Review

Correspondence *Fédération des Pathologies du Sommeil, Hôpital Pitié-Salpêtrière, 47–83 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France

Email isabelle.arnulf@psl.aphp.fr

Introduction

Parkinsonism, which is defined by the association of slow movements, difficulty walking, muscle rigidity, and sometimes tremor, characterizes a group of neurodegenerative movement disorders that affect 1–2% of adults over 65 years of age. Idiopathic Parkinson's disease (PD) is the most common cause of parkinsonism, and dopaminergic agents provide important benefits in terms of relief of motor symptoms. By contrast, 5–10% of cases of 'atypical' parkinsonism are poorly levodopa-sensitive and include lesions in other motor systems ('Parkinson-plus' syndromes). For example, progressive supranuclear palsy (PSP) is characterized by parkinsonism, abnormal eye movement, and postural instability including falls in the early stages of the disease, and multiple system atrophy (MSA) is characterized by parkinsonism plus cerebellar or autonomic dysfunction.

Major advances have been made in the treatment of PD during the past few decades, including fine control of dopamine substitution, and functional neurosurgery. These advances have, however, unmasked nondopaminergic and extranigral symptoms (cognitive, mood, psychiatric, sleep and vegetative disturbances) that are not alleviated or only poorly alleviated by these treatments. Sleep disturbances are frequent symptoms that have recently been recognized in PD and other movement disorders. The disturbances include insomnia, abnormal movements during sleep (e.g. periodic leg movements, rapid eye movement [REM] sleep behavior disorders [RBDs]) and excessive daytime sleepiness. Insomnia has a serious impact on a patient's quality of life. RBDs are enacted dreams that can cause patient or bed-partner injuries. Daytime sleepiness exposes the patients to risk of a driving accident. The mechanisms of these sleep disturbances are not fully known, but they include a clear drug–disease interaction.

Insomnia

Insomnia is defined as a recurrent difficulty to fall asleep or stay asleep, with daytime psychological or cognitive consequences.¹ As there are large between-individual differences in sleep needs, there is no standard definition for insomnia on the basis of time asleep or number of awakenings, as determined by sleep or rest–activity monitoring. A community-based survey determined that 60.3% of patients with PD had a sleep problem, a substantially higher proportion than in patients with diabetes mellitus (45%), or in elderly controls (33%).² There was no difference between groups regarding difficulty falling asleep, but frequent (38.9%) or early (23.4%) awakenings were twice as frequent in PD as in other groups, and felt more distressing to patients with PD than to other groups. In hospital surveys, 76% of patients with PD complained of 'broken sleep', and 18% complained of poor sleep.³ As many as 52.5% of patients with MSA have complained of sleep fragmentation, compared with 38.7% patients with PD.⁴ The most severe and specific insomnia is, however, observed in patients with PSP.⁵

Night-time motor problems as a cause of insomnia

Most patients with PD report two to five awakenings during the night (twice as many as are experienced by controls),⁶ with the patient being awake for 30–40% of the night (Figure 1).^{7, 8} Sleep monitoring does not provide additional information on the cause of insomnia in patients with parkinsonism, except for a specific, severe decrease in REM sleep in patients with PSP.⁵ Insomnia is a nonspecific symptom that does not imply the presence of a selective lesion in any sleep system, except in the case of PSP, in which cholinergic lesions in the brainstem can encompass the REM-sleep executive systems. Rather, any condition that increases arousal can cause insomnia. The frequency of insomnia increases with advanced motor stages of PD and a need for a higher daily dose of dopaminergic therapy, an indicator of dopamine denervation. Indeed, slowed movements during the night, difficulties turning in bed or adjusting blankets, pain, cramps, nocturnal and early morning dystonia, and frequent need to pass urine, are reported by patients with advanced PD as the main causes of their insomnia.³ The PD Sleep Scale (Box 1) can be helpful for identifying the causes of insomnia.⁹ In patients with advanced PD, the alleviation of nocturnal akinesia and dystonia using subthalamic nucleus stimulation at night resulted in a substantial decrease in time awake at night,¹⁰ and led to long-term improvement of insomnia in spite of a major reduction in drug dose.^{11, 12}

Figure 1 Sleep histograms from patients with parkinsonism.

