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 and ICSD-2)

The specific DSM-5 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 requires the following criteria for the clinical diagnosis of RBD:^[6]

• Presence of REM sleep without atonia (RSWA) on polysomnography (PSG)
• The presence of at least one of the following conditions: (1) sleep-related behaviors, by history, that have been injurious, potentially injurious, or disruptive (e.g., dream enactment behavior); (2) abnormal REM sleep behavior documented during PSG monitoring
• Absence of epileptiform activity on electroencephalogram (EEG) during REM sleep (unless RBD can be clearly distinguished from any concurrent REM sleep-related seizure disorder)
• 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 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.

Genetics

Nightingale et al suggested in a study that 36% of persons with narcolepsy experience symptoms of RBD.^[23] This link led to the identification of a strong association of RBD with HLA class II genes.^{[24, 25, 26]}

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Epidemiology

According to DSM-5, the prevalence of REM sleep behavior disorder 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]

RBD occurs predominantly in males.^[27] 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.^[27]

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Prognosis

The prognosis of 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.

No deaths have been reported in idiopathic cases of RBD; however, patients and bed partners may experience serious injury.^[28] In the reported cases, 32% of patients had injured themselves and 64% had assaulted their spouse.^[4] Subdural hematomas occurred in two patients.^[4] In secondary cases, the morbidity and mortality rates depend on the underlying disease itself.

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Mortality/morbidity

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] Based on findings from sleep studies, most individuals (50%) with initially “idiopathic” RBD will eventually develop a neurodegenerative disease, most notably, one of the synucleinopathies (e.g., Parkinson disease, multiple system atrophy, dementia with Lewy bodies). REM sleep behavior disorder often predates any other sign of these disorders by many years (often more than a decade).

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Patient Education

Educate the patient and his or her 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.)

For patient education information, see the Sleep Disorders Center, as well as REM Sleep Behavior Disorder, Disorders That Disrupt Sleep (Parasomnias), and Sleep Disorders and Aging.

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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.^[29] The dream-enacting behaviors are usually nondirected and may include punching, kicking, leaping, crying out, or running from bed while still in REM sleep.^[30] For example, a man may dream that he is rescuing his wife from an attack, while in reality, at that moment, he actually is striking her. Some patients may strangle their bed partner. 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 RBD.

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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^[31] ; 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^[32]

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 REM sleep behavior disorder (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, 28, 33]} 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 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, 34]}

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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, 28, 33]} 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.^[28] Clonazepam is ineffective in approximately 10% of patients.

Several studies demonstrated the beneficial effect of melatonin on RBD.^{[30, 35]} 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^[30] ; Kunz and Bes suggested that melatonin restores RBD-related desynchronization of the circadian rhythms.^[36] 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.^[28] The newer generations of antidepressants, particularly venlafaxine and mirtazapine, are frequent precipitators or aggravators of RBD.^[37]

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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