What is rapid eye movement sleep

Sleep is a reversible state of disconnection from the environment including reduced consciousness, skeletal muscle mobility, and metabolism ¹. All forms of sensory responses are markedly decreased to varying degrees depending on the sleep cycle stage. Although this phenomenon is observed in all species that have been studied and occupies a significant fraction of the human lifespan, the purpose and function of sleep, particularly rapid eye movement (REM) sleep remain poorly understood ².

Sleep is measured primarily by polysomnography which is considered the gold standard for diagnosing sleep disorders ². Polysomnography reveals that sleep architecture has several distinct stages that vacillate between the non-rapid eye movement (NREM) stages and rapid eye movement (REM) stages ¹. The rapid eye movement (REM) stage is of particular interest due to its association with a wide variety of pathological, psychological, and physiological phenomenon.

The hallmark of sleep physiology is the sleep-wake cycle in which a person vacillates between non-rapid eye movement (NREM) stages and rapid eye movement (REM) sleep throughout the night. The switches between non-rapid eye movement (NREM) stages and rapid eye movement (REM) sleep are controlled by reciprocal inhibition of monoaminergic and cholinergic neurons ¹. Cholinergic neurons become highly active during REM. This increase in cholinergic activity is accompanied by a drastic decrease in adrenergic and serotonergic neuron activity and is reversed in NREM sleep. This results in the series of distinct stages of differing wakefulness levels that characterize the different stages of normal sleep.

Polysomnogram is used to identify the 3 stages of non-rapid eye movement (NREM) sleep (N1-N3) and rapid eye movement (REM) sleep by measuring specific EEG waveform rhythms and events outlined briefly below ³:

• Alert wakefulness: low-amplitude mixed frequency electroencephalogram (EEG)
• Drowsy wakefulness: alpha waves with 8 to 13 Hz peaks
• N1 stage: 4 to 7 Hz Theta waves (sawtooth)
• N2 stage: 11 to 16 Hz spindles (bursts of waves) and 0.5 to 2 Hz K-complexes (biphasic waves)
• N3 stage: 0.5 to 3 Hz Delta waves (large and slow)
• Rapid eye movement (REM) sleep (stage R): theta waves or wave-like patterns

The onset of sleep begins with wakefulness and progresses rapidly to rapid eye movement (REM) sleep by approximately 60 to 90 minutes ³. This is followed by cyclical alterations between rapid eye movement (REM) and non-rapid eye movement (NREM) every 90 to 120 minutes until awakening. Most rapid eye movement (REM) sleep occurs during the second half of the night, with NREM sleep dominating the first half of the night.

A variety of parameters are used to measure rapid eye movement (REM) sleep including time to onset, length of the rapid eye movement (REM) stage, and amount of eye movement that occurs during rapid eye movement (REM) ³. Rapid eye movement (REM) latency refers to the amount of time that elapses between the onset of sleep to the first REM stage. Rapid eye movement (REM) density refers to the number of eye movements during REM sleep, and changes have been associated with sleep deprivation and depression.

Sleep architecture is influenced by two separate processes: process S and process C ⁴. Process S is also called the “homeostatic sleep drive” and increases in activity with each hour spent awake. Process C refers to the circadian rhythm and is responsible for maintaining appropriate sleep/wake cycles by promoting sleep during the night and wakefulness during the day. This drive increases throughout the day until bedtime when it begins to decline in order to promote sleep consolidation.

Over 50 million Americans suffer from sleep loss, which is defined as sleep duration less than the average of 7 to 8 hours per night ⁵. Acute and chronic sleep loss results in a wide variety of detrimental consequences. Acute sleep loss results in a number of deleterious symptoms including daytime somnolence diminished memory and hampered concentration. Chronic sleep loss has been consistently associated with an increased risk of serious diseases including diabetes, obesity, and depression. Moreover, sleep deprivation is associated with significantly increased cardiovascular disease including hypertension, heart attack, and stroke ⁵. Sleep disorders are readily treatable and are an important factor in the comprehensive care of patients.