(A) Healthy 60-year-old woman with normal sleep. (B) 54-year-old woman with Parkinson's disease (PD) treated with levodopa 300 mg/day and bromocriptine 30 mg/day, who reported frequent night-time awakenings, daytime sleepiness, and hallucinations (arrow indicates a hallucination in which she saw a stranger in the room) that were synchronous with abnormal irruption of rapid eye movement (REM) sleep during the daytime (narcolepsy-like phenotype). (C) 80-year-old man with mild PD, complaining of falling asleep 2–3 hours after each levodopa intake (arrows), who displayed severe hypersomnia. (D) 62-year-old woman with de novo untreated PD, who complained of disturbing night-time hallucinations (arrow indicates a hallucination in which she saw her daughter in the hospital room) that emerged from REM sleep. The x-axis displays the time of night and day (clock hours), the y-axis displays the stages of sleep and wakefulness, with awakening (A), non-REM sleep stage 1 (1), stage 2 (2), stage 3 (3) and stage 4 (4), and REM sleep (R).

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Box 1 Parkinson's Disease Sleep Scale.^a

^APermission obtained from the BMJ Publishing Group Ltd © Chaudhuri KR et al. (2002) J Neurol Neurosurg Psychiatry 73: 629–635. ^bThe adjectives are placed at each extremity of a 10 cm visual-analog scale. The patient places a cross mark on this line.

Restless legs syndrome (RLS) is more prevalent (12–20.8%) in PD than in the general population.^{13, 14} It is mostly of mild severity, but it worsens insomnia. PD patients with RLS seem to have lower ferritin levels than those without.¹³ Poor sleep quality also correlates with depression and anxiety scores.¹⁵ Dopaminergic agents, which have long been considered to be stimulants, have been shown to have a deleterious effect on sleep when given at bedtime.¹⁶

Rapid eye movement sleep behavior disorders

RBDs are dream-enacting behaviors—for example, laughing, talking, shouting, kicking, or fighting invisible enemies—during sleep.¹ Normal REM sleep is associated with an active blockade of motor output (a transient paralysis termed muscle atonia), which is unblocked during RBD, allowing prominent motor activity. RBD behaviors can be violent enough to disrupt sleep and cause injuries to the patient or their sleeping partner, but RBD does not induce daytime sleepiness. Sleep monitoring demonstrates enhanced tonic muscle activity (REM sleep without atonia) and increased phasic muscle twitches during REM sleep in patients with RBD.¹

Association with synucleopathies

RBD can occur without concomitant medical disorders ('idiopathic' RBD), but is mostly reported in patients with neurodegenerative disorders (Table 1). RBD affects 30–90% of patients with synucleopathies (conditions characterized by aggregation of -synuclein, forming Lewy bodies within neurons), but is rare in tauopathies.²⁵ However, in a toxic form of parkinsonism with tau protein deposits, observed in the French West Indies (and possibly caused by eating soursop, a tropical fruit), we found that 7 out of 10 patients had severe RBD.²⁶ In addition, RBD might be triggered or exacerbated by antidepressants.²⁷ Most,^{28, 29} but not all,³⁰ series of RBD patients with parkinsonism contain more men than women, a ratio that is consistently observed in idiopathic RBD.³¹ Whether men experience or enact more violent dreams than women, or whether wives are more attentive to nocturnal patient symptoms than husbands, is unknown.

Table 1 Prevalence of rapid eye movement sleep behavior disorders and rapid eye movement sleep without atonia in neurodegenerative diseases.

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Complex behaviors during dreams suggest cortical involvement

The frequency of RBD activity varies between individuals and from night to night in the same individual. One third of patients with PD have at least one episode per week.^{29, 30} Typical behaviors during RBD include talking, laughing, yelling, gesturing, punching and kicking, all conditions that can be disturbing and dangerous for a sleeping partner (Figure 2 and Supplementary Movie 1 online). Compared with patients with idiopathic RBD, who are usually selectively referred for violent behaviors, systematic investigations of sleep have revealed that the RBD behaviors are less frequent and violent in parkinsonism.²⁸ Indeed, we also observed quiet behaviors, including drinking soup, singing a song, cutting beans or giving a lecture, which were mentioned incidentally by the bed partner as being nondisturbing.^{26, 30} Interestingly, the complexity of these behaviors and the presence of intelligible speech suggest that not only the brainstem, but also the cortex (and especially Broca's area), are activated during RBD.³⁰

Figure 2 Rapid eye movement sleep behavior disorder.

