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Parkinson’s Disease and Sleep/Wake Disturbances
Abstract
Sleep disturbances are a common non-motor feature in patients with Parkinson's disease (PD). Early diagnosis and appropriate management are imperative for enhancing patient quality of life. Sleep disturbances can be caused by multiple factors in addition to age-related changes in sleep, such as nocturnal motor symptoms (rigidity, resting tremor, akinesia, tardive dyskinesia, and the "wearing off" phenomenon), non-motor symptoms (pain, hallucination, and psychosis), nocturia, and medication. Disease-related pathology involving the brainstem and changes in the neurotransmitter systems (norepinephrine, serotonin, and acetylcholine) responsible for regulating sleep structure and the sleep/wake cycle play a role in emerging excessive daytime sleepiness and sleep disturbances. Additionally, screening for sleep apnea syndrome, rapid eye movement sleep behavior disorder, and restless legs syndrome is clinically important. Questionnaire-based assessment utilizing the PD Sleep Scale-2 is useful for screening PD-related nocturnal symptoms. In this review, we focus on the current understanding and management of sleep disturbances in PD.
... Sleep disturbance is a major non-motor complaint of Parkinson's disease (PD) with extensive impact on patient quality of life. Approximately 40% to 90% PD patients exhibit sleep disturbances, including insomnia, excessive daytime sleepiness, REM sleep behavior disorder, nocturnal motor and nonmotor symptoms and a fragmented sleep-wake behavior [110][111][112][113]. Similar sleep disturbances occur in several mouse models of PD. ...
... Genetic deletion of D 2 R significantly decreases wakefulness in mice [162]. Moreover, patients with Parkinson's disease, who exhibit dopaminergic lesions in the striatum and nigrostriatal, suffer from severe sleep disorders including insomnia, sleep fragmentation, excessive daytime sleepiness, and REM sleep behavior disorders [110][111][112][113]. ...
... Degenerative changes in the hypothalamus by altering melatonin secretion promote sleep disorders. 92 Both nocturnal motor and non-motor symptoms may contribute to sleep disturbances. The motor symptoms are wearingoff phenomenon, tremor, akinesia, rigidity, medication-related dyskinesia, and dystonia. ...
... Forty to 90% of patients with PD are reported to suffer from sleep disorders that might contribute to disease progression. 1 The definition of excessive daytime sleepiness (EDS) is the inability to sustain wakefulness and alertness throughout the main waking episodes of the day, which causes moments of irrepressible need for sleep or unintentional lapses into drowsiness or sleep. 2 Previous longitudinal studies have found that older people with EDS are at higher risk of developing PD. 3,4 In addition, EDS might be a component of PD pathology rather than a result of insufficient nighttime sleep. ...
We aimed to explore excessive daytime sleepiness (EDS) and correlates of clinical characteristics by using cross-sectional and longitudinal analyses from the Parkinson's Progression Markers Initiative (PPMI) database. 423 parkinson's disease (PD) patients (EDS: non -EDS (nEDS) = 357:66) and 195 healthy controls (HCs) (EDS: nEDS = 171:24) were enrolled in our study at baseline. Multiple linear and linear mixed-effects models were used to research the relationships between EDS/daytime sleepiness severity and clinical characteristics. Relationships between the change rates of clinical characteristics and daytime sleepiness severity were further investigated through multiple linear regression models. Mediating effect analysis was used to determine whether autonomic dysfunction was the mediator between cognition assessments and daytime sleepiness severity. PD patients with EDS and greater daytime sleepiness severity presented faster cognitive decline, high possibility for rapid eye movement (REM) sleep behavior disorder (RBD), autonomic dysfunction, depression, and anxiety from cross-sectional and longitudinal analyses. Furthermore, HC individuals with EDS showed a higher striatal binding ratio (SBR) of the right putamen, right striatum, and mean striatum. Autonomic dysfunction may act as a mediator between PD and cognitive decline. In early PD, EDS and daytime sleepiness severity were related to several clinical variables, suggesting that EDS might play an essential role in regulating PD progression.
