Keywords REM Sleep Behavior Disorder - Sleep - REM - Parasomnias - Synucleinopathies - Sleep
Wake Disorders - Polysomnography - Drug Therapy
Palavras-chave Transtorno do Comportamento do Sono REM - Sono REM - Parassonias - Sinucleinopatias
- Transtornos do Sono-Vigília - Polissonografia - Tratamento Farmacológico
INTRODUCTION
REM Sleep Behavior Disorder (RBD) is characterized by the loss of atonia of skeletal
muscles during REM sleep, associated with acting out behaviors during dreams and/or
nightmares.[1 ] Knowledge of this pathology is crucial to avoid harm to the patient and their bed
partner, as well as to predict, when occurring in isolated form in middle-aged and
older adults, neurodegenerative diseases, such as synucleinopathies. Therefore, the
proper diagnosis of the condition will help enroll these patients in future neuroprotective
trials before the motor and cognitive symptoms become clinically manifest.
The first description of REM sleep without atonia (RWA) and dream-related behaviors
was made by Jouvet (1965) in cats with lesions in the subcoeruleus nucleus region.
In the 1970s, Japanese authors described this condition in patients during alcohol
withdrawal and called it Stage I-REM with tonic electromyography. In 1986, Schenck
and colleagues described a series of patients who exhibited dream-enacting behaviors
and loss of atonia during REM sleep, coining for the first time the term RBD[2 ]
[3 ] Preceding RBD scientific descriptions, several artistic works portrayed probable
episodes compatible with this diagnosis.[3 ] In Don Quixote de la Mancha (1605 - 1615), Miguel de Cervantes describes several
sleep disorders, including a probable episode of RBD[4 ] ([Figure 1 ]).
Figure 1 Probable REM Sleep Behavior Disorder episode in Miguel Cervantes Don Quixote de La
Mancha: they found Don Quixote in the strangest costume in the world. (…) on his head,
he had a little greasy red cap (…), and in his right hand he held his unsheathed sword,
with which he was slashing about on all sides, uttering exclamations as if he were
fighting some giant: and the best of it was his eyes were not open, for he was fast
asleep, and dreaming that he was doing battle with the giant. For his imagination
was so wrought upon by the adventure he was going to accomplish, that it made him
dream he had already reached the kingdom of Micomicon and was engaged in combat with
his enemy; and believing he was slaying the giant, he had given so many sword cuts
to the (wine) skins that the whole room was full of wine. (…) despite all this the
poor gentleman never woke up until the barber brought a great pot of cold water from
the well and flung it with one dash all over his body, on which Don Quixote woke up,
but not so completely as to understand what was the matter. Source: Gustave Doré,
in: Illustrations for Don Quixote de la Mancha, 1863. Accessed in https://pt.wikipedia.org/wiki/Dom_Quixote_(Gustave_Dor%C3%A9 ) - public domain image.
PHYSIOPATHOLOGY
In the study of REM sleep physiology, there are two cellular groups (“REM on” and
“REM off” cells) that play a role in the initiation and maintenance of REM sleep through
reciprocal inhibition between these groups (Mesopontine “Flip-Flop” model).[5 ] The “REM on” cells consist of the precoeruleus nucleus (glutamatergic) and sublaterodorsal
nucleus (SLD) (glutamatergic and GABAergic), located in the caudal tegmentum of the
pontis. On the other hand, the “REM off” cells are formed by the ventrolateral part
of the periaqueductal gray and the pontine ventrolateral tegmentum (both GABAergic),
located in the rostral tegmentum of the pons.[6 ]
These two “REM on” cell nuclei probably have different functions. The precoeruleus
nucleus likely regulates electroencephalographic activity, while the SLD nucleus is
responsible for muscular atonia and the inhibition of “REM off” cells. These cellular
groups are heavily modulated by cholinergic neurons (pedunculopontine nucleus and
laterodorsal tegmental nucleus), which are activated during REM sleep, and by monoaminergic
cells (locus coeruleus and raphe nucleus), which are inhibited during REