Narrative review

Respiratory disease Neurology General medicine

Volume 207 - Issue 6

REM sleep behaviour disorder: not just a bad dream

Authors: Elie Matar and Simon JG Lewis

Med J Aust 2017; 207 (6): 262-268. || doi: 10.5694/mja17.00321
Published online: 18 September 2017

Treatment is effective and involves treatment of underlying causes, modification of the sleep environment, and pharmacotherapy

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Rapid eye movement (REM) sleep behaviour disorder (RBD) is a parasomnia characterised by the loss of the normal atonia during the REM stage of sleep, resulting in overt motor behaviours that usually represent the enactment of dreams. Patients will seek medical attention due to sleep-related injuries or unpleasant dream content.
Idiopathic RBD which occurs independently of any other disease occurs in up to 2% of the older population. Meanwhile, secondary RBD is very common in association with certain neurodegenerative conditions. RBD can also occur in the context of antidepressant use, obstructive sleep apnoea and narcolepsy.
RBD can be diagnosed with a simple screening question followed by confirmation with polysomnography to exclude potential mimics.
Treatment for RBD is effective and involves treatment of underlying causes, modification of the sleep environment, and pharmacotherapy with either clonazepam or melatonin.
An important finding in the past decade is the recognition that almost all patients with idiopathic RBD will ultimately go on to develop Parkinson disease or dementia with Lewy bodies. This suggests that idiopathic RBD represents a prodromal phase of these conditions.
Physicians should be aware of the risk of phenoconversion. They should educate idiopathic RBD patients to recognise the symptoms of these conditions and refer as appropriate for further testing and enrolment into research trials focused on neuroprotective measures.

Rapid eye movement (REM) sleep denotes the stage of sleep most commonly associated with vivid dreaming and is characterised by rapid ballistic eye movements and an electroencephalogram pattern that closely resembles the waking state.1 Several physiological changes occur during REM sleep, the most important of which is a generalised inhibition of skeletal muscle tone (atonia) that allows subjects to remain still despite this phase of heightened brain activity.

REM sleep behaviour disorder (RBD) is a parasomnia that results from the loss of the normal atonia during REM sleep, thus manifesting as overt motor behaviours thought to represent the enactment of dreams or nightmares. These behaviours range from complex violent movements to vocalisations and even simply an elevation of chin or limb muscle tone on electromyography.2

Although idiopathic RBD (iRBD) has a relatively low prevalence in the general population, its relevance must be appreciated, especially in general practice, sleep medicine, neurology and psychiatry.3

This article provides an overview of RBD and explores the link between iRBD and neurodegenerative disease. Citations were derived from a comprehensive search of online databases including MEDLINE, Embase, the Cochrane Database of Systematic Reviews, and BMJ Clinical Evidence using the search terms “REM Sleep Behavio*” and “Rapid Eye Movement Sleep”. A summary of the clinical features, diagnosis, management and follow-up of RBD is shown in Box 1.

Clinical features and diagnosis of RBD

The core characteristics of RBD are abnormal sleep behaviours and unpleasant dreams. A review of the clinical history of 203 consecutive patients with iRBD referred to a tertiary sleep centre found that the most common motor behaviours included punching (88%), kicking (82%), falling out of bed (77%), gesturing (73%), and knocking down the night stand (66%).4 Injury to the bed partner occurred in 21% of patients. Vocalisations such as talking (96%), screaming (90%), moaning (64%), laughing (54%) and crying (44%) were also common. Only about half of the patients were themselves aware of these abnormal behaviours.

