Parkinson’s disease (PD) is a neurodegenerative disorder of the brain with loss of dopaminergic cells and manifests as motor and non-motor symptoms. Amongst non-motor symptoms, sleep dysfunctions are quite common and can affect 60–90% of patients.1 In one study prevalence of sleep disorders was reported to be up
to 98%.2

 

Excessive daytime sleepiness (EDS) is one of commonest sleep dysfunctions in a PD patient and it can present as symptomatic daytime somnolence with frequent sleep periods that the patient cannot resist1 and secondly, as sudden onset of sleep without the awareness of it (sleep attacks). EDS can be present in up to 33–75% of patients.3,4 However Barone et al reported in the PRIAMO study that the prevalence of EDS is 21%.5 The reason for the variation is the different non-standardised scales applied to diagnose EDS or different tools used to define EDS.

Despite hundreds of studies done about the sleep disorders in PD, several questions remain unanswered and in busy outpatient clinics the important symptom of sleep disorders, especially EDS, is still ignored and not asked. In one study, just over half of patients had told their doctor about nocturnal problems.6

Emphasising the importance of EDS in PD is necessary because at times simple measures can be taken to manage EDS. For example, sleep apnoea syndrome will lead to poor quality sleep at night and treatment will be expected to improve EDS. The purpose of this article is to provide an overview about EDS in PD focusing on
its pathophysiology and treatment.

Impact on quality of life

Non-motor symptoms of PD cause significant impairment of quality of life7,8 and several studies have showed that sleep disorders cause a lot of distress and impact on health related quality of life (HR-QoL).9,10,11 A Chinese study showed that non-motor symptoms, such as sleep and fatigue, are independently and negatively associated with HR-QoL in PD and that improving non-motor symptoms should be viewed as an important part in the management of PD.12 In another study done on patients taking levodopa within the first five years of disease onset, non-motor symptoms such as depression, sleep disturbances and fatigue have more predictive value for worsening of HR-Qol than the motor symptoms.13

In the longitudinal SCOPA-PROPARK cohort study, patients who have autonomic dysfunction, night-time sleep problems, and cognitive dysfunction were found to be at risk of deterioration in HR-QoL.14 Pal et al showed that PD patients with sleep dysfunctions are more susceptible to mood disturbances such as anxiety and depression which correlate with the severity of sleep dysfunction and these sleep and mood disturbances also adversely affect the quality of life of caregivers.

In caregivers, 40% had sleep disturbances, 21% had depression, and 10.5% had anxiety.15 Their depression, anxiety and sleep scores correlated with those of their patients. Similar results were shown in another study with a high rate of sleep disturbances and depression in caregivers of PD patients and they correlated with those of the PD patient.16 In non-PD patients daytime sleepiness was the only sleep disturbance symptom that was associated with mortality, incident CVD morbidity and mortality, MI, and CHF.17

Pathophysiology

A prospective study of 3,078 Japanese-American men with seven years follow up done by Abbot et al on the Honolulu Asia Aging population showed that sleepiness might herald PD, in particular because of neuronal loss in the locus coeruleus, hypothalamus, and other areas associated with the promotion of wakefulness and EDS also intensify with disease severity. However EDS was defined as being sleepy most of the day and no proper scales were used for the assessment of EDS and the cause of EDS was not investigated.18

Another prospective study on a large cohort showed that daytime sleepiness is one of the non-motor symptoms predating clinical diagnosis of PD.19 Compared to the patients who were not napping in the daytime, the patients who napped for more than one hour each day had a 50% higher chance of reporting PD, but this study used daytime napping as a surrogate for EDS and also relied on self reporting for identification of PD.

Another interesting study on 84,794 female nurses in USA doing night shift work showed that compared to nurses who have never worked rotating night shifts, those with 15 years or more of night shift work had a 50% lower risk of PD, after adjustment for age and smoking. Those nurses who reported sleeping for nine or more hours per day have higher incidence of developing PD as compared to those sleeping six hours or less, so habitual longer sleep duration in the daytime may be an earlier marker of PD. In other words working in the night shift may be protective against PD or low tolerance against night shift may be an early marker of PD.20 This study however, was not designed to evaluate the association of night shift or sleep pattern and PD so further studies are needed to replicate these findings.

