of 232 patients with PD were included in a population-based prevalence study in 1993. Patients were followed prospectively and reexamined after 4 and 8 years. At all study visits, the authors administered semistructured interviews to obtain information on clinical and demographic variables. Standardized rating scales of parkinsonism, depression, and cognitive impairment were used. The diagnosis of EDS was based on a sleep questionnaire and in 2001 also on the Epworth Sleepiness Scale. Population-averaged logistic regression models for correlated data were performed to study the relationship between EDS and various demographic and clinical variables.
Results: Of the 232 patients included at baseline, 138 were available for re-evaluation after 4 years and 89 patients after 8 years. Frequency rates of EDS increased from 5.6% in 1993 to 22.5% in 1997 and 40.8% in 2001, with an 8-year prevalence of 54.2%. In the majority of patients, EDS was a persistent feature. In the logistic regression model, EDS was related to age, gender, and use of dopamine agonists. In those never having used dopamine agonists, hypersomnia was associated with the Hoehn and Yahr stage only.
Conclusion: Excessive daytime sleepiness is a frequent and highly persistent feature in Parkinson disease, with multifactorial underlying pathophysiology. The authors' findings indicate that both age and disease related disturbances of the sleep-wake regulation contribute to hypersomnia in PD. Treatment with dopamine agonists also contributed to excessive daytime sleepiness in our patients.
Sleep problems experienced by patients with Parkinson disease (PD) are important in management of the disease. In a previous cross-sectional study, we found that 15% of patients with PD compared to 1% of healthy elderly people were diagnosed with severe somnolence (excessive daytime sleepiness [EDS]).1 The frequency and reasons for patients developing hypersomnia are still controversial. In addition to PD pathology, insomnia and parasomnias during the night and sedative drugs have been suggested to cause daytime sleepiness. In addition, several lines of evidence suggest that dopaminergic drugs have a more or less important role in the origin of sudden sleep attacks and symptoms of hypersomnia in general.2–7
To further explore the relative importance of drugs, disease, and other clinical and demographic features for emergence of EDS in PD, we prospectively studied the development of EDS over 8 years in a population-based cohort of patients with PD.
Methods.
Study population.
In a prevalence study of PD in the Stavanger area of Western Norway on January 1, 1993, the crude prevalence rate was 110.9 per 100,000 inhabitants (245 patients).8 Patient recruitment was described previously in detail.9 All patients were diagnosed by neurologists of the study group, according to published diagnostic criteria.10 To date, a subgroup of 22 deceased patients has been assessed neuropathologically after they had given written informed consent. In all subjects, cell loss and α-synuclein–positive Lewy bodies were found in the surviving neurons of substantia nigra, confirming the clinical diagnosis of PD.11
In 1993, 232 of the 245 patients with PD in the Stavanger area were evaluated for daytime somnolence and nocturnal sleeping problems.1,10 Seven were rediagnosed as not having PD, three patients died between prevalence day and examination, two patients refused to participate, and one could not be evaluated due to severe dementia. A total of 138 patients with PD were examined for sleeping problems in 1997 and 89 in 2001. During the 8-year follow-up period, 126 patients had died and 17 either refused to participate or data were incomplete due to severe illness or dementia.
Study design.
In this prospective, longitudinal, community-based study of EDS in patients with PD, the same standardized examination program was used in 1993, 1997, and 2001. Patients who were difficult to transport to the outpatient clinic were examined at their homes or nursing homes. A close family member or a daily caregiver was asked to attend the session for support and additional clinical and demographic information for all patients with a Mini-Mental State Examination (MMSE)12 score <28.
Clinical assessment.
Patients were evaluated by clinical examination, the Unified Parkinson's Disease Rating Scale (UPDRS),13 Hoehn and Yahr staging,14 diagnostic criteria for dementia (DSM-III-R),15 the Montgomery and Aasberg Depression Rating Scale (MADRS),16 and the MMSE. The disease subtype in each patient was classified as either tremor dominant (TD), postural instability gait difficulty (PIGD), or indeterminate, as described in previous studies.17,18
Assessment of sleep disorders.
