Sleep disturbance in Parkinson disease

  • Abstract
  • Full Text
  • References

Abstract

Sleep disturbance is common in patients with Parkinson disease (PD), but it is often undetected due to inadequate history taking and poor self-reporting. Impaired sleep can have a severe impact on health, general well being, and quality of life. Sleep problems in PD have many potential causes, including the direct effect of PD itself, adverse events of anti-Parkinsonian medications, daytime sleep disturbance, age related causes, and other comorbidities. Patients with PD and their sleep partners should be asked about sleep disturbances and other night-time symptoms. Treatment strategies rely on identifying causal factors and need to be tailored to the individual and reviewed regularly.

Keywords:

Excessive day-time somnolence, Parkinson disease, Rapid eye movement, Restless legs syndrome, Sleep behavior disorder, Sleep disorders

Article Outline

  1. Introduction
  2. Epidemiology
  3. Pathophysiology of sleep dysfunction in PD
  4. Causes
  5. Assessment of sleep disturbance
  6. Treatment options
  7. Conclusion
  8. References

Abstract

Sleep disturbance is common in patients with Parkinson disease (PD), but it is often undetected due to inadequate history taking and poor self-reporting. Impaired sleep can have a severe impact on health, general well being, and quality of life. Sleep problems in PD have many potential causes, including the direct effect of PD itself, adverse events of anti-Parkinsonian medications, daytime sleep disturbance, age related causes, and other comorbidities. Patients with PD and their sleep partners should be asked about sleep disturbances and other night-time symptoms. Treatment strategies rely on identifying causal factors and need to be tailored to the individual and reviewed regularly.

Keywords:

Excessive day-time somnolence, Parkinson disease, Rapid eye movement, Restless legs syndrome, Sleep behavior disorder, Sleep disorders

1. Introduction

This article will review the epidemiology, pathophysiology, and management of sleep disturbance in Parkinson disease (PD). We identified references for this article by searching PubMed database and Google Scholar up to 2011, with Medical Subject Headings (MeSH) terms of “Parkinson disease,” “night-time symptoms,” “sleep disorders,” “elderly,” and ”dopaminergic therapy.” Only English-language literature was included in the search and information was also obtained from international proceedings published in journals specializing in Parkinsonism and related disorders.

In his original monograph, James Parkinson evidently documents sleep-related disturbances associated with PD as: “His attendants observed, that of late the trembling would sometimes begin in his sleep, and increase until it awakened him: when he always was in a state of agitation and alarm”.1 Sleep disturbance in patients with PD may be caused by direct complications of the disease, adverse events from PD medications, age-related alterations in sleep patterns, associated comorbidities, neuropsychiatric complications of PD, or a combination of the above.

In recent times, there has been increased interest in attempting to better qualify and quantify sleep problems in PD. This has led to some understanding and better management of nocturnal symptoms that plague patients with PD. The U.K. National Institute of Clinical Health and Effectiveness (NICE) recognizes the nonmotor symptoms (NMSs) and their management, which encompass sleep-related problems in PD, as an unmet need.2,3,4

Sleep disturbances in PD are often poorly recognized, yet early identification and treatment to maintain or improve quality of sleep can facilitate improvement in motor symptoms,5,6,7,8 improve quality of life (QoL) for caregivers and patients, may delay institutionalization, and may reduce healthcare costs.4

Furthermore, poor nocturnal sleep quality can lead to poor daytime functioning and excessive daytime somnolence (EDS), which may, in turn, be associated with increased cardiovascular risk and cognitive impairment.9,10

Sleep disturbance is reported by around 25% of spouses of patients with PD.11 Sleep disturbances in both patients with PD and their sleep partners contribute to caregiver burden and correlate with levels of depression in carers.12,13

2. Epidemiology

Estimates of the prevalence of sleep disturbance in PD range from 25%–98%.5,14 Differences in methodology and selection bias are thought to account for this wide variation. Sleep problems are approximately twice as common in patients with PD (60%–64%) as in age and sex matched controls (33%)6,7 and are also more prevalent than in those with other chronic conditions.15,16

Sleep disturbance can occur in the early clinical stages of PD and may even predate the onset of PD. There is conflicting evidence as to whether the degree of sleep disorder correlates with Hoehn and Yahr staging of PD.14,16,17

The NMSQuest (a validated NMS questionnaire) study reported that sleep problems such as restless legs syndrome (RLS), EDS, and rapid eye movement sleep behavior disorder (REMSBD) are significantly more common in patients with PD compared with controls.18

Smith and colleagues11 reported that 27% of male and 48% female spouses of patients with PD experienced night-time disturbances. The FAQT-study (prospective German cohort study evaluating determinants of quality of life) investigators reported a high prevalence of sleep disturbances in partners of patients with PD associated with13:

  • Higher Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores [odds ratio (OR) 2.8 per 10-point increase, p=0.008]
  • Poor sleep in the patient with PD (OR 4.0, p=0.008)
  • Male patients (OR 5.0, p=0.008)
  • Increasing care-giving frequency (OR 7.4 for daily caregiving frequency, p=0.004)

Neuropsychiatric symptoms such as depression, anxiety, apathy, and cognitive impairment are common in PD and may impair sleep.19,20,21,22 Sleep disorders are also more prevalent in patients with PD who later develop cognitive impairment and may herald more complex subtypes of PD.23

In advanced PD, motor symptoms of nocturnal “off” periods, early morning akathisia, dystonia, freezing, and tremor can be very troublesome. Nocturia is reported by up to 62% of patients with PD18 and has been linked to impaired sleep in up to 70.4% of those with idiopathic PD.24

3. Pathophysiology of sleep dysfunction in PD

The pathophysiology of sleep dysfunction in PD is multifactorial, complex, and, as of yet, incompletely understood. Sleep dysfunction, like other nonmotor features of PD, is known to predate the onset of motor dysfunction. REMSBD and depression might precede the expression of motor features by more than a decade.2,25This has often led to misdiagnosis, inappropriate referrals, and delayed treatment.26

3.1. Lewy body pathology and dopamine dysfunction

The progression of Lewy body pathology in PD closely correlates with the occurrence of NMSs predating the motor dysfunction,27,28 suggesting that Lewy body deposition and neuronal dysfunction commence in the olfactory bulb and lower medulla. Motor features appear only when the substantia nigra pars compacta is affected by loss of dopaminergic neurons. The axons from the key dopaminergic areas (substantia nigra pars compacta, ventral tegmental area, and the hypothalamus) project extensively to form the four main pathways—the mesocortical, mesolimbic, nigrostriatal, and tuberoinfundibular pathways—that mediate NMS such as sleep, cognition, and pain.21 11C-raclopride positron emission tomography (PET) imaging in patients with PD has demonstrated dopamine dysfunction in the hypothalamus.29

3.2. Degeneration in raphe nucleus and locus coeruleus

As sleep disturbance may precede motor dysfunction, it is postulated that degeneration occurs in areas such as raphe nucleus (serotonin) and locus coeruleus (noradrenaline) thereby constituting the pre-clinical stages 1 and 2 of Braak’s pathological staging of PD.27 These nuclei play a critical role in the sleep-wake cycle and thalamocortical arousal, and their degeneration leads to disruption of basic sleep architecture [both rapid eye movement (REM) and non–REM], thereby manifesting as insomnia, parasomnias and hallucinations.30,31

3.3. Influence of the pedunculopontine and retro-rubral nuclei on REMSBD

The pedunculopontine nucleus and the retro-rubral nucleus have been implicated in the pathogenesis of REMSBD due to their strong influences on REM atonia and phasic generator circuitry.31

3.4. Destabilization of the flip-flop-switch regulation of sleep-wake cycle

Saper32 proposed the flip-flop-switch pattern of regulation of the sleep-wake cycle, describing that the brain could be either “off” (asleep by activating the ventrolateral preoptic area, the sleep promoter) or “on” (in quiet wakefulness with the activation of the tuberomammillary nucleus, the wake-promoting area along with locus coeruleus and the raphe nuclei). The suprachiasmatic nucleus regulates the internal rhythm between the two switches. The hypothalamic peptide that is virtually undetectable in narcolepsy; hypocretin 1 (orexin) is thought to have a complex relationship in the dopaminergic systems within the basal ganglia and may function as an external regulator of the flip-flop switch promoting wakefulness.31,33 Destabilization of this switch and its regulators occur in PD secondary to dopaminergic dysfunction and neuronal degeneration, resulting in rapid transitions to sleep intruding on wakefulness. The hypothesis of dopaminergic medications reducing levels of hypocretin 1 and producing sleepiness could not be confirmed by cerebrospinal fluid (CSF) analysis in three patients with PD and EDS associated with dopamine agonist (DA) use.34

3.5. Age-related changes

In addition to these PD related changes, there are age-related changes in sleep and circadian rhythm. Older people often sleep for shorter periods of time at night and have more daytime naps than their younger counterparts. Sleep architecture also alters with ageing, with reduced Stages 3 and 4 of non–REM sleep. Around 40% of older people experience some form of sleep disturbance and these are more common in those with physical and psychological problems.35

4. Causes

The main causes of nocturnal sleep problems and EDS are nocturnal motor symptoms of PD, adverse effects of medications used for PD, NMSs of PD (including neuropsychiatric symptoms, sleep dysfunction, dysautonomia), other comorbidities, concomitant medications, and age-related alterations in sleep patterns (Tables 1 and 2).

Table 1Causes of night-time problems in Parkinson disease.
Motor function related Akinesia (difficulty turning)
Restless legs syndrome
Periodic limb movements of sleep
Treatment-related motor function Nocturnal “off’-period-related tremor
Dystonia
Dyskinesia
“Off”-period-related pain
Paraesthesia
Muscle cramps
Neuropsychiatric/parasomnias Depression
Anxiety (generalized, panic attacks, social phobia)
“Off’-period-related panic attacks
Apathy
Cognitive dysfunction
Vivid dreams
Altered dream content
Nightmares
Night terrors
Sleep talking
Nocturnal vocalizations
Somnambulism
Hallucinations
Sleep dysfunction Insomnia (sleep-onset, sleep-maintenance)
Rapid eye movement sleep behavior disorder
Non–rapid-eye-movement-related sleep disorders
Akathisia
Autonomic “Off”-period-related incontinence of urine
Nocturia
Nocturia with secondary postural hypotension
Medications

Adapted from Chaudhuri KR. Nocturnal symptom complex in PD and its management. Neurology 2003;61(Suppl 3):S17–S23.

