Rapid eye movement behavior disorder (RBD) is a parasomnia involving dream reenactment behavior associated with loss of atonia during rapid eye movement (REM) sleep. These symptoms may bring serious harm to the individual themselves and their sleeping partners. RBD may be secondary to medication use, such as antidepressants. There is a strong correlation between RBD and the development of neurodegenerative alpha-synucleinopathies (i.e., Parkinson disease, dementia with Lewy-bodies, and multiple system atrophy). Symptoms of RBD may precede these disorders by years to decades. Counseling and management of RBD focus on injury prevention and the potential need for treatment of neurodegenerative disorders.
Predisposing factors for rapid eye movement behavior disorder include elderly age, male sex, and neurological disorders. RBD is most suggestive in those with neurodegenerative synucleinopathies, including Lewy-body dementia, Parkinson disease, olivopontocerebellar degeneration, multiple-system atrophy, and Shy-Drager syndrome. However, it can also be observed in other neuropathologic classifications such as tauopathies and amyloidopathies. RBD may be secondary to neurologic diseases that disrupt the brainstem control of muscle atonia of REM sleep, for example, stroke, brainstem neoplasm, Guillain-Barré syndrome, Machado-Joseph disease, Tourette syndrome, autism, mitochondrial encephalomyopathy, and multiple sclerosis. Studies have also suggested associations with traumatic brain injury (TBI), post-traumatic stress syndrome (PTSD), congenital, and neurodevelopmental disorders. The underlying correlation, however, is not clearly understood.
Currently, the most common precipitating factor of acute RBD involves medication-induced loss of REM atonia in patients being prescribed serotonin reuptake inhibitors (fluoxetine), anticholinesterase inhibitors (rivastigmine), tricyclic antidepressants (mirtazapine, protriptyline, amitriptyline, nortriptyline, desipramine, imipramine), monoamine oxidase inhibitors (phenelzine and selegiline), and beta-blockers (bisoprolol). Other acute transient forms of RBD involve toxic metabolic consumption—most commonly involving ethanol use.
RBD with concomitant narcolepsy may be considered a distinct phenotype of RBD. It is characterized by less violent or complex behavior during REM sleep, earlier age of onset, equal sex distribution, and hypocretin deficiency (a lab diagnosis specific for narcolepsy type 1).
Limited studies on the prevalence of idiopathic rapid eye movement behavior disorder have been performed, and this disorder is likely underdiagnosed. Studies suggest a prevalence of 0.5% to 2% in the general population. The prevalence significantly increases in the elderly population, with RBD presenting between 5% to 13% in adults aged 60 to 99 years old. Among the elderly population, approximately 60% of cases are idiopathic, and 40% of cases are suggestive of an underlying neurologic disorder. The onset of symptoms is typically seen during the sixth or seventh decade of life. There is a male predominance amongst the older population, but there is a more equal distribution between males and females under the age of 50 years.
There is a strong link between RBD and psychiatric disorders. RBD is found to be 5-fold and 10-fold more likely to develop in patients receiving antidepressants and patients with psychiatric disorders, respectively.
A prime feature of rapid eye movement behavior disorder is the intermittent loss of atonia during REM sleep that leads to motor behaviors associated with dreaming. Muscle atonia during normal REM sleep is controlled within the pontine tegmentum and medial medulla. Excitatory glutamatergic neurons within the dorsal subcoeruleus nucleus activate the spinal cord inhibitory interneurons thereby initiating REM sleep atonia. Animal models and diagnostic imaging of case reports suggesting interruption or disinhibition of these areas of the brainstem is the pathophysiology of RBD.
The neurodegenerative alpha-synucleinopathies consist of glial cytoplasmic inclusions, which are aggregates of insoluble alpha-synuclein protein. However, it is unclear if the link between this neurodegenerative classification and RBD is a result of these accumulated aggregates or through another pathology.
Rapid eye movement behavior disorder exhibits abnormal behaviors during REM sleep that may disrupt sleep and lead to injury. Sleep-related injuries are common and may include harm to sleeping partners. Symptoms are usually associated with the enactment of undesirable or violent dreams where the patient is being attacked, chased, or compromised. The patient often wakes up abruptly with prompt alertness and is able to recount the dream coherently. The observed sleep behavior corresponds to dream actions. An event would likely appear at least 90 minutes after sleep onset and more frequently during the latter half of sleep due to the typical pattern of REM sleep. The pattern of events, however, may occur differently with concomitant history of narcolepsy due to the atypical patterns of REM sleep in this disorder.