There are several predisposing factors for developing EDS. O’Suilleabhain and Dewey21 reported that somnolence in patients with PD, which is on average 25% higher than in other neurological diseases, is related to PD stage, levodopa dose, and the use of a dopamine agonist. However, Arnulf et al 2002 concluded in their study that in PD patients with sleepiness, severity of sleepiness is not dependent on nocturnal symptoms, motor symptoms, disease severity or cognitive impairment but they found that 20% of the PD patients have obstructive sleep apnoea and it can predispose PD patients to EDS. They also suggested that EDS is because of the neurodegenerative process occurring in brain.22

Iranzo suggested that dementia, hallucinations, circadian sleep-wake cycle disruption, depression, obstructive sleep apnoea and genetic susceptibility can be the predisposing factors,23 but he further commented that the role of these factors is still not very clear in causing EDS and especially the role of genetic factors were debated without any conclusion.24,25

Mechanism of EDS

The mechanism of EDS is complex and involves neurodegenerative processes as well as the effects of dopaminergic drugs. There is degeneration of cholinergic neurons in basal forebrain, serotonergic neurons in raphe nucleus, noradrenergic neurons in locus coeruleus, dopaminergic neurons in ventral tegmental area and orexin neurons in hypothalamus. Each of these neuronal groups sub-serves distinct aspects of wakefulness-related functions of the brain and behavioural arousal. At the onset of sleep the cell groups or nuclei in the ventral lateral preoptic area (VLPO) and the median preoptic nucleus (MnPN) of the hypothalamus turn the arousal switch off in wake mediating nuclei. VLPO and MnPN neurons are sources of projections to arousal-regulatory systems in the posterior and lateral hypothalamus and the rostral brainstem.26 Balance between this sleep-wake switch is maintained by internal circadian rhythm and sleep needs.27 Loss of early orexogenic/hypocretin cells in the posterior part of hypothalamus even prior to the onset of drug treatment was associated with narcolepsy-like symptoms in early PD patients.28 This study proved the point that narcolepsy-like symptoms in PD patients are partly because of loss of hypocretin cells.

Other factors such as depression, poor sleep hygiene and primary sleep disorders can also lead to EDS28 but neurodegenerative processes are mainly responsible for EDS and dopaminergic drugs and other factors as mentioned above contribute towards it.29, 22

Presentation

As discussed above, sleep disorders can impair quality of life in PD patients and they can also affect the caregivers’ quality of life. Two recent Chinese studies showed that clinical factors that showed the highest predictive value for worse health related quality of life were non-motor symptoms, such as depression, sleep disorders, and fatigue and so these non-motor symptoms are independently and negatively associated with health related quality of life in PD.12, 13 EDS was correlated more to anxiety than any other neuropsychiatric disorder.30

Sleep attacks (sudden, irresistible, overwhelming sleepiness without awareness of falling asleep) were identified as a separate entity to the EDS. Frucht et al reported them first in 1999 as a new side effect of the dopamine agonist and they reported eight patients falling asleep and five of these patients fell asleep without any warning whilst driving hence causing road traffic accidents. The attacks ceased once the dopamine agonist was stopped.31 This finding sparked a debate and Chaudhuri et al added that it’s a class effect and patients with these symptoms should be screened actively in the clinic.32

A study of 2,952 PD patients in two German counties showed that out of these patients 177 had sudden, unexpected, and irresistible sleep episodes while engaged in some activity such as eating and 51% of these patients didn’t have appropriate warning signs. According to this study roughly 1% of the PD patient population seems to be at risk for sleep attacks without appropriate warning signs and without accompanying daytime sleepiness. Sleep attacks occurred with all dopamine agonists and there was no difference between ergot and non-ergot dopamine agonist.33 But Olanow et al presented their view that these events are not sudden, usually predictable, and that a screening tool such as the Epworth Sleepiness Scale (ESS) might be useful to detect preceding sedation in patients at risk.34

Hobson et al showed that EDS was present in 51% of PD patients and 3.8% suffered with at least one episode of sudden onset of sleep while driving and in 0.3% (three patients) it occurred without warning.4