Table 2Non–Parkinson disease-related causes of night-time problems in the elderly.
Age-related sleep changes Altered sleep architecture
Altered circadian rhythm
Medical or health problems Sleep apnea
Periodic limb movements of sleep
Pain (chronic arthritis)
Heart failure
Palpitations
Frequency of micturition
Gastroesophageal reflux disease
Constipation
Allergies
Mental disorders, e.g. depression, anxiety
Dementia (increases non–rapid eye movement light sleep and decreases in non–rapid eye movement deep sleep)
Medications Beta-blockers
Sleeping medications (e.g. benzodiazepines)
Sedative antidepressants and antipsychotics
Theophylline and caffeine
Other factors Nicotine, alcohol
Sedentary behavior
Daytime napping
Sadness or bereavement/stress

4.1. Motor function/treatment related

The longest time patients with PD spend without any pharmacological intervention is at night. This is to avoid the stimulating effect of dopaminergic therapy, which may result in impaired sleep. However, the long period without any drug treatment can result in nocturnal “off” periods, the resultant akinesia leading to difficulty turning in bed, stiffness, early morning dystonia, and tremor. There may also be an increase in NMSs of pain and muscle cramps that should respond to dopaminergic therapy. Sleep may also be fragmented due to night-time “off” dyskinesias and akathisia (restless legs).

Treating these nocturnal “off” symptoms has to be balanced against the alerting/arousal effects of dopaminergic therapy which might generate insomnia, vivid dreams, and “on” dyskinesias.

4.2. Neuropsychiatric disorders

Depression affects around 40% of patients with PD.37 The symptom complex of depression in PD may be hard to distinguish from early cognitive impairment22; it is linked to dysfunction of dopaminergic, serotoninergic, and norepinephrinergic pathways in the limbic system.38 Depression is independently associated with sleep disorders (e.g., early morning wakening) and can also exacerbate motor and drug-related symptoms.

Anxiety disorders often coexist with depression and motor fluctuations and are usually the result of neurobiological or neuropeptide abnormalities associated with PD.20 These may manifest as generalized anxiety states, panic attacks, and social phobia. If related to a dopamine-dependent “wearing off” state, anxiety can respond to treatment of the motor dysfunction with dopaminergic therapy.39 Some anxiety states are independent of the dopaminergic state these are usually more difficult to treat but may respond to anxiolytics or antidepressants.

Apathy is a specific symptom of PD, occurring with or without depression, for which a dopaminergic basis is possible. The Geriatric Depression Scale can help distinguish true depressive symptoms from those of apathy.40,41 Apathy is generally associated with EDS.

Cognitive dysfunction is usually a feature of advanced PD, but can occur early as a frontal dysexecutive syndrome, manifesting as impaired adaptive response against competing alternatives.42 Visuospatial and visuoperceptual deficits have also been noted in patients with PD.43 Mild cognitive impairment (MCI) has been identified in 72/126 (56%) of patients with early PD.44 The caudate and corticostriatal pathways are implicated in early cognitive changes.45 Brain metabolism and dopamine uptake is impaired in cortical targets of striatal dopaminergic targets.46,47 Sleep disturbances related to cognitive impairment include EDS, nocturnal hallucinations, and altered dream content.

4.3. Sleep dysfunction

Sleep architecture studies in PD reveal reduced total sleep time and sleep efficiency, sleep arousals and fragmentation, while circadian variation of symptoms are also reported enabling classification into the “morning better,” “morning worse,” and a nonaffected group.36,48

REMSBD is a parasomnia with a population prevalence of 0.5%.49,50 REMSBD causes loss of the normal skeletal muscle atonia during REM sleep. This enables patients to enact their dreams, which can be unpleasant or vivid. Spouses and partners report vocalizations (talking, shouting and vocal threats) and abnormal movements (limb jerks, falling out of bed, and violent assaults). This may result in injury to the individual or their sleep partner. REMSBD disturbs the sleep of patient and partner, impacts on QoL for patient and partner, often results in poor quality sleep, so there is EDS, and it can endanger the sleep partner.51

The diagnosis can usually be made from the clinical history but may sometimes require polysomnography with video telemetry for confirmation. A total of 11 out of 33 consecutive patients with PD were diagnosed as having REMSBD by a combination of structured clinical interview and polysomnography; clinical interview alone would not have identified half of these patients.51,52 REMSBD may predate the diagnosis of PD and represent a preclinical stage: 11 of 29 men aged ≥ 50 years developed a Parkinsonian disorder 3.7±1.4 (standard deviation) years after the diagnosis of REMSBD and 12.7±7.3 years after the onset of REMSBD.53REMSBD seems to be associated with degeneration of lower brainstem nuclei, such as the pedunculopontine nucleus and locus coeruleus which have connections with the dopaminergic ventral tegmental area in the midbrain. These observations are consistent with the Braak hypothesis27 that the preclinical Stages 1 and 2 of PD start in the olfactory and medullary area of the brainstem and progress rostrally. Individuals with olfactory disturbances and REMSBD have also been shown to be at increased risk of developing PD.54 After diagnosis of REMSBD in patients without parkinsonism, Postuma and colleagues reported the estimated 5-year risk of developing PD after being diagnosed with REMSBD is 17.7% and the 10-year risk 40.6%.55 REMSBD may also be associated with other nonmotor manifestations of PD, e.g., hallucinations, orthostatic hypotension, and dementia.56

Insomnia is probably the most common sleep disturbance in patients with PD.57 It is often multifactorial and may be related to motor, NMSs, depression, anxiety, obstructive sleep apnea, urinary problems, or any combination of these. Sleep-onset insomnia (difficulty in falling asleep) is usually associated with PD itself, but can occasionally be brought on by dopaminergic therapy, e.g., selegiline may delay onset of sleep as a result of its amphetamine metabolites. Amantadine and anticholinergics may produce an alerting effect and selective serotonin reuptake inhibitors (SSRIs) need to be avoided at bedtime given that they may impair sleep onset.48Sleep-maintenance insomnia (difficulty in maintaining sleep for periods of time) is usually a result of akinesia and other “off”-state related motor and NMSs, e.g., RLS, periodic limb movements of sleep (PLMS), nocturia, and reversal of sleep patterns.5,58

RLS is an urge to move the legs, to relieve unpleasant or uncomfortable sensations brought about by rest, which tends to worsen in the evening.59 It is associated with insomnia, anxiety, and depression.60 RLS has a two-fold increase in prevalence in PD compared with the general population (although the diagnostic criteria for RLS have not been validated in PD)61 and along with PLMS (repetitive, rhythmic jerking movements of the limbs during sleep) is known to cause frequent sleep disruption.62,63 In advanced PD of the akinetic rigid phenotype, akathisia is common (and symptoms are similar to those of RLS) probably related to changes in the mesocortical dopamine pathways.64 PD often precedes RLS suggesting RLS may be a secondary phenomenon. RLS may be associated with iron deficiency and in such cases will respond to iron replacement therapy. RLS may also be associated with renal impairment.

EDS describes a tendency to fall asleep in the daytime, which may interfere with social functioning, cognition and contribute to accidents and falls.65,66 Care must be taken to differentiate EDS from symptoms of chronic fatigue that also occur in PD. EDS can occur in the early stages of PD67 and may even predate the diagnosis of PD.68 EDS has a higher prevalence in patients with PD than in controls (affecting approximately 50% of patients with PD), does not appear to be age-related, and is more severe in the later stages of PD.69,70 Thus, EDS may be related to the underlying neurodegeneration.

The manifestations of EDS are profoundly variable; some feel sleepy and slowly drift off to sleep, while others have rapid-onset sleep without any preceding drowsiness resembling narcolepsy.31

There is evidence of a correlation between EDS and the use of dopamine agonists, but not with levodopa.65,71,72,73 So-called “sleep attacks” (falling asleep without a prodrome) are rare and may be associated with dopamine agonist usage.

In most instances EDS will be multi-factorial due to a combination of sleep fragmentation, depression, coexistent sleep apnea, and the use of hypnotics, antidepressants, and DAs.

4.4. Nocturia

Nocturia is a common problem in older age. However, symptoms of overactive bladder syndrome are more common in patients with PD than age-matched controls and these symptoms worsen as PD progresses.18,74,75 Both the presence and severity of urinary symptoms appear to correlate with the extent of dopaminergic neurone depletion.76

The high incidence of nocturia in patients with PD is likely due to a combination of reduced bladder capacity, increased urine formation at night, impairment of sleep due to “off” period, urgency, and detrusor overactivity.

4.5. Obstructive sleep apnea

Snoring and obstructive sleep apnea (OSA) are three times more common in patients with PD as controls and may occur in up to 50% of patients with PD.77 OSA may also occur in conjunction with RLS, PLMS, or REMSBD.67,69 Patients with PD with OSA typically have a normal body mass index unlike patients without PD but with OSA.69

Reduced neural output causes relative weakness of the muscles around the upper airway leading to partial or complete airways collapse. The resultant hypoxia promotes sufficient awakening to stimulate breathing. These microawakenings leave the individual in a state of light sleep, which is nonrestful, so he or she is fatigued and somnolent during the day. His or her sleep partner may be aware of the patient’s loud snoring, periods of apnea, and gasping. Correct diagnosis is essential for these patients to have specific and targeted treatment.

OSA can be diagnosed by overnight oxygen saturation monitoring and polysomnography.78 It can be treated by overnight continuous positive airway pressure (CPAP).

4.6. Other causes

It is all too easy to ascribe every symptom to the PD. A thorough search should also be made for non–PD related causes of nocturnal disturbances in patients with PD, e.g., other medical ailments and adverse events of medications.

5. Assessment of sleep disturbance

Given the varied nocturnal symptoms in patients with PD, the first step toward management is identification of such problems by qualitative and quantitative means. Specific questioning of patient and sleep partner should include:

  • Sleep pattern, including insomnia, EDS, and “sleep attacks”
  • RLS
  • Vivid dreams and hallucinations
  • Acting out dreams (REMSBD)
  • Nocturnal motor symptoms (including PLMS)
  • Nocturia and other urinary symptoms
  • Medication (PD and non–PD)
  • Comorbidities
  • Snoring and apneic attacks

The gold standard for quantification of sleep disorders is polysomnography and sleep latency tests; however, these are costly and often of limited availability.

5.1. Scales and measures

Sleep dysfunction can be assessed (presence and severity) by several scales, of which six are recommended by the Movement Disorder Society (MDS).79 This is shown in Table 3. These are all screening tools that cannot diagnose specific sleep disturbances in PD but can assess severity and response to treatment.

Table 3Sleep scales in Parkinson disease.
Scale Number of items to complete Assessment details
Parkinson’s Disease Sleep Scale 15 Nocturnal disturbance and excessive daytime somnolence
Time scale: Over previous weeks
Pittsburgh Sleep Quality Index 19 Sleep quality
Time scale: Over the previous month
Scales for Outcomes in Parkinson’s Disease Sleep Scale 12 Sleep quality, daytime sleepiness and night-time sleep disturbances
Time scale: Over the previous month
Epworth Sleepiness Scale 8 Daytime sleepiness presence and severity
Time scale: In recent times
Inappropriate Sleep Composite Score 6 Risk of sudden onset of sleepiness while driving
Stanford Sleepiness Scale 1 General level of daytime sleepiness
Time scale: At that specific moment in time

The Parkinson’s Disease Sleep Scale (PDSS) is a 15-question visual analogue scale that can be used at the bedside and is available in five languages (English, German, Italian, Swedish, and Spanish).80 It has robust test–retest reliability and good discriminatory powers between patients with PD and healthy individuals.58 The PDSS has recently been revised and validated (PDSS-2) to include an extended spectrum of nocturnal disturbances, and may better reflect response to treatment.81 The 12-item Scales for Outcomes in Parkinson’s disease-Sleep (SCOPA-SLEEP) scale assesses both night-time and daytime sleep; though validated, it does not address some of the night-time symptoms of PD very well.82 The Epworth Sleepiness Scale (ESS) is very specific for assessing EDS in eight daily situations but lacks test–retest reliability and cross-cultural differences.83

Depression may be assessed by a variety of scales, such as the Geriatric Depression Scale (GDS), Montgomery-Asberg Depression Rating Scale (MADRS), and the Zung self-rating depression scale. Anxiety may be assessed using the State Trait Anxiety Inventory and the Hospital Anxiety and Depression (HAD) scale.

Objective measurements of sleep in PD patients include polysomnography (PSG), multiple sleep latency tests (MSLT) and maintenance of wakefulness test (MWT). PSG includes objective assessment of the entire gamut of standardized measurements of brain activity, respiratory functions, eye movements, and electromyography (EMG) to measure sleep architecture and provide quantitative measurements of sleep disturbance, which are useful for diagnosing sleep apnea, PLMS, and REMSBD. The MSLT and MWT are useful for evaluation of EDS and the ability to remain awake.

5.2. Evaluation of nocturnal sleep disorders

Clues to the presence of nocturnal sleep disturbances may be obtained by interviewing the bed partner. Snoring and respiratory pauses would suggest OSA, whereas kicking during the night would point to PLMS and dream enactment behaviors suggest REMSBD. However, the differentiation of these conditions is not always clear-cut as there is considerable overlap in symptomatology. PSG is essential for diagnosis of PLMS, which is an intermittent, rhythmic movement of the legs mainly occurring in non–REM sleep. Although PSG is the gold standard, thorough interviews of the patient and their sleep partner are invaluable bedside tools.

5.3. Evaluation of EDS

It is generally assumed that EDS worsens nocturnal symptoms and vice versa. However, EDS can occur without significant nocturnal problems.48 A good pointer for EDS is an elevated ESS score, which predicts the occurrence of sleepiness and dozing while driving.84 Subjective reports of EDS underestimate those diagnosed by MSLT.85

6. Treatment options

The approach to managing sleep disturbances in patients with PD (especially in the older population) requires a holistic view,74 bearing in mind that some of the symptoms may arise from the interplay of other comorbidities. Well being of the sleep partners or carers is also important in formulating a treatment plan. Ensuring good sleep hygiene is a key element to managing all sleep disturbances (Table 4).86

Table 4Good sleep hygiene.
Avoid daytime napping
Increase daytime exercise
Avoid alcohol, caffeine, and tobacco
Avoid heavy meals or excessive liquid late in the day
Go to bed only when sleepy
Go to bed to sleep, not to read or watch television
Try to maintain a regular sleep pattern
If unable to sleep, get up and engage in relaxing activity, i.e., reading a book, and then return to bed when drowsy

Bed rails and straps can help make turning in bed easier as can silk sheets. Spouses of patients with REMSBD may need to move in to a separate bed or bedroom as may those of patients with severe snoring.

Treatment should be targeted at the causal factors disrupting sleep, whether PD or comorbidity related and may consist of non-pharmacological as well pharmacological strategies (Table 5). However, the patient should be warned that full resolution of symptoms is unlikely and that a strategy to improve one symptom may worsen another.

Table 5Potential pharmacologic treatments for sleep disturbances in Parkinson disease.
Symptom Pharmacologic treatment
“Off” symptoms Prolonged release levodopa
Rotigotine patch
Dystonia Prolonged release levodopa
Rotigotine patch
Akathisia Clozapine89
Restless legs syndrome Reduce antidepressants
Periodic limb movements of sleep Ropinirole
Pramipexole
Iron
Rapid eye movement sleep behavior disorder Clonazepam
Melatonin
Insomnia Melatonin
Quetiapine
Benzodiazepines/zolpidem
Sedating antihistamines
Excessive daytime somnolence Reduce dopaminergic drugs, antihistamines, and hypnotics
Modafinil
Methylphenidate
Sleep attacks Review non-ergot dopamine agonists
Depression Antidepressants
Overactive bladder Antimuscarinics
Obstructive sleep apnea Review sedative medication
Continuous positive airways pressure

6.1. Nocturnal sleep disturbances

6.1.1. Sleep fragmentation and insomnia due to symptoms of PD

Some nonpharmacological strategies include:

  • Having a hot bath before bedtime, which may shorten sleep-onset time by inducing sleep during the cooling phase
  • Light bedtime snacks may alleviate symptoms of night-time hunger
  • Avoiding fluid intake in the evening may reduce nocturia
  • Relaxation techniques may help reduce stress and muscle tension

Subtle changes in PD medication regimens may result in major benefits in nocturnal sleep quality and subsequent daytime alertness. Strategies to improve nocturnal motor symptoms may worsen insomnia or induce vivid dreams. There often needs to be a degree of trial and error, and patients should be counselled regarding this. Targeting the individual’s most troublesome symptoms is most likely to result in the best improvements in QoL.

Bedtime dosing of sustained-release levodopa preparations can help in reducing early morning PD symptoms, e.g., dystonia87 and the addition of a catechol-O-methyltransferase inhibitor (COMT-I), such as entacapone or tolcapone, to the bedtime dose of levodopa can prolong its effect.88 Alternatively, a nocturnal (on wakening) use of standard formulation or sustained-release levodopa may be helpful.

Nocturnal symptoms may also benefit from the judicious use of a DA. In the RECOVER trial, transdermal rotigotine showed statistical improvement in almost all domains of PDSS-2: sleep-onset insomnia, early morning tiredness, nocturnal restlessness of limbs, early morning dystonia, early morning tremors, limb pain, muscle cramps, and breathing problems.90 In EASE-PD, addition of prolonged release ropinirole to levodopa improved sleep as evidenced by change in baseline PDSS score.91 A post-hoc subgroup analysis of EASE-PD showed improvements in early morning motor symptoms and global quality of sleep in those with PDSS scores ≤ 100 and in global quality of sleep for those with PDSS scores > 100.92 The subgroup of PDSS with scores ≤ 100 have troublesome nocturnal symptoms in the form of greater daily awake ‘off’ time, reduced night-time sleep, and worse QoL compared with those with PDSS scores > 100. The CLinical Efficacy Of Pramipexole And Transdermal Rotigotine in Advanced Parkinson’s Disease (CLEOPATRA-PD) study showed equal benefit of pramipexole or transdermal rotigotine over placebo.93

The hypnosedative zolpidem may be useful both for its sedative (insomnia) and muscle relaxing effects (insomnia and motor problems of PD).94

Melatonin (3 mg at night) has been shown to improve subjective sleep quality in a number of PD patients although there was no change in objective measures using PSG.95

Deep brain stimulation (DBS) of the subthalamic nuclei (STN) helps improve motor symptoms and sleep architecture (increased total sleep time and improved sleep maintenance) in PD,96 but would not be recommended purely for this purpose.

6.1.2. Sleep fragmentation due to obstructive sleep apnea

Although CPAP is the most effective treatment for OSA, there are no data specific for its use in patients with PD.

6.1.3. Sleep fragmentation due to RLS and PLMS

Some nonpharmacological measures include:

  • Good sleep hygiene
  • Avoidance of alcohol, tobacco and caffeine
  • Avoidance of drugs that exacerbate RLS: serotonergic and tricyclic antidepressants, antihistamines, and dopamine-receptor antagonists
  • Correction of iron deficiency: iron replacement has been effective in reduction of RLS symptoms in non-Parkinsonian patients97 and, hence, should be considered if ferritin levels are low. Although controlled trials are lacking, oral iron as ferrous sulphate concomitantly with vitamin C for absorption of food may be tried.98 The cause of iron deficiency will need to be ascertained

The drug of choice for RLS and PLMS is a DA (pramipexole, ropinirole, or rotigotine).99 When a DA cannot be used, e.g., the cognitively impaired or produces untoward effects, e.g., orthostatic hypotension, then alternatives include opiates, anticonvulsants (gabapentin), and benzodiazepines.100

6.1.4. REMSBD

Where REMSBD manifests as aggressive and/or violent behavior, environmental adjustment should be considered to protect the patient and his or her bed partner,98 e.g., padding the floor, using raised padded bed rails, and sleeping in different rooms.

Low-dose clonazepam (0.5–1.0 mg), at night has been reported to improve REMSBD in 80%–90% patients101but controlled trials are lacking. Higher doses of clonazepam may run the risk of adverse effects of nocturnal confusion, daytime sleepiness, and worsening of OSA (if present).

