Parkinsonism

Parkinsonism (or parkinsonian syndrome, or Parkinson syndrome) is defined by the association of slow movements (bradykinesia) with either muscle rigidity (hypertonia), 4 to 6 Hz resting tremor, or postural instability.¹ The main cause of parkinsonism is idiopathic Parkinson’s disease (PD), a neurodegenerative disorder with a progressive (but not exclusive) loss of dopaminergic neurons. PD is characterized by asymmetrical parkinsonism, progressive worsening, and important initial benefit from levodopa. When PD is fully developed, the clinical picture is unmistakable.²

PD is primarily a disease of the elderly. Its prevalence increases with age from about 0.9 % among persons 65 to 69 years old to 5% among persons 80 to 84 years old, with a slight male preponderance.³ Only a small percentage of patients, mostly with the genetic forms, develop parkinsonism before the age of 45 years.

Major therapeutic advances have been accomplished in PD during the last decades, including fine dopamine substitution and functional neurosurgery. After several years of honeymoon on dopaminergic treatment, most patients develop motor complications, including dyskinesia (abnormal involuntary movements) at the peak of effect of levodopa and painful dystonia (often confused with cramps) at the beginning or the end of effect of levodopa, or early in the morning. Patients use dopaminergic substitutive treatment on daily schedules that becomes stricter and more frequent as the disease progresses. Currently, it is common to treat patients with a 10-year duration with 20 tablets per day, including small doses of levodopa every 3 hours, dopamine agonists every 5 hours, and various pills to prevent the side effects (nausea, orthostatic hypotension, hallucinations) of these treatments.

The improvements brought by dopamine substitution can also unmask the nondopaminergic and nonmotor symptoms (mood, cognitive, psychiatric, sleep, and vegetative disturbances) that are not alleviated or are poorly alleviated by these treatments. The most important of these dopamine-unresponsive symptoms are falls (with the risk of fractures) and dementia (which is the major motive for placement in an institution).

Sleep disturbances are common—and newly recognized—nonmotor symptoms. They include insomnia, abnormal movements during sleep (periodic leg movements [PLMs], rapid eye movement [REM] sleep behavior disorder), and excessive daytime sleepiness. The mechanisms of the sleep disturbances are not fully known, but they include a clear interaction between drug and disease. A long interview, followed by sleep monitoring and video monitoring during night and day, are useful tools to understand and adequately treat these patients.

Atypical Parkinsonism

It is important to differentiate PD from atypical parkinsonism, because treatment and prognosis are different. Indeed, 5% to 10% patients have atypical parkinsonism (or Parkinson plus syndromes) characterized by lesions in other systems, poor levodopa benefit, and worse prognosis. Sleep problems are more common and more severe in atypical parkinsonism than in PD. A specific sleep-associated respiratory symptom, stridor, predisposes some patients with atypical parkinsonism to die during the night and must be looked for.

Atypical parkinsonism is a spectrum of disorders, listed here by decreasing incidence: progressive supranuclear palsy (PSP; Steele-Richardson-Olszewski syndrome) associates parkinsonism, abnormal eye movements with limitation of up and down gaze, swallowing problems, dysarthria, cognitive impairment and early falls.⁴ Multiple system atrophy (MSA) contains the former striatonigral atrophy, Shy-Drager syndrome, and olivopontocerebellar syndrome and associates parkinsonism and cerebellar or autonomic dysfunctions, such as urinary incontinence, erectile dysfunction or orthostatic hypotension, with a fairly intact cognition.⁵ Exceptional diseases include Guadeloupean parkinsonism,⁶ Parkinson-dementia complex of Guam, and Parkinson-hypoventilation syndrome.⁷

Dementia with Lewy bodies is the second most common cause of dementia after Alzheimer’s disease. These patients develop a prominent initial cognitive impairment (mostly affecting visuospatial performance), early hallucinations, and parkinsonism (often sensitive to levodopa), that fluctuates over days or weeks.⁸ Mild parkinsonian symptoms can also be observed in patients with Huntington’s disease and spinocerebellar ataxia. All these neurodegenerative disorders are also classified according to the mechanism of neuronal loss (Table 87-1), whether it is associated with a deposit of alpha-synuclein in Lewy bodies, a hallmark of synucleopathies (PD, MSA, dementia with Lewy bodies), or of tau protein, a hallmark of tauopathies (PSP, Alzheimer’s disease, Guadeloupean parkinsonism, Parkinson-dementia complex of Guam), or secondary to a polyglutamine disease (Huntington’s disease, spinocerebellar ataxia). Although the major emphasis in this chapter is on Parkinson’s disease, much of the discussion also applies to the other degenerative disorders associated with parkinsonism.

