REM Sleep Behavior Disorder

Background

Rapid eye movement (REM) sleep behavior disorder (RBD) is a sleep disorder characterized by the loss of normal voluntary muscle atonia during REM sleep, in association with complex motor behavior while dreaming.^{[1, 2, 3, 4]}

Diagnostic Criteria (DSM-5-TR and ICSD-3-TR)

The specific DSM-5-TR criteria for rapid eye movement sleep behavior disorder are as follows:^[5]

• Recurrent episodes of arousal during sleep associated with vocalization and/or complex motor behaviors that arise during rapid eye movement (REM) sleep
• On waking from these episodes, the individual is not confused or disoriented and is completely alert
• Either of the following is present: REM sleep without atonia on polysomnographic recordings; or a history suggestive of REM sleep behavior disorder and an established synucleinopathy diagnosis (e.g., Parkinson’s disease, multiple system atrophy)
• The episodes cause significant distress or impairment in social, occupational or other areas of functioning which may include serious injury to self or the bed partner
• The disturbance cannot be explained by the effects of a drug of abuse or medication
• The episodes cannot be attributed to another mental disorder or medical condition

The International Classification of Sleep Disorders, Third Edition, Text Revision requires all the following criteria for the diagnosis of RBD:^[6]

• Repeated episodes of sleep-related vocalization and/or complex motor behaviors.
• These behaviors are documented by polysomnography to occur during REM sleep, or based on clinical history of dream enactment, are presumed to occur during REM sleep.
• Presence of REM sleep without atonia (RSWA) on polysomnography (PSG)
• Sleep disorder not better explained by another sleep disorder, a medical or neurologic disorder, a mental disorder, medication use, or a substance use disorder

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Etiology

The precise etiology and neural structures involved in rapid eye movement sleep behavior disorder (RBD) are unknown. Based on animal (cats, rats), lesional, and neuropathologic studies, sleep-regulating nuclei, particularly the pontine tegmentum, are thought to be involved in the pathogenesis of RBD. Also, a complex interplay of various neurochemical systems, such as the noradrenergic, cholinergic, and serotonergic systems, seems to exist in the pathogenesis of the condition.^{[1, 7]}

Normally, generalized atonia of skeletal muscles occurs during REM sleep. This atonia results from active inhibition of the final common pathway of spinal motor neurons by way of the medullary magnocellular reticular formation (MCRF); this suppresses anterior horn cell activity via projections of the ventral lateral reticulospinal tract.

Various pontine nuclei are known to influence the REM and non-REM sleep circuits, including the locus coeruleus(LC), pedunculopontine nucleus (PPN), and laterodorsal tegmental nucleus (LDTN).^[8] In addition, forebrain cortical and subcortical structures and the substantia nigra, thalamus, hypothalamus, basal forebrain, and frontal cortex are also involved. However, their precise roles are unknown.

Idiopathic RBD

RBD may be idiopathic. However, several studies have suggested that idiopathic RBD is a potential marker for the later development of neurodegenerative disorders characterized by alpha-synuclein deposition. These include Parkinson disease, multiple system atrophy, dementia with Lewy bodies, and pure autonomic failure, with the risk varying among different studies. (RBD is less frequently associated with nonsynucleinopathies.)^{[1, 2, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18]}

In fact, studies have suggested that RBD may be associated with alpha-synuclein–mediated degeneration of sleep-regulating nuclei in the brainstem, particularly the pontine tegmentum.

In essence, RBD may be the prodrome of neurodegenerative disease, such as diffuse Lew body (DLB) disease or Parkinson disease.^{[1, 19]} In experimental studies in cats, bilateral pontine lesions resulted in a persistent absence of REM atonia associated with prominent motor activity during REM sleep similar to that observed in RBD in humans.

Studies by Eisensehr et al using iodine 123 (¹²³ I) immunoperoxidase technique (IPT) single photon-emission computed tomography (SPECT) scanning demonstrated that striatal presynaptic dopamine transporters are reduced in idiopathic RBD.^[20]

Studies by Fantini et al demonstrated impairment of cortical activity in idiopathic RBD, particularly in the occipital region during both wakefulness and REM sleep, compared with controls.^[21] Results were similar to those of functional studies, such as of the perfusion and metabolic impairment pattern, observed in DLB disease and in Parkinson disease. Similar cortical activity in the frontal and temporal regions was impaired only during wakefulness.

Research evidence suggests, therefore, that many cases of idiopathic RBD may not be truly idiopathic, leading some to suggest the term cryptogenic rather than idiopathic.^[22]

Secondary RBD

In addition, RBD may occur in association with various neurologic conditions (ie, secondary RBD), including vascular lesions, brainstem neoplasms, demyelinating disease, autoimmune/inflammatory disorders, and neurodegenerative disorders.