Abnormal, violent behavior during rapid eye movement sleep behavior disorder in a 68-year-old man with advanced Parkinson's disease. The patient dreams that he is arguing and fighting with a stranger. He has imperfect muscle atonia during rapid eye movement sleep and is therefore able to move, but he does not stand up. Note that his movements are extremely fast and coordinated, and his face is expressive and does not show parkinsonism, despite is the fact that he has been weaned from levodopa for 12 hours.³⁰ See also Supplementary Movie 1 online.

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Arm and leg movements, speech, laughter and tears are frequent in PD patients with RBD, but behaviors that are common in sleepwalking¹ (a condition associated with non-REM sleep), such as standing up, walking and appropriate use of objects in the vicinity, are rare.²⁹ The movements during RBD are purposeful, nonstereotyped and complex, in contrast to nocturnal frontal lobe epilepsy and periodic leg movements. Some patients might, however, display gross, startle-like body jerks that resemble increased normal REM sleep twitching or aborted complex behaviors, but do not share the focal location, distribution and propagation of myoclonus.³⁰

In addition to enacted dreams, patients with RBD experience abnormal dreaming phenomena. Compared with dreams of matched controls, patients' dreams contain more aggressive content (the dreamer being an aggressor, despite normal and even decreased levels of daytime aggressiveness), more frequent presence of animals, and less sexual content.³² Interestingly, the dreamers are usually not the primary aggressors during these nightmares, but rather try, by fighting back, to protect themselves or their loved ones from an external aggressor.

Extranigral, nondopaminergic pathology

The exact cause of RBD in parkinsonism is largely unknown, but a nondopaminergic lesion of the system controlling atonia during REM sleep has been strongly implicated (Figure 3).³³ A cat model of RBD has been generated by creating lesions of the perilocus ceruleus in the pons. The animals displayed complex behaviors during REM sleep, including grooming, licking, being on watch, and hunting invisible prey.³⁴ Lesions of the pathway descending from this nucleus through the pons and the medial medulla (at the level of the magnocellularis nucleus) also result in REM sleep without atonia and with complex movements.^{34, 35} Muscle atonia is imperfect in rats after lesions are created in the sublaterodorsalis nucleus.^{36, 37} The equivalent of these nuclei in humans is the subceruleus nucleus in the pons. In two PD patients with RBD and hallucinations, this nucleus was found to contain Lewy bodies.³⁸ Interestingly, the subceruleus–ceruleus complex is affected from the early stages of PD.³⁹ RBD persists during subthalamic stimulation, suggesting that its pathophysiology does not involve the basal ganglia loop.

Figure 3 Brain pathology in rapid eye movement sleep behavior disorders.

(A) -Aminobutyric-acid (GABA)-immunoreactive neurons in the rostral part of the rat SLD).³⁶ The SLD is equivalent to the cat perilocus ceruleus (peri-LC). SLD blockade with GABA antagonists induces muscle atonia and a rapid eye movement (REM)-sleep-like state. Lesioning of the ventral SLD causes REM sleep episodes without atonia.³⁷ Permission obtained from Federation of European Neuroscience Societies © Boissard R et al. (2003) Eur J Neurosci 18: 1627–1639. (B) Frontal section at the P4 level of the cat pons. Bilateral coagulation of or injections of ibotenic acid into the peri-LC (red circles) induced REM sleep without atonia and REM sleep behavior disorders (RBDs).³⁴ (C) Schematized section cut perpendicular to Meynert's brainstem axis in humans, showing the distribution pattern of Parkinson's disease (PD)-related pathology in the lower brainstem.³⁹ Early neuronal loss and Lewy body pathology are observed in the lower brainstem, possibly causing the RBDs that precede PD onset. The blue shading in the ceruleus–subceruleus complex indicates that 17 out of 30 incidental cases had PD-related pathology in this area.³⁹ Permission obtained from American Association of Neuropathologists, Inc. © Del Tredici K et al. (2002) J Neuropathol Exp Neurol 61: 413–426. (D) Lewy bodies stained with anti--synuclein antibodies, observed in large numbers in melanized and nonmelanized neurons in the subceruleus nucleus of a 69-year-old man with idiopathic PD, RBD, and sudden daytime REM sleep episodes temporally associated with severe visual hallucinations. PD-related pathology was sparse in the upper brainstem and cortex.³⁸ Abbrevations: BC, brachium conjunctivum; CS, ceruleus–subceruleus complex; DTN, dorsal tegmentum nucleus; LDT, laterodorsal tegmentum nucleus; MEV, mesencephalic trigeminal nucleus; MLE, medial lemniscus; MLF, medial longitudinal fascicle; MPB, medial parabrachial nucleus; PNC, central pontine nucleus; PPN, pedonculopontine nucleus; PRNr, rostral pontine reticular nucleus; SCP, superior cerebellar peduncle; SLD, sublaterodorsal nucleus; V4, fourth ventricle; VTN, ventral tegmental nucleus.