Table 87-1 Prevalence of REM Sleep Disorders in Neurodegenerative Diseases

Insomnia

The history of the sleep complaint in PD should include all the features the physician would obtain from any patient with a sleep complaint. It must also include disease-specific questions on nocturnal akinesia, daytime fatigue in relation to medication intake, and psychiatric symptoms. A careful description from the bed partner is essential to determine the presence and frequency of movements during sleep (and their timing), arousals and awakenings, and periods of daytime sleepiness. In PD, most patients report two to five long awakenings during the night (twice more than controls),¹¹ lasting 30% to 40% of the night.^12,13 Compared to controls and to patients with diabetes mellitus, there were no differences between groups regarding difficulty falling asleep, but frequent (38.9%) or early (23.4%) awakenings were twice as common in PD patients than in other groups, and they were felt as more distressing.¹⁴

In patients with moderate to severe PD, special attention should be paid on sensory and motor symptoms during the night. Sensory discomfort during the night is common in PD patients. It includes various types of nonsystematized body pain, restless legs syndrome (RLS) in 12% to 21% patients^15,16 (which can be difficult to distinguish from leg pain, because the urge to move is common in PD), and painful dystonia. The dystonia includes the classic early morning dystonia, a long-lasting, postural contraction of the toes in flexion or extension (sometimes with internal rotation of the ankle) that occurs during the second part of the night, is painful, and makes walking difficult. Severe dystonia of the leg, neck, and back muscles can occur only at night, when dopamine levels are low. Abnormal motor phenomena include, in addition to dystonia, severe nighttime bradykinesia. Bradykinetic patients have difficulty turning in bed, readjusting blankets or pillows, sitting, standing up, and walking to the toilet.¹⁷ A simple urine voiding can take 20 minutes instead of 5 minutes and be incomplete, with a further need to pass urine in the night. All these symptoms can curtail sleep by one third, if not more, with mostly long intranight awakenings. The difficulty with moving during the night can further increase the anxiety levels.

Eventually, a deleterious effect on sleep of dopamine agonists (which have been considered stimulants for a long time), when given at bedtime, can be observed.¹⁸ At the extreme of this spectrum, some patients use supraoptimal doses of levodopa and dopamine agonists day and night, and they stay awake and hyperactive at night; hypersexuality and addictive behavior, including using computers and gambling, can occur. This condition is now identified as the dopamine dysregulation syndrome and affects up to 11% patients with PD.¹⁹ Two scales, the PD Sleep Scale and the Scales for Outcomes in Parkinson’s Disease—Sleep (SCOPA-Sleep) can be helpful for research purposes on sleep quality in PD.^20,21 A checklist of useful questions when investigating a sleep complaint in a PD patient is displayed in Table 87-2.

Table 87-3 Neuronal Loss in Arousal Systems in Brains of Patients with Parkinson’s Disease

Abnormal Movements during Sleep and REM Sleep Behavior Disorder

When a patient is referred for sudden jerks during the night, the clinical diagnosis should establish whether these movements are stereotyped and periodic, suggesting periodic leg movements during sleep (PLMS), or nonstereotyped, suggesting REM sleep behavior disorder (RBD). In addition, various types of myoclonia can occur in PD, including the violent dystonic myoclonia (looking like a transient strong exacerbation of the rest tremor) at the beginning or the end of action of levodopa. Violent dystonic myoclonia occurs during wakefulness but sometimes occurs during the night.

REM sleep behavior disorder is dream-enacting activity, such as laughing, talking, swearing, crying, shouting, kicking, slapping, boxing, or fighting invisible enemies during sleep.²² This condition can be violent enough to disrupt sleep and injure the patient or bed partner, although this is mostly rare. It does not induce daytime sleepiness. In addition to fully expressed complex actions, most patients also have abrupt movements and jerks such as simple aborted proximal or distal movements of the limbs (“looking like a flipper-ball,” reported one spouse).