... Current DBS approaches are typically not optimized to treat non-motor symptoms of PD, however. Sleep-wake disturbances, which include insomnia, sleep fragmentation, REM sleep behavior disorder, and excessive daytime sleepiness, are debilitating non-motor symptoms of PD (Baumann, 2019;Bruin et al., 2012;Suzuki et al., 2015Suzuki et al., , 2011. The propensity to fall asleep unintentionally within a matter of seconds while conducting daily routines is a major factor impacting the quality of life of some people with PD (Frucht et al., 1999;Hobson et al., 2002;Salawu and Olokoba, 2015;Yeung and Cavanna, 2014), yet an effective treatment option remains elusive for excessive daytime sleepiness (Rodrigues et al., 2016). ...
Excessive daytime sleepiness is a recognized non-motor symptom that adversely impacts the quality of life of people with Parkinson's disease (PD), yet effective treatment options remain limited. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for PD motor signs. Reliable daytime sleep-wake classification using local field potentials (LFPs) recorded from DBS leads implanted in STN can inform the development of closed-loop DBS approaches for prompt detection and disruption of sleep-related neural oscillations. We performed STN DBS lead recordings in three nonhuman primates rendered parkinsonian by administrating neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Reference sleep-wake states were determined on a second-by-second basis by video monitoring of eyes (eyes-open, wake and eyes-closed, sleep). The spectral power in delta (1–4 Hz), theta (4–8 Hz), low-beta (8–20 Hz), high-beta (20–35 Hz), gamma (35–90), and high-frequency (200–400 Hz) bands were extracted from each wake and sleep epochs for training (70% data) and testing (30% data) a support vector machines classifier for each subject independently. The spectral features yielded reasonable daytime sleep-wake classification (sensitivity: 90.68 ± 1.28; specificity: 88.16 ± 1.08; accuracy: 89.42 ± 0.68; positive predictive value; 88.70 ± 0.89, n = 3). Our findings support the plausibility of monitoring daytime sleep-wake states using DBS lead recordings. These results could have future clinical implications in informing the development of closed-loop DBS approaches for automatic detection and disruption of sleep-related neural oscillations in people with PD to promote wakefulness.
... Among sleep-related symptoms, insomnia is considered a common NMS in PD [4], which can markedly affect motor symptoms and impair patients' QoL [2,4]. Moreover, in patients with PD, insomnia has been described more frequently than other sleep disorders and can appear concomitantly with excessive daytime sleepiness (EDS) or rapid eye movement (REM) sleep behavior disorder [4,5]. Moreover, insomnia in PD may also cause EDS in a bidirectional relation or even represents a part of a circadian sleep-wake rhythm dysregulation [4]. ...
Background:
Sleep-related symptoms, especially insomnia, are frequently reported by patients with Parkinson's disease (PD) and can markedly affect motor symptoms and impair patients' quality of life. Melatonin has been shown to improve sleep in PD patients. This pilot study aimed at evaluating the effects of a 3-month treatment with 2 mg melatonin prolonged-release (PR) on sleep and motor disability in PD patients.
Materials and methods:
Twelve PD patients under stable antiparkinsonian treatment were enrolled in the study. Before treatment (T0), motor dysfunction was assessed with Unified Parkinson's Disease Rating Scale (UPDRS-III) and sleep architecture with polysomnography. Subjective sleep quality was also assessed through Pittsburgh Sleep Quality Index (PSQI) and daytime somnolence with Epworth Sleepiness Scale (ESS). Patients then started melatonin PR and all measures were repeated at the end of treatment after 3 months (T1).
Results:
Sleep latency significantly decreased from T0 to T1, but no other significant differences were found in PSG parameters. Melatonin PR treatment significantly reduced the ESS scores from T0 to T1, while the PSQI scores presented a trend of improvement from T0 to T1. Motor dysfunction was not improved by melatonin PR, although there was a trend in decreasing UPDRS-III. Both clinical global improvement and patient clinical global impression documented an improvement in insomnia symptoms at T1.