Rapid eye movement sleep pathophysiology

There are a broad variety of pathologies that interrupt normal sleep physiology. A few of the most common are are included below:

Physiological disruptions of sleep

Narcolepsy is the result of the inherited loss of orexin-releasing neurons in the lateral hippocampus which causes somnolence, sleep cycle disruptions and cataplexy ⁶. A hallmark feature of narcolepsy is episodes of uncontrollable sleepiness that results in waking refreshed referred to as “sleep attacks.” This is due to aberrant activation of REM sleep circuits that result in the paralysis or hypotonia characteristic of narcolepsy ⁶. Cataplexy is pathognomic for this condition and consists of loss of muscle tone that is often induced by stressors such as loud noises or heightened emotions. Hypnagogic (upon going to sleep) and hypnopompic (upon waking) hallucinations are more common in narcoleptics than the general patient population as is sleep paralysis (most common upon waking).

Obstructive sleep apnea (OSA) is the cessation of airflow despite normal respiratory effort due to partial or complete obstruction of the upper airway ⁷. Polysomnography is the gold standard test to diagnose obstructive sleep apnea (OSA). Rapid eye movement (REM) sleep has been correlated with the severity of sleep apnea secondary to the differences in sleep positions between REM and NREM sleep ⁷. In particular, apneic episodes can be observed with PSG and are more prevalent during rapid eye movement (REM) sleep due to the prevalence of patients sleeping in the supine position. This is associated with increased frequency of apneic episodes with no effect on the duration of episodes.

Psychiatric disruptions of sleep

Major depressive disorder has been associated with decreases in REM latency, increased REM density, and a prolonged first REM cycle ⁸. Multiple studies have shown that antidepressants (including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants) and cognitive behavioral therapy both serve to normalize sleep architecture. Nearly all antidepressants cause increased REM latency and reduce total REM sleep time. Interestingly, shortened REM latency persists during remission and is even present in patients with a strong family history of depression who do not present with symptoms of major depressive disorder.

Bipolar disorder is characterized by the broad range of sleep disturbances that are observed as a patient fluctuates between episodes of mania, bipolar depression, and euthymia ⁸. REM latency is shorter, and REM density increased in both the manic and depressed episodes. Euthymic bipolar disorder patients experience similarly shortened REM latencies, yet experience increased total REM sleep. Of note are the positive correlations that exist between the duration of the first REM period with manic symptoms and REM density with depressive symptoms that last greater than three months.

Schizophrenia is associated with several changes in REM sleep, including reduced REM latency, higher REM density, and the failure to rebound from REM sleep deprivation ⁸. These changes have not been proven to be consistent, however. Appropriate treatment with antipsychotics has been associated with increased total sleep time and REM latency. Several differences exist between typical and atypical antipsychotics which suggests that the second-generation antipsychotics have additional beneficial effects of sleep via management of other psychiatric symptoms such as depression and cognitive impairment.

Parasomnias are a class of pathologies defined as behavioral manifestations of partial arousals from sleep, particularly REM sleep ⁹. Parasomnias can present with physiological abnormalities that occur during the REM stage including impaired or painful sleep-related erections, bradycardia, and cardiac sinus-arrest. Other parasomnias include phenomena that are associated with REM sleep such as dreaming and can manifest as nightmare disorder. Other disorders involve the aberrations of REM-related muscle atonia which results in behavioral disorders such as recurrent isolated sleep paralysis and REM behavior disorder.

Insomnia is characterized by the dysfunction of sleep onset or maintenance that are not caused by substances or secondary medical conditions ¹⁰. Studies have shown that insomnia is associated with decreased total REM sleep and slow wave sleep. Sedative-hypnotics that promote GABA signaling such as zolpidem or triazolam are the first-line treatment for patients experiencing sleep-onset type insomnia, although 5-HT2 (serotonin) inhibitors are recently being developed as potential treatments for insomnia ¹¹.

