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Published in final edited form as: Clin Geriatr Med. 2019 Sep 6;36(1):119–130. doi: 10.1016/j.cger.2019.09.005

Overview of Sleep and Circadian Rhythm Disorders in Parkinson Disease

Priti Gros 1, Aleksandar Videnovic 2
PMCID: PMC6921931  NIHMSID: NIHMS1539292  PMID: 31733692

INTRODUCTION

Parkinson disease (PD) is the second most common neurodegenerative disease. Up to 98% of PD patients report experiencing at least one non-motor symptom (NMS)1,2, among which sleep disorders are some of the most common. NMS are under-reported and under-recognized by PD patients, caregivers and healthcare providers2. Common barriers to seeking help included acceptance of symptoms, lack of awareness that a symptom is associated with PD and belief that no treatments are available2.

In a cross-sectional survey of 358 PD patients, up to 30% of PD patients failed to report sleep disorders to their healthcare providers2; their prevalence can be as high as 40% in other studies1. Sleep disorders are associated with significant quality of life impairment3. Further interventions need to be put in place to encourage PD patients to report sleep disorders. Moreover, greater awareness about common sleep disorders in PD amongst healthcare providers can potentially lead to timely diagnosis and appropriate treatment.

In this review, we discuss common sleep problems in PD including insomnia, excessive daytime sleepiness (EDS), sleep-disordered breathing including obstructive sleep apnea (OSA), restless legs syndrome (RLS), circadian rhythm disorders and REM sleep behavior disorders (RBD).

MOST COMMON SLEEP DISORDERS ASSOCIATED WITH PARKINSON’S DISEASE

1). INSOMNIA

Definition

Insomnia is the persistent difficulty to initiate, maintain, consolidate sleep or to generate an overall good sleep quality, despite satisfying opportunity for sleep and resulting in daytime impairment4. PD patients report more often sleep fragmentation and early awakenings, rather than sleep initiation difficulty5.

Epidemiology

Insomnia is thought to be the most common sleep disorder in PD, with its prevalence varying from 30-80%6,7 With disease progression, the sleep maintenance problem increases in prevalence6.

Pathophysiology

The elements contributing to insomnia in PD are multiple. Insomnia in PD appears to be associated with PD duration and depression5,6The sleep regulatory centers and circadian rhythm circuits are affected by the neurodegenerative process itself 8. Moreover, PD patients are commonly affected by multiple symptoms such as nocturnal hypokinesia, dystonia, pain, mood changes and nocturia, which can impair sleep 9,10. Dopaminergic agents also have an impact on sleep, although their exact effects on various PD stages, including issues of timing and dosing of these medications, remain yet to be clarified 5.

Diagnosis

A thorough sleep history, including a sleep log and the bed partner’s perspective is necessary. Questionnaires can be helpful to capture night sleep disturbances, and daytime impairments11. Multiple questionnaires have been validated in PD, among which the PD sleep scale (PDSS) and its second version PDSS-II, the Scale for outcomes in PD (SCOPA) sleep scale have been the most commonly used 12 Polysomnography should be considered if comorbid sleep disorders are suspected.

Clinical implications

Insomnia and depression are closely related, with one often co-existing with the other5. PD patients with insomnia tend to have more advanced PD and is often associated with balance problems (known as postural instability) and gait difficulties, frequent wearing off of the levodopa effect, autonomic dysfunction, and hallucinations5,13. Another element to consider is the concomitant presence of other sleep disorders such as OSA, RBD and RLS which can contribute to sleep fragmentation and overall poor sleep. Insomnia and poor sleep quality are associated with lower health-related quality of life14.

Management

The first step in managing insomnia in PD is to review possible contributors. PD patients should be evaluated for potential nocturnal motor symptoms. Controlled released levodopa or a dopamine agonist can be considered. One such agonist, transdermal rotigotine patch has the advantage to provide a stable plasma level for 24 hours15 and has been shown to help with subjective sleepiness and sleep architecture16.

The most recent evidence-based medicine update on treatment of NMS authored by Seppi et al. concluded that eszopiclone and melatonin are “possibly useful” for treatment of insomnia in PD18. Non-pharmacological circadian based interventions such as light therapy are non-invasive feasible options for treatment of insomnia in PD19.

Mood disorders should be screened and treated. Venlafaxine, tricyclic antidepressants, cognitive-behavioral therapy and even the dopamine agonist pramipexole have good evidence for their use for mood disorders in PD 18.