Conclusions:
These findings suggest that melatonin may improve sleep symptoms in PD patients, although further evidence is needed in larger controlled studies to confirm these results and explore the possible direct and indirect influence of sleep improvement on motor dysfunction.
... 11 Other studies have suggested that the neuronal cholinergic system (NCS) is implicated in the pathogenesis of hypertension. 12 Suzuki et al 13 have speculated that a deficient NCS is accompanied by impaired cognitive performance in OSAS patients and a significant role in wakefulness and breathing for ACh was demonstrated by Otuyama et al in individuals with sleep-disordered breathing. 14 These reports revealed that NCS was responsible for regulating the presence of EDS and hypertension. ...
Purpose
Simultaneous occurrence of hypertension and excessive daytime sleepiness (EDS) is very common in obstructive sleep apnea syndrome (OSAS), although no study has specifically addressed this issue. The present study explored the risk factors for co-occurrence of OSAS-related EDS and hypertension.
Patients and Methods
A total of 161 OSAS patients were studied after undergoing an eight-hour in-laboratory polysomnography for one night. The OSAS severity assessment depends on the number of breathing disturbances per hour of sleep. EDS was defined using the Epworth Sleepiness Scale (ESS) scores of ≥13. Hypertension was defined according to direct cuff blood pressure (BP) measurements. Beat-to-beat R-R interval data were incorporated in polysomnography for heart rate variability analysis. The low-frequency/high-frequency band ratio was used to reflect sympathovagal balance. The study participants were divided into four groups based on the presence of EDS and/or hypertension: EDS with hypertension (n = 53), EDS without hypertension (n = 27), no EDS with hypertension (n = 38), and no EDS or hypertension (n = 43). Clinical, polysomnographic and heart rate data were compared and studied among the four groups. Plasma acetylcholine (ACh) levels were assessed to explore the effects of the non-neuronal cholinergic system and the co-occurrence of EDS and hypertension.
Results
Patients with EDS and hypertension had more severe OSAS severity indices compared to control patients. Increased cardiac sympathovagal imbalance and nocturnal hypoxemia regulated the presence of EDS and hypertension. Further plasma biomarker analysis revealed that both ESS scores and BP levels were associated with significantly elevated plasma norepinephrine, interleukin-6 and superoxide dismutase levels and significantly decreased ACh levels. Logistic regression analyses showed that ACh was the only factor significantly associated with co-occurrence of EDS and hypertension after controlling for confounders using odds ratio of 0.932, with a 95% confidence interval of 0.868 to 1.000 (P = 0.049).
Conclusion
The results suggested that OSAS coupled with both EDS and hypertension is a more severe phenotype of the respiratory disorder. The presence of EDS and hypertension was accompanied by sympathovagal imbalance, and co-occurrence of these two conditions may be related to decreased plasma ACh levels.
... Sleep disorders are common nonmotor symptoms of PD patients, and it has been reported that 40% to 90% of PD patients are affected by sleep disorders [127,128]. Decreased sleep efficiency, and REM behavior disorder (RBD), which is defined as REM sleep without atonia and excessive daytime sleepiness or narcolepsy-like symptoms, are particularly noticeable in PD patients [129,130]. PD patients also often experience insomnia, nightmares, nocturia, restless leg syndrome, and obstructive sleep apnea [129,131,132]. ...
The majority of neurodegenerative diseases are pathologically associated with protein misfolding and aggregation. Alzheimer’s disease (AD) is a type of dementia that slowly affects memory and cognitive function, and is characterized by the aggregation of the β-amyloid protein and tau neurofibrillary tangles in the brain. Parkinson’s disease (PD) is a movement disorder typically resulting in rigidity and tremor, which is pathologically linked to the aggregation of α-synuclein, particularly in dopaminergic neurons in the midbrain. Sleep disorders commonly occur in AD and PD patients, and it can precede the onset of these diseases. For example, cognitively normal older individuals who have highly fragmented sleep had a 1.5-fold increased risk of subsequently developing AD. This suggests that sleep abnormalities may be a potential biomarker of these diseases. In this review, we describe the alterations of sleep in AD and PD, and discuss their potential in the early diagnosis of these diseases. We further discuss whether sleep disturbance could be a target for the treatment of these diseases.
