Management Recommendations on Sleep Disturbance of Patients with Parkinson's Disease

INTRODUCTION Sleep disturbance is one of the most common nonmotor symptoms in Parkinson's disease (PD). Sleep disturbance affects 40–98% of PD patients in the world.[123] In China, the prevalence of PD patients with sleep disturbance ranges from 47.66% to 89.10%.[456789] Sleep disturbance usually has adverse impact on the quality of life of PD patients. A possible pathogenesis of PD with sleep disturbance include thalamocortical pathway degeneration and changes of neurotransmitter systems.[3] The etiology of sleep disturbance is multifactorial, involving degeneration of areas regulating sleep, sleep structure affected by drugs, sleep disturbance induced by drug, and sleep fragmentation by multiple factors.[3] Although three reviews on the sleep disturbances of PD have recently been published, there is no consensus of recommendations on the management of PD patients with sleep disturbance.[1310] This consensus aims to provide recommendations for PD patients with sleep disturbances based on the current available evidence and expert opinions. LITERATURE SEARCH, ARTICLES REVIEW, AND CONSENSUS MEETINGS A consensus committee, including neurologists in PD from China and the United Kingdom, was established to review the literature on the sleep disturbance of PD. The committee members aligned their opinions with controversial clinical questions using the current evidence and clinical experience in two face-to-face meetings followed by electronic communication. Literature search was conducted in PubMed between January 2000 and August 2017 using keywords including “Parkinson's disease,” “parkinsonism,” “sleep disturbance,” “sleep disorder,” “insomnia,” “excessive daytime sleepiness,” “obstructive sleep apnea,” “REM sleep behavior disorder,” “RBD,” “restless legs syndrome,” “RLS,” “nocturia,” “sleep-related movement disorders,” “parasomnias,” “sleep-disordered breathing,” “SBD,” “diurnal,” “deep brain stimulation,” and “sleep attack.” Two consensus meetings were separately held in Suzhou (August 27, 2017) and Zhuhai (December 2, 2017) of China. Based on the predetermined criteria, the quality of each article was evaluated, which was consistent with the method of previous published articles.[1112] The efficacy of each drug was defined as “efficacious,” “likely efficacious,” “unlikely efficacious,” “nonefficacious,” and “insufficient evidence.” Implications of each treatment for clinical practice were also defined as “clinically useful,” “possibly useful,” “investigational,” “unlikely useful,” and “not useful.” Safety of each treatment was defined as “acceptable risk without specialized monitoring,” “acceptable risk with specialized monitoring,” “unacceptable risk,” and “insufficient evidence to make conclusions on the safety of the intervention.” Based on the International Classification of Sleep Disorders (the third edition)[13] and clinical experience, five types of sleep disturbance in PD were selected for this consensus including insomnia, excessive daytime sleepiness (EDS), rapid eye movement (REM) sleep behavior disorder (RBD), restless legs syndrome (RLS), and sleep-disordered breathing (SDB). INSOMNIA The prevalence of insomnia in PD is 27–80%.[10] In China, this prevalence is 30.0–86.8%.[914151617181920] Key factors related with insomnia of PD patients include female gender, disease duration of PD, depression, anxiety, and others, which may lead to sleep fragmentation. Main causes related to sleep fragmentation include night motor dysfunction and nocturia.[3] Some drugs (e.g., selegiline) may increase the risk of insomnia.[10] PD patients usually have impairment in the upper brainstem and low midbrain, which is a key to the sleep–wake regulation. In addition, PD may have an impact on arousal system.[21] Insomnia in PD patients can be diagnosed utilizing clinical history, questionnaires, polysomnography (PSG), and actigraphy.[3] If insomnia in PD is neither iatrogenic nor due to motor complications of PD, cognitive behavioral therapy including suggestions for sleep–wake behavior hygiene, stimulus control therapy, sleep restriction, relaxation, as well as cognitive techniques should be considered.[10] Music therapy may be another option for the treatment of insomnia in PD patients.[22] A double-blind controlled study found that single dose of levodopa/carbidopa (Sinemet CR) could not significantly improve total sleep time, sleep latency, and sleep fragmentation of PD patients[23] (quality score, 62.5%). Another randomized placebo-controlled study demonstrated that administration of Sinemet CR could not significantly improve the objective sleep parameters of PD patients including sleep latency, total sleep time, and awakening times[24] (quality score, 75%). Based on the evidence, Sinemet CR is deemed nonefficacious in improving insomnia in patients with PD. A randomized, placebo-controlled study showed that ropinirole could increase the PD sleep scale (PDSS) score of PD patients, suggesting that it can improve the sleep quality of PD patients[25] (quality score, 90%). Another double-blind, placebo-controlled