Melatonin may improve REMSBD in doses up to 12 mg at night102; adverse effects include morning headaches, morning drowsiness, and delusions or hallucinations. Symptomatic improvement of REMSBD in PD patients has also been reported with pramipexole.103 A small case series reported improvement of REMSBD with donepezil.104

6.1.5. Depression

Depression and anxiety may respond to improvements in motor symptoms due to adjustments in dopaminergic therapy. Pramipexole has also been shown to be of similar antidepressant activity as fluoxetine105 better than sertraline106 in improving mood when used as an adjunct to levodopa. This may be a class effect of DAs at the limbic dopamine D3 receptors, as both pramipexole and pergolide showed comparable benefits in MADRS scores.107 In the EASE-PD Adjunct Study, prolonged-release ropinirole also improved mood as assessed by the Beck Depression Inventory.91

The evidence base for choosing an antidepressant in PD is poor and so no particular antidepressant can be recommended over another.108,109 However, it is perhaps worth noting that bupropion and sertraline appear to inhibit dopamine reuptake21,110 and so, theoretically may benefit motor symptoms as well as mood.

6.1.6. Nocturnal hallucinations/vivid dreams

Symptomatic improvement may be achieved by reduction (or removal) of evening doses of antiparkinsonian medications. Occasionally, atypical neuroleptics may be necessary; adverse events may be avoided by starting at low doses and gradually titrating up to the effective dose for that individual. Clozapine has been shown to reduce psychosis, anxiety, and hypersexuality in patients with PD.111 However, use is limited by a need to regularly monitor blood count and prescribing being limited (in many parts of the United Kingdom) to consultant psychiatrists. Quetiapine is the drug of choice in clinical practice at a starting dose of 12.5–25 mg.

6.1.7. Nocturia

Some nonpharmacological measures to reduce nocturia include:

  • Good sleep hygiene
  • Avoidance of caffeine, alcohol
  • Bladder training: voiding of urine before sleeping
  • Reduction of fluid intake beyond the evening
  • Bedside commode, pads, or conveen sheath urinal

Overactive bladder syndrome may benefit from drugs with antimuscarinic properties, such as tolterodine, oxybutynin, and solifenacin, but these drugs have the potential to cause or worsen confusion. If nonpharmacological and pharmacological measures fail, then botulinum toxin may be beneficial.112

Prostatism is a common comorbidity and may indicate a need for urodynamic studies if obstructive symptoms are significant.

6.2. EDS

Some nonpharmacological measures to reduce EDS include:

  • Good sleep hygiene
  • Avoiding sedentary activities and participating in external activities (day centers) may provide stimulation
  • Avoid driving due to increased risk of vehicle accidents during periods of “sleep attacks”
  • Physical exercise appropriate to level of functioning may help increase daytime wakefulness; avoidance of strenuous exercise for 3–4 hours prior to sleep

It may be necessary to reduce the dose or stop using DAs completely.85 EDS may worsen with all dopaminergic therapy but is more marked with DAs than levodopa. In more severe cases of EDS, e.g., where the individual is falling asleep during meals or mid-conversation, then the stimulant modafinil may be of benefit, although the trial evidence is conflicting.113,114 Methylphenidate may be worth trying, when all other options fail.115 Caffeine (an adenosine A2A receptor antagonist) may be a more affordable alternative, albeit with no evidence base for its use in EDS.

7. Conclusion

Sleep disturbances are common in patients with PD and their sleep partners, but they are often overlooked by an emphasis on the motor manifestations of PD. The presence and cause(s) of sleep disturbances need to be identified as appropriate management can significantly improve the QoL of the person with PD and his or her caregiver. A number of assessment tools have been developed to aid in the detection and management of sleep problems in patients with PD.

It is imperative upon all healthcare professionals dealing with patients with PD to update them and gain experience in the diagnosis and management of these conditions. Although the evidence base is weak, all patients with PD will potentially benefit from advice on good sleep hygiene, while more specific pharmacological therapies will need to be tailored to each individual’s sleep problem(s). Patients and caregivers should be warned of the potential limitations of therapeutic interventions and treatment should be targeted at their most troublesome symptoms.