REM sleep behavior disorder occurs with variable within-subject and within-night frequency. One third of PD patients have at least one episode per week that is remembered by either themselves or their bed partners or caregivers.^23,24 Typical activities during RBD include talking, laughing, yelling, gesturing, punching, and kicking, all conditions that may be disturbing and dangerous in a couple bed (Videos 87-1 and 87-2). Compared to patients with idiopathic RBD, who are usually selectively referred for violence, RBD is less common and less violent in parkinsonism when sleep is systematically investigated.²⁵ Indeed, we also observed quiet activities including drinking soup, singing a song, cutting beans, and giving a lecture, which were mentioned incidentally by the bed partner as not disturbing.^23,26

Arm and leg movements, speeches, laughter, and tears are common, but standing up, walking, and using appropriately the objects in the vicinity is exceptional in PD patients with RBD,²⁴ although it is common in sleepwalking.²² The eyes are usually closed. Rare PD patients with overlap between sleepwalking and RBD have been reported.²⁷ The movements during RBD are purposeful, nonstereotyped, and complex, but they can also consist of short and abrupt jerks. In addition to enacted dreams, RBD patients experience abnormal dreaming phenomena. Compared to 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 animals, and less sex.²⁸ There is often a sharp contrast between the placid personality of the PD patients during daytime and their aggressiveness during RBD.

A new area of research pertains to the disappearance of parkinsonism during an RBD episode. In a large series, spouses of PD patients report that their husbands have unusually strong and rapid movements during RBD, with a loud voice, as if they were transiently cured from PD.²³ Movements are faster, stronger, and smoother. Speech is more intelligible, louder, and better articulated, and facial expression is normal (with no more parkinsonian amimia). This clinical improvement has been confirmed on sleep and video monitoring, performed after a 12-hour withdrawal of dopaminergic drugs. During the RBD, there is no bradykinesia, tremor, or dystonia. Movements are surprisingly fast, ample, coordinated, and symmetrical (asymmetry is a feature of PD). In two incidental case reports, patients with PSP had totally lost the ability to speak during the daytime but still spoke while asleep during RBD (Video 87-3).^29,30 Analyzing the quality of movements during RBD and finding the cause of this spontaneous improvement could help in treating the patients and provide a window into motor control during sleep.

Schenck and coworkers first discovered that RBD, which is violent enacting of dreams, may be an early manifestation of parkinsonism or dementia with Lewy bodies.³¹ Whether RBD is a red flag for developing other disturbances in PD has been investigated. The incidence of RBD is 15% to 60% in PD as against almost 100% in multiple system atrophy and dementia with Lewy bodies. This suggests that more-extensive brain lesions predispose to greater risk of RBD. Following this idea, several teams examined the question of whether patients with PD plus RBD would be more cognitively impaired than those without RBD. In a small group of PD patients without dementia, patients with RBD had lower electroencephalographic (EEG) frequencies than patients without RBD, suggesting either bottom-up consequences of the brainstem lesions causing RBD or early loss of cortical neurons in RBD patients.³² In 110 patients with PD, the subgroup with clinical RBD had altered executive functioning, compared to the group without RBD or hallucinations. This cognitive decline was more marked (with additional impairment of memory and logical abilities) in the presence of hallucinations.³³ In 34 nondemented patients with PD for a mean 5 years, the 18 patients with polygraphically confirmed RBD showed lower performance on episodic verbal memory, executive functioning, and visuospatial and visuoperceptual processing than the 16 patients without RBD.³⁴ In a larger group of 65 patients with PD (13 of them having dementia), including patients with and without clinical RBD, 77% of patients had clinical RBD in the group with dementia versus 27% in the group without dementia.³⁵ With respect to the onset of parkinsonism, RBD patients were demented earlier than the non-RBD patients.

REM sleep behavior disorder also exposes PD patients to a 2.7-fold higher risk of hallucinations.³⁶ It is tempting to bring together RBD and hallucinations as manifestations of a common dysfunction of REM sleep systems. We indeed have found that the hallucinations coincided with abnormal REM sleep irruptions during daytime, as awake dreams, in 10 PD patients with severe hallucinations and RBD.³⁷

Daytime Sleepiness

Frucht and colleagues noted that some patients with PD experienced sleep attacks (or sudden onsets of sleep) when treated with dopamine agonists.³⁸ Due to the high risk of accident in sleepy drivers, the level of daytime sleepiness must be regularly checked in PD patients, especially when the dopaminergic treatment is changed. This is particularly true in young patients who have new-onset PD and receive high doses of dopamine agonists. Daytime sleepiness in PD can be self-reported, but it is better reported by the caregiver, because some patients are unaware of being abnormally sleepy.³⁹ Napping after lunch is common in PD patients, and it is often perceived as beneficial. The Epworth Sleepiness Scale score has been well validated in PD,⁴⁰ with an abnormal threshold above 10, but it is poorly predictive of sleep attacks.⁴¹ Some authors have added specific questions on the ability to fall asleep when driving, eating, working, or performing a routine activity at home,⁴¹ which better predict the risk of driving accident. Questioning patients who have daytime sleepiness about hallucinations, and vice versa, is useful. These two symptoms are often associated, but they are underreported because many patients are afraid of being considered insane.

Stridor

Stridor corresponds to a partial obstruction of the larynx, resulting in a harsh, high-pitched inspiratory noise. Unlike in obstructive sleep apnea (collapse of the pharynx), which does not expose the patient to immediate vital risk, stridor is a life-threatening condition (Video 87-4). The larynx obstruction usually begins during the night and is observed in 42% of unselected patients with MSA.⁴² It can be recognized quite easily by mimicking it to the caregiver, or by an audio recording made during the night, but it is not detected on the usual apnea-monitoring devices. Nighttime stridor is alleviated by the application of nasal continuous positive airway pressure,⁴³ which can avoid tracheotomy and provides a long-term benefit on quality of sleep and median survival time.

Sleep Benefit

In PD, a specific, positive restoration of fluent mobility can occur on awakening from sleep and before taking medication and is named sleep benefit. Based on questionnaires, the frequency of this phenomenon varies from 10% to 20% to 55% of cases.^44,45 The restored mobility lasts a mean of 84 minutes, and patients may be able to skip their first dose of levodopa.⁴⁴ When examining 10 patients with sleep benefit on awakening after a PSG, the motor benefit is small and unrelated to the sleep structure, levodopa serum levels, or sleep chronotype.⁴⁶

Insomnia

Sleep problems, and especially insomnia, are common in all forms of parkinsonism. A community-based survey determined that 60.3% of PD patients had sleep problems, significantly more than in patients with diabetes mellitus (45%), or in aged controls (33%).¹⁴ These percentages increase to 76% of PD patients who claim having “broken sleep” in hospital samples and 18% complaining of a poor sleep.¹⁷ As many as 52.5% of patients with multiple system atrophy complain of sleep fragmentation, compared to 38.7% of PD patients.⁴⁷ But the most severe and specific insomnia is observed in patients with PSP.^48–50

REM Sleep Behavior Disorder

REM sleep behavior disorder affects 30% to 90% patients with synucleinopathies but is rare in tauopathies.⁵¹ The prevalence of RBD in the various diseases comorbid with parkinsonism is shown in Table 87-1. Patients with PD are more agitated during the night than patients with Alzheimer’s disease. In an interview of 108 caregivers of 60 patients with Alzheimer’s disease and 48 patients with PD, PD patients were reported to exhibit twice as much disruptive behavior at night (mostly combativeness, incoherent speech, and hallucinations) than patients with Alzheimer’s disease.⁵² Most,^24,25 but not all,²³ series of RBD patients with parkinsonism contain more men than women, a ratio that is more consistently observed in idiopathic RBD.⁵³ Patients with the tremor-predominant form of PD (usually a more benign form of the disease) have RBD less often than those with the bradykinetic-hypertonia form.^54,55

Excessive Daytime Sleepiness

Excessive daytime sleepiness affects on average one third of patients with PD. Case-controlled epidemiologic studies performed in various countries consistently found higher sleepiness scores and higher percentages (16% to 74%) of abnormal somnolence in PD patients than in age- and sex-matched controls.^11,56–58 The incidence of sleepiness was 6% per year in a prospective series.⁵⁹ Sleepiness can precede the onset of PD; sleepy adults in a large Asian longitudinal study developed PD later in life 3.3 times more often than nonsleepy adults.⁶⁰ The most worrying aspect of sleepiness in PD is sleep attacks, or sudden onsets of sleep without prodrome, that have first been described in patients using the new nonergot dopamine-agonist drugs pramipexole and ropinirole.³⁸ Examples of sleep attacks include patients falling asleep during stimulating life conditions, such as eating a meal (the head drooping in the plate), walking, attending work, carrying a child on an escalator, and, the most dangerous situation, while driving a car. The percentage of PD patients having experienced sleep attacks varies from 1% to 14%,^41,61 and 1% to 4% PD patients report having experienced sleep attacks while driving.