 In another study looking at driving and road traffic accidents in PD patients, a total of 82% of 6,620 patients held a driving license, and 60% of them are still driving. Of the patients holding a driving license, 15% had been involved in and 11% had caused at least one accident during the past five years. Sleep attacks at the wheel usually occurred in easy driving situations. The risk of causing accidents was significantly increased for patients who felt moderately impaired by PD, had an increased Epworth Sleepiness Scale (ESS) score, and had experienced sudden onset sleep while driving. Patients with advanced (subjective) disease severity, higher age, an increased ESS score, and longer disease duration gave up driving and a majority of these PD patients were females.35 In another study on patients with PD and driving, it was concluded that EDS can predict worsening of driving performance in response to distraction and thus can lead to more safety errors.36 DVLA must be notified if PD patients are suffering from EDS or sleep attacks.

Diagnosis

Clinical history is the most important factor in diagnosing sleep disorders in PD. Symptoms of EDS are often ignored and in one study only half of the patients told a doctor about them6 and Chaudhuri et al has also reiterated this fact recently.37 A detailed history of nocturnal symptoms with EDS, sleep attacks, REM behavioral sleep symptoms (RBD), restless legs symptoms (RLS) especially in the night, nocturia and other urinary symptoms, mood disorders, snoring, medication list and history from the partner are important.

The Movement Disorder Society commissioned a taskforce to examine the scales for the sleep disorders in PD and they critiqued and rated nineteen scales and only six scales out of them fulfilled their criteria.38 The Epworth sleepiness scale (ESS) is recommended for rating daytime sleepiness to screen and to measure severity so will assess subjective EDS and a score of ≥10 is suggestive of EDS and ≥15 is suggestive of pathological sleepiness.39 Razmy40 used the Multiple Sleep Latency Test (MSLT) for the objective measure of daytime sleepiness ie. shorter sleep latencies means higher level of sleepiness as in the past a mean latency of no greater than five minutes were considered indicative of an objective level of excessive daytime sleepiness (normal >8 minutes41) but Arnulf and Konofel showed that the correlation between ESS and MSLT was weak and normal ESS does not exclude EDS.22

Inappropriate sleep composite score (ISCS) was suggested for rating severe daytime sleepiness or sleep attacks to screen and to measure severity. PD sleep scale (PDSS) is recommended for rating overall sleep problems to screen and to measure severity. It is a visual analogue scale that can be filled by the patient with 15 items and the severity index of 0–10 (10 being the excellent/never response). Item number 15 is the question about daytime dozing off and it is shown to be strongly correlated with ESS score so high PDSS score was correlated with low ESS, hence low probability of EDS and low PDSS score correlates with high ESS hence high probability of EDS. High ESS score was shown to be consistent with subjective reporting of patients with poor nocturnal sleep, daytime tiredness and sleepiness hence the reliability of PDSS is optimum but the limitation of the scale is that it will not be able to tell the cause of sleep disorder and not specific for the screening the PD specific sleep disorders as RBD or RLS.42

The Pittsburgh sleep quality index (PSQI) is for overall sleep disturbances but is not specific for PD as it is more for the screening of sleep habits with not enough attention to sleep disturbances and daytime sleepiness.

The SCOPA-SLEEP (Scales for outcome in Parkinson’s disease-sleep) is recommended for rating overall sleep problems both to screen and to measure severity, and for rating daytime sleepiness in PD as well as sleep attacks with good reliability, internal consistency and repeatability but is not specific for special problems in PD like pain, hallucinations or tremors etc.43

Out of all the above scales ESS, PDSS and SCOPA-SLEEP are frequently used for sleep disorders in PD although ESS does not assess the disease specific symptoms.

Treatment

The clinical history, review of the comorbidities and PD related factors contributing towards the EDS are important to consider. Many PD related motor symptoms such as motor fluctuations, nocturnal off symptoms, RLS, REM sleep disorders, periodic limb movements (PLM disorder) and dyskinesia should be looked for and treated accordingly. Nocturia and pain can cause disrupted sleep leading to EDS.