Several common substances and medications are associated with rapid eye movement sleep disruption. Alcohol is commonly used substances for self-medication and significantly delays the first onset of REM sleep ³.

Rapid eye movement sleep behavior disorder

Rapid eye movement sleep behavior disorder is a rapid eye movement (REM) sleep parasomnia characterized by dream enactment during sleep and loss of muscle atonia during REM sleep ¹². Patients act out during their dreams while being in the rapid eye movement (REM) stage of the sleep. This enactment may be violent and can lead to injury to themselves or others without any conscious awareness. A patient can recall the contents of the dream upon awakening. Most patient’s with rapid eye movement (REM) behavior disorder will eventually manifest neurodegenerative diseases like parkinsonism, Lewy body dementia, Parkinson disease and multiple system atrophy (MSA) ¹. In fact, several studies have shown that the majority of patients who experience rapid eye movement sleep behavior disorder are subsequently diagnosed with one or more of these syndromes.

Rapid eye movement sleep behavior disorder can be a disturbing disorder for both patients and their bed partners. Both are prone to injuries due to violent behavior ¹³. Patients may be advised to create a safer environment in the bedroom to avoid injuries.

There are also secondary cases of rapid eye movement sleep behavior disorder associated with narcolepsy or use of antidepressant medications ¹³. Secondary causes of rapid eye movement sleep behavior disorder may need to be evaluated through a complete sleep history and review of medications. Any precipitating factors or medications causing or exacerbating rapid eye movement sleep behavior disorder need to be avoided. In proper clinical settings, brain imaging with MRI and EEG may be recommended to evaluate for a secondary cause of rapid eye movement sleep behavior disorder. This is the only parasomnia where polysomnography is required to diagnose rapid eye movement sleep behavior disorder and rule out severe obstructive sleep apnea (OSA) as a cause of “pseudo rapid eye movement sleep behavior disorder.”

The overall prevalence of “spontaneous” rapid eye movement sleep behavior disorder is estimated to be about 1% in the general population and 2% in older individuals ¹⁴. Rapid eye movement sleep behavior disorder is more prevalent in elderly males than females with a male to female ratio of 9 to 1 ¹⁵. There is a strong association of rapid eye movement sleep behavior disorder with many neurodegenerative disorders. rapid eye movement sleep behavior disorder can be a precursor to more serious conditions involving alpha-synuclein neuropathies such as parkinsonism, multiple system atrophy or dementia with Lewy body where prevalence can be as high as 76% to 81% of affected individuals ¹⁶. In a case series, about half of the patients with rapid eye movement sleep behavior disorder converted to a neurologic disorder within 12 years ¹⁷.

Patients should be informed that they are at risk of developing neurodegenerative disorders. Most patients with spontaneous rapid eye movement sleep behavior disorder can eventually develop a neurodegenerative disorder. The rate of conversion is about 50% every 10 years ¹⁸.

Treatment consists of preventive measures while sleeping to avoid injury to the patient as well as the bed partner. In severe cases, the patient may be prescribed melatonin or clonazepam ¹³. Melatonin is the first-line treatment, and in refractory cases, clonazepam in lower doses may be tried.

