Diagnosis and Management of Sleep Disorders in Individuals with Parkinson Disease

Parkinson disease (PD) is a neurodegenerative movement disorder that affects 1% to 2% of individuals aged >65 years.¹ Although the cardinal symptoms of PD are motor findings (eg, bradykinesia, resting tremor, rigidity, postural instability), PD is a multifaceted condition with widespread brain involvement and associated nonmotor symptoms.^1,2

Sleep disorders are highly prevalent nonmotor manifestations of PD, affecting 80% of people by 5 years after PD diagnosis.¹ Some sleep disorders precede diagnosis, acting as harbingers of PD. The exact pathophysiology is unknown, but autonomic ganglia and many brainstem nuclei (eg, raphe nucleus, locus coeruleus, pedunculopontine nucleus) have been implicated.³ PD is classified as a synucleinopathy due to pathogenic accumulation of α-synuclein protein in the substantia nigra, brainstem, and peripheral nervous system. Progression is theorized to occur in a caudo-rostral pattern from the peripheral to the central nervous system, possibly contributing to the early onset of sleep disorders in PD (Figure).^4,5

Figure. Timeline of the onset of sleep disorders, other nonmotor symptoms, and motor symptoms in Parkinson disease (PD). Many nonmotor symptoms can start 1 to 2 decades before the onset of motor symptoms. Rapid eye movement sleep behavior disorder (RBD) is considered isolated RBD until the onset of parkinsonism. As PD advances, symptoms develop and progress, leading to increased disease burden.
Abbreviations: EDS, excessive daytime sleepiness; LMRP, leg motor restlessness phenomenon; MCI, mild cognitive impairment; OSA, obstructive sleep apnea; PD, Parkinson disease; RBD, rapid eye movement sleep behavior disorder; RLS, restless leg syndrome.
Data from reference 24.

Sleep is an essential state for proteostasis, neurotoxin clearance by the glymphatic system (the brain’s waste clearance pathway), and memory consolidation.⁶ Sleep disorders interrupt this process. Although sleep disorders in PD are often less conspicuous than their motor counterparts, they contribute substantially to disease burden for people with PD and their caregivers. People with PD are susceptible to a wide range of sleep disorders, which broadens with progression of the disease from the premotor to the motor stage.¹ In this review, we summarize diagnostic and management approaches for common sleep disorders in PD (Table).

Insomnia Symptoms
Individuals with insomnia experience difficulty falling asleep or staying asleep, or experience early morning awakenings, which can result in fatigue, impaired cognition, mood disturbances, and impaired quality of life. Insomnia is the most common sleep disorder in PD, affecting ~30% of individuals at diagnosis and increasing to 80% in the later stages of the disease.¹ Insomnia related to PD is often multifactorial, so comprehensive clinical assessment is essential. Ancillary data from sleep diaries, bed partners, and questionnaires (eg, Insomnia Severity Index,⁷ STOP-Bang,⁸ 7-item General Anxiety Disorder scale,⁹ 9-item Patient Health Questionnaire¹⁰) may help narrow diagnostic possibilities. Differentiating PD-related symptoms from other causes for awakenings and psychophysiologic issues can be difficult, but is necessary to determine the best treatment options. Screening for comorbid medical disorders (eg, pain, frequent nocturnal urination, mood disorders) and sleep disorders is important.

Motor symptoms (eg, bradykinesia, tremors, nocturnal hypokinesia) and autonomic dysfunction (eg, nocturia, impaired temperature regulation, dizziness from orthostatic hypotension) can impair sleep onset and maintenance. In the late stages of PD, circadian rhythm disruptions can become more prominent with memory decline and impaired melatonin regulation. This often results in premature sleep initiation and early morning rising.¹ Medications should be closely examined for side effects exacerbating insomnia, particularly any stimulants or stimulating antidepressants (eg, venlafaxine, bupropion). Polysomnography (PSG) testing is important to consider if there is concern for underlying sleep apnea, periodic limb movements in sleep, or rapid eye movement sleep behavior disorder (RBD).¹

Insomnia management in PD is multimodal. Treating underlying medical and psychiatric conditions and sleep disorders, and reducing or eliminating exacerbating medications, should be prioritized. Deep brain stimulation and modification of dopaminergic medication dosage and timing (eg, using long-acting carbidopa at bedtime) can mitigate motor symptoms that interfere with sleep.¹ First-line insomnia treatments, such as sleep hygiene adjustments and cognitive behavioral therapy for insomnia, should be used in most cases.^1,11

