We evaluated the frequency and severity of excessive daytime
sleepiness in an outpatient population with Parkinson's disease in
comparison to age-matched controls and examined its relationship with
anti-parkinsonian drug therapy and sleep history. Increased daytime
sleepiness and involuntary sleep episodes have been described in
Parkinson's disease, but the etiology is not completely understood.


The Epworth Sleepiness Scale (ESS), a validated questionnaire for
daytime sleepiness, was prospectively administered to 99 consecutive
outpatients with Parkinson disease and 44 age-matched controls. In
addition, a short sleep- screening questionnaire was used.


The ESS revealed significantly increased daytime sleepiness in PD
patients compared to controls (7.5 ± 4.6 vs. 58 ± 3.0, r = 0.013).
The ESS score was abnormally high (10 or more) in 33 % of PD patients
and 11.4% of controls (P = 0.001).


ESS was not different between PD patients on levodopa monotherapy and
those on levodopa and dopamine agonists, or between patients taking
ergoline or non-ergoline dopamine agonists. In PD patients and in
controls, sleepiness was significantly associated with reported heavy
snoring.


Increased daytime sleepiness is more frequent in-patients with PD
than in elderly controls. Similar to controls, increased daytime
sleepiness in PD patients is correlated with heavy snoring.



Spontaneous dozing as a sign of excessive daytime sleepiness (EDS)
has been observed in almost 50% of patents in a series of Parkinson's
disease (PD) 12 years age and an increased need for daytime sleep in
some parkinsonian patients was described as early as 1979. Despite
that, only the more recent debate about drug induced "sleep attacks"
has triggered awareness for EDS in parkinsonian patients.


Whereas EDS in PD was attributed to nocturnal sleep fragmentation in
earlier reports, current debate focuses on the relation between
daytime sleepiness and dopaminergic therapy. In addition, a
disturbance of sleep wakefulness regulation has been postulated to
constitute an integral part of the clinical spectrum of Parkinson's
disease.


We evaluated the prevalence and severity of daytime sleepiness in
outpatients with Parkinson's disease in comparison with normal
controls, and assessed its relationship with items from the sleep
history.


A total of 99 consecutive patients with a diagnosis of idiopathic
Parkinson's disease (PD) according to established criteria seen at
the PD outpatient clinic were included. Patients with atypical
parkinsonism, drug-induced psychosis, typical and atypical
neuroleptic treatment, or dementia were excluded. All patients
received a questionnaire upon registration and were asked to complete
it in the waiting room.


The questionnaire consisted of the Epworth sleepiness scale (ESS)
plus a seven-item sleep screening instrument. The ESS is an eight-
item questionnaire in which the probability to fall asleep is
assessed for eight situations that are differently conductive to
sleep. The majority of questions capture involuntary sleep episodes.
Each answer is rated by the subject on a scale (from 0 to 3
for "recent times."


In the sleep screening instrument, overall sleep quality was rated on
a scale from 1 (extremely bad) to 10 (excellent). Patients were asked
to estimate sleep latency and total sleep time, as well as the
average number of awakenings per night. Patients also indicated if
they held regular siestas and their average duration. They were also
asked if movements and/or vocalizations occurred during sleep or
dreaming.


Snoring was classified in three levels; 0) no snoring; 1) occasional
mild or moderate snoring; 2) or heavy snoring, defined as frequent
loud and irregular snoring, optionally with breathing stops. This
classification was made based on patients' and bed
partners'/caregivers' accounts. One investigator was available during
outpatient clinic hours to help with any questions regarding the
questionnaire. Additional information about PD duration and disease
stage and current medications and comorbidity was pro- vided by the
attending doctor on a separate sheet and cross-checked by the
investigators with the patient's history. Controls were recruited
among elderly relatives of the hospital staff and elderly outpatients
with peripheral neurological disease.