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Disappearance of parkinsonism during enacted dreams

Interestingly, several spouses sleeping with PD patients reported that they observed a sharp contrast between the slow limited movements and unintelligible low voice of their affected spouse when awake, and the fast, vigorous movements with loud speech that the same patient exhibited during enacted dreams. We recently conducted a study on the quality of movements during RBD in 100 consecutive PD patients without dementia.³⁰ During the interview, all spouses of RBD patients reported an improvement of motor control during the dreams. Movements were improved in 87% of patients (faster in 87%; stronger in 87%; smoother in 51%), speech was better in 77% of patients (more intelligible in 77%; louder in 38%; better articulated in 57%), and facial expression was normalized (loss of parkinsonian amimia) in 47% of patients. This clinical improvement was confirmed on sleep and video monitoring, which was performed after a 12-hour withdrawal of dopaminergic drugs. During REM sleep, there was no evidence of bradykinesia, tremor or dystonia. Movements were surprisingly fast, wide, coordinated, and symmetrical. The restored motor control during REM sleep suggests a transient 'levodopa-like' re-establishment of the basal ganglion loop. Alternatively, parkinsonism might disappear through REM-sleep-related disjunction between pyramidal and extrapyramidal systems. Analyzing the quality of movements during RBD and finding the cause of this spontaneous improvement could both help in the treatment of patients and provide insights into motor control during sleep.

Excessive daytime sleepiness

Excessive daytime sleepiness is defined as a disabling trend to doze or fall asleep in various circumstances (e.g. reading, as a passenger in a car, during a meeting) that interferes with family, professional and social life. In view of the high risk of accidents for sleepy drivers, the level of daytime sleepiness must be regularly checked in patients with PD, especially when the dopaminergic treatment is changed. Sleepiness can be easily self-assessed using the Epworth sleepiness scale (Box 2).⁵⁴ A score greater than 10 indicates abnormal sleepiness. A score greater than 7 has a 75% sensitivity (and a 50% specificity) for predicting the risk of a driving accident.⁵⁵ The scale has been validated in large populations of patients with PD. Case–control epidemiological studies performed in various countries consistently found higher sleepiness scores and a higher incidence (range 16–74%, but usually around 33%) of abnormal somnolence in patients with PD than in age-matched and sex-matched controls.^{6, 56, 57} This range of values probably reflects differences in referral patterns between centers, as well as geographical variations in the probabilities of detecting various pathologies. The incidence of sleepiness was 6% per year in a prospective series of patients with PD.⁵⁸ It is possible that sleepiness precedes PD onset, as sleepy adults in a large Asian longitudinal study were 3.3 times more likely than nonsleepy adults to develop PD later in life.⁵⁹

Box 2 Epworth Sleepiness Scale.^a

 

How likely are you to doze off or fall asleep in the following situations, in contrast to feeling just tired? This refers to your usual way of life in recent times. Even if you have not done some of these things recently, try to work out how they would have affected you. Use the following scale to choose the most appropriate number for each situation:

0 = would never doze

1 = slight chance of dozing

2 = moderate chance of dozing

3 = high chance of dozing

^APermission obtained from American Sleep Disorders Association and Sleep Research Society © Johns MW (1991) Sleep  14: 540–545.

The most worrying aspect of sleepiness in PD is the sleep attack, defined as 'sudden onset of sleep, without prodroma', which has been described in patients who use the new nonergot dopamine agonist drugs pramipexole and ropinirole.⁶⁰ Examples of sleep attacks include patients falling asleep during stimulating life conditions, such as eating a meal (the head dropping onto the plate), walking, attending work, carrying a child on an escalator, and, in the most dangerous situation, while driving a car. Estimates of the percentage of patients with PD experiencing sleep attacks vary from 1–14%,^{55, 61} with 1–4% of patients reporting sleep attacks while driving.