Long acting dopamine agonists can help in the treatment of these symptoms. Similarly depression and anxiety with hallucinations will cause fragmented sleep. PD medications especially dopamine agonist have got a soporific effect so can lead to significant EDS.44 This is a class effect so changing to another dopamine agonist will not help.16,45 Patients on multiple drugs such as levodopa, catechol-o-methl transferase should have their dopamine agonist doses reviewed before any change in the medication.46

Good sleep hygiene is very important and patients should be asked to reduce fluid intake before going to bed and avoid caffeine-containing drinks. Bedtime should be scheduled and patients should try and sleep during this time and not spend time in bed awake, avoiding daytime naps, promoting day time activities and exercise will help in reducing EDS.47 Having a hot bath two hours before the bedtime may be helpful along with additional behavioural therapy measures such as stimulus control.48

Evidence for the drugs to manage EDS is scanty. Modafinil is wake-promoting drug used in the treatment of narcolepsy and its mode of action is unknown. Few studies showed it to be moderately effective in the PD patients as well.49-53 but they were either case reports or studies done on a small number of patients.

Another double blinded, randomised study done on 40 PD patients with EDS didn’t show any improvement in EDS as a primary endpoint and secondary outcome measures such as MSLT, Fatigue Severity Scale, Hamilton Depression Scale, and global impression scores also showed no difference between modafinil and placebo. The PD motor status was not affected and adverse events were minimal.54 Modafinil induces and inhibits several cytochrome P450 isoenzymes and has the potential for interacting with drugs from all classes. Modafinil dose should be reduced in the elderly, in patients with hepatic disease and in patients with severe renal insufficiency. Common side effects of modafinil include insomnia, headache, nausea, nervousness and hypertension.55 It is also known to cause agitation and hallucinations.56

Methylphenidate (methyla-phenyl-2-piperidineacetate) is also used in EDS and in narcoleptic patients shown to have good therapeutic index. Similarly, Amphetamine and its D-isomer (dexamphetamine) are used but have got potential for abuse.57

Ondo et al administered sodium oxybate nocturnally on patients with EDS in PD and it showed to improve night time and daytime sleep problems and daytime fatigue. Its efficacy was shown to be better or equalling when it was used in narcoleptic patients. Adverse effects included dizziness, nocturia/enuresis, nausea, daytime sleepiness, reduced alertness, and rebound morning tremor. The mechanism of action is not known.58

A small study done by Hywnn et al on PD patients after unilateral DBS showed non-motor symptoms improvement and the largest mean decrease of NMS scores was in the categories of mood (−9.3 points ±13.8), sleep (−9 points ±13.3), and miscellaneous (−7 points ±8.7).59 In the 24 months follow up after bilateral STN-DBS, Lyons and Pahwa showed increased total sleep with improvement in bradykinesia scores from the Unified Parkinson’s Disease Rating Scale (UPDRS) and decreased early morning dystonia but no change in daytime sleepiness.60 Similarly, Hjort and colleagues showed improvement in the quality of sleep with STN-DBS and nocturnal motor symptoms but no effect on EDS, nocturia or sleep fragmentation.61 Several studies showed that bilateral STN-DBS improve the subjective quality of sleep, continuous sleep time and sleep efficiency but no change in sleep architecture.62-64 or central sleep modulation.65 However in a recent one year follow up study on five advanced PD patients with deep brain stimulation of pedunculopontine tegmental nucleus, not only did the night time sleep improve remarkably but the daytime sleepiness symptoms got better as well66 so future interventions hopefully will be able to provide an efficacious treatment for this disabling symptom in PD.

Conclusion

EDS is one of the commonest dysfunctions of sleep in PD patients and can cause significant impairment of the quality of life of the patient as well as the caregiver. EDS can predate PD and there are several predisposing factors. Neurodegeneration of brain and dopaminergic drugs to treat PD are the main causes for EDS. Different scales are used to diagnose EDS but ESS, PDSS and SCOPA-SLEEP are frequently used for sleep disorders in PD although ESS does not assess the disease specific symptoms. Good sleep hygiene and modafinil can help in the management of EDS. There is a need for better drugs and interventions to treat EDS in the future.

Conflict of interest: none declared

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