Excessive daytime sleepiness in Parkinson’s disease

Prevalence.

A number of studies have sought to estimate the frequency of sleep disorders in patients with PD. The results have varied widely, reflecting the influence of different variables such as the definition of sleep disturbance, the method of ascertainment, and the population under study, i.e., community versus hospital-based.1–9⇓⇓⇓⇓⇓⇓⇓⇓ In general, these early studies have indicated that more than half and as many as 80 to 90% of PD patients have some disturbance of sleep patterns. Two community-based studies addressed this problem. The first was based in Norway, and 239 PD patients were interviewed and examined.5 These patients were compared with 100 normal age-matched controls and 100 patients with diabetes mellitus. The questionnaire focused on patient experience during the night and inquired about specific details relating to, e.g., sleep initiation, awakenings, and early awakening. Sixty percent of the PD patients, 45% of those with diabetes mellitus, and 33% of normal age-matched controls reported a sleeping problem. Of those PD patients who responded positively, 44% had painful cramps, 29% had dystonia, and 27% classified their nighttime problems as moderate or severe. Interestingly, 37 to 40% of the controls reported cramps and 21 to 27% reported dystonia. However, these differences were not significant. Only 19% of the diabetic patients and 11% of the healthy controls reported that their sleep problems were moderate or severe. Among the different types of sleep disorders, the only significant difference between the PD patients and the controls was the disturbance related to early awakening, which occurred in 23% of PD patients and in only 11% of each of the respective control groups. A second study6 performed in Germany was based on a questionnaire that was mailed to 6,101 patients, 2,952 of whom completed it appropriately. The questionnaire surveyed a variety of issues relating to sleep disorders, including “sleep attacks,” and correlated these with such factors as daytime somnolence or drug therapy. The questionnaire also included the Epworth Sleepiness Scale (ESS). In this study, 580 patients experienced the so-called “sleep attacks.”

In a multicenter prospective study organized by the Canadian Movement Disorders Group, patients underwent a questionnaire-based analysis of sleep function, including excessive daytime sleepiness and sudden onset of sleep. Fifty-one percent of patients exhibited features of excessive daytime sleepiness.7 Another recent hospital-based questionnaire study evaluated 101 PD patients and an equivalent number of age-matched controls.9 Seventy-six percent of patients reported feeling sleepy during the day and 54% reported having abnormal nighttime sleep, compared to 47% and 37%, respectively, in the controls. A total of 41% of PD patients had ESS scores of 10 or above compared to 24% of controls, and 19% of PD patients had scores of 15 or above compared to 5% of controls. In this study there was an association between the sensation of sleepiness and the ESS score.

Although the detailed results of these studies may differ, there is a clear consensus among all of them that sleep abnormalities and excessive daytime drowsiness are common problems in PD. One suspects that a significant proportion of PD patients never seek medical attention for their symptoms, and many probably never volunteer features of their sleep disturbance unless specifically asked.

Excessive daytime sleepiness and other sleep disturbances.

Insomnia, hypersomnia, and parasomnia may all occur in PD and contribute to excessive daytime somnolence (table). Difficulty with sleep initiation is relatively uncommon in PD, but may be seen, for example, in relation to the amphetamine-like effects of selegiline or the alerting effect of higher doses of levodopa. A more common problem, however, is that of sleep maintenance. Patients wake after 2 or 3 hours of sleep and feel relatively refreshed. They are unable to return to sleep except for short periods. During the day they take frequent naps, and the total period of sleep in a 24-hour day is relatively normal.8 A variety of factors may contribute to fragmented sleep, including bradykinesia, pain, anxiety, and depression. Sleep maintenance insomnia may be an early feature of PD, and its frequency has been assessed as 34% of PD patients.1