2). EXCESSIVE DAYTIME SLEEPINESS

Definition

Excessive daytime sleepiness (EDS) is the difficulty to remain awake and alert during the day which leads to unintended episodes of sleep or drowsiness4. Sleep attacks can occur in patients with EDS and are defined by unintended and inappropriate episodes of falling sleep with minimal or no prodrome of drowsiness4.

Epidemiology

The prevalence of EDS in PD ranges from 20% to 75%20,21. A multi-center longitudinal study showed similar prevalence of EDS in untreated PD patients compared to healthy controls22; however, EDS increased in prevalence over time in PD while it remained unchanged among controls.

Pathophysiology

Multiple factors are associated with EDS in PD, such as PD stage, comorbid sleep disorders and use of dopaminergic agents. Liguori et al. suggested that EDS can occur independently of other sleep-wake disorders23, possibly because neurodegeneration itself affect regions such as the hypothalamus and various brainstem nuclei responsible for sleep wake regulation24. Dopaminergic drugs have been associated with EDS and sleep attacks, dopamine agonists being the most frequent offending agents25. Dopaminergic drugs have possibly a dose related effect on EDS22.

Diagnosis

Epworth Sleepiness Scale (ESS) is a commonly used screening tool. Certain electrophysiological tests are the gold standard and they include the multiple sleep latency test (MSLT) and the maintenance of wakefulness test (MWT)26. Comorbid sleep disorders such as RLS, OSA and RBD may influence EDS and therefore should be screened or tested with polysomnography.

Clinical implications

EDS is associated with older age, advanced PD stage, presence of postural instability and gait disturbance, autonomic dysfunction and mood disorders 20,27,28. EDS is also associated with worse motor function, cognitive impairment and worse quality of life. Several studies revealed dissociation between the degree of daytime sleepiness and quality of nocturnal sleep; this raises a possibility for differential effects of PD-specific neurodegeneration on wake – promoting versus sleep regulatory centers.

Management

Management of EDS requires identifying possible reversible causes. Decreasing or discontinuing dopamine agonist25 as well as treating OSA, RLS or RBD if present can improve EDS29,30. Timed light therapy demonstrated a significant improvement in ESS score in a randomized placebo-controlled study31. Seppi et al. concluded that modafinil was “possibly useful” for treatment of EDS18. Caffeine is currently “investigational” as there is insufficient evidence18. A recent study for the use of sodium oxybate in treating EDS showed significant improvement of ESS and MSLT. However the study sample was small and long term polysomnographic monitoring is necessary to assess treatment related complications32. It is a controlled drug with special requirements that is best left to be managed by sleep specialists.

3). SLEEP RELATED BREATHING DISORDERS

Definition

Sleep related breathing disorders (SBD) include obstructive sleep apnea (OSA), central sleep apnea, sleep related hypoventilation and sleep related hypoxemia. In PD, OSA is the most common form of SBD and will be the focus of this section.

Epidemiology

The prevalence of OSA in PD is from 20-60% 33,34. There is a significant variability in study methodologies including scoring system used by different sleep laboratories35. For example, three different standard hypopnea definitions lead to important scoring differences and therefore differences in the estimations of OSA prevalence in the general population 36 Further understanding of the mechanism of OSA in PD is necessary to better interpret potential scoring biases35.

Pathophysiology

High BMI is typically associated with higher risk of OSA in the general population37, but is not associated with the severity of the OSA in PD38. This suggests that the mechanism of OSA may be different in PD. Upper airway obstruction (UAO) in PD such as laryngopharyngeal motor dysfunction has been reported as a possible mechanism of OSA39. Interestingly, certain studies have reported responsiveness of OSA to levodopa40,41.

Diagnosis

Polysomnography (PSG) or home sleep apnea testing is recommended for the diagnosis of sleep apnea in the general population42. In PD, home sleep apnea testing has been validated in one study with a level III portable monitoring43. It was found to have a reasonable specificity for moderate to severe OSA and therefore suitable to “rule in” OSA but not to “rule it out”43.

Clinical implications

OSA is associated with excessive daytime sleepiness and cognitive dysfunction44. RBD is associated with less severe OSA in PD, possibly because of the increased motor activity during REM sleep45. PD patients with RBD and OSA have however worse cognitive dysfunction45.

Management

Seppi et al. concluded that CPAP is “likely efficacious” and “possibly useful” in improving sleep and daytime sleepiness18. Prolonged continuous positive airway pressure treatment improved anxiety, cognitive function and overall sleep quality after 12 months of CPAP use30. An alternative to CPAP, such as carbidopa/levodopa CR (controlled release formulation) at bedtime possibly improves OSA in PD40.