Mechanisms of sleepiness

The mechanisms of sleepiness and sleep attacks in PD might include a complex drug–disease interaction. Most arousal systems (Figure 4 and Table 2), including the noradrenergic neurons in the locus ceruleus,⁶⁷ the serotonergic neurons in the raphe,⁶⁷ the cholinergic neurons in the basal forebrain,⁶⁷ and the orexinergic neurons (also affected in primary narcolepsy) in the hypothalamus,^{68, 69} are affected by neuronal loss and Lewy bodies in the brains of individuals with PD. Despite marked cell loss, however, the cerebrospinal fluid levels of orexin are mostly normal in PD and MSA. The wake–active dopaminergic neurons in the ventral periaqueducal gray matter and the histamine neurons in the hypothalamus are intact in the brains of individuals with PD.^{70, 71}

Figure 4 Key components of the ascending arousal systems in the human brain.

Abbreviations: 5-HT, 5-hydroxytryptamine (serotonin); ACh, acetylcholine; BF, basal forebrain; DA, dopamine; GABA, -aminobutyric acid; His, histamine; LC, locus ceruleus; LH, lateral hypothalamus; NE, norepinephrine; ORX, orexin; Raphe, median raphe nucleus; TMN, tuberomamillary nucleus; vPAG, ventral periaqueductal gray matter.

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Table 2 Severity of neuronal loss of the ascending arousal systems in the brains of patients with Parkinson's disease.

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The sedative effects of dopamine agonists have recently been recognized. The use of these agents exposes patients with PD to a twofold to threefold higher risk of sleep attacks.^{55, 56, 61} The risk of sleep attack is similar for ergot agonists (e.g. bromocriptine, pergolide) and nonergot agonists (e.g. pramipexole, ropinirole). The risk increases with increasing daily dosage and decreases with drug withdrawal. By contrast, levodopa rarely has sedative effects.⁶² It is currently unknown why drugs that are supposed to stimulate the alerting brain system (and do so when given at bedtime)¹⁶ have sedative effects during the daytime. This effect cannot be explained, at these high doses, by the biphasic effect (i.e. presynaptic sedative effect at low dose, postsynaptic alerting effect at high dose) of dopamine agonists that has been described in animals.⁷²

Stridor

Stridor is a partial obstruction of the larynx, which results in a harsh, high-pitched inspiratory noise. In contrast to obstructive sleep apnea (a pharynx collapse), which does not expose the individual to an immediate risk of death, stridor is a life-threatening condition. The larynx obstruction usually begins during the night, and was observed in 42% of unselected patients with MSA.⁷⁶ It can be recognized quite easily by mimicking the associated noise to the caregiver, or by conducting an audio recording during the night, but it is not detected on standard apnea monitoring devices. Interestingly, night-time stridor is alleviated by the application of nasal continuous positive airway pressure,⁷⁷ which can avoid tracheotomy and provide long-term benefits with regard to quality of sleep and median survival time.⁷⁸

Conclusions

The recent resurgence of interest in sleep disturbances in parkinsonism benefits both the movement disorder and sleep fields. The mechanisms of sleep disorders in PD point to a complex interaction between lesions in sleep–wake systems, movement disorders and adverse effects of dopaminergic agents. A specific, complex REM sleep disorder contributes to RBD, hallucinations and excessive daytime sleepiness, and cohorts of patients with idiopathic RBD can provide insights into preclinical PD and dementia. The range of behaviors observed during RBD is a precious, objective insight into dream content and motor control during sleep, as shown by the recently recognized alleviation of parkinsonism during RBD.

From the clinical point of view, physicians now take a more active interest in the patient's night-time suffering, and are increasingly aware of public health issues relative to alertness while driving with PD. The management of sleep and alertness problems benefits from thorough analysis of their potential causes, through clinical interviews, standardized scales, and night-time and daytime sleep monitoring. Each treatment can be assessed with regard to its sleep–wakefulness effects. For example, small doses of sedative antidepressant can improve sleep continuity but worsen an underlying RBD. By contrast, clonazepam alleviates RBD but might worsen sleep apnea. Dopamine agonists given in the evening can improve RLS. Levodopa at night might dramatically alleviate akinesia and dystonia, but higher doses might increase wakefulness. As in the case of other motor and nonmotor symptoms in PD, subtle adjustments in drug regimens could lead to major changes in night-time sleep quality and daytime alertness of patients.

Acknowledgments

The sleep studies performed by the authors in patients with parkinsonism were in part financed by grants from Inserm, Fondation Lilly, Fédération pour la Recherche sur le Cerveau, and France-Parkinson.

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