References

  1. Parkinson, J. An essay on the shaking palsy. J Neuropsychiatry Clin Neurosci. 2002; 14: 223–236
  2. Chaudhuri, K.R., Healy, D., and Schapira, A.H.V. The non motor symptoms of Parkinson’s disease. Diagnosis and management. Lancet Neurol. 2006; 5: 235–245
  3. The National Institute for Clinical Excellence (NICE). Parkinson’s disease diagnosis and management in primary and secondary care. Clinical guideline 35, http://www.nice.org.uk/nicemedia/pdf/cg035quickrefguide.pdf; [accessed 30.04.12].
  4. Shulman, L.M., Taback, R.L., Rabistein, A.A., and Weiner, W.J. Non-recognition of depression and other non-motor symptoms in Parkinson’s disease. Parkinsonism Relat Disord. 2002; 8: 193–197
  5. Lees, A.J., Blackburn, N.A., and Campbell, V.L. The nighttime problems of Parkinson’s disease. Clin Neuropharmacol. 1988; 11: 512–519
  6. Tandberg, E., Larsen, J.P., and Karlsen, K. Excessive daytime sleepiness and sleep benefit in Parkinson’s disease: a community-based study. Mov Disord. 1999; 14: 922–927
  7. Karlsen, J., Larsen, J.P., Tandberg, E., and Jørgensen, K. Fatigue in patients with Parkinson’s disease.Mov Disord. 1999 Mar; 14: 237–241
  8. Pahwa, R., Poewe, W., Lyons, K.E., and Boroojerdi, B. Changes in early morning motor status following adjunctive treatment of advanced Parkinson’s disease with rotigotine transdermal system in two large, placebo-controlled trials (PREFER and CLEOPATRA-PD). Mov Disord. 2009; 24: S280
  9. Pal, P.K., Thennarasu, K., Fleming, J., Schulzer, M., Brown, T., and Calne, S.M. Nocturnal sleep disturbances and daytime dysfunction in patients with Parkinson’s disease and in their caregivers.Parkinsonism Relat Disord. 2004; 10: 157–168
  10. Medcalf, P. Good practice in the assessment and management of nocturnal Parkinson’s disease symptoms. Age Ageing. 2005; 34: 435–438
  11. Smith, M.C., Ellgring, H., and Oertel, W.H. Sleep disturbances in Parkinson’s disease patients and spouses. J Am Geriatr Soc. 1997; 45: 194–199
  12. Fernandez, H.H., Tabamo, R.E.J., David, R.R., and Friedman, J.H. Predictors of depressive symptoms among spouse caregivers in Parkinson’s disease. Mov Disord. 2001; 16: 1123–1125
  13. Happe, S. and Berger, K. FAQT study investigators. The association between caregiver burden and sleep disturbances in partners of patients with Parkinson’s disease. Age Ageing. 2002; 31: 349–354
  14. Schrag, A., Ben Shlomo, Y., and Quinn, N. How common are complications of Parkinson’s disease?.J Neurol. 2001; 249: 419–423
  15. Trenkwalder, C. Sleep dysfunction in Parkinson’s disease. Clin Neurosci. 1998; 5: 107–114
  16. Porter, B., Macfarlane, R., and Walker, R. The frequency and nature of sleep disorders in a community-based population of patients with Parkinson’s disease. Eu Jn Neurol. 2008; 15: 50–54
  17. Goetz, C.G., Ouyang, B., Negron, A., and Stebbins, G.T. Hallucinations and sleep disorders in PD: ten-year prospective longitudinal study. Neurology. 2010; 75: 1773–1779
  18. Chaudhuri, K.R., Martinez-Martin, P., Schapira, A.H., Stocchi, F., Sethi, K., Odin, P. et al. An international multicentre pilot study of the first comprehensive self-completed non motor symptoms questionnaire for Parkinson’s disease: the NMSQuest study. Mov Disord. 2006; 21: 916–923
  19. Burn, D.J. Beyond the iron mask; towards better recognition and treatment of depression associated with Parkinson’s disease. Mov Disord. 2002; 17: 445–454
  20. Richard, I.H., Schiffer, R.B., and Kurlan, R. Anxiety and Parkinson’s disease. J Neuropsychiatry Clin Neurosci. 1996; 8: 383–392
  21. Chaudhuri, K.R. and Schapira, A.H.V. Non-motor symptoms of Parkinson’s disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 2009; 8: 464–474
  22. Aarsland, D., Andersen, K., Larsen, J.P., Lolk, A., and Kragh-Sorensen, P. Prevalence and characteristics of dementia in Parkinson’s disease. Arch Neurol. 2003; 60: 387–392
  23. Naismith, S.L. and Lewis, S.G. “DASH” symptoms in patients with Parkinson’s disease: Red flags for early cognitive decline. Jn Clin Neurosci. 2011; 18: 352–355
  24. Kumar, S., Bhatia, M., and Behari, M. Sleep disorders in Parkinson’s disease. Mov Disord. 2002; 17: 775–781
  25. Naidu, Y. and Chaudhuri, K.R. Early Parkinson’s disease and non motor issues. J Neurol. 2008;255: 33–38
  26. O’Sullivan, S.S., Williams, D.R., Gallagher, D.A., Massey, L.A., Silveira-Moriyama, L., and Lees, A.J.Non motor symptoms as presenting complaints in Parkinson’s disease: a clinicopathological study.Mov Disord. 2008; 23: 101–106
  27. Braak, H., Del Tredici, K., Rüb, U., de Vos, R.A., Jansen Steur, E.N., and Braak, E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003; 24: 197–210
  28. Wolters, E. and Braak, J. Parkinson’s disease: premotor clinicopathological correlations. Neural Trans. 2006; 70: 309–319
  29. Politis, M., Piccini, P., Pavese, N., and Brooks, D.J. Evidence of dopamine dysfunction in the hypothalamus of patients with Parkinson’s disease: an in vivo 11C-raclopride study. Exp Neurol. 2008;214: 112–116
  30. MacMohan, D. Why excessive daytime sleepiness is an important issue in Parkinson’s disease.Adv Clin Neurol Rehabil. 2005; 5: 46–49
  31. Rye, D.B. and Jankovic, J. Emerging views of dopamine in modulating sleep/wake state from an unlikely source: PD. Neurology. 2002; 58: 341–346
  32. Saper, C.B., Chou, T.C., and Scammell, T.E. The sleep switch: the hypothalamic control of sleep and wakefulness. Trends Neurosci. 2001; 24: 726–731
  33. Nishino, S., Ripley, B., Overseem, S., Lammers, G.J., Mignot, E. et al. Hypocretin (orexin) deficiency in human narcolepsy. Lancet. 2000; 355: 39–40
  34. Ripley, B., Overseem, S., Fujuki, N., Nevsimalova, S., Uchino, M., Yesavage, J. et al. CSF hypocretin/orexin levels in narcolepsy and other neurological conditions. Neurology. 2001; 57: 2253–2258
  35. Ganguli, M., Reynolds, C.F., and Gilby, J.E. Prevalence and persistence of sleep complaints in a rural older community sample: the MoVIES project. J Am Geriatr Soc. 1996; 44: 778–784
  36. Chaudhuri, K.R. Nocturnal symptom complex in PD and its management. Neurology. 2003; 61: S17–S23
  37. Veazey, C., Aki, S.O., Cook, K.F., Lai, E.C., and Kunik, M.E. Prevalence and treatment of depression in Parkinson’s disease. J Neuropsychiatry Clin Neurosci. 2005; 17: 310–323
  38. Remy, P., Doder, M., Lees, A., Turjanski, N., and Brooks, D. Depression in Parkinson’s disease. Loss of dopamine and noradrenaline innervations in the limbic system. Brain. 2005; 128: 1314–1322
  39. Lemke, M.R., Brecht, H.M., Koester, J., Kraus, P.H., and Reichmann, H. Anhedonia, depression, and motor functioning in Parkinson’s disease during treatment with pramipexole. J Neuropsychiatry Clin Neurosci. 2005; 17: 214–220
  40. Schrag, A., Barone, P., Brown, R.G., Leentjens, A.F.G., McDonald, W.M., Starkstein, S. et al. Depression rating scales in Parkinson’s disease: critique and decommendations. Mov Disord. 2007; 22: 1077–1092
  41. Ertan, F.T., Ertan, T., Kiziltan, G., and Uygucgil, H. Reliability and validity of the Geriatric Depression Scale in depression in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2005; 76: 1445–1447
  42. Dubois, B. and Pillon, B. Cognitive deficits in Parkinson’s disease. J Neurol. 1997; 244: 2–8
  43. Uc, E., Rizzo, M., Anderson, S., Qian, S., Rodnitzky, R.L., and Dawson, J.D. Visual dysfunction in Parkinson’s disease without dementia. Neurology. 2005; 65: 1907–1913
  44. Williams-Gray, C., Foltynie, T., Brayne, C., Robbins, T.W., and Barker, R.A. Evolution of cognitive dysfunction in an incident Parkinson’s disease cohort. Brain. 2007; 130: 1787–1798
  45. Emre, M. What causes mental dysfunction in Parkinson’s disease?. Mov Disord. 2003; 18: S63–S71
  46. Lewis, S., Dove, A., Robbins, T., Barker, R.A., and Owen, A.M. Cognitive impairments in early Parkinson’s disease are accompanied by reductions in activity in frontostriatal neural circuitry.J Neurosci. 2003; 23: 6351–6356
  47. Rinne, J., Portin, R., Ruottinen, H., Nurmi, E., Bergman, J., Haaparanta, M. et al. cognitive impairment and the brain dopaminergic system in Parkinson’s disease – [F-18]fluorodopa positron emission tomographic study. Arch Neurol. 2000; 57: 470–475
  48. Garcia-Borreguero, D., Larosa, O., and Bravo, M. Parkinson’s disease and sleep. Sleep Med Rev. 2003; 7: 115–129
  49. Schenck, C.H. and Mahowald, M.W. REM sleep behaviour disorder: clinical, developmental, and neuroscience perspectives 16 years after its formal identification in SLEEP. Sleep. 2002; 25: 120–138
  50. Olson, E.J., Boeve, B.F., and Silber, M.H. Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases. Brain. 2000; 123: 331–339
  51. Comella, C.L., Nardine, T.M., Deiderich, N.J., and Stebbins, G.T. Sleep-related violence, injury, and REM sleep behaviour disorder in Parkinson’s disease. Neurology. 1998; 51: 526–529
  52. Fantini, M.L., Ferini-Strambi, L., and Montplaisir, J. Idiopathic REM sleep behaviour disorder: toward a better nosologic definition. Neurology. 2005; 64: 780–786
  53. Schenck, C.H., Bundlie, S.R., and Mahowald, M.W. Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder.Neurology. 1996; 46: 388–393
  54. Stiasny-Kolster, K., Doerr, Y., Moller, J.C., Höffken, H., Behr, T.M., Oertel, W.H. et al. Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for alpha-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain. 2005; 128: 126–137
  55. Postuma, R.B., Gagnon, J.F., Vendette, M., Fantini, M.L., Massicotte-Marquez, J., and Montplaisir, J.Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behaviour disorder.Neurology. 2009; 72: 1296–1300
  56. Postuma, R.B., Gagnon, J.F., Vendette, M., Charland, K., and Montplaisir, J. Manifestations of Parkinson disease differ in association with REM sleep behaviour disorder. Mov Disord. 2008; 23: 1665–1672
  57. Gjerstad, M.D., Boeve, B., Wentzel-Larsen, T., Aarsland, D., and Larsen, J.P. Occurrence and clinical correlates of REM sleep behaviour disorder in patients with Parkinson’s disease over time. J Neurol Neurosurg Psychiatry. 2008; 79: 387–391
  58. Dhawan, V., Healy, D.G., Pal, S., and Chaudhuri, K.R. Sleep-related problems of Parkinson’s disease. Age Ageing. 2006; 35: 220–228
  59. Hening, W.A. and Allen, R.P. Restless legs syndrome (RLS): the continuing development of diagnostic standards and severity measures. Sleep Med. 2003; 4: 95–97
  60. Earley, C.J. and Silber, M. Restless legs syndrome: understanding its consequences and the need for better treatment. Sleep Med. 2010; 11: 807–815
  61. Möller, J.C., Unger, M., Stiasny-Kolster, K., and Oertel, W.H. Restless legs syndrome (RLS) and Parkinson’s disease (PD)—related disorders or different entities?. J Neurol Sci. 2010; 289: 135–137
  62. Garcia-Borreguero, D., Odin, P., and Serrano, C. Restless legs syndrome and PD: a review of the evidence for a possible association. Neurology. 2003; 61: 49–55
  63. Ondo, W.G., Vuong, K.D., and Jankovic, J. Exploring the relationship between Parkinson’s disease and restless legs syndrome. Arch Neurol. 2002; 59: 421–424
  64. Comella, C.L. and Goetz, C.G. Akathisia in Parkinson’s disease. Mov Disord. 1994; 9: 545–549
  65. Frucht, S., Rogers, J.D., Greene, P.E., Gordon, M.F., and Fahn, S. Falling asleep at the wheel: motor vehicle mishaps in persons taking pramipexole and ropinirole. Neurology. 1999; 52: 1908–1910
  66. Ondo, W.G., Dat Vuong, K., Khan, H., Atassi, F., Kwak, C., and Jankovic, J. Daytime sleepiness and other sleep disorders in Parkinson’s disease. Neurology. 2001; 57: 1392–1396
  67. Fabrini, G., Barbanti, P., Aurilia, C., Vanacore, N., Pauletti, C., and Meco, G. Excessive daytime sleepiness in de novo and treated Parkinson’s disease. Mov Disord. 2002; 17: 1026–1030
  68. Abbott, R.D., Ross, G.W., White, L.R., Tanner, C.M., Nelson, J.S., and Petrovitch, H. Excessive daytime sleepiness and the future risk of Parkinson’s disease. Mov Disord. 2005; 20: S101
  69. Arnulf, I., Konofal, E., Merino-Andreu, M., Mesange, V., Welter, M.L., Lacomblez, L. et al. Parkinson’s disease and sleepiness – an integral part of PD. Neurology. 2002; 58: 1019–1024
  70. Arnulf, I. Excessive daytime sleepiness in parkinsonism. Sleep Med Rev. 2005; 9: 185–200
  71. Antonini, A. Daytime somnolence and night sleep disturbances in Parkinson’s disease: background and future treatment prospective. Neurol Sci. 2007; 28: S6–S8
  72. Valko, P.O., Waldvogel, D., Weller, M., Bassetti, C.L., Held, U., and Baumann, C.R. Fatigue and excessive daytime sleepiness in idiopathic Parkinson’s disease differently correlate with motor symptoms, depression and dopaminergic treatment. Eur J Neurol. 2010; 17: 1428–1436
  73. Paus, S., Brecht, H.M., Köster, J., Seeger, G., Klockgether, T., and Wüllner, U. Sleep attacks, daytime sleepiness, and dopamine agonists in Parkinson’s disease. Mov Disord. 2003; 18: 659–667
  74. Porter, B. and Walker, R. The night time problems facing Parkinson’s patients. CME J Geriatr Med. 2006; 8: 99–103
  75. Iacovelli, E., Gilio, F., Meco, G., Fattapposta, F., Vanacore, N., and Brusa, L. Bladder symptoms assessed with overactive bladder questionnaire in Parkinson’s Disease. Mov Disord. 2010; 25: 1203–1209
  76. Winge, K., Friberg, L., Werdelin, L., Nielsen, K.K., and Stimpel, H. Relationship between nigrostriatal dopaminergic degeneration, urinary symptoms, and bladder control in Parkinson’s disease. Eur J Neurol. 2005; 12: 842–850
  77. Oerlemans, W.G. and de Weerd, A.W. The prevalence of sleep disorders in patients with Parkinson’s disease: a self-reported, community-based survey. Sleep Med. 2002; 3: 147–149
  78. Diederich, N.J., Vaillant, M., Leischen, M., Mancuso, G., Golinval, S., Nati, R. et al. Sleep apnoea syndrome in Parkinson’s disease. A case-control study in 49 patients. Mov Disord. 2005; 20: 1413–1418
  79. Högl, B., Amulf, J., Comella, C., Ferreira, J., Iranzo, A., Tilley, B. et al. Scales to assess sleep impairment in Parkinson’s disease: critique and recommendations. Mov Disord. 2010; 25: 2704–2716
  80. Chaudhuri, K.R., Pal, S., DiMarco, A., Whately-Smith, C., Bridgman, K., Mathew, R. et al. The Parkinson’s disease sleep scale: a new instrument for assessing sleep and nocturnal disability in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2002; 73: 629–635
  81. Trenkwalder, C., Kohnen, R., Högl, B., Metta, V., Sixel-Doring, F., Frauscher, B. et al. Parkinson’s disease sleep scale-validation of the revised version PDSS-2. Mov Disord. 2011; 22: 1245–1251
  82. Marinus, J., Visser, M., van Hilten, J.J., Lammers, G.J., and Stiggelbout, A.M. Assessment of sleep and sleepiness in Parkinson’s disease. Sleep. 2003; 26: 1049–1054
  83. Johns, M.W. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale.Sleep. 1991; 14: 540–545
  84. Hobson, D.E., Lang, A.E., Martin, W.R., Razmy, A., Rivest, J., and Fleming, J. Excessive daytime sleepiness and sudden-onset sleep in Parkinson’s disease: a survey by the Canadian Movement Disorders Group. JAMA. 2002; 287: 455–463
  85. Razmy, A., Lang, A.E., and Shapiro, C.M. Predictors of impaired daytime sleep and wakefulness in patients with Parkinson disease treated with older (ergot) vs newer (nonergot) dopamine agonists.Arch Neurol. 2004; 61: 97–102
  86. MacMahon, D.G. Why excessive daytime sleepiness is an important issue in Non-motor symptoms in Parkinson’s disease: an under diagnosed problem. Adv Clin Neurol Rehab. 2005; 5: 46–49
  87. Spivak, B., Mester, R., Abesgaus, J., Wittenberg, N., Adlersberg, S., Gonen, N. et al. Cloazpine treatment for neuroleptic-induced tardive dyskinesia, parkinsonism, and chronic akathisia in schizophrenic patients. J Clin Psychiatry. 1997; 58: 318–322
  88. Van den Kerchove, M., Jacquy, J., Gonce, M., and De Deyn, P.P. Sustained-release Levodopa in parkinsonian patients with nocturnal disabilities. Acta Neurol Belg. 1993; 93: 32–39
  89. Stacy, M. Sleep disorders in Parkinson’s disease: epidemiology and management. Drugs Aging. 2002; 19: 733–739
  90. Trenkwalder, C., Kies, B., Rudzinska, M., Fine, J., Nikl, J., Honczarenko, K. et al. RECOVER Study Group. Rotigotine effects on early morning motor function and sleep in Parkinson’s disease: a double-blind, randomized, placebo-controlled study (RECOVER). Mov Disord. 2011; 26: 90–99
  91. Pahwa, R., Stacy, M.A., Factor, S.A., Lyons, K.E., Stocchi, F., Hersh, B.P. et al. EASE-PD adjunct study investigators. Ropinirole 24-hour prolonged release: randomized, controlled study in advanced Parkinson’s disease. Neurology. 2007; 68: 1108–1115
  92. Ray Chaudhuri, K., Martinez-Martin, P., Rolfe, K.A., Cooper, J., Rockett, C.B., Giorgi, L. et al.Improvements in nocturnal symptoms with ropinirole prolonged release in patients with advanced Parkinson’s disease. Eur J Neurol. 2011; 19: 105–113
  93. Poewe, W., Rascol, O., Quinn, N., Tolosa, E., Oertel, W.H., Martignoni, E. et al. SP 515 investigators. Efficacy of pramipexole and transdermal rotigotine in advanced Parkinson’s disease. Lancet Neurol. 2007; 6: 513–520
  94. Abe, K., Hikita, T., and Sakoda, S. A hypnotic drug for sleep disturbances in Parkinson’s disease.No To Shinkei. 2005; 57: 301–305
  95. Medeiros, C.A., Carvalhedo de Bruin, P.F., Lopes, L.A., Magalhaes, M.C., de Lourdes Seabra, M., and de Bruin, V.M. Effect of exogenous melatonin on sleep and motor dysfunction in Parkinson’s disease: A randomised, double blind, placebo-controlled study. J Neurol. 2007; 254: 459–464
  96. Cicolin, A., Lopiano, L., Zibetti, M., Torre, E., Tavella, A., Guastamacchia, G. et al. Effects of deep brain stimulation of the subthalamic nucleus on sleep architecture in parkinsonian patients. Sleep Med. 2004; 5: 207–210
  97. Trenkwalder, C., Paulus, W., and Walters, A.S. The restless legs syndrome. Lancet Neurol. 2005; 4: 465–475
  98. Comella, C.L. Sleep disorders in Parkinson’s disease. Curr Treat Opt Neurol. 2008; 10: 215–221
  99. Hogl, B., Rothdach, A., Wetter, T.C., and Trenkwalder, C. The effect of cabergoline on sleep, periodic leg movements in sleep, and early morning motor functions in patients with Parkinson’s disease.Neuropsychopharmacol. 2003; 28: 1866–1870
  100. Thorpy, M.J. and Adler, C.H. Parkinson’s disease and sleep. Neurol Clin. 2005; 23: 1187–1208
  101. Schenck, C.H. and Mahowald, M.W. Rapid eye movement sleep insomnias (review). Neurol Clin. 2005; 23: 1107–1126
  102. Boeve, B.F., Silber, M.H., and Ferman, T.J. Melatonin for treatment of REM sleep behaviour disorder in neurologic disorders: results in 14 patients. Sleep Med. 2003; 4: 281–284
  103. Schmidt, M.H., Koshal, V.B., and Schmidt, H.S. Use of pramipexole in REM sleep behaviour disorder: results form a case series. Sleep Med. 2006; 7: 418–423
  104. Ringman, J.M. and Simmons, J.H. Treatment of REM sleep behaviour disorder with donepezil: a report of three cases. Neurology. 2000; 55: 870–871
  105. Goldberg, J., Burdick, K.E., and Endick, C.J. Preliminary randomised placebo controlled trial of pramipexole added to mood stabilisers for treatment of resistant bipolar depression. Am J Psychiatry. 2004; 161: 564–566
  106. Barone, P., Scarzella, L., Marconi, R., Antonini, A., Morgante, L., Bracco, F. et al. Pramipexole versus sertraline in the treatment of depression in Parkinson’s disease. A national multicentre parallel group randomized study. J Neurol. 2006; 253: 601–607
  107. Rektorova, I., Rektor, I., Bares, M., Dostal, V., Ehler, E., Fanfrdlova, Z. et al. Pramipexole and pergolide in the treatment of depression in Parkinson’s disease: a national multicentre prospective randomised study. Eur J Neurol. 2003; 10: 399–406
  108. Menza, M., Dobkin, R.D., Marin, H., Mark, M.H., Gara, M., Buyske, S. et al. A controlled trial of antidepressants in patients with Parkinson disease and depression. Neurol. 2009; 72: 886–892
  109. DeFronzo Dobkin, R., Menza, M., Bienfait, K., Gara, M., Marin, H., Mark, M.H. et al. The impact of antidepressant treatment on cognitive functioning in depressed patients with Parkinson’s disease.J Neuropsychiatry Clin Neurosci. 2010; 22: 188–195
  110. Schmitt, J.A., Ramaekers, J.G., Kruizinga, M.J., van Boxtel, M.P., Vuurman, E.F., and Riedel, W.J.Additional dopamine reuptake inhibition attenuates vigilance impairment induced by serotonin reuptake inhibition in man. J Psychopharmacol. 2002; 16: 207–214
  111. Troster, A.I., Friedman, J.H., and Lantigua, R. Clozapine use in Parkinson’s disease: a retrospective analysis of a large multicentred clinical experience. Mov Disord. 1998; 13: 377–382
  112. Giannantoni, A., Rossi, A., Mearini, E., Del Zingaro, M., Porena, M., and Berardelli, A. Botulinum toxin A for overactive bladder and detrusor muscle overactivity in patients with Parkinson’s disease and multiple system atrophy. J Urol. 2009; 182: 1453–1457
  113. Adler, C.H., Caviness, J.N., Hentz, J.G., Lind, M., and Tiede, J. Randomised trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson’s disease. Mov Disord. 2003; 18: 287–293
  114. Ondo, W.G., Fayle, R., Atassi, F., and Jankovic, J. Modafinil for daytime somnolence in Parkinson’s disease: double blind, placebo controlled parallel trial. J Neurol Neurosurg Psychiatry. 2005; 76: 1636–1639
  115. Menza, M., Dobkin, R.D., Marin, H., and Bienfait, K. Sleep disturbances in Parkinson’s disease. Mov Disord. 2010; 25: S117–S122