4). RESTLESS LEGS SYNDROME

Definition

Restless legs syndrome (RLS) is the urge to move the legs usually associated with leg discomfort4. The latter – by definition - must be caused or exacerbated by inactivity and be at least partially relieved by movement. Symptoms start or worsen in the evening or night, and cause significant discomfort4. RLS is closely associated with periodic limb movement of sleep (PLMs), which usually are simple stereotyped movements that can also be associated with nocturnal or diurnal disturbance4.

Epidemiology

A meta-analysis found that the prevalence of RLS is 14% in PD, slightly higher in patients who previously received PD treatment (15%) compared to drug-naïve patients (11%)46. A study found that RLS is associated with an increased risk of incident PD (0.37% of PD incidence in the RLS population versus 0.13% in the controls)47. Lee et al. suggested that the development of RLS in PD was associated with the duration of antiparkinsonian therapy48. In a similar vein, other investigators have reported a lack of association between untreated PD and RLS.49 Other studies suggest that PD patients with RLS have older age at PD onset, more advanced PD stages, severe limb parkinsonism, depression, anxiety, dysautonomia and worse nutritional status 53,54.

Pathophysiology

Ferini-Strambi et al. recently reviewed the literature around three main pathophysiological hypotheses50: (1) Given the common responsiveness to dopaminergic therapy, RLS and PD may share a common dopaminergic pathophysiology as well as possible genetic links51; (2) RLS in PD may have a different mechanism than idiopathic RLS and (3) RLS and PD may be two different diseases50. In other words, the interaction between RLS and PD has not been settled. In addition, there is evidence of a link between RLS and diminished iron stores in many RLS cases (with or without concomitant PD)55,61.

Diagnosis

The criteria required to diagnose RLS are described by the third edition of International Classification of Sleep Disorders (ICSD-3)4. RLS has multiple mimics including non-PD conditions such as myalgia, leg cramps and arthritis. These need to be excluded by the clinician. Concomitant PD related leg symptoms such as limb stiffness and dystonia may also mimic RLS52.

Clinical implications

RLS may be the underlying cause of insomnia, such difficulty in sleep initiation. In addition, RLS is commonly associated with periodic limb movement of sleep (PLMS) and as a consequence it can also affect sleep maintenance, can worsen sleep quality, negatively affect mood and be associated with poor quality of life.

Management

The presence of a low serum ferritin level and search for medications potentially responsible for RLS exacerbation should be assessed55. Evidence-based recommendations suggest dopamine agonists including pramipexole 56, rotigotine57, ropinirole58 as well as non-dopaminergic options such as gabapentin enacarbil59, pregabalin60 and IV iron61. However, dopamine agonists (DAs) can lead to augmentation (requirement of ever increasing doses) or worsening of symptoms after a transient period of amelioration61. In such cases, DAs may be suspended or transitioned to a long acting dopaminergic or non-dopaminergic agent62. Subthalamic nucleus deep brain stimulation may improve RLS in PD 63,64.

5). CIRCADIAN RHYTHM DISORDERS

Circadian rhythm disorders are characterized by a chronic or recurrent sleep disturbance due to alteration of the circadian system or a misalignment between the endogenous circadian rhythm and socially determined sleep-wake schedules4. PD itself is influenced by the circadian rhythm. PD patients may experience diurnal fluctuations in motor and non-motor symptoms despite stable pharmacokinetics of dopaminergic medications. They may also experience seasonal fluctuations, as their disease progresses65,66.

Mechanisms underlying these fluctuations remain unclear. Neurodegeneration affects central structures responsible for the regulation of sleep and wakefulness. PD-specific changes may affect input to the hypothalamic supraschiasmatic nucleus (SCN), the central pacemaker of the circadian system. For example, reduced exposure to ambient light and the degeneration of dopamine containing cells in the retina of PD patients, may negatively affect input to the SCN that is needed for alignment of dark/light cycles. Dopaminergic therapy has a possible bidirectional influence on the circadian rhythm 67.

Light is the main “zeitgeber” (timegiver) for the SCN, and may also have a direct alerting effect68. In PD, light therapy (LT) improves daytime sleepiness, sleep fragmentation, sleep quality, ease of falling sleep and mood31. Furthermore, some studies even suggest LT has a positive effect on motor function in PD 69.

The use of chronotherapeutics in PD including timed bright light, physical exercise and melatonin is the subject of ongoing research. These therapies have the potential to be available, inexpensive and non-invasive70. Further studies will be necessary to optimize PD tailored protocols55.