For the evaluation of daytime somnolence and nighttime sleeping problems, all included patients completed a self-constructed sleepiness questionnaire, the Stavanger Sleepiness Questionnaire (SSQ).10 The same questionnaire was used by the authors in previous studies of EDS in PD, covering both daytime and nighttime sleeping problems.1,10,19 Based on the baseline distribution of the number and duration of sleeping periods during daytime, daytime somnolence was classified into groups of no daytime somnolence and EDS. Those who slept more than 2 hours during daytime or fell asleep three times or more during daytime were deemed to have EDS. In addition, the Epworth Sleepiness Scale (ESS)20 was included in the 2001 examination program and the scores were compared to the SSQ scores. Patients with EDS according to the SSQ had a mean ESS score of 16.3 (SD = 5.7) compared to a mean ESS score of 5.7 (SD = 4.4) in patients without EDS (p < 0.005).
As a part of the SSQ, patients were also asked whether they had a nighttime sleeping problem and what kind of sleeping problem. Use of sedative due to sleeping problems implied insomnia. For the evaluation of possible REM sleep behavior disorder (RBD), the patients and their caregiver or close family member were asked to rate the severity of motor and vocal activity during sleep using a scale from 0 to 3. RBD was suspected when patients scored 2 (very active during sleep, tend to wake up spouse) or 3 (very active physically and verbally, have been hitting or hurting myself or caregiver while sleeping). For the evaluation of periodic limb movements in sleep (PLMS) suspect features, patients were asked to rate nighttime problems caused by sudden muscle jerks during sleep on a scale from 0 to 3. PLMS was suspected when patients scored 2 (moderate nighttime problem) or 3 (major nighttime problem).
Statistical analysis.
SPSS 11.0 (SPSS Inc., Chicago, IL) and Stata (StataCorp LP, College Station, TX) were used for statistical analyses. We used Mann-Whitney tests to compare continuous variables and Pearson χ2 tests for categorical variables of patients with and without EDS in 2001.
The relationship between EDS and demographic and clinical variables was analyzed by population-averaged logistic regression models for correlated data (Stata procedure xtgee) using all observations available. Because there were three consecutive examinations, unstructured correlations were used. Covariates considered for the multivariate model were age, sex, disease type (PIGD, TD, or intermediate), disease duration, UPDRS motor and activities of daily living (ADL) scores, Hoehn and Yahr staging, MMSE score, MADRS score, l-Dopa dose, use of agonists at baseline (yes or no), hallucination (present or absent), and insomnia (present or absent). For evaluation of EDS without the influence of dopamine agonists, the same analyses were performed after exclusion of all patients ever having used dopamine agonists. Significant covariates from the final population-averaged logistic regression model were used to identify patients with low levels of these risk factors, and the proportion of EDS for these patients at each occasion was investigated to judge whether EDS occurred independently of the identified risk factors. A two-sided p value <0.05 was considered significant. The 8-year prevalence of EDS was calculated by adding the number of cases with EDS at baseline and all new cases divided by the mean population during the middle of the observation period.21
Results.
Features associated with EDS.
Demographic and clinical features at baseline and follow-up visits are given in table 1. In the univariate analysis, EDS was associated with severity of parkinsonism, cognitive impairment, and presence of hallucinations at each study visit. Patients with EDS were older and had longer disease duration compared to those not diagnosed with EDS. The total MADRS score was higher for patients with EDS in 1993 and 1997. RBD suspect features were reported more often in patients with EDS in 1993 only (p < 0.001), whereas PLMS suspect features were present more often in 2001 (p = 0.05). Insomnia was more frequent in patients without EDS in 2001. There were no differences in daily levodopa dose at any study visit. Treatment with dopamine agonists was, however, more frequent in patients with EDS in 1997.
Table 1 Demographic and clinical data at baseline and follow-up visits in patients with PD with and without EDS
Table 2 summarizes demographic and clinical data at baseline (1993) of patients not treated with dopamine compared to patients who received dopamine at baseline or during the follow-up period. A total of 66 patients had used dopamine agonists during the study period. These 66 patients were younger, had been treated longer, were prescribed higher daily levodopa doses (p < 0.005), and reported more often RBD suspect features (p = 0.01) than patients without dopamine treatment. The frequency of EDS, stage of parkinsonism, frequency of insomnia and hallucinations, and cognitive functioning were comparable in the two groups.
Table 2 Demographic and clinical data at baseline of patients with Parkinson disease treated and not treated with dopamine agonists during the study period
In the population-averaged logistic regression model, including data for all patients, EDS was related to age (p = 0.01, odds ratio [OR] 1.05, 95% CI: 1.01 to 1.10), male gender (p = 0.045, OR 0.55, 95% CI: 0.29 to 0.98), and the use of dopamine agonists at baseline (p = 0.007, OR 2.62, 95% CI: 1.30 to 5.27) (table 3). For the Hoehn and Yahr stage, a trend toward association with EDS was found (p = 0.068; OR 1.05, CI: 0.99 to 1.12).