Rapid eye movement sleep behavior disorder causes

Rapid eye movement sleep behavior disorder occurs because of the failure to inhibit spinal motor neuron during rapid eye movement (REM) sleep ¹³. A strong association between rapid eye movement sleep behavior disorder and future development of a neurodegenerative disorder has been well established ¹⁹. Neurodegenerative disorders linked to alpha-synuclein positive intracellular inclusions, for example, parkinsonism, Lewy body dementia, and multiple system atrophy (MSA), are associated with alpha-synucleinopathies. Nuclei in the pons control rapid eye movement (REM) sleep. Lesions in pons can lead to the development of these synucleinopathies and rapid eye movement sleep behavior disorder ¹⁶. A progressive degeneration of these nuclei may explain the rapid eye movement sleep behavior disorder as a prodrome before full onset of the disease spectrum. Neuroimaging studies have shown progressive dopaminergic abnormalities in patients with rapid eye movement sleep behavior disorder ²⁰. Dopaminergic agents like antidepressants may, therefore, worsen rapid eye movement sleep behavior disorder. In narcolepsy, about 50% of patients may manifest rapid eye movement sleep behavior disorder. Lack of orexin in narcolepsy may fail to stabilize REM sleep and results in a lack of muscle atonia during rapid eye movement (REM) sleep ²¹.

Causes of “secondary” rapid eye movement sleep behavior disorder, especially in younger individuals, include narcolepsy or use of antidepressant medications. Prevalence of rapid eye movement sleep behavior disorder in narcolepsy has been reported to be to be as high as 36% ²¹. Antidepressant medications can precipitate rapid eye movement sleep behavior disorder-type symptoms in up to 6% of cases ²². Other secondary causes of rapid eye movement sleep behavior disorder may include vascular lesions, tumors, demyelinating disease, autoimmune, or inflammatory disorders.

Obstructive sleep apnea (OSA) may mimic rapid eye movement sleep behavior disorder and is referred to as “pseudo rapid eye movement sleep behavior disorder” ²³.

Rapid eye movement sleep behavior disorder pathophysiology

There are 2 systems involved in normal rapid eye movement (REM) sleep; one generates muscle atonia and other for suppresses motor-skeletal activity. Muscle atonia involves active inhibition by neurons in the medulla. Locomotion involves input from forebrain, and the thalamus influences spinal motor neurons. Several brainstem pontine regions have been implicated in rapid eye movement sleep behavior disorder pathophysiology including the peri-locus coeruleus region, pedunculo-pontine nucleus and laterodorsal tegmental nucleus ²⁴. Supra-spinal mechanism handles rapid eye movement (REM) atonia. During rapid eye movement (REM) sleep, nuclei from the pons excite neurons in the medulla, which then transmit descending inhibitory projections to spinal alpha motor-neurons resulting in hyperpolarization and muscle atonia. It is the disinhibition of these neurons that leads to muscle activity during the REM stage of sleep ¹⁹.

Rapid eye movement sleep behavior disorder symptoms

Physicians should get a thorough sleep history regarding nocturnal movements to assess the nature of parasomnia. Sleep history may help to identify whether the symptoms are happening during the REM or non-REM stage of the sleep. A history of epileptic activity may be explored. Patients themselves may not know of motor activity during sleep. In a study of 203 patients ²⁵ with rapid eye movement sleep behavior disorder, only about half of the patients knew of their symptoms. The movements may be short and range in severity. These may include punching, kicking, falling out of bed, gesturing, or knocking over the nightstand. Patients may have vocalizations during an attack. Schenck et al. ²⁶ reported dream enactment in 87% of their study population. Patients had the vivid, intense, action-filled and, violent dreams coincident with the onset of rapid eye movement sleep behavior disorder. Sleep-related injuries occurred in 79% of patients in this series of patients.

Symptoms predominantly occur in the second half of the night when the rapid eye movement (REM) sleep is most prevalent and usually occur during the last REM sleep period.

In milder forms, patients may sleep through the event, but in severe cases, patients may transiently wake up but then fall asleep.

Patients may be examined for the development of any neurodegenerative disorders.