References

  1. Parkinson, J. An essay on the shaking palsy. J Neuropsychiatry Clin Neurosci200214223–236

  2. Chaudhuri, K.R., Healy, D., and Schapira, A.H.V. The non motor symptoms of Parkinson’s disease. Diagnosis and management. Lancet Neurol20065235–245


  3. The National Institute for Clinical Excellence (NICE). Parkinson’s disease diagnosis and management in primary and secondary care. Clinical guideline 35, http://www.nice.org.uk/nicemedia/pdf/cg035quickrefguide.pdf; [accessed 30.04.12].


  4. Shulman, L.M., Taback, R.L., Rabistein, A.A., and Weiner, W.J. Non-recognition of depression and other non-motor symptoms in Parkinson’s disease. Parkinsonism Relat Disord20028193–197


  5. Lees, A.J., Blackburn, N.A., and Campbell, V.L. The nighttime problems of Parkinson’s disease. Clin Neuropharmacol198811512–519


  6. Tandberg, E., Larsen, J.P., and Karlsen, K. Excessive daytime sleepiness and sleep benefit in Parkinson’s disease: a community-based study. Mov Disord199914922–927


  7. Karlsen, J., Larsen, J.P., Tandberg, E., and Jørgensen, K. Fatigue in patients with Parkinson’s disease.Mov Disord1999 Mar14237–241


  8. Pahwa, R., Poewe, W., Lyons, K.E., and Boroojerdi, B. Changes in early morning motor status following adjunctive treatment of advanced Parkinson’s disease with rotigotine transdermal system in two large, placebo-controlled trials (PREFER and CLEOPATRA-PD). Mov Disord200924S280


  9. Pal, P.K., Thennarasu, K., Fleming, J., Schulzer, M., Brown, T., and Calne, S.M. Nocturnal sleep disturbances and daytime dysfunction in patients with Parkinson’s disease and in their caregivers.Parkinsonism Relat Disord200410157–168


  10. Medcalf, P. Good practice in the assessment and management of nocturnal Parkinson’s disease symptoms. Age Ageing200534435–438


  11. Smith, M.C., Ellgring, H., and Oertel, W.H. Sleep disturbances in Parkinson’s disease patients and spouses. J Am Geriatr Soc199745194–199


  12. Fernandez, H.H., Tabamo, R.E.J., David, R.R., and Friedman, J.H. Predictors of depressive symptoms among spouse caregivers in Parkinson’s disease. Mov Disord2001161123–1125


  13. Happe, S. and Berger, K. FAQT study investigators. The association between caregiver burden and sleep disturbances in partners of patients with Parkinson’s disease. Age Ageing200231349–354