Table 3 Association between EDS and various features in multivariate analyses (GEE): Analyses performed for all patients (n = 232) and for patients not treated with dopamine agonists (n = 166)
In a second analysis, the data for all patients who had used dopamine agonists during the study period (n = 66) were discarded and the logistic regression model was rerun on the data for the remaining 166 patients. In this analysis, EDS was associated with the Hoehn and Yahr staging only (p = 0.043, OR 1.07, 95% CI: 1.0 to 1.15) (table 3).
Development of EDS over the 8-year study period.
Eighty-nine patients with PD were examined at all three study visits, 49 of whom never used dopamine agonists during the study period. The frequency of EDS in all patients increased from five (5.6%) in 1993 to 20 patients (22.5%) in 1997 to 40 (44.9%) in 2001. The proportion of patients with an ESS score >10 in 2001 was identical (44.9%). In the subgroup of patients who never used dopamine agonists, the prevalence of EDS increased from two patients (4.1%) in 1993 to nine patients (18.4%) in 1997 to 20 patients (40.8%) in 2001. The corresponding prevalence rate of EDS measured by ESS (cutoff 11 points) was 36.8% in 2001. The 8-year prevalence for EDS was 54.2% for all patients compared to 46.5% in those never being treated with dopamine agonists during the study period.
All patients with EDS in 1993 also reported EDS in 1997. However, four patients diagnosed with EDS in 1997 did not fulfill the criteria for EDS in 2001. Parkinsonism and cognitive decline had progressed in all four patients. One patient had discontinued dopamine agonists and reduced levodopa dose substantially. Another patient had improved nocturnal sleep after introduction of sleeping pills between 1997 and 2001. One patient showed a decrease in the MADRS score from 21 in 1997 to 9 in 2001. He also showed severe cognitive decline with a decrease in the MMSE score from 23 in 1997 to 8 in 2001. In the last patient, there was no apparent explanation, but he still fell asleep twice each day.
Discussion.
Few longitudinal studies of EDS in patients with PD have been conducted, and they have been of either rather short duration or with small numbers of patients.19,22,23 In this community-based study, patients were diagnosed carefully with PD according to published diagnostic criteria9 and followed prospectively over 8 years. A wide range of measurement instruments were used to assess various motor and nonmotor features with potential influence on wakefulness and sleep. To assess nighttime sleeping problems and daytime somnolence, we used a self-constructed sleep questionnaire, the SSQ, at each study visit. The ESS, which was not developed when our study was initiated, was added to the study procedures in 2001 to make our results more comparable with findings from previous investigations. Both the SSQ and the ESS are easy to complete and are not time-consuming. Nevertheless, both are based on self-perception and several issues may be critical for obtaining “true” information, as reported in a recent review.24 Amnesia occurring few minutes before a nap may explain a possible false-negative diagnosis in some of the patients.25 In addition, patients may in general be inconsistent when completing questionnaires, and this may be particularly relevant for patients developing cognitive impairment. Thus, although we found a high and increasing frequency of EDS, the prevalence rates found in our cohort may still be an underestimate of daytime somnolence in PD.
There is a large range of prevalence rates of EDS found in PD, varying from 16 to 50%.26–29 This variation is not surprising because most studies are clinic based and cross-sectional, assessing selected patient cohorts with different disease duration and severity and according to different diagnostic criteria. In a previous population-based study, we found that moderate to severe somnolence is far more common in patients with PD than among healthy elderly.10 In contrast, mild somnolence was shown to be as frequent in control groups as among patients with PD.10 In addition, in a 4-year follow-up study, the frequency of EDS among surviving patients had increased from 8 to 29%.19 In the present report on the 8-year follow-up of our population-based cohort, the occurrence of EDS has further increased to be present in >40% of the patients. Of importance, the prevalence of EDS was similar using the widely used cutoff score of 11 points on the ESS at the 8-year study visit. These results highlight the high frequency and importance of hypersomnia in PD.
The principal goal of this study was to deduce whether EDS in PD was more closely related to the disease process itself or to treatment with dopaminergic drugs. Given the complexity of brain-drug interactions and other possible causative mechanisms, firm conclusions or simplistic unidirectional answers were not expected from the study. Nevertheless, our results provide valuable insights into the multifactorial genesis of EDS in patients with PD.