Treatment of insomnia with medication may be necessary, but complications and side effects are common in the PD population. Melatonin can improve sleep quality and symptoms of daytime sleepiness, and enforces a proper sleep–wake cycle if there are circadian rhythm abnormalities.¹² The low side effect profile of melatonin makes it a favorable pharmaceutical option. Benzodiazepines, nonbenzodiazepine hypnotics, sedating antidepressants, and antihistamines have conflicting evidence. Benzodiazepines (eg, temazepam, flurazepam, lorazepam) can provide short-term relief, but are rarely beneficial for long-term use. They are associated with a ≥50% increase in falls and fractures in older people.¹² Nonbenzodiazepine hypnotics (eg, zolpidem, eszopiclone, zaleplon) have comparatively better side effect profiles, but carry many similar risks. Although trazodone is frequently prescribed for individuals with insomnia, oversedation is a potential concern, and its efficacy has been under scrutiny.¹² Mirtazapine is also commonly prescribed, but may cause dream enactment and worsen symptoms associated with restless legs syndrome (RLS).¹³ Certain antidepressants (eg, tricyclics) and antihistamines (eg, diphenhydramine) have anticholinergic effects which can increase constipation and cognitive impairment in people with PD. Many other over-the-counter medications or herbal medications marketed to improve sleep lack sufficient data and are not recommended for use in this population.¹²

Obstructive Sleep Apnea
Obstructive sleep apnea (OSA) has increased prevalence in individuals with PD, occurring in 20% to 70% of individuals with PD despite their overall lower body mass index (BMI) than that of the general population.¹⁴ Rigidity of oropharyngeal muscles and increased supine positioning may contribute to PD-related OSA.¹ People with PD and OSA may have worse functional and cognitive scores, increased mood changes, and elevated daytime sleepiness levels. OSA also exacerbates insomnia and RBD. Intermittent hypoxemia and sleep disruption may perpetuate underlying PD pathophysiology.¹⁴ PSG is the gold standard to assist in the diagnosis of OSA in individuals with PD.

Positive airway pressure therapy is a first-line treatment and has been shown to result in improvement in both motor and nonmotor symptoms.¹⁴ Masks that are easier to put on and remove should be prioritized to account for movement and cognitive symptoms in PD. Oral appliances and hypoglossal nerve stimulation may be good alternatives for those who cannot tolerate positive airway pressure therapy.

REM Sleep Behavior Disorder
RBD is a parasomnia identified in 25% to 50% of people with PD, compared with .5% to 1% in the general population of individuals aged >60 years.¹ RBD is characterized by dream enactment during REM sleep.¹² Symptom severity can range from subtle, unnoticed movements to more violent and potentially dangerous behaviors. Diagnosis is based on history and impaired atonia during REM sleep with abnormal movements on video PSG.¹ It is theorized that α-synuclein accumulation in the brainstem inhibits pathways responsible for muscle atonia during REM sleep.^1,6 RBD is associated with a worse overall PD prognosis and rapidly progressing dementia. Whether this represents an increased intrinsic severity of disease or is secondary to frequent sleep disruptions impairing clearance of brain toxins by the glymphatic system is unclear.^1,6

RBD may begin a few years before, in conjunction with, or after the onset of PD motor symptoms.^1,12 In cases of RBD preceding parkinsonism, age at onset tends to be older (>50 years) than in other RBD populations.¹ The presence of hyposmia, color vision impairment, decreased gut motility, or orthostasis increases the likelihood of underlying PD.¹ Presence of both RBD and hyposmia is correlated with poor cognitive dysfunction and the akinetic-rigidity phenotype.¹⁵ The goal of treatment is to improve sleep quality and minimize injury risk for individuals and their bed partners. Nonpharmaceutical intervention includes modification of sleeping environments (eg, padding floors and the bed frame, removing potentially dangerous objects, blocking access to windows). Bed partners may need to sleep in a separate room or place a pillow between themself and the individual with RBD.¹⁶