Based on findings from sleep studies, most individuals (50%) with initially “idiopathic” RBD will eventually develop a neurodegenerative disease. RBD is thought to be a prodromal marker of neurodegenerative synucleinopathies and is present in a majority of patients with Parkinson disease (50%), multiple system atrophy (80–90%), dementia with Lewy bodies(80%).^[23]  REM sleep behavior disorder often predates any other sign of these disorders by many years (often more than a decade).  

Genetics

Nightingale et al suggested in a study that 36% of persons with narcolepsy experience symptoms of RBD.^[24] This link led to the identification of a strong association of RBD with HLA class II genes.^{[25, 26, 27]}

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Epidemiology

According to DSM-5-TR, the prevalence of REM sleep behavior disorder (RBD) is approximately 0.38%–0.5% in the general population. Prevalence in patients with psychiatric disorders is greater, possibly related to medications prescribed for psychiatric disorders.^[5]

REM sleep disorder is present concurrently in approximately 30% of patients with narcolepsy. When comorbid with narcolepsy, RBD presents in younger patients with equal frequency in males and females.^[5]   

RBD occurs predominantly in males.^[28] In a report by Olson et al involving 93 patients with RBD, only 12 patients (13%) were female.^[4]

Typically, RBD is a disease of elderly persons.^[9] The risk increases after the sixth decade, although the disease may occur at any age, including in childhood.^[28]

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Prognosis

The prognosis of rapid eye movement sleep behavior disorder (RBD) depends on its etiology. In idiopathic cases, the symptoms are controlled with medications. In secondary cases, the prognosis depends on the underlying primary disease. For example, patients with Parkinson disease and RBD have poorer cognitive performance and a greater risk of dementia compared to patients with Parkinson disease but without RBD.^[23]

No deaths have been reported in idiopathic cases of RBD; however, patients and bed partners may experience serious injury.^[29] In the reported cases, 32% of patients had injured themselves and 64% had assaulted their spouse.^[4] Subdural hematomas occurred in two patients.^[4]

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Patient Education

Educate the patient and their bed partner for environmental safety. Potentially dangerous objects should be removed from the bedroom, and the mattress should be placed on the floor or a cushion placed around the bed. (See Treatment.)

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History

Routine medical history should include questions that screen for abnormal sleep movements and altered dreams.

The presenting complaint is violent dream-enacting behaviors during REM sleep, often causing self-injury or injury to the bed partner.^[30]  These behaviors usually occur in the second half of the night when REM sleep is more prevalent.^[31]  

The dream-enacting behaviors are usually nondirected and may include punching, kicking, biting, leaping, crying out, or running from bed while still in REM sleep.^[32] For example, a person may dream that they are rescuing their spouse from an attack, while in reality, at that moment, the person is actually striking their spouse. Some patients may strangle their bed partner.^[31] Directed behavior, such as homicide, has not been reported.

The patient may be wakened or may wake spontaneously during an attack and recall vividly the dream that corresponds to the physical action. In some cases, an extended prodrome of prominent limb and body movements occurs before the development of rapid eye movement sleep behavior disorder (RBD).

The presence of a witness who can report abnormal behaviors during sleep is helpful. A detailed clinical history should be elicited from the bed partner or roommate. Recorded home videos can be helpful in differentiation RBD from other parasomnias and nocturnal epileptic seizures.^[31]

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Approach Considerations

The most important diagnostic studies in rapid eye movement sleep behavior disorder (RBD) include the following:

• Polysomnographic video recording - This is the most important diagnostic test in RBD;^[33]  on PSG, at least some tonic or phasic abnormalities of muscle tone are observed during REM sleep accompanying the attack, although usually patients have both.
• Monitoring electro-oculogram (EOG)
• EEG^{[3, 11]}
• Electrocardiogram (ECG)
• PSG to evaluate respiration for sleep apnea
• Multiple electromyography (EMG) channels using chin, bilateral extensor digitorum, and tibialis anterior muscles^[34]

Routine laboratory tests are usually not helpful. Imaging studies are not indicated in idiopathic cases but are indicated if neurologic dysfunction is suggested by history and neurologic examination.^[4] Moreover, a study demonstrated that IPT-SPECT may be a useful tool in the diagnosis of RBD.

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Medical Care

The neurologist may consult a sleep specialist for the proper diagnosis and treatment of rapid eye movement sleep behavior disorder (RBD). RBD is treated symptomatically with various medications. However, the response varies in individual cases; therefore, all available medications should be tried before considering the patient's RBD as intractable.

Clonazepam is highly effective in almost 90% of patients with RBD.^{[4, 29, 35]} It demonstrates a complete benefit in 79% of patients with the disorder and a partial benefit in 11% of patients. There is little evidence of tolerance or abuse of this drug.

Symptoms relapse promptly on discontinuation of medications in almost all patients; therefore, pharmacologic treatment should be continued indefinitely.