A total of 99 PD patients (58 male, 41 female) with a mean age of
67.7 ± 10.3 years, a mean symptomatic PD duration of 7.4 ± 6.7 years,
and a mean Hoehn and Yahr stage of 2.3 ± 0.7 in on and 2.8 ± 0.9 in
off were included.


We also studied 44 controls (24 male, 20 female) with a mean age of
65.6 ± 10.0 years. No significant difference was found for age
between patients and controls.


Eighty-seven patients were levodopa treated (mean dose, 596 ± 352
mg/day); 41 patients look dopamine agonists, namely pergolide (n =
20, 3.6 ± 2.0 mg/day), ropinirole (n = 15, 8.2 ± 6.8 mg/day),
pramipexole (n = 3; range, 1.1 - 2.1 mg/day}, and bromocriptine (n =
3; range, 2.5-15 mg/day). One patient received subcutaneous
apomorphine on demand in addition to levodopa and pergolide. Other
parkinsonian drugs were entacapone (n = 14,800 ± 272mg/day),
selegiline (n 6,8.3 ± 2.6 mg/day), and amantadine (n = 18,267 ± 69
mg/day.). Levodopa was used as a monotherapy in 51 of the patients
and in combination with dopamine agonists in 36. Five patients were
receiving dopamine agonist monotherapy; 7 had no treatment.


The Epworth sleepiness score was significantly higher in PD patients
(7.5 ± 4.6; range, 0-20) than in controls (5.8 ± 3.0; range, 0-11),
indicating that that PD patients were significantly more sleepy than
controls (Table 1). Thiry-three percent of PD patients but only 11.4
percent of controls had elevated Epworth sleepiness scores ³ 10 (P =
0.001, X2 test). An Epworth score ³ 15 was found in 4% of the PD
patients, and none of the controls. A total of 68.4% of the PD
patients and 45.5% of controls took a regular afternoon nap (P =
0.008 X2 test). The mean duration of naps was longer in PD patients.


No correlations were found between EDS and sleep quality, estimated
sleep duration, and number of awakenings. Subjective sleep quality
correlated positively with estimated night sleep duration and
negatively with sleep latency and awakening .



Snoring was reported with almost identical frequencies in the PD and
control groups (no snoring, 31.6%/ 27.9%; occasional snoring,
52%/53.5%; frequent loud and irregular (heavy) snoring, 16.3%/l8.6%
(all not significant). There was a significant impact of reported
severity of snoring on ESS in both PD patients (P = 0.016) and
controls (P = 0.007). In PD patients, this effect was restricted to
patients who re- ported frequent loud snoring (post hoc unpaired /
tests). They had had significant higher ESS scores (10.5 ± 5.7) than
patients who did not report snoring (6.9 ± 3.5; P < 0.01). No
difference was found between PD patients with occasional, mild
snoring and those without snoring. In the control group, the patients
who reported no snoring had significant lower ESS scores (3.8 ± 2.3)
than patients who reported occasional (6.5 ± 2.8; P < 0.01) or heavy
snoring (7.5 ± 2.7; P < 0.01; ).


Patients on levodopa monotherapy were older (73.4 ± 8.0 years) than
patients on a combination of levodopa and dopamine agonists (63.6 ±
8.0 years; P < 0.001), had a higher age at disease onset (66.6 ± 9.9
vs. 53.8 ± 8.1 years, P < 0,001), and a shorter disease duration (6.2
± 7.2 vs. 9.8 ± 6.3 years; P = 0.047).


ESS did not differ significantly between patients treated with
levodopa only and patients on a combination of levodopa and dopamine
agonists (levodopa only group 8.0 ± 5.0, levodopa and dopamine
agonists 7.6 ± 4.1; P = 0.41). Furthermore, ESS was similar in
patients treated with levodopa plus ergot dopamine agonists (n = 22;
ESS, 7.8 ± 4.2) and those treated with levodopa plus non-ergot
dopamine agonists (n = 14; ESS, 7.3 ± 4.0; P = 0.71). ESS was not
correlated with levodopa or dopamine agonist dose.