Objective:
Our study aimed to explore the associative relationship between neurodegenerative diseases and sleep disorders.
Patients:
This 15-year retrospective longitudinal nationwide population-based matched case-control study used data extracted from the National Health Insurance Research Database. We evaluated 25,589 patients diagnosed with neurodegenerative diseases between 2000 and 2015 and a matched control of 102,356 patients without neurodegenerative diseases.
Results:
Sleep disorders were an independent risk factor for the development of neurodegenerative diseases (adjusted odds ratio (OR): 1.794, 95% confidence interval (CI): 1.235-2.268, P < 0.001), with a positive dose-effect relationship (adjusted OR (95% CI): <1 year: 1.638 (1.093-2.872), P < 0.001; 1-5 years: 1.897 (1.260-3.135), P < 0.001; >5 years: 2.381 (1.467-3.681), P < 0.001. Moreover, patients with sleep disorder and comorbid depression had a significantly higher risk of neurodegenerative disorders (adjusted OR: 5.874). Subgroup analysis showed that insomnia was associated with Alzheimer's disease, Pick's disease and essential tremor (adjusted OR (95% CI): 1.555 (1.069-1.965), 1.934 (1.331-2.445) and 2.089 (1.439-2.648), respectively). Obstructive sleep apnea was associated with Parkinson's disease, essential tremor, and primary dystonia (adjusted OR (95% CI): 1.801 (1.239-2.275), 5.523 (3.802-6.977), and 4.892 (3.365-6.178), respectively). Other specific sleep disorders were associated with Pick's disease, Parkinson's disease, essential tremor, and primary dystonia (adjusted OR (95% CI): 8.901 (6.101-11.010), 1.549 (1.075-1.986), 2.791 (1.924-3.531), and 9.114 (6.283-10.506), respectively).
Conclusion:
Sleep disorders are associated with the subsequent development of neurodegenerative disorders. Moreover, sleep disorder patients with comorbid depression have a higher risk of neurodegenerative diseases.
Sleep-wake maintenance represents a central nervous system-derived homeostatic process. Thus, patients with neurologic conditions represent a uniquely vulnerable population for sleep-wake disorders (SWD), including both obstructive and centrally mediated sleep disordered breathing. In neurology patients requiring positive airway pressure (PAP) support to treat sleep disordered breathing, there are unique challenges that may be encountered. It has been suggested that in patients with complex neurological conditions, PAP adherence may be even poorer than the general population. Improved troubleshooting and optimization of adherence to PAP therapy in this population will positively impact sleep disordered breathing, but this benefit may also extend to optimizing management of the patient’s neurologic disease. Specific guidance to optimize PAP adherence based on neurologic disease is outlined here for attention deficit hyperactivity disorder, neurodevelopmental disorders, headache, epilepsy, stroke, neurodegenerative disorders, demyelinating disease, and neuromuscular conditions.
Somnolence is a recognized adverse effect of dopamine agonists. Two new dopamine agonists, pramipexole and ropinirole, have been reported to cause sudden-onset sleep spells in patients with Parkinson disease (PD) while they were driving. The frequency of these spells and whether driving should be restricted has yet to be established.
To determine the frequency of and predictors for sudden-onset sleep and, particularly, episodes of falling asleep while driving among patients with PD.
Prospective survey conducted between January and April 2000 in 18 clinics directed by members of the Canadian Movement Disorders Group; 638 consecutive highly functional PD patients without dementia were enrolled, of whom 420 were currently drivers.
Excessive daytime sleepiness and sudden-onset sleep as assessed by the Epworth Sleepiness Scale and the Inappropriate Sleep Composite Score. The latter score, designed for this study, addressed falling asleep in unusual circumstances. The 2 scales were combined in 3 separate formats: dozing off, sudden unexpected sleep, and sudden blank spells.