Rapid eye movement sleep behavior disorder diagnosis

According to the third edition of the International Classification of Sleep Disorders (ICSD-3), a diagnosis of rapid eye movement sleep behavior disorder requires all of the following ²⁷:

• Repeated episodes of sleep-related vocalization and/or complex motor behaviors
• Behaviors are documented by polysomnography to occur during REM sleep or, based on the clinical history of dream enactment, are presumed to occur during REM sleep
• Presence of REM sleep without atonia (RSWA) on polysomnography
• An absence of epileptiform activity during REM sleep, unless rapid eye movement sleep behavior disorder can be clearly distinguished from any concurrent REM sleep-related seizure disorder
• Sleep disturbance not better explained by another sleep disorder, medical or neurologic disorder, mental disorder, medication use, or substance use disorder

Rapid eye movement sleep behavior disorder is the only parasomnia which requires an in-facility polysomnogram to diagnose rapid eye movement sleep behavior disorder.

The characteristic polysomnographic finding of rapid eye movement sleep behavior disorder is REM sleep without atonia (RSWA). It is an elevation of motor tone during REM sleep as measured by electromyography (EMG) activity in the chin and/or limb leads ²⁸.

Formal polysomnographic criteria for REM sleep without atonia developed by the American Academy of Sleep Medicine require either of the following ²⁷:

• Sustained elevation of chin electromyography (EMG) activity during REM sleep (greater than 50% of the 30-second epoch duration compared with minimum amplitude in non-REM sleep)
• Excessive bursts of transient muscle activity in the chin or limb electromyography (EMG) during REM sleep, defined by the presence of 5 (50%) or more mini-epochs (30-second epoch is divided into 10 sequential 3-second mini-epochs), containing bursts of transient muscle activity. In rapid eye movement sleep behavior disorder, excessive transient muscle activity bursts last 0.1 to 5.0 seconds and are at least 4 times as high in amplitude as the background empirical mode decomposition (EMD) activity.

Optimally, both upper and lower extremity EMG should be used when evaluating for rapid eye movement sleep behavior disorder. Alternate EMG derivations that make use of upper extremity EMG to improve sensitivity for detecting REM sleep without atonia are reviewed separately.

The disorder needs to be differentiated from other parasomnias including both REM and non-REM sleep parasomnias including nightmares, night terrors, sleepwalking and sleep talking. Periodic leg movements may present with limb movement while sleeping but generally occur during the non-REM stage of the sleep and have distinctive diagnostic criteria on polysomnography.

Epileptic disorders like sleep-related hyperosmolar epilepsy (frontal lobe epilepsy) may present with motor activity during sleep. However, compared with rapid eye movement sleep behavior disorder, these patients are generally younger and unaware of their symptoms.

Rapid eye movement sleep behavior disorder treatment

The primary goal of treatment is to provide patients with a safe sleeping environment for them and their bed partners. Healthcare professionals can achieve this through non-pharmacologic approaches and pharmacotherapy if needed.

It is important to counsel patients and their bed partners on avoidance of potentially hazardous and injuries objects near the patients, for example, firearms or glass objects. Bed partners should be educated on the disease, and the patient’s enactments during dreams are not under voluntary control.

Sleeping alone may be advisable in severe cases. Many patients may require padded bed rails or must sleep in a sleeping bag ²⁹.

Patients may be advised to stop SSRI and tricyclic antidepressants that are known to cause or exacerbate rapid eye movement sleep behavior disorder ³⁰.

Regarding pharmacotherapy, melatonin is now considered the first-line therapy in the treatment of rapid eye movement sleep behavior disorder ³¹. Its mechanism of action is unknown, but in doses between 6 to 18 mg, it augments REM atonia and improves rapid eye movement sleep behavior disorder symptoms. Patients are typically started at doses of 3 mg, and then doses are increased in 3-mg increments until the rapid eye movement sleep behavior disorder symptoms resolve.

Low-dose clonazepam (0.5 to 1 mg at bedtime) has been traditionally used to control rapid eye movement sleep behavior disorder symptoms. Its mechanism of action is not clear either but may help suppress unpleasant dreams ³⁰. Its use may be limited due to side effects. In one study, 39% of patients reported side effects ²⁵.

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