The abnormal sleep-related behavior includes gesturing, talking, shouting, laughing, grabbing, punching, kicking, sitting up, flailing arms, or leaping from the bed. Some behavior may cause injuries that require immediate medical attention. It is uncommon to exhibit walking. The eyes are typically closed during an event. The patient would not typically interact with the environment but rather only behave in association with the dream. Increased periodic limb movement may occur that may disrupt the sleeping partner.
Acute forms of RBD can be exhibited with intense REM sleep rebound due to withdrawal effects from REM suppressing drugs. These include alcohol, sedative-hypnotic medications, drug intoxication, or antidepressants.
The diagnosis of rapid eye movement behavior disorder is comprised of two features: loss of normal atonia during REM sleep and dream enactment behavior. Evaluation involves in-lab video polysomnography (vPSG), but may also be diagnosed with suggestive clinical history when video polysomnography is unavailable or does not meet the polysomnography criteria for REM behavior disorder. Polysomnography involves concurrent recording of many physiologic variables. In this case, the emphasis is on the evaluation of the video, electroencephalogram, electrooculogram, and electromyogram to assess the loss of REM atonia. The electromyogram is placed on the chin and the lower extremities bilaterally. Additional placements can be considered for the upper extremities as some patients may exhibit arm and hand behaviors during REM sleep. The gold standard for tone evaluation includes manual scoring during REM sleep allowing for subjectivity. Also, there is no universal standard for the definition of abnormal REM atonia, and transitory myoclonic movements can be displayed during normal REM sleep. The most present evidence-based data for identifying REM without atonia in the evaluation of RBD notes that any chin electromyography activity combined with increased limb electromyography activity in greater than 27% of REM sleep consistently differentiates REM behavior disorder from control.
The International Classification of Sleep Disorders, 3 ed., states that diagnostic criteria for RBD must include the following:
Validated questionnaires have been established to screen patients for RBD. Two single-question questionnaires have been established; the Mayo Sleep Questionnaire, and the RBD1Q. The Mayo sleep question was tested in the general population and queried the bed partners (sensitivity 98% and specificity 74%); it asks “Have you ever seen the patient appear to ‘act out his or her dreams’ (punched or flailed arms in the air, shouted, or screamed) while sleeping?” The RBD1Q was tested in a sleep center and queries the patient directly (sensitivity 98% and specificity 87%); it asks “Have you ever been told, or suspected yourself, that you seem to ‘act out your dreams’ while asleep (for example, punching, flailing your arms in the air, making running movements, etc.)?” Other questionnaires included the 13-item RBDQ-HK (82% sensitivity and 87% specificity), 14-item RBDSQ (96% sensitivity and 56% specificity), and the 5-item Innsbruck Questionnaire (91% sensitivity, 86% specificity).
Idiopathic RBD is uncommon. Therefore, in the general population, the positive predictive value of questionnaires with the highest specificity may be low, which suggests the continued importance of evaluation with polysomnography. However, polysomnography may be less important in patients with neurodegenerative synucleinopathy, where the prevalence of RBD can exceed 50%.
The primary treatment goal of rapid eye movement behavior disorder is to reduce the risk of injury to the patient and bed partners. The change in routine sleep habits may prove challenging and difficult for the patient and their bed partners. Their risk for injury, however, needs to be emphasized. Patients and sleeping partners should be educated on the following:
Primary pharmacological treatments of RBD include melatonin and clonazepam. Clonazepam is a very effective treatment for RBD and considered the first-line pharmacological therapy since the mid-1980s. Although clonazepam’s mechanism of action in RBD is not clearly understood, animal studies have suggested its effect on the serotonergic pathway plays a role. Clonazepam is a long-acting benzodiazepine with a half-life of 30 to 40 hours and peak effect within 1 to 4 hours after ingestion. The recommended initial dose is 0.25 mg 30 minutes prior to bedtime, and a gradually increased dose to as high as 4 mg has been reported. As observed in studies, the low dose required for treatment offers a low concern for abuse and tolerance. Common side effects, however, have been observed, including residual morning sleepiness, increased fall risk, memory dysfunction, impotence, and unstable gait. Responders may note an initial period of symptomatic suppression with the reemergence of more complex behavior. Caution of use should be considered in those with dementia, fall risk, and obstructive sleep apnea due to the exacerbation of associated symptoms. In those with concomitant insomnia or complaints of residual morning sleepiness, clonazepam can be taken up to two hours prior to bedtime. Abrupt cessation of clonazepam will exhibit prompt relapse. Clonazepam can significantly reduce periodic limb movement syndrome but will not normalize REM sleep atonia.