These clinical features form the basis of a number of simple screening questionnaires that have been developed to identify potential RBD in the general population.5-8 Postuma and colleagues6 have validated a single-question RBD screening tool (RBD1Q) where a positive response to the question “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)?” had a 94% sensitivity and 87% specificity for detecting polysomnography-confirmed RBD. This and other similar questionnaires demonstrate that population-based screening for RBD is tractable and can be effectively performed by any practitioner in the clinic setting.5,7-9

Polysomnography remains the gold standard test for the diagnosis of RBD where excessive muscle activity in the chin (mentalis) or limb muscles must be demonstrated on electromyography during the REM stage of sleep10 (Box 2). Other features of REM sleep, such as REM sleep latency, duration of REM sleep and percentage of REM sleep time are usually normal.11 Synchronised audiovisual recording of sleep is also helpful and often used in conjunction with polysomnography for capturing behaviour.

The sensitivity and specificity of the above diagnostic tools are summarised in Box 3.

Differential diagnosis

Sleep enactment behaviours can occur in healthy, often young individuals in the context of excessive fatigue or alcohol use.12,13 These dream enactment behaviours may even be normal in women in the post-partum period.14 In addition to non-REM parasomnias such as sleepwalking and night terrors, a number of other important RBD mimics need to be excluded on the basis of polysomnography including obstructive sleep apnoea15 (in which dream enactment behaviours may occur during arousals), nocturnal frontal lobe epilepsy16 and periodic limb movements in sleep.17

Epidemiology

Cross-sectional studies estimate the prevalence of RBD to be about 0.5% of the general population and up to 2% in people over the age of 60 years.18-20 The prevalence may be higher in older populations, with one study finding 8.9% of people aged 70–89 years reporting symptoms consistent with RBD.21 Epidemiological studies are thought to underestimate the true prevalence with a bias towards the reporting of violent behaviours while more subtle motor behaviours go undetected.21

A male predominance is generally seen in RBD patients with a male to female ratio ranging from 2:1 and up to 9:1 in some studies.18,22-24 This figure is considered to be similarly skewed by reporting bias, as men tend to have more violent and injurious dream enactment behaviours compared with women.23 The under-representation of RBD in women may also be explained by the reduced tendency among men to seek medical attention and the difficulty of detecting RBD in older women who tend to outlive their spouses.25

The onset of RBD typically occurs in the sixth to seventh decade of life, with a lag time to diagnosis of up to 10 years.23,24,26,27 Young onset RBD (occurring in patients aged younger than 50 years) is less common and as a rule is almost always associated with secondary causes such as antidepressant use, narcolepsy and psychiatric illness.24,27 Unlike in the older population, males and females are represented equally in this group suggesting confounding gender associations with these factors.27 Similarly, RBD in the paediatric population is a distinct entity and usually occurs in the setting of narcolepsy or comorbid malignant or neurodevelopmental abnormalities.28

Secondary RBD and disease associations

We have known for some time that RBD is a prominent feature of neurodegenerative conditions characterised by the histopathological inclusion of α-synuclein (denoted as Lewy bodies and neurites). The primary diseases in this category are Parkinson disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). In PD, 34–47% of patients experience symptoms of RBD,29,30 and up to 58% when including patients with polysomnography-confirmed REM sleep without atonia.30 RBD is even more common in DLB; a clinicopathological study of 172 patients with RBD found that the most common pathological diagnosis was DLB (45% of cases).31 Overall, about 70% of patients with DLB screen positive for symptoms of RBD32 — an association strong enough that it is considered to be a diagnostic feature of the disorder.33 RBD may be even more common in MSA, with a recent study of 19 consecutive patients finding them all to have polysomnography-confirmed RBD irrespective of reported symptoms.34

Although much rarer, there have been occasional reports of RBD in association with other neurological disorders including progressive supranuclear palsy,35 corticobasal degeneration,36 Machado–Joseph disease,37 epilepsy,38 multiple sclerosis,39 Guillain–Barré disease,40 amyotrophic lateral sclerosis41 and Huntington disease.42 There is contention about the role of RBD in Alzheimer’s disease (AD), as the first reported autopsy-proven case of AD and RBD was found to involve a Lewy body variant of AD.43 To date, large clinicopathological series of RBD have found AD pathology to be rare (< 1%).31 RBD has also been reported in neurodevelopmental disorders such as autism44 and Tourette syndrome,45 as well as among a number of paraneoplastic disorders such as limbic encephalitis and cerebellar degeneration.46-48 RBD can also occur in the setting of discrete ischaemic, demyelinating or neoplastic lesions affecting regions of the brain (primarily brainstem pontine structures) involved in the control of REM sleep.49,50