Excessive daytime sleepiness was present overall in 327 (51%) of the 638 patients and in 213 (51%) of the 420 drivers. Patients taking a variety of different dopamine agonists had no differences in Epworth sleepiness scores, in the composite score, or in the risk of falling asleep while driving. Sixteen patients (3.8%) had experienced at least 1 episode of sudden onset of sleep while driving (after the diagnosis of PD); in 3 (0.7%), it occurred without warning. The 2 risk factors associated with falling asleep at the wheel were the Epworth Sleepiness Scale score (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.06-1.24) and the Inappropriate Sleep Composite Score (OR, 2.54; 95% CI, 1.76-3.66). A standard Epworth Sleepiness Scale score of 7 or higher predicted 75% of episodes of sleep behind the wheel at a specificity of 50% (exclusion of the question related to driving provided 70% sensitivity and 52% specificity), whereas a score of 1 on the Inappropriate Sleep Composite Score generated a sensitivity of 52% and specificity of 82%.
Excessive daytime sleepiness is common even in patients with PD who are independent and do not have dementia. Sudden-onset sleep without warning is infrequent. The Epworth score has adequate sensitivity for predicting prior episodes of falling asleep while driving and its specificity can be increased by use of the Inappropriate Sleep Composite Score. It is unknown if routinely performing these assessments could be more effective in predicting future risk for these rare sleep attacks. Patients should be warned not to drive if they doze in unusual circumstances.
Background: Over 50% of persons with idiopathic REM sleep behavior disorder (RBD) will develop Parkinson disease (PD) or dementia. At present, there is no way to predict who will develop disease. Since polysomnography is performed in all patients with idiopathic RBD at diagnosis, there is an opportunity to analyze if baseline sleep variables predict eventual neurodegenerative disease. Methods: In a longitudinally studied cohort of patients with idiopathic RBD, we identified those who had developed neurodegenerative disease. These patients were matched by age, sex, and follow-up duration to patients with RBD who remained disease-free and to controls. Polysomnographic variables at baseline (i.e., before development of neurodegenerative disease) were compared between groups. Results: Twenty-six patients who developed neurodegenerative disease were included (PD 12, multiple system atrophy 1, dementia 13). The interval between polysomnogram and disease onset was 6.7 years, mean age was 69.5, and 81% were male. There were no differences between groups in sleep latency, sleep time, % stages 2-4, % REM sleep, or sleep efficiency. However, patients with idiopathic RBD who developed neurodegenerative disease had increased tonic chin EMG activity during REM sleep at baseline compared to those who remained disease-free (62.7 +/- 6.0% vs 41.0 +/- 6.0%, p = 0.020). This effect was seen only in patients who developed PD (72.9 +/- 6.0% vs 41.0 +/- 6.0%, p = 0.002), and not in those who developed dementia (54.3 +/- 10.3, p = 0.28). There was no difference in phasic submental REM EMG activity between groups. Conclusions: In patients with REM sleep behavior disorder initially free of neurodegenerative disease, the severity of REM atonia loss on baseline polysomnogram predicts the development of Parkinson disease. Neurology (R) 2010; 74: 239-244
This authoritative guide to sleep medicine is also available as an e-dition, book (ISBN: 1416003207) plus updated online reference! The new edition of this definitive resource has been completely revised and updated to provide all of the latest scientific and clinical advances. Drs. Kryger, Roth, and Dementand over 170 international expertsdiscuss the most recent data, management guidelines, and treatments for a full range of sleep problems. Representing a wide variety of specialties, including pulmonary, neurology, psychiatry, cardiology, internal medicine, otolaryngology, and primary care, this whos who of experts delivers the most compelling, readable, and scientifically accurate source of sleep medicine available today. Includes user-friendly synopses of important background information before all basic science chapters. Provides expert coverage of narcolepsy * movement disorders * breathing disorders * gastrointestinal problems * neurological conditions * psychiatric disturbances * substance abuse * and more. Discusses hot topics such as the genetic mechanisms of circadian rhythms * the relationship between obesity, hormones, and sleep apnea * sleep apnea and arterial hypertension * and more. Includes a new section on Cardiovascular Disorders that examines the links between sleep breathing disorders and cardiovascular abnormalities, as well as the use of sleep related therapies for congestive heart failure. Provides a new section on Womens Health and Sleep Disorders that includes information on the effects of hormonal changes during pregnancy and menopause on sleep. Features the fresh perspectives of 4 new section editors. Employs a more consistent chapter organization for better readability and easier navigation.