Due to the small number of patients in the no treatment and dopamine
agonists-only groups, comparisons were restricted to the levodopa-
only group and the combined levodopa/dopamine agonists group.


In this prospective study, PD patients had higher scores of daytime
sleepiness than controls (7.5 ± 4.6 vs; 5.8 ± 3.0). Daytime
sleepiness did not differ between patients on levodopa monotherapy
and patients with a combination of levodopa and ergoline or non-ergot
dopamine agonists. A significant correlation between ESS and reports
of heavy snoring was found.


Daytime sleepiness has been recognized in PD for a long time, with
widely varying frequencies according to the definition used; Tandberg
and coworkers encountered excessive daytime sleepiness defined
as ''falling asleep three times or more, or total sleep time more than

2 hours" during daytime in 15.5% of PD patients." Factor and
colleagues reported that spontaneous daytime dozing occurred in
almost: 50% of the patients.' Reliable and validated measures of
sleepiness such as the ESS4,5,12 and poly-graphic tests have only
more recently been used.


The increased Epworth scores in this series are in line with other
recent studies in PD patients Ondo and coworkers found even higher
Epworth scores (11.1 ± 5.9), possibly due to longer disease duration
in their patients . In contrast, in the study by Tan and colleagues,
using a Mandarin version of the ESS, the scores were notably lower
(5.6); however, they were still significantly higher than in control
Apart from cultural differences in the understanding of ESS
questions, genetic differences in sleep propensity could possibly
explain these divergent findings.


In this study, ESS scores were not different between parents on
levodopa monotherapy and those receiving a combination of levodopa
plus a dopamine agonist. Likewise, there were no differences between
patients taking ergoline or non-ergoline agonists nor was there any
association between ESS scores and levodopa or agonist dose. These
findings are in accordance with other studies reporting similar
frequencies or severities of EDS in patients taking different
agonists. Levodopa and dopamine agonist doses in this series were
lower than commonly used in monotherapy, and our failure to detect
correlations between levodopa and dopamine agonist

dose and the ESS may be related to the fact that our patients were
not exposed to the higher part of dose spectra. Some studies have
clearly shown a dose-response relationship regarding dopaminergic-
induced somnolence.


The possible contribution of heavy snoring 10 EDS has not been
recognized in PD patients before, although it is well known for ocher
subject groups. Loud and irregular (heavy) snoring (in contrast to
primary snoring) is a classic symptom of sleep disordered breathing
(SDB) such as obstructive sleep apnea syndrome or upper airway
resistance syndrome . Sleep disordered breathing is a well-known
major cause of excessive daytime sleepiness in the general
population, with a prevalence between 2. and 4% in men over 50 years.


There is a long-standing controversy about sleep disordered breathing
in idiopathic PD. Previous studies have reported no, increased
central, or increased obstructive apneas in PD. Some of these studies
were performed in very small subject groups. A recent evaluation of
SDB in 83 patients with different parkinsonian syndromes (76 with
idiopathic PD) used sophisticated techniques (capnography, calibrated
induction plethysmography, and calculation of labored breathing
index, in addition to standard polysomnography and oxymetry). In that
study, clinical or subclinical signs of sleep disordered breathing
(mostly obstructive) were detected in more than 50% of the patients.
Another recent polygraphic study found an increased apnea-hypopnea
index

in 20% of PD patients . Still, it appears unlikely that SDB accounts
for the excess daytime sleepiness of PD patients over controls,
because it occurs in similar frequency in both groups. In

line with this finding, in a recent polysomnographic study, the
obstructive sleep apnea hypopnea index did not correlate with daytime
sleepiness.


Although there is a definite causal role for dopaminergic therapies
regarding EDS in PD, patients with sleep disordered breathing should
nevertheless not be overlooked and, if needed, treated appropriately.