Apart from neurological disease, there is also significant overlap between RBD and narcolepsy. About 50% of patients with narcolepsy have evidence of REM sleep without atonia, and the mechanism thought to underlie this is distinct from the synuclein pathology associated with iRBD.51

RBD can also occur in the context of certain medications. In otherwise healthy controls, REM sleep atonia can be induced by tricyclic and serotonergic antidepressants.52,53 RBD has also been reported with β-blockers, possibly through them binding to central noradrenergic and serotonergic receptors.54 These medications may be more likely to unveil RBD behaviour in patients with a predisposition, such as those with PD and narcolepsy.55 RBD has also been described in association with alcohol withdrawal.40

Idiopathic RBD as a predictor of neurodegeneration

An important message for physicians new to the field is that iRBD is the strongest and most specific predictor of synuclein-mediated neurodegenerative disease. Indeed, in the majority of cases where secondary causes have been eliminated, RBD can be regarded as a prodromal state of PD, DLB or MSA.56

One of the earliest longitudinal series describing this relation was carried out in 1996 by Schenck and colleagues, who found that 38% of older men with iRBD developed a Parkinsonian disease or dementia after a mean interval of 12.7 years from onset of symptoms.57 Sixteen years later, the authors published a follow-up of the same patients after finding that 81% had converted to mainly PD or DLB, and in some cases, Lewy body variant of AD.58 Another recent study followed a large cohort of 174 patients with iRBD referred to a tertiary sleep centre for up to 15 years and demonstrated that the risk of developing a defined neurodegenerative condition was 91% at 14 years.59 The median conversion time from the diagnosis of RBD was 7.5 years (11 years from time of symptom onset). The main neurodegenerative diseases represented at the first follow-up interval were DLB in 29, PD in 22 and MSA in two patients. A large multicentre trial of 279 patients, but with a shorter mean follow-up duration of 3.8 years, affirms the results from the single-centre trials.60

There is emerging evidence showing that neuropsychological, biological and clinical markers of neurodegeneration can be detected in patients with iRBD who are otherwise asymptomatic. Prospective serial dopamine transporter imaging in iRBD can detect progressive nigrostriatal dopaminergic deficiency before onset of any motor symptoms akin to those seen in patients with PD.61,62 Additionally, various magnetic resonance imaging studies have revealed structural and functional brain alterations associated with iRBD, similar to changes seen in PD and DLB.63,64 Electroencephalographic65 and perfusion abnormalities66 consistent with neurodegeneration have also been described.

Early cognitive deficits have been consistently reported in a high proportion of asymptomatic patients with iRBD.67 Comprehensive neuropsychological testing of 112 subjects with polysomnography-confirmed iRBD found that 50% of patients compared with 8% of control subjects had evidence of mild cognitive impairment.68 Further, the pattern of cognitive deficits seen in iRBD is similar to synucleinopathy-associated dementias, frequently involving visuospatial, attention and executive domains.68

The clinical markers of neurodegeneration are not just restricted to cognitive function. A recent Chinese study comparing patients with iRBD to PD and controls found both motor and non-motor deficits in patients with iRBD.69 Involvement of olfaction, gastrointestinal, and cardiovascular functions has been confirmed in other studies of iRBD and found to be predictive of impending conversion to neurodegenerative disease.70,71

Adding to the case that iRBD represents a synucleinopathy are recent in vivo studies that found α-synuclein aggregates in nerve fibres obtained from biopsies of the colon and submandibular glands in patients with iRBD and PD but not in age-matched healthy controls.72,73 Reports of patients with iRBD who have undergone post-mortem examination are scarce but revealing.74 Brainstem-predominant Lewy body disease with some neuronal loss was found in each case and particularly affected key structures known to be associated with REM sleep and PD.