Although clonazepam is the first-line therapy and considered the most effective pharmacological therapy, melatonin may be the preferred initial therapy due to better tolerability and favorable side effect profile, particularly in those with comorbid obstructive sleep apnea and memory problems. Melatonin is an endogenous hormone that is secreted from the pineal gland in association with circadian rhythm, and its secretion is influenced by light exposure. Although the mechanism of action is unclear, melatonin of 3 to 12 mg at bedtime is the recommended dose and appears effective in reducing RBD symptoms and exhibits an objective reduction of REM without atonia. Some patients may require higher doses, and this is often well tolerated without side effects, although potential dose-related side effects may include morning sleepiness, morning headaches, delusions, hallucinations, and dizziness. The benefit of melatonin has been observed to persist for weeks upon cessation of melatonin, while the discontinuation of clonazepam has often displayed immediate return of symptoms. Melatonin receptor agonists in the treatment of RBD have not been well studied.
Few other medications have been studied and considered as second-line therapy for RBD. Limited studies have suggested a benefit from pramipexole, a dopamine agonist; however, results are contradictory. While paroxetine and L-DOPA have not proven to be consistently effective in RBD and studies, there is a suggestion they may cause medication-induced RBD or even exacerbate RBD symptoms. Acetylcholinesterase inhibitors such as donepezil have limited data on efficacy for RBD symptoms, but this medication may be considered in the case of concomitant alpha-synucleinopathy.
Other second- or third-line therapies have been observed with some benefit; however, these are only based on anecdotal evidence. These include zopiclone, benzodiazepines other than clonazepam (temazepam, triazolam, alprazolam), desipramine, carbamazepine, Yi-Gan San (herbal medicine), and sodium oxybate.
Limited studies have been performed on dual therapies.
Treating comorbid obstructive sleep apnea with continuous positive airway pressure may decrease the frequency and severity of RBD symptoms. Medication reconciliation is necessary to identify medications prone to inducing loss of REM atonia. Management should be discussed with ordering providers and the patient that may require discontinuation, reduction of dose, or earlier intake of medication.
Many conditions may mimic the appearance of rapid eye movement behavior disorder symptoms. Taking an appropriate history and conducting in-lab video polysomnography is necessary to distinguish the definitive diagnosis.
Primary causes of arousal disorders are often non-REM parasomnias, which include confusional arousals, sleepwalking, and sleep terrors. These disorders typically occur during childhood in the first half of the night during non-REM sleep without dream recall. These clinical findings, however, may be observed concomitantly with objective findings of REM without atonia and have been characterized as parasomnia overlap syndrome. Other associated parasomnias may include sleep-related eating disorder, sexsomnia, or rhythmic movement disorder.
Secondary causes of arousal disorders include obstructive sleep apnea and periodic limb movement disorder. In these cases, the apnea or movement led to arousal or disturbance that may provoke a disturbing nocturnal behavior. Treatment of the underlying sleep disorder often improves symptoms.
Trauma-associated sleep disorder has recently been characterized as a novel parasomnia. The patient demographics tend to be younger males with traumatic experiences as the temporal onset of disturbing nocturnal behaviors and nightmares. They may or may not have posttraumatic disorders. Objective findings include REM without atonia. Disruptive nocturnal behaviors captured in the lab are rare.
It is important to differentiate RBD behaviors from nocturnal seizures, including juvenile myoclonic epilepsy, grand mal seizure, benign rolandic, Landau-Kleffner syndrome, and sleep-related hypermotor epilepsy (formerly known as nocturnal frontal lobe epilepsy). Patients with epilepsy may exhibit prodromal symptoms such as mood changes and auras, such as irregular blinking or loss of bladder/bowel control. Another differentiating behavior between RBD and seizures is the presentation of postictal states that may appear as confusion, headaches, nausea, temporary neurofocal deficits, sensory deficits, and/or suppressed alertness following the seizure.