6). REM SLEEP BEHAVIOR DISORDER

Definition

Rapid eye movement sleep behavior disorder (RBD) is a parasomnia described as repeated sleep-related vocalization and/or complex motor behaviors during REM sleep. Polysomnography reveals that the normal loss of muscle tone during REM sleep is lost (loss of muscle atonia)4. Patients often appear as “acting up their dreams” 4.

Epidemiology

A meta-analysis estimated the prevalence of RBD in PD at 23.6% and 3.4% in the general population71. Similarly, the DeNoPa cohort reported the prevalence of RBD as 25% in PD subjects compared to 2% in healthy controls72. Idiopathic RBD (iRBD) is considered a strong prodrome of synucleinopathies (PD and other related disorders). A recent large multicentre study reported a phenoconversion rate (non-PD affected individuals transitioning to PD) of 6.3% per year and 73.5% after 12 years follow-up73. RBD precedes onset of parkinsonism by a median time of 13 years 74, but may do so as far as 50 years in advance 75.

Pathophysiology

RBD has been related to a pontomedullary dysfunction of structures that regulate REM sleep including the locus coeruleus/subcoeruleus complex76.

Diagnosis

Screening questionnaires are available, including the RBD Sleep Behavior Disorder Screening Questionnaire (RBDSQ)77. Given the prevalence of RBD mimics, polysomnography with electromyographic analysis is the gold-standard78. The ICSD-3 criteria include repeated observed episodes of sleep related vocalization and/or complex motor behaviors occurring during dream mentation, leading patient to report “dream enactment”4. There should be a clinical suspicion or electrophysiologic confirmation that these behaviors occur during REM sleep4 or polysomnographic evidence REM sleep without atonia (RSWA)4. Other causes for the symptoms should be excluded such as another sleep or psychiatric disorder, substance or medication use4.

Clinical implications

RBD, when comorbid with PD, is associated with a poorer prognosis for the latter. There is higher risk of more severe motor dysfunction, hallucinations, cognitive impairment and autonomic dysfunction 79,80. Given its strong association with PD and related disorders, counselling selected iRBD patients (with soft neurodegenerative signs and above 50 y.o) about the potential risk of neurodegeneration may be considered 81.

Management

The most important first step in managing RBD is counselling patients and their bedpartner about bedroom safety82. Potential causing, or aggravating agents should be reassessed including antidepressants83. Mimics such as severe OSA should be screened and treated82. There is no level 1 efficacy data to date for the treatment of RBD in PD. Melatonin and clonazepam have both shown efficacy in several studies 84,85.

CONCLUSION

PD is associated with multiple sleep disorders, which are common and significantly impair quality of life. Routine inquiry about sleep problems from healthcare providers can increase its detection and clinical management. Sleep disorders have unique considerations in PD and have been reviewed in this article. Further research should focus on improving screening and diagnostic tools in the PD population. Mechanisms-oriented and patient centered therapeutic plans should be further developed. Level 1 efficacy data for treatment of most sleep disorders in PD are still lacking.

KEY POINTS.

  • Sleep disorders are among the most common non-motor symptoms of Parkinson’s disease, can occur at any stage of the disease and significantly affect quality of life.

  • This article aims to provide an overview of different sleep disorders affecting PD patients including insomnia, excessive daytime sleepiness, sleep-disordered breathing, restless legs syndrome, circadian rhythms disorders and REM sleep behavior disorders.

  • Non-pharmacological and pharmacological treatment options are used in the management of disorders of sleep in PD

  • Further research on the pathophysiology and treatment of sleep dysfunction associated with PD is needed.

SYNOPSIS.

Sleep disorders are common among PD patients and significantly affect quality of life. They are often under-recognized and under-treated. Improved awareness of common sleep problems in PD among healthcare providers is necessary. Mechanisms of sleep disorders in PD remain poorly understood. Tailored treatment and evidence for efficacy are lacking. The purpose of this review is to provide an overview and update on the most common sleep disorders in PD. We review specific features of the most common sleep disorders in PD, including insomnia, excessive daytime sleepiness, sleep-disordered breathing, restless legs syndrome, circadian rhythm disorders and REM sleep behavior disorders. For each disorder, an overview and update on the definition, epidemiology, pathophysiology, diagnosis, clinical features and treatment are presented. Areas of further research interests are discussed.

Acknowledgments

FUNDING

We would like acknowledge research support form NIH/NINDS. Grant number: R01NS099055.

Footnotes

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DISCLOSURE STATEMENT

The authors have nothing to disclose.

CONFLICT OF INTERESTS

The authors declare that they have no conflict of interest.

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