Pathogenesis of RBD

The pathophysiology underlying RBD is not fully understood but presumably can arise from any number of nervous system pathologies that converge primarily on the brainstem structures responsible for inhibition of spinal motor neurons during REM sleep,21 operating via multiple neurotransmitter systems including glutamate, noradrenaline, serotonin, γ−aminobutyric acid, dopamine and orexin.75

These brainstem regions (such as the subcoeruleus complex) have been shown to be affected by α-synuclein disease in post-mortem studies of patients with iRBD, PD, DLB and MSA74,76,77 (Box 4). Interestingly, the timing linking iRBD and the development of other motor and non-motor features of a neurodegenerative disorder are aligned with the neuropathological staging system of Lewy body disease developed by Braak and colleagues.76 Thus, it would seem to fit that RBD, along with other non-motor symptoms resulting from brainstem pathology, would manifest before the onset of the motor and cognitive symptoms mediated by structures affected later in the course of the disease.

RBD in narcolepsy affects younger populations who generally do not go on to develop neurodegenerative conditions and is therefore a different clinical entity subserved by distinct pathomechanisms. Narcolepsy in humans is characterised by loss of orexin-producing cells in the hypothalamus.78 Orexins (or hypocretins) are excitatory neuropeptides produced in the hypothalamus that play a role in regulating a variety of bodily functions such as wakefulness, appetite and energy expenditure. Thus, loss of orexinergic projections to the subcoeruleus and other brainstem regions important in muscle atonia is thought to underlie RBD in narcolepsy.53

Management

The priority in symptomatic RBD is to minimise the likelihood of injury and eliminate unpleasant dreams. This is especially true for patients with more violent dream enactment behaviours, as these have been reported to occasionally result in life-threatening injuries with forensic implications.79 Unfortunately, no published large randomised control trial data exist regarding pharmacological intervention in RBD. Instead, treatment decisions are currently informed by case series and best practice guidelines generated through expert consensus.80

In the first instance, it is generally agreed that any potentially offending medications which may exacerbate RBD (eg, tricyclic antidepressants, selective serotonin reuptake inhibitors, lipophilic β-blockers) should be safely withdrawn whenever possible. Clinicians should be guided by patient history and examination to investigate and treat any of the other potentially secondary causes of RBD mentioned above. In patients with sleep fragmentation disorders such as sleep apnoea, treatment with continuous positive airway ventilation may in some cases relieve dream enactment behaviours.81

In patients with injurious motor behaviours, non-pharmacological measures, particularly the modification of the sleeping environment, is considered essential to minimise risk of injury to the patient and their bed partner. Examples of protective measures include placing a mattress on the floor, sleeping in a separate room from partners, pillow barricades and removal of potentially dangerous objects.19,80 Other restraining measures are occasionally employed, such as padded bed rails and sleeping bags. Clinicians should advocate home modification as an important adjunct to pharmacological therapy, or even as monotherapy if it is shown to be effective.

Pharmacotherapy

Currently, melatonin and clonazepam are the only recommended first-line medications for the treatment of symptomatic RBD. A head-to-head trial has not been performed and information regarding dosing, efficacy and adverse effects are based only on observational studies.82 As in the United States and the United Kingdom, use of these medications in RBD is currently off-label in Australia and can be prescribed by any treating physician provided the patient has undergone the appropriate assessment.