The most compelling evidence of dopaminergic drugs as a cause of EDS is the well-established observation of acute drowsiness related to single doses of the drugs.30,31 In particular, dopamine agonists may provoke sleepiness in some patients.24 In line with these data, we found that the use of dopamine agonists, but not the daily levodopa dose, was significantly associated with EDS in this study. However, the frequency of EDS was nearly as high among patients who had never used dopamine agonists compared to those who used agonists and with the same dramatic increase over the 8-year period. This strongly suggests that, although dopamine agonists provoke somnolence in some patients, other factors have a more important role in the development of EDS.
Unexpectedly, the patients' age was strongly associated with EDS in the model including all patients, whether they used dopamine agonists or not, whereas a trend toward significance was found for disease severity. Previous studies of somnolence in different age groups have shown that this complaint increases with increasing age,32 but in multifactorial analysis, age was not found to be independently related to EDS in prevalence studies of PD.19,33,34 Using a longitudinal approach with long-term follow-up, our findings indicate that aging processes also contribute to EDS in PD. This observation suggests and confirms the proposal that a combination of age-related and disease-related biologic changes in certain areas of the brain induce or predispose to hypersomnia. However, the far higher occurrence of EDS among patients with PD than among healthy elderly of similar age may indicate that aging only modestly contributes to the emergence of EDS in PD.
As mentioned above, there is a complex interrelationship between the different factors examined as possible causes of EDS in PD. In the model including all patients, the Hoehn and Yahr staging only showed a trend toward significance as a risk factor for EDS. In the second model in which the data for patients who used dopamine agonists were discarded, the staging of parkinsonism became significant. The importance of disease pathology as a cause of EDS in PD is further supported by the high degree of persistence of EDS in our patients. In a previous 4-year follow-up study,19 EDS was found to be persistent in all patients, and also in this 8-year study, most patients first diagnosed with EDS continued to complain of severe somnolence. The exception was four patients diagnosed with EDS in 1997 who had less somnolence in 2001. In some of these patients, there was a rational cause of the reduced somnolence. Still, our main finding is that EDS is a persistent feature in the majority of patients with PD and behaves like a clinical symptom that is caused by damage or malfunction of biologic systems or structures.
Sleep/wake regulation is a complex system involving loci situated in the upper brainstem and midbrain and their ascending pathways.35 Recently, wake-active nonstriatal dopaminergic neurons in the ventral periaqueductal gray matter were found to cause increased total sleep when damaged.36 Given that disease pathology in PD spreads systematically from lower brainstem areas to the midbrain prior to disease onset and then continues progression to mesocortex and eventually neocortex,37,38 one would expect EDS a) to potentially predate PD and b) to increase in prevalence as the disease progresses. Interestingly, an increased risk of developing PD was recently demonstrated in elderly men with EDS derived from the Honolulu-Asia Aging Study.39 This finding together with our results of a dramatic increase in EDS during the course of disease supports the assumption that the disease pathology itself contributes to EDS in patients with PD.
In addition to disease pathology, dopaminergic drugs, and age, several other factors may contribute to daytime somnolence. Nocturnal insomnia, parasomnias, sedative drugs, and dementia have been suggested to cause EDS. We did address most of these factors in our analysis, but did not assess in detail the influence of sleep apnea on EDS. However, we believe that this, like other medical conditions leading to sleep fragmentation or early awaking, would result in reduced nighttime sleep quality and duration. In contrast, our results contradict a major influence of the majority of nighttime sleeping problems on EDS in patients with PD, as insomnia, RBD, and PLMS suspect features did not relate to EDS in the multivariate model. In contrast, we found that patients diagnosed with EDS reported less insomnia than those without EDS in 2001. Similar observations were made in previous studies.33,34
Both cognitive impairment and EDS are frequent in PD. Furthermore, the development of hypersomnia over time was nearly as dramatic as the emergence of dementia among patients with PD.40 In the univariate analysis, we found a clear association between cognitive impairment and EDS. In the multivariate analysis, however, dementia was not associated with EDS, which is in line with previous studies.19,33,34 In contrast, we found a significant association between male gender and EDS in the multivariate analyses. Although some studies indicate slight male preponderance in PD in general,41 we are unaware of similar findings in previous studies of EDS except for our own cross-sectional study published previously.8 Careful interpretation of this finding is therefore recommended until further studies have clarified this issue.
Footnotes
-
Disclosure: The authors report no conflicts of interest.
Received November 15, 2005. Accepted in final form May 4, 2006.
References
Disputes & Debates: Rapid online correspondence
REQUIREMENTS
If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.