Sleep disturbances are frequent in parkinsonian patients. They are enhanced by motor symptoms, particularly at night, non-motor symptoms (pain, depression..) and by cognitive dysfunction, which could predict cognitive decline. Insomnia, rapid eye movement sleep behavior disorder and excessive daytime sleepiness with sleep attacks will be described together with a review of their treatment.
Between 74 and 98% of all Parkinson patients suffer from sleep disturbances, which often cause a significant reduction in life quality. Up to 88% complain of repeated awakening and up to 67% of sleep onset disturbances. The causes of sleep disturbances are multifactorial. Besides disease-related changes of the sleep structure, motor symptoms typical for Parkinson's disease during sleep and disturbances of the breathing pattern are mainly artificially induced by Parkinsonian medication. These induced sleep disturbances should be taken into account. Besides a structurized patient's and partner's history to evaluate nocturnal problems of motion and breathing pattern the use of polygraphy and polysomnography may be helpful in diagnosing. In addition, the use of a 24 h blood pressure measurement can be necessary to monitor autonomous disturbances and hypotensive phases as a possible cause of nocturnal exogenous psychosis. The treatment of sleep disturbances should be a problem orientated therapy according to the individual causes of sleep abnormalities especially taking into account the nocturnal antiparkinson medication.
Background: Although the relative incidence of violent behavior during sleep (VBS) is presumed to be low, no epidemiologic data exist to evaluate the prevalence of the phenomenon or to begin to understand its precursors or subtypes. This study examined the frequency of violent or injurious behavior during sleep and associated psychiatric risk factors.
Method: A representative United Kingdom sample of 2078 men and 2894 women between the ages of 15 to 100 years (representing 79.6% of those contacted) participated in a telephone interview directed by the Sleep-EVAL expert system specially designed for conducting such diagnostic telephone surveys.
Results: Two percent (N=106) of respondents reported currently experiencing VBS. The VBS group experienced more night terrors and daytime sleepiness than the non-VBS group. Sleep talking, bruxism, and hypnic jerks were more frequent within the VBS than the other group, as were hypnagogic hallucinations (especially the experience of being attacked), the incidence of smoking, and caffeine and bedtime alcohol intake. The VBS group also reported current features of anxiety and mood disorders significantly more frequently and reported being hospitalized more often during the previous 12 months than the non-VBS group. Subjects with mood or anxiety disorders that co-occurred with other nocturnal symptoms had a higher risk of reporting VBS than all other subjects.
Conclusion: We have identified a number of sleep, mental disorder, and other general health factors that characterize those experiencing episodes of VBS. These findings suggest that specific factors, perhaps reflecting an interaction of lifestyle and hereditary contributions, may be responsible for the observed variability in this rare but potentially serious condition.
Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia manifested by vivid, often frightening dreams associated with simple or complex motor behavior during REM sleep. The polysomnographic features of RBD include increased electromyographic tone +/− dream enactment behavior during REM sleep. Management with counseling and pharmacologic measures is usually straightforward and effective. In this review, the terminology, clinical and polysomnographic features, demographic and epidemiologic features, diagnostic criteria, differential diagnosis, and management strategies are discussed. Recent data on the suspected pathophysiologic mechanisms of RBD are also reviewed. The literature and our institutional experience on RBD are next discussed, with an emphasis on the RBD–neurodegenerative disease association and particularly the RBD-synucleinopathy association. Several issues relating to evolving concepts, controversies, and future directions are then reviewed, with an emphasis on idiopathic RBD representing an early feature of a neurodegenerative disease and particularly an evolving synucleinopathy. Planning for future therapies that impact patients with idiopathic RBD is reviewed in detail.