Clonazepam is a long-acting benzodiazepine and was recognised as an effective therapy by Schenck and colleagues in their original series describing RBD.83,84 Clonazepam has been shown in several studies to be effective in reducing RBD behaviours and frequency of unpleasant dreams in most patients.80 The usual starting dose is 0.25–0.50 mg orally at bedtime and slow up-titration as required to a maximum dose of 2 mg, depending on tolerability and response. A response is generally seen within the first week of starting the medication, although it may vary depending on the frequency and severity of RBD at baseline. Dream enactment tends to return if the medication is abruptly stopped. Curiously, despite the reported reduction in overt dream enactment behaviour, polysomnography of patients treated with clonazepam still shows excessive electromyographic activity during REM sleep.85 Based on this finding, the proposed mechanism of action of clonazepam is thought to be via its inhibitory influence on locomotor pattern generators rather than by restoring REM sleep atonia per se.80 Unfortunately, clonazepam is associated with many adverse effects (such as morning sedation, dizziness, confusion), with a retrospective study showing about 58% of patients experiencing moderate to severe side effects sometimes resulting in discontinuation.86 Therefore, clonazepam should be used with caution in older people and those with concomitant neurological conditions. Clonazepam should be avoided in patients with untreated obstructive sleep apnoea due to potential augmentation of apnoeas.

Melatonin is a hormone naturally secreted by the pineal gland to modulate circadian rhythm in humans. A small double-blind randomised cross-over trial and several case series have shown that melatonin may be equally effective for the treatment of symptomatic RBD at doses ranging from 3 to 12 mg taken 30 minutes before sleep.80,87,88 As with clonazepam, it is generally advised to start at the lower dose and increase every 2–4 weeks as required. However, melatonin may be more tolerable than clonazepam, with a recent retrospective comparative study in patients treated pharmacologically for RBD finding that melatonin-treated patients reported fewer adverse effects.87 Reported side effects were dose related and mainly included morning headache and morning somnolence. On a practical note, there is little evidence distinguishing between different preparations of melatonin for this indication, and in Australia the slow release formulation (which can be compounded) is most commonly used. Interestingly, polysomnography recorded from melatonin-treated patients shows a decrease in the proportion of REM sleep without atonia. This suggests that melatonin specifically targets structures associated with REM atonia; however, the mechanism by which this occurs is unknown. More data are required to firmly establish the efficacy of melatonin and enable standardised dosage regimens.

For patients refractory to the above medications, limited and conflicting data exist regarding the efficacy of other agents such as pramipexole, paroxetine and certain acetylcholinesterase inhibitors.82

Prognosis and implications for future neuroprotective measures

Recognising that most patients presenting with iRBD over the age of 50 years proceed to develop a synucleinopathy represents an unprecedented window of opportunity for potential disease prevention. At the same time, in the absence of existing neuroprotective measures, topics such as screening for RBD, disclosure of this information to patients and the nature of their follow-up and assessment are still being debated.

Disclosure of risk to the patient

On the basis of ethical considerations, most physicians support the disclosure of risk of neurodegenerative disease to patients with iRBD.89 It is important to remember that although patients are at an increased risk of developing a neurodegenerative disorder, it is by no means definitive, as current risk estimates are derived from studying selected patient populations. Such open discussions with patients are important for minimising misinformation and encourage the reporting of early symptoms of disease such as motor slowing or cognitive decline. Also, by understanding their condition, patients can give informed consent to participate in local and international research trials aimed at developing neuroprotective strategies.

Neuroprotective trials and research in iRBD

While neuroprotective trials are yet to commence, the International RBD Study Group released a consensus statement outlining a framework for devising such trials.90 In addition, the International Parkinson and Movement Disorder Society has released standardised research criteria for diagnosing prodromal PD and has identified RBD as having the highest predictive value of all the biomarkers.91 Other important research questions pertaining to optimal polysomnographic criteria for RBD and the automation of its detection will also be highly relevant to the methodology for impending neuroprotective studies.

Given the complexities surrounding iRBD, clinicians are encouraged to refer patients with diagnosed iRBD to sleep physicians and neurologists with an interest in the disorder. Such specialists will be able to monitor for the development of Parkinsonism or cognitive decline and arrange ancillary testing including neuroimaging, neuropsychology, and smell and colour vision testing. By this avenue, patients could also be offered the opportunity to enrol in existing research programs and neuroprotective trials once they commence. General practitioners involved in the long term care of such patients will also need to be vigilant regarding the emergence of any cognitive or motor symptoms and to monitor for adverse interactions or side effects of any prescribed medications.