study found that ropinirole could increase the PDSS score of PD patients[26] (quality score, 90%). Based on the results of these studies, ropinirole is considered efficacious in improving insomnia in patients with PD. A randomized, placebo-controlled study found that transdermal rotigotine patch could significantly increase the PDSS score of patients with advanced PD[27] (quality score, 90%). Further five studies (2 randomized controlled trials [RCTs] and 3 open studies) demonstrated that rotigotine could significantly improve the PDSS-2, sleep efficiency, sleep fragmentation, and sleep quality of PD patients[2829303132] (quality score, 93% for RECOVER study and 85% for Pierantozzi et al.). Based on the results of these studies, rotigotine patch is considered efficacious in improving insomnia in patients with PD. A randomized, placebo-controlled study found that pramipexole could significantly increase the PDSS score of patients with advanced PD[27] (quality score, 90%). Based on the results of the study, pramipexole is considered efficacious in improving insomnia in patients with PD. Insomnia is also listed as a side effect of dopamine agonists. A single-center prospective observational study found that compared to monotherapy with LD, the combination of rasagiline and LD significantly decreased the sleep latency and elongated sleep time of PD patients[33] (quality score, 61%). A double-blind, baseline-controlled study found that rasagiline may be beneficial to the sleep quality of PD patients with sleep disturbance.[34] Based on the result of the study, rasagiline is likely efficacious in improving insomnia in patients with PD. A RCT found that eszopiclone could significantly decrease wakeness and improve sleep quality of PD patients[35] (quality score, 95%). Based on the result of the study, eszopiclone is efficacious in improving insomnia in patients with PD. A randomized preliminary study found that doxepin could improve the insomnia symptoms of PD patients, although only six PD patients were included in this study[36] (quality score, 68%). Based on the result of the study, doxepin is likely efficacious in improving insomnia in patients with PD. Two RCTs demonstrated that melatonin could prolong the sleep duration and improve the sleep quality of PD patients[3738] (quality score, 76% for Dowling and 75% for Medeiros). Based on the results of these studies, melatonin is efficacious in improving insomnia in patients with PD. An open study found that quetiapine was effective and safe in patients with PD.[39] Based on the result of this study, there is insufficient evidence for the efficacy of quetiapine in improving insomnia in PD patients. In addition, one RCT found that the respective incidence of insomnia with respect to the use of placebo, ropinirole, and rotigotine was similar in the treatment of early PD patients (5%, 6%, and 6%, respectively).[40] However, 17 studies were included in the management of insomnia in PD patients [Table 1].Table 1: Conclusions on the management of insomnia in PD patientsRecommendations Before treatment, both the cause and the subtype of insomnia in PD patients need to be carefully evaluated. PD patients with insomnia should be treated based on definite etiology (e.g., akinesia and drugs). If the insomnia is related to nocturnal motor symptoms, dopaminergic therapy (dopamine agonists [e.g., rotigotine transdermal patch], long-acting LDs [Sinemet], and monoamine oxidase B inhibitors) should be optimized initially (expert opinion) Cognitive-behavioral therapy is the preferred option in PD patients with insomnia regardless of etiology (Level A recommendation by the American Academy of Sleep Medicine) Dopamine agonists (e.g., rotigotine, pramipexole, and ropinirole), eszopiclone, and melatonin followed by rasagiline and doxepin may be considered for the management of insomnia in patients with PD (evidence based) The pharmacological treatment of the insomnia in PD patients includes the treatment of insomnia itself and secondary insomnia in the context of PD progression. The treatment of insomnia in PD patients refers to the drugs for single insomnia approved by the Food and Drug Administration. If the insomnia of PD patients still cannot improve after optimization treatment for nocturnal motor symptoms, traditional drugs for treating insomnia could be considered. Antidepressants and anxiolytic drugs may also improve the insomnia of PD patients (expert opinion). EXCESSIVE DAYTIME SLEEPINESS The prevalence of EDS in patients with PD is 21–76%.[310] In China, this prevalence is 13.2–46.9%.[4517414243] In patients with early PD, the prevalence of EDS could increase from 11.8% at baseline to 23.4% after 5 years. The prevalence of EDS can be influenced by male gender, older age, nontremor subtype, autonomic dysfunction, cognitive impairment, depression and anxiety, disease severity, and

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   Rotigotine effects on early morning motor function and sleep in Parkinson's disease: A double‐blind, randomized, placebo‐controlled study (RECOVER) · 2010

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