  14. Schrag, A., Ben Shlomo, Y., and Quinn, N. How common are complications of Parkinson’s disease?.J Neurol2001249419–423


  15. Trenkwalder, C. Sleep dysfunction in Parkinson’s disease. Clin Neurosci19985107–114


  16. Porter, B., Macfarlane, R., and Walker, R. The frequency and nature of sleep disorders in a community-based population of patients with Parkinson’s disease. Eu Jn Neurol20081550–54


  17. Goetz, C.G., Ouyang, B., Negron, A., and Stebbins, G.T. Hallucinations and sleep disorders in PD: ten-year prospective longitudinal study. Neurology2010751773–1779


  18. Chaudhuri, K.R., Martinez-Martin, P., Schapira, A.H., Stocchi, F., Sethi, K., Odin, P. et al. An international multicentre pilot study of the first comprehensive self-completed non motor symptoms questionnaire for Parkinson’s disease: the NMSQuest study. Mov Disord200621916–923


  19. Burn, D.J. Beyond the iron mask; towards better recognition and treatment of depression associated with Parkinson’s disease. Mov Disord200217445–454


  20. Richard, I.H., Schiffer, R.B., and Kurlan, R. Anxiety and Parkinson’s disease. J Neuropsychiatry Clin Neurosci19968383–392


  21. Chaudhuri, K.R. and Schapira, A.H.V. Non-motor symptoms of Parkinson’s disease: dopaminergic pathophysiology and treatment. Lancet Neurol20098464–474


  22. Aarsland, D., Andersen, K., Larsen, J.P., Lolk, A., and Kragh-Sorensen, P. Prevalence and characteristics of dementia in Parkinson’s disease. Arch Neurol200360387–392


  23. Naismith, S.L. and Lewis, S.G. “DASH” symptoms in patients with Parkinson’s disease: Red flags for early cognitive decline. Jn Clin Neurosci201118352–355


  24. Kumar, S., Bhatia, M., and Behari, M. Sleep disorders in Parkinson’s disease. Mov Disord200217775–781


  25. Naidu, Y. and Chaudhuri, K.R. Early Parkinson’s disease and non motor issues. J Neurol2008;25533–38


  26. O’Sullivan, S.S., Williams, D.R., Gallagher, D.A., Massey, L.A., Silveira-Moriyama, L., and Lees, A.J.Non motor symptoms as presenting complaints in Parkinson’s disease: a clinicopathological study.Mov Disord200823101–106


  27. Braak, H., Del Tredici, K., Rüb, U., de Vos, R.A., Jansen Steur, E.N., and Braak, E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging200324197–210


  28. Wolters, E. and Braak, J. Parkinson’s disease: premotor clinicopathological correlations. Neural Trans200670309–319


  29. Politis, M., Piccini, P., Pavese, N., and Brooks, D.J. Evidence of dopamine dysfunction in the hypothalamus of patients with Parkinson’s disease: an in vivo 11C-raclopride study. Exp Neurol2008;214112–116


  30. MacMohan, D. Why excessive daytime sleepiness is an important issue in Parkinson’s disease.Adv Clin Neurol Rehabil2005546–49


  31. Rye, D.B. and Jankovic, J. Emerging views of dopamine in modulating sleep/wake state from an unlikely source: PD. Neurology200258341–346


  32. Saper, C.B., Chou, T.C., and Scammell, T.E. The sleep switch: the hypothalamic control of sleep and wakefulness. Trends Neurosci200124726–731


  33. Nishino, S., Ripley, B., Overseem, S., Lammers, G.J., Mignot, E. et al. Hypocretin (orexin) deficiency in human narcolepsy. Lancet200035539–40


  34. Ripley, B., Overseem, S., Fujuki, N., Nevsimalova, S., Uchino, M., Yesavage, J. et al. CSF hypocretin/orexin levels in narcolepsy and other neurological conditions. Neurology2001572253–2258


  35. Ganguli, M., Reynolds, C.F., and Gilby, J.E. Prevalence and persistence of sleep complaints in a rural older community sample: the MoVIES project. J Am Geriatr Soc199644778–784


  36. Chaudhuri, K.R. Nocturnal symptom complex in PD and its management. Neurology200361S17–S23


  37. Veazey, C., Aki, S.O., Cook, K.F., Lai, E.C., and Kunik, M.E. Prevalence and treatment of depression in Parkinson’s disease. J Neuropsychiatry Clin Neurosci200517310–323


  38. Remy, P., Doder, M., Lees, A., Turjanski, N., and Brooks, D. Depression in Parkinson’s disease. Loss of dopamine and noradrenaline innervations in the limbic system. Brain20051281314–1322


  39. Lemke, M.R., Brecht, H.M., Koester, J., Kraus, P.H., and Reichmann, H. Anhedonia, depression, and motor functioning in Parkinson’s disease during treatment with pramipexole. J Neuropsychiatry Clin Neurosci200517214–220


  40. Schrag, A., Barone, P., Brown, R.G., Leentjens, A.F.G., McDonald, W.M., Starkstein, S. et al. Depression rating scales in Parkinson’s disease: critique and decommendations. Mov Disord2007221077–1092


  41. Ertan, F.T., Ertan, T., Kiziltan, G., and Uygucgil, H. Reliability and validity of the Geriatric Depression Scale in depression in Parkinson’s disease. J Neurol Neurosurg Psychiatry2005761445–1447


  42. Dubois, B. and Pillon, B. Cognitive deficits in Parkinson’s disease. J Neurol19972442–8


  43. Uc, E., Rizzo, M., Anderson, S., Qian, S., Rodnitzky, R.L., and Dawson, J.D. Visual dysfunction in Parkinson’s disease without dementia. Neurology2005651907–1913


  44. Williams-Gray, C., Foltynie, T., Brayne, C., Robbins, T.W., and Barker, R.A. Evolution of cognitive dysfunction in an incident Parkinson’s disease cohort. Brain20071301787–1798


  45. Emre, M. What causes mental dysfunction in Parkinson’s disease?. Mov Disord200318S63–S71


  46. Lewis, S., Dove, A., Robbins, T., Barker, R.A., and Owen, A.M. Cognitive impairments in early Parkinson’s disease are accompanied by reductions in activity in frontostriatal neural circuitry.J Neurosci2003236351–6356


  47. Rinne, J., Portin, R., Ruottinen, H., Nurmi, E., Bergman, J., Haaparanta, M. et al. cognitive impairment and the brain dopaminergic system in Parkinson’s disease – [F-18]fluorodopa positron emission tomographic study. Arch Neurol200057470–475


  48. Garcia-Borreguero, D., Larosa, O., and Bravo, M. Parkinson’s disease and sleep. Sleep Med Rev20037115–129


  49. Schenck, C.H. and Mahowald, M.W. REM sleep behaviour disorder: clinical, developmental, and neuroscience perspectives 16 years after its formal identification in SLEEP. Sleep200225120–138


  50. Olson, E.J., Boeve, B.F., and Silber, M.H. Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases. Brain2000123331–339


  51. Comella, C.L., Nardine, T.M., Deiderich, N.J., and Stebbins, G.T. Sleep-related violence, injury, and REM sleep behaviour disorder in Parkinson’s disease. Neurology199851526–529


  52. Fantini, M.L., Ferini-Strambi, L., and Montplaisir, J. Idiopathic REM sleep behaviour disorder: toward a better nosologic definition. Neurology200564780–786


  53. Schenck, C.H., Bundlie, S.R., and Mahowald, M.W. Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder.Neurology199646388–393


  54. Stiasny-Kolster, K., Doerr, Y., Moller, J.C., Höffken, H., Behr, T.M., Oertel, W.H. et al. Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for alpha-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain2005128126–137


  55. Postuma, R.B., Gagnon, J.F., Vendette, M., Fantini, M.L., Massicotte-Marquez, J., and Montplaisir, J.Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behaviour disorder.Neurology2009721296–1300


  56. Postuma, R.B., Gagnon, J.F., Vendette, M., Charland, K., and Montplaisir, J. Manifestations of Parkinson disease differ in association with REM sleep behaviour disorder. Mov Disord2008231665–1672


  57. Gjerstad, M.D., Boeve, B., Wentzel-Larsen, T., Aarsland, D., and Larsen, J.P. Occurrence and clinical correlates of REM sleep behaviour disorder in patients with Parkinson’s disease over time. J Neurol Neurosurg Psychiatry200879387–391


  58. Dhawan, V., Healy, D.G., Pal, S., and Chaudhuri, K.R. Sleep-related problems of Parkinson’s disease. Age Ageing200635220–228


  59. Hening, W.A. and Allen, R.P. Restless legs syndrome (RLS): the continuing development of diagnostic standards and severity measures. Sleep Med2003495–97


  60. Earley, C.J. and Silber, M. Restless legs syndrome: understanding its consequences and the need for better treatment. Sleep Med201011807–815


  61. Möller, J.C., Unger, M., Stiasny-Kolster, K., and Oertel, W.H. Restless legs syndrome (RLS) and Parkinson’s disease (PD)—related disorders or different entities?. J Neurol Sci2010289135–137


  62. Garcia-Borreguero, D., Odin, P., and Serrano, C. Restless legs syndrome and PD: a review of the evidence for a possible association. Neurology20036149–55


  63. Ondo, W.G., Vuong, K.D., and Jankovic, J. Exploring the relationship between Parkinson’s disease and restless legs syndrome. Arch Neurol200259421–424


  64. Comella, C.L. and Goetz, C.G. Akathisia in Parkinson’s disease. Mov Disord19949545–549


  65. Frucht, S., Rogers, J.D., Greene, P.E., Gordon, M.F., and Fahn, S. Falling asleep at the wheel: motor vehicle mishaps in persons taking pramipexole and ropinirole. Neurology1999521908–1910


  66. Ondo, W.G., Dat Vuong, K., Khan, H., Atassi, F., Kwak, C., and Jankovic, J. Daytime sleepiness and other sleep disorders in Parkinson’s disease. Neurology2001571392–1396


  67. Fabrini, G., Barbanti, P., Aurilia, C., Vanacore, N., Pauletti, C., and Meco, G. Excessive daytime sleepiness in de novo and treated Parkinson’s disease. Mov Disord2002171026–1030


  68. Abbott, R.D., Ross, G.W., White, L.R., Tanner, C.M., Nelson, J.S., and Petrovitch, H. Excessive daytime sleepiness and the future risk of Parkinson’s disease. Mov Disord200520S101