Conclusion

RBD is a treatable parasomnia with significant potential harm for patients and their spouses. Arguably one of the most important developments in neurology and sleep medicine in the last decade is the recognition that RBD may be the earliest symptom of a Lewy body disorder such as PD and DLB. This has created a concerted effort on the part of scientists and clinicians to undertake trials focused on neuroprotection in this cohort of patients. Physicians from a wide range of fields should be aware of this recent discovery and ensure that patients with RBD are appropriately diagnosed, treated, educated and followed up.

Box 1 – Proposed flow diagram for diagnosis, investigation, treatment and follow-up of patients with rapid eye movement (REM) sleep behaviour disorder

DLB = dementia with Lewy bodies. MSA = multiple system atrophy. PD = Parkinson’s disease. RBD = REM sleep behaviour disorder. SSRI = serotonin selective reuptake inhibitor. TCA = tricyclic antidepressant.

Box 2 – Representative polysomnography showing (A) normal rapid eye movement (REM) sleep in a healthy individual and (B) REM sleep without atonia in an individual with idiopathic REM sleep behaviour disorder

ECG = electrocardiogram. EOG = electro-oculogram. FDS = flexor digitorum superficialis. F3, F4, C3, C4, O1, O2 = electroencephalographic electrode configuration in the frontal, central and occipital scalp according to the International 10–20 system, contralaterally referenced to the mastoid processes (M1, M2). TA = tibialis anterior. EOG channels show bursts of rapid eye movements characteristic of the REM stage of sleep. Chin (mentalis muscle), upper limb (right and left FDS) and lower limb (TA) electromyography recording channels are also shown. Red arrows (B) highlight excessive limb muscle activity in REM sleep in the affected individual.

Box 3 – Sensitivity and specificity of rapid eye movement sleep behaviour disorder (RBD) diagnosis based on screening questionnaire, single-item question screening and video polysomnography

Sensitivity

Specificity

RBD screening questionnaire*

88–98%

56–95%

Single-item RBD screening question^†

94%

87%

Polysomnography^‡

89–98%

75–100%

* Note that variation in these measures may be accounted for by differences in the questionnaires used and the populations studied.5-9 † Based on the single-item RBD question: “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.)?”6 ‡ Differences in detection by polysomnography depend on detection protocol used (Neikrug AB, Ancoli-Israel S. Diagnostic tools for REM sleep behavior disorder. Sleep Med Rev 2012; 16: 415–429).

Box 4 – Immunostaining for α-synuclein in the locus coeruleus of a patient with Parkinson disease and rapid eye movement sleep behaviour disorder at autopsy

Section shows α-synuclein-positive Lewy bodies (arrows) and Lewy neurites (asterisk) using peroxidase immunohistochemistry. Photograph courtesy of Professor Glenda Halliday, University of Sydney.

Authors

Elie Matar^1,2
Simon JG Lewis^1,2

1. Brain and Mind Centre, University of Sydney, Sydney, NSW
2. Royal Prince Alfred Hospital, Sydney, NSW

Correspondence: simon.lewis@sydney.edu.au

Competing interests

No relevant disclosures.

Acknowledgements

This work was conducted by the ForeFront project team and SJGL is supported by an NHMRC–ARC Dementia Research Development Fellowship (1110414). ForeFront is a large collaborative research group dedicated to the study of neurodegenerative diseases and is funded by grants from the National Health and Medical Research Council of Australia (1037746), Dementia Research Team (1095127), NeuroSleep Centre of Research Excellence (1060992), Australian Research Council Centre of Excellence in Cognition and its Disorders Memory Program (CE110001021) and the Sydney Research Excellence Initiative 2020. We thank Dr Negar Memarian for providing the polysomnography recording data shown in Box 2.

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