The clinical progression of rapid eye movement behavior disorder is dependent on the etiology. Idiopathic RBD and RBD associated with neurodegenerative disorders are often slowly progressive. Whereas, medication-induced RBD may occur acutely and improve upon discontinuing the medication. Prognosis with treatment is good in acute and idiopathic RBD. In RBD associated with neurodegenerative disorders, the prognosis is dependent on the underlying disorder.
Amongst those with confirmed diagnosed neurodegenerative alpha-synucleinopathies, it is estimated that the correlation with RBD is significantly high: 30 to 50% of Parkinson disease, 75% of Lewy-body dementia, and 70% to 90% of multiple system atrophy. The conversion rate risk over five years is approximately 33% and is even higher over 10 to 14 years, increasing to 82% to 96%. Prognosis of RBD with Parkinson disease has a higher risk for dementia, and RBD with Lewy-body dementia has a higher mortality risk.
The primary complications concerning rapid eye movement behavior disorder are the risk of injury and the potential prodromal symptoms linking neurodegenerative alpha-synucleinopathies. The injuries sustained during an event may require immediate medical attention and/or involve sleeping partners causing legal implications. Management for RBD primarily involves injury risk mitigation through behavioral changes and/or pharmacologically. Early diagnosis and management of RBD provide a therapeutic window to treat the potential underlying neurodegenerative disorder.
Patients with rapid eye movement behavior disorder and their sleeping partners are prone to injuries during their sleep that can result in serious harm. The sleeping partner could be a target of a violent dream reenactment behavior leading to the patient being arrested on charges of domestic assault. Therapeutic management should include injury risk mitigation discussions with both the patient and their sleeping partner.
It is ethically important to disclose potential risks for the development of neurodegenerative disease to patients diagnosed with RBD. An open discussion with family members offers an opportunity for improved understanding and avoiding misinformation about the disease process. It is recommended to counsel patients that Parkinson’s disease and other neurodegenerative disorders can be treatable. The prompt diagnosis of RBD may provide an early therapeutic window for neuroprotective therapies. Ongoing collaborative studies for symptomatic and neuroprotective therapy are being conducted by the International Rapid Eye Movement Sleep Behavior Disorder Study Group.
There is a high risk with rapid eye movement behavior disorder for the development of alpha-synucleinopathy pathology after 10 years from diagnosis.
There are currently no guidelines on counseling and management regarding potential phenoconversion of RBD to alpha-synucleinopathy. The approach may include a discussion with the patient to understand this risk. The patient should be recommended to seek consultation from their primary care provider, sleep specialist, and/or neurologist if associated symptoms were to manifest such as memory issues, constipation, gait abnormalities, orthostatic hypotension, or neurofocal deficits.
Prodromal alpha-synucleinopathy is possible in younger patients less than 50 years old, but nondegenerative disorders should be considered, including autoimmunity, narcolepsy, and REM-suppressing medication use.
There is a lack of controlled, randomized, double-blind studies for the treatment of RBD. However, injury prevention is critical in the management of RBD. Clonazepam is highly effective in treating RBD to reduce injury risks.
Low risk for adverse reaction favors melatonin over clonazepam as initial pharmacological therapy for RBD.
Other etiology may resemble RBD symptoms and behaviors, necessitating evaluation with a formal vPSG to rule out malingering, psychogenic movement disorder, NREM parasomnias, sleep-related epilepsy syndrome, and obstructive sleep apnea. As physicians may be called upon for legal proceedings, this becomes more paramount when an illegal act was presented to occur during sleep.
The evaluation and management of newly diagnosed rapid eye movement behavior disorder require a multi-disciplinary effort involving a sleep specialist, neurologist, and primary care provider to maximize these patient’s wellbeing. Injury prevention is paramount and may require both pharmacological and non-pharmacological interventions. The looming prognosis of a neurodegenerative disorder in association with RBD will likely provoke anxiety and mood disruption and will require management on its own. Including family members is also a key element of support for these patients.
Unfortunately, there are no established means of predicting the development of neurodegenerative disease nor effective management to slow down the disease process. This makes the discussion with patients on the prognostic timeline and the decision of optimal treatment management truly difficult. Close follow-ups and multi-disciplinary communication are key.
Future research is needed to identify potential biomarkers and neuroprotective strategies to prevent further neurodegeneration in high-risk individuals.
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