Hypersomnia can be equated to excessive daytime drowsiness or sleepiness, which is often associated with fatigue, tiredness, lack of energy, or exhaustion.8 These, in turn, may lead to frequent naps and the occurrence of these naps at inappropriate times, e.g., when watching television, during a meal, or while driving. This gave rise to the concept of “sudden onset of sleep.” There has been considerable debate about whether such episodes constitute “sleep attacks” or merely an extension of excessive daytime sleepiness.10,11⇓ Many have argued that the amnestic effect of sleep eradicates a perception of sleepiness before the onset of sleep. In support of the view that sudden onset of sleep is an extension of excessive daytime drowsiness, many have focused on the issue of driving. In the Canadian study, 3.8% of patients had experienced at least one episode of sudden onset of sleep while driving.7 In these patients, an ESS score of 7 or higher predicted 75% of episodes. In the New York study, 20.8% of PD patients who were drivers experienced sleep episodes while driving compared to 6% of controls.9 Again, the ESS score was higher in those who experienced such events (11.6) versus those who did not (8.4). In a questionnaire survey, Paus et al.,6 in a follow-up structured telephone interview, identified 177 patients who had experienced sudden unexpected and irresistible sleep episodes. Ninety-one of these denied any warning signs. Seventy-five percent of patients had an ESS score of 10 or more; 18% had an ESS score of 10 or less and experienced sleep attacks without warning signs. The authors estimated that approximately 1% of the PD population might be at risk for sleep attacks without appropriate warning or accompanying daytime sleepiness. Interestingly, one polysomnographic study of two PD patients showed sudden and irresistible onset of sleep with a rapid transition from wakefulness to sleep stage 2 within seconds and without sudden onset of rapid eye movement (REM) sleep.12,13⇓ These PD patients might represent a relatively rare subgroup. In the great majority it appears that episodes of sleep are preceded by excessive daytime somnolence or warning signs of sleep onset.

Parasomnias, including REM behavior disorder (RBD) are associated with PD and can precede the diagnosis. One study suggested that up to 38% of PD patients’ experience RBD a mean of 3.7 years before the onset of the PD itself.14 However, RBD is not specific for PD and can occur in multisystem atrophy or Lewy body dementia.15–17⇓⇓ RBD is characterized by aggressive behavior and complex movements during the night, including kicking, flailing, and gesticulating. Patients can recall vivid and sometimes violent dreams. Their behavior can result in self-injury and injury to the bed partner.

Causes of sleep disturbance in PD.

The primary neurodegenerative process of PD can lead to sleep abnormalities. For example, there is degeneration of the mesocorticolimbic dopaminergic neurons associated with the ascending reticular activating system, as well as degeneration of pathways arising from the dorsal raphe and locus coeruleus All of these may contribute to sleep disturbance and impaired arousal during the day.18,19⇓ Excessive daytime sleepiness, for example, has been observed in patients with PD who were receiving no medication.

Two studies have suggested that up to two-thirds of PD patients complain that bradykinesia or akinesia disrupts sleep patterns.4,20⇓ Periodic leg movements are also more common in PD patients, 21 although the relationship between PD and restless legs syndrome (RLS) remains controversial. Depression is a major feature of PD and is a common cause of disrupted sleep patterns.22,23⇓ Nocturia, particularly in elderly men, is a common cause of disturbed sleep and may exacerbate sleep problems in PD patients.

Drugs used in the treatment of PD may often be associated with drowsiness. This has been documented mostly among patients receiving dopaminergic treatments, but it is also seen in patients taking anticholinergics and amantadine. Conversely, selegiline may have an awakening effect because of its amphetamine-like action, although this may not be significant in causing disturbed sleep.6 Levodopa and the DA agonists can all cause drowsiness, and this has been well documented in the phase III studies of DA agonists. Frucht et al.10 initially documented sudden onset of sleep episodes in patients taking pramipexole or ropinirole, both of which are D2/D3 agonists. However, it has become clear that both excessive daytime sleepiness and the sudden onset of sleep, whether an extension of daytime sleepiness or not, are seen with all dopaminergic agents, including levodopa and the entire spectrum of DA agonists. Paus et al.6 found that levodopa monotherapy carried the lowest risk for sleep attacks, followed by DA agonist monotherapy and then by a combination of levodopa with a DA agonist.6 No significant differences in the risk for sleep episodes were found among the DA agonists. Hobson et al.7 failed to find any significant difference in sleepiness scores between drug classes. Again, there was no clear indication of an association between any particular DA agonist and sleepiness or the risk for sudden onset of sleep. Current driving recommendations in the United Kingdom are that patients taking dopaminergic therapy for PD should be warned of the risk for sleepiness and sleep episodes and should be advised not to drive if they experience such events or to stop driving if they are feeling sleepy.

Management of sleepiness in PD.

It is important to consider the differential diagnosis of excessive daytime sleepiness in PD and not to assume that this is a reflection of the underlying diagnosis or its treatment. PD patients as a whole tend to fall within the age range at which sleep disturbance in general becomes more common. Therefore, it is important to consider alternative diagnoses such as sleep apnea or RLS. Nocturia should be investigated in its own right to exclude urinary infection, primary detrusor instability, and prostatism in men. Pain in PD may be a reflection of the primary diagnosis or, alternatively, may also reflect other pathologic processes such as arthritis or degenerative disk disease.

The first stage of management often employs simple strategies such as a review of sleep hygiene. Many PD patients develop a routine of going to bed early in the evening and, perhaps not surprisingly, waking in the early hours of the morning. This is then followed by frequent naps during the day, such that the total sleep period nears the normal 6 to 8 hours. Consolidation of sleep during the night may help a significant proportion of patients. Simple sleep hygiene, such as regular bedtime, regular meals, appropriate bedroom environment, i.e., dark and quiet, are simple steps to be considered early.

A review of medication is important. Although the study of Paus et al.6 did not find any association between selegiline and nighttime arousal, this drug is best scheduled for the morning as a single daily dose. Other medications should be reviewed, particularly sedative drugs that are taken during the day and may contribute to excessive daytime sleepiness. Antidepressants, particularly the tricyclics, are often best scheduled for the evening rather than the morning. A review of dopaminergic therapy is important and a preference should be given to simplification. However, reducing dopaminergic therapy will inevitably reduce motor control. This, in turn, can have a deleterious effect on nighttime sleep; therefore, changes need to be made judiciously. The dose of some DA agonists may need to be reduced, e.g., pramipexole doses of 4 mg per day or higher are associated with greater somnolence but not necessarily any greater anti-parkinson effect.24 Similar considerations will relate to other DA agonists. Inevitably, therefore, each PD patient must be assessed on an individual basis with regard to the advantages and disadvantages of the modification of their dopaminergic therapy. PD patients with pronounced daytime somnolence may respond to modafinil.25

There are certain specific instances in which changes in the dose, drug, or timing may be important. For example, nocturnal disability improves in patients who are given nighttime cabergoline.26 Refractory nighttime disturbances may respond to apomorphine.27 RBD may respond to clonazepam or additional dopaminergic therapy.28,29⇓ Alternatively, clozapine may also be helpful, particularly at low doses.30

Conclusion.

Sleep disturbance and excessive daytime drowsiness are common in PD. Both have multifactorial etiologies. Disturbances of sleep and alertness in PD patients can, in the experience of most clinicians, result in a significant deterioration of quality of life, although this has not as yet been accurately measured in PD. There are many management options to improve sleep and daytime drowsiness in PD. Initially, this must involve an accurate diagnosis followed by judicious modification of existing dopaminergic therapy or careful introduction of new drugs. The issue of sudden onset of sleep in its relation to excessive daytime drowsiness remains a matter of debate. It is clear that the frequency of sleep episodes during the day is more common among PD patients and is increased by all dopaminergic therapies. Patients need to be counseled appropriately, particularly with regard to driving. Fortunately, the regulatory authorities have taken a measured approach to this problem, given its relative rarity and the considerable impact that a ban on driving might have on PD patients receiving drug therapy for their motor symptoms.