The goal of pharmaceutical management of RBD should not be to eliminate behaviors, but rather to decrease frequency and severity of behaviors to mitigate risk of injury.¹⁶ Educating patients on side effects, frequency and quality of behaviors, and management expectations is important. Recommended pharmaceutical agents include immediate-release melatonin, clonazepam, or rivastigmine.¹⁶ Melatonin is a preferred treatment given its low side effect profile. Mild sedation, vivid dreams, and sleep fragmentation are possible complications associated with melatonin treatment. Clonazepam should be used with caution in older people and people with PD who are susceptible to falls and sedating effects. Clonazepam may worsen mentation, daytime sedation, gait instability, and OSA. Rivastigmine is a second-line agent with less serious side effects (eg, gastrointestinal symptoms, skin irritation at the transdermal patch site, bradycardia) and also may benefit people with PD and dementia.¹⁶ Pramipexole may have some benefit in people with isolated RBD. However, supporting evidence is limited overall and especially in people with PD.¹⁷ Deep brain stimulation has not been shown to alleviate RBD symptoms in people with PD.¹

Disordered Limb Movements Impairing Sleep
RLS is diagnosed on the basis of clinical history and cardinal symptoms (ie, urge to move the legs, uncomfortable sensation that is alleviated by voluntary movements, worsening during the evening and periods of inactivity, and not explained by another condition). RLS affects 10% to 55% of people with PD compared with 5% to 10% of the general population.¹ RLS incidence increases after PD diagnosis.¹ Confounding conditions in PD (eg, wearing-off of dopaminergic medications, rigidity, tremor, cramps, dystonia, akathisia) can make diagnosis of RLS difficult. 

Leg motor restlessness phenomena (LMRP) is a separate entity characterized by an urge to move the legs in the absence of the cardinal symptoms of RLS. LMRP may present as nocturnal restlessness and is thought to represent a nighttime hypodopaminergic state.¹⁸ LMRP is more common in medication-naive individuals with PD early in the disease course.¹⁸

Periodic limb movements of sleep (PLMS) is characterized by stereotyped, repetitive limb movements during non-REM sleep, predominantly in the lower extremities. PLMS is considered significant when it occurs >15 times/hour on PSG.^19,20 Although PLMS is frequently identified in people with PD, data on the prevalence of PLMS are limited. A higher frequency of PLMS has been linked to increased severity of PD.¹⁹ Movements may disrupt sleep and contribute to daytime fatigue and impaired quality of life. 

Brain iron deficiency is the leading proposed pathophysiologic mechanism for RLS and PLMS.²⁰ Iron stores should be assessed and replaced aggressively with oral or intravenous iron as a first-line treatment for these conditions. RLS is also linked with dopaminergic dysfunction, but is typically a hyperdopaminergic state rather than hypodopaminergic in PD, making RLS medication treatment complex.²¹

Dopamine agonists (DAs) are no longer recommended as a first-line treatment for RLS due to risk of augmentation (a worsening of RLS symptoms over time induced by excessive dopaminergic stimulation) and other side effects (eg, gastrointestinal symptoms, sleepiness, impulse control disorders).²⁰ DAs are frequently used to manage PD, which can worsen coexisting RLS over time. In this population, limiting bedtime and nocturnal dopamine (DA or levodopa) should be considered. However, if LMRP is suspected, treatment with long-acting DAs or long-acting carbidopa at bedtime may be helpful.¹⁸ For both RLS and LMRP, α2δ ligands (gabapentin and pregabalin) are recommended as first-line agents.¹⁸ Reduction of exacerbating medications (eg, serotonergic antidepressants) should also be considered.¹ In refractory cases, treatment with low-dose opioids results in symptom improvement, but close monitoring is required.²⁰ For PLMS, treatment with either DAs or α2δ ligands could be considered, with close monitoring.

Hypersomnia
PD-related hypersomnia and excessive daytime sleepiness (EDS) affects 21% to 76% of individuals with PD and may substantially decrease quality of life.²² Causes are multifaceted, including PD itself, untreated sleep disorders, medication side effects (eg, dopaminergic medications), and other medical or psychiatric disorders, especially mood disorders.¹

Diagnostic PSG with multiple sleep latency testing may be used to understand the severity of hypersomnia, but treatment is often initiated on the basis of patient history. Management should first focus on treatment of underlying causes. When these are optimally treated, use of wake-promoting medications is reasonable to improve quality of life. Modafinil is a recommended medication for PD-related hypersomnia, and armodafinil also may be considered.²³ Sodium oxybate has shown evidence for improvement of PD-related EDS, but the cost of this medication may be prohibitive.²³ Treatment with other stimulants, such as methylphenidate, can be considered in refractory cases.²³

Conclusion
Sleep disorders in PD are often overlapping, difficult to differentiate from PD symptoms, and complex to treat, and can contribute considerably to disease burden. Proper history and evaluations are essential for implementation of appropriate targeted treatments to optimize health, symptom management, and quality of life.