  69. Arnulf, I., Konofal, E., Merino-Andreu, M., Mesange, V., Welter, M.L., Lacomblez, L. et al. Parkinson’s disease and sleepiness – an integral part of PD. Neurology2002581019–1024


  70. Arnulf, I. Excessive daytime sleepiness in parkinsonism. Sleep Med Rev20059185–200


  71. Antonini, A. Daytime somnolence and night sleep disturbances in Parkinson’s disease: background and future treatment prospective. Neurol Sci. 200728S6–S8


  72. Valko, P.O., Waldvogel, D., Weller, M., Bassetti, C.L., Held, U., and Baumann, C.R. Fatigue and excessive daytime sleepiness in idiopathic Parkinson’s disease differently correlate with motor symptoms, depression and dopaminergic treatment. Eur J Neurol2010171428–1436


  73. Paus, S., Brecht, H.M., Köster, J., Seeger, G., Klockgether, T., and Wüllner, U. Sleep attacks, daytime sleepiness, and dopamine agonists in Parkinson’s disease. Mov Disord200318659–667


  74. Porter, B. and Walker, R. The night time problems facing Parkinson’s patients. CME J Geriatr Med2006899–103


  75. Iacovelli, E., Gilio, F., Meco, G., Fattapposta, F., Vanacore, N., and Brusa, L. Bladder symptoms assessed with overactive bladder questionnaire in Parkinson’s Disease. Mov Disord2010251203–1209


  76. Winge, K., Friberg, L., Werdelin, L., Nielsen, K.K., and Stimpel, H. Relationship between nigrostriatal dopaminergic degeneration, urinary symptoms, and bladder control in Parkinson’s disease. Eur J Neurol200512842–850


  77. Oerlemans, W.G. and de Weerd, A.W. The prevalence of sleep disorders in patients with Parkinson’s disease: a self-reported, community-based survey. Sleep Med20023147–149


  78. Diederich, N.J., Vaillant, M., Leischen, M., Mancuso, G., Golinval, S., Nati, R. et al. Sleep apnoea syndrome in Parkinson’s disease. A case-control study in 49 patients. Mov Disord2005201413–1418


  79. Högl, B., Amulf, J., Comella, C., Ferreira, J., Iranzo, A., Tilley, B. et al. Scales to assess sleep impairment in Parkinson’s disease: critique and recommendations. Mov Disord2010252704–2716


  80. Chaudhuri, K.R., Pal, S., DiMarco, A., Whately-Smith, C., Bridgman, K., Mathew, R. et al. The Parkinson’s disease sleep scale: a new instrument for assessing sleep and nocturnal disability in Parkinson’s disease. J Neurol Neurosurg Psychiatry200273629–635


  81. Trenkwalder, C., Kohnen, R., Högl, B., Metta, V., Sixel-Doring, F., Frauscher, B. et al. Parkinson’s disease sleep scale-validation of the revised version PDSS-2. Mov Disord2011221245–1251


  82. Marinus, J., Visser, M., van Hilten, J.J., Lammers, G.J., and Stiggelbout, A.M. Assessment of sleep and sleepiness in Parkinson’s disease. Sleep2003261049–1054


  83. Johns, M.W. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale.Sleep199114540–545


  84. Hobson, D.E., Lang, A.E., Martin, W.R., Razmy, A., Rivest, J., and Fleming, J. Excessive daytime sleepiness and sudden-onset sleep in Parkinson’s disease: a survey by the Canadian Movement Disorders Group. JAMA2002287455–463


  85. Razmy, A., Lang, A.E., and Shapiro, C.M. Predictors of impaired daytime sleep and wakefulness in patients with Parkinson disease treated with older (ergot) vs newer (nonergot) dopamine agonists.Arch Neurol20046197–102


  86. MacMahon, D.G. Why excessive daytime sleepiness is an important issue in Non-motor symptoms in Parkinson’s disease: an under diagnosed problem. Adv Clin Neurol Rehab2005546–49


  87. Spivak, B., Mester, R., Abesgaus, J., Wittenberg, N., Adlersberg, S., Gonen, N. et al. Cloazpine treatment for neuroleptic-induced tardive dyskinesia, parkinsonism, and chronic akathisia in schizophrenic patients. J Clin Psychiatry199758318–322


  88. Van den Kerchove, M., Jacquy, J., Gonce, M., and De Deyn, P.P. Sustained-release Levodopa in parkinsonian patients with nocturnal disabilities. Acta Neurol Belg19939332–39


  89. Stacy, M. Sleep disorders in Parkinson’s disease: epidemiology and management. Drugs Aging200219733–739


  90. Trenkwalder, C., Kies, B., Rudzinska, M., Fine, J., Nikl, J., Honczarenko, K. et al. RECOVER Study Group. Rotigotine effects on early morning motor function and sleep in Parkinson’s disease: a double-blind, randomized, placebo-controlled study (RECOVER). Mov Disord20112690–99


  91. Pahwa, R., Stacy, M.A., Factor, S.A., Lyons, K.E., Stocchi, F., Hersh, B.P. et al. EASE-PD adjunct study investigators. Ropinirole 24-hour prolonged release: randomized, controlled study in advanced Parkinson’s disease. Neurology2007681108–1115


  92. Ray Chaudhuri, K., Martinez-Martin, P., Rolfe, K.A., Cooper, J., Rockett, C.B., Giorgi, L. et al.Improvements in nocturnal symptoms with ropinirole prolonged release in patients with advanced Parkinson’s disease. Eur J Neurol201119105–113


  93. Poewe, W., Rascol, O., Quinn, N., Tolosa, E., Oertel, W.H., Martignoni, E. et al. SP 515 investigators. Efficacy of pramipexole and transdermal rotigotine in advanced Parkinson’s disease. Lancet Neurol20076513–520


  94. Abe, K., Hikita, T., and Sakoda, S. A hypnotic drug for sleep disturbances in Parkinson’s disease.No To Shinkei200557301–305


  95. Medeiros, C.A., Carvalhedo de Bruin, P.F., Lopes, L.A., Magalhaes, M.C., de Lourdes Seabra, M., and de Bruin, V.M. Effect of exogenous melatonin on sleep and motor dysfunction in Parkinson’s disease: A randomised, double blind, placebo-controlled study. J Neurol2007254459–464


  96. Cicolin, A., Lopiano, L., Zibetti, M., Torre, E., Tavella, A., Guastamacchia, G. et al. Effects of deep brain stimulation of the subthalamic nucleus on sleep architecture in parkinsonian patients. Sleep Med20045207–210


  97. Trenkwalder, C., Paulus, W., and Walters, A.S. The restless legs syndrome. Lancet Neurol20054465–475


  98. Comella, C.L. Sleep disorders in Parkinson’s disease. Curr Treat Opt Neurol200810215–221


  99. Hogl, B., Rothdach, A., Wetter, T.C., and Trenkwalder, C. The effect of cabergoline on sleep, periodic leg movements in sleep, and early morning motor functions in patients with Parkinson’s disease.Neuropsychopharmacol2003281866–1870


  100. Thorpy, M.J. and Adler, C.H. Parkinson’s disease and sleep. Neurol Clin2005231187–1208


  101. Schenck, C.H. and Mahowald, M.W. Rapid eye movement sleep insomnias (review). Neurol Clin2005231107–1126


  102. Boeve, B.F., Silber, M.H., and Ferman, T.J. Melatonin for treatment of REM sleep behaviour disorder in neurologic disorders: results in 14 patients. Sleep Med20034281–284


  103. Schmidt, M.H., Koshal, V.B., and Schmidt, H.S. Use of pramipexole in REM sleep behaviour disorder: results form a case series. Sleep Med20067418–423


  104. Ringman, J.M. and Simmons, J.H. Treatment of REM sleep behaviour disorder with donepezil: a report of three cases. Neurology200055870–871


  105. Goldberg, J., Burdick, K.E., and Endick, C.J. Preliminary randomised placebo controlled trial of pramipexole added to mood stabilisers for treatment of resistant bipolar depression. Am J Psychiatry2004161564–566


  106. Barone, P., Scarzella, L., Marconi, R., Antonini, A., Morgante, L., Bracco, F. et al. Pramipexole versus sertraline in the treatment of depression in Parkinson’s disease. A national multicentre parallel group randomized study. J Neurol2006253601–607


  107. Rektorova, I., Rektor, I., Bares, M., Dostal, V., Ehler, E., Fanfrdlova, Z. et al. Pramipexole and pergolide in the treatment of depression in Parkinson’s disease: a national multicentre prospective randomised study. Eur J Neurol200310399–406


  108. Menza, M., Dobkin, R.D., Marin, H., Mark, M.H., Gara, M., Buyske, S. et al. A controlled trial of antidepressants in patients with Parkinson disease and depression. Neurol200972886–892


  109. DeFronzo Dobkin, R., Menza, M., Bienfait, K., Gara, M., Marin, H., Mark, M.H. et al. The impact of antidepressant treatment on cognitive functioning in depressed patients with Parkinson’s disease.J Neuropsychiatry Clin Neurosci201022188–195


  110. Schmitt, J.A., Ramaekers, J.G., Kruizinga, M.J., van Boxtel, M.P., Vuurman, E.F., and Riedel, W.J.Additional dopamine reuptake inhibition attenuates vigilance impairment induced by serotonin reuptake inhibition in man. J Psychopharmacol200216207–214


  111. Troster, A.I., Friedman, J.H., and Lantigua, R. Clozapine use in Parkinson’s disease: a retrospective analysis of a large multicentred clinical experience. Mov Disord199813377–382


  112. Giannantoni, A., Rossi, A., Mearini, E., Del Zingaro, M., Porena, M., and Berardelli, A. Botulinum toxin A for overactive bladder and detrusor muscle overactivity in patients with Parkinson’s disease and multiple system atrophy. J Urol20091821453–1457


  113. Adler, C.H., Caviness, J.N., Hentz, J.G., Lind, M., and Tiede, J. Randomised trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson’s disease. Mov Disord200318287–293


  114. Ondo, W.G., Fayle, R., Atassi, F., and Jankovic, J. Modafinil for daytime somnolence in Parkinson’s disease: double blind, placebo controlled parallel trial. J Neurol Neurosurg Psychiatry2005761636–1639


  115. Menza, M., Dobkin, R.D., Marin, H., and Bienfait, K. Sleep disturbances in Parkinson’s disease. Mov Disord201025S117–S122