An important aspect of management of patients with RBD is environmental safety. Potentially dangerous objects should be removed from the bedroom, and the mattress should be placed on the floor or a cushion should be placed around the bed.

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Long-Term Monitoring

Because rapid eye movement sleep behavior disorder (RBD) has strong relationships with many neurodegenerative disorders, such as Parkinson disease, multiple system atrophy, and dementia, the neurologist always should explore the possibility of RBD in these conditions.

RBD symptoms may be the first manifestations of these disorders and may precede the onset of other typical symptoms and signs by several years. Therefore, careful follow-up is needed to assess the risk of neurodegenerative disorder development, for patient counseling, and to plan for potential neuroprotective trials.^{[4, 11, 13, 14, 36]}

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Guidelines Summary

In 2023, the American Academy of Sleep Medicine (AASM) published guidelines on the management of rapid eye movement sleep behavior disorder (RBD) in adults.^[37]  All recommendations summarized below are conditional based on the strength of evidence from a systematic review of the literature.^[38]

For adults with idiopathic (isolated) RBD, the guidelines suggest the following treatments over no treatment:^[37]

• Clonazepam
• Immediate-release melatonin
• Pramipexole

Transdermal rivastigmine is suggested over no treatment for the management of mild cognitive impairment in adults with idiopathic (isolated) RBD.^[37]

For adults with RBD due to a medical condition, the guidelines suggest the following treatments over no treatment:^[37]

• Clonazepam
• Immediate-release melatonin

Transdermal rivastigmine is suggested over no treatment for the management of secondary RBD in patients with Parkinson disease.^[37]

The guidelines suggest against deep brain stimulation for the treatment of secondary RBD due to a medical condition.^[37]

For adults with drug-induced RBD, the guidelines suggests discontinuation of the inciting drug.  However, the severity of comorbid conditions for which the inciting drug is taken and the consequences of eliminating treatment must be taken into consideration before drug discontinuation.^[37]

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Medication Summary

The treatment of rapid eye movement sleep behavior disorder (RBD) can be challenging in some patients with underlying neurodegenerative conditions. Clonazepam has proven to be a highly successful treatment for RBD.^{[4, 29, 35]} It is effective in nearly 90% of patients (complete benefit in 79% of patients and partial benefit in another 11% of patients), with little evidence of tolerance or abuse. The response usually begins within the first week, often on the first night.

The initial dose is 0.5 mg at bedtime. If this is ineffective, doses can be increased to 1–2 mg. With continued treatment for years, moderate limb twitching with sleep talking and more complex behaviors may reemerge. Nevertheless, control of the violent behaviors persists. The treatment should be continued indefinitely, as violent behaviors and nightmares relapse promptly with discontinuation of medications in almost all patients.

The specific mechanism of action of clonazepam in RBD is unknown but may reflect in part its serotonergic properties. In a minority of patients, particularly elderly persons, clonazepam may increase the risk of confusion or falls and may worsen obstructive sleep apnea.^[29] Clonazepam is ineffective in approximately 10% of patients.

Several studies demonstrated the beneficial effect of melatonin on RBD.^{[32, 39]} The effective dose of melatonin was 3–6 mg taken orally at bedtime. Only 36% of patients experienced adverse effects, which resolved with decreased dosing. The dosage may be increased every 5–7 days to 12 mg/day in some cases, if tolerated. The mechanism of melatonin is unclear^[32] ; Kunz and Bes suggested that melatonin restores RBD-related desynchronization of the circadian rhythms.^[40] Polysomnographic studies showed possible direct restoration of the mechanisms producing REM sleep muscle atonia.

Other medications, such as tricyclic antidepressants, may be effective in some patients with RBD. However, tricyclics are also known to actually precipitate RBD.^[29] The newer generations of antidepressants, particularly venlafaxine and mirtazapine, are frequent precipitators or aggravators of RBD.^[41]

Levodopa may be very effective in patients in whom RBD is the harbinger of Parkinson disease. In addition, anecdotal reports exist of responses to carbamazepine, clonidine, and L-tryptophan in patients with RBD.

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Clonazepam (Klonopin)

• Dosing, Interactions, etc.

Clinical Context:  Clonazepam is very effective in the treatment of RBD in small doses. Its exact mechanism of action is unknown. There is little evidence of tolerance or abuse of the drug when it is administered in such small doses.

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Class Summary

By binding to specific receptor sites, these agents appear to potentiate the effects of gamma-aminobutyric acid (GABA) and facilitate inhibitory GABA neurotransmission and other inhibitory transmitters.

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Levodopa/carbidopa (Sinemet, Parcopa)

• Dosing, Interactions, etc.

Clinical Context:  Levodopa/carbidopa may be very effective in patients in whom RBD is a harbinger of Parkinson disease. It comes in strengths of 25/100 mg, 25/250 mg, and 10/100 mg.

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Class Summary

These agents often are indicated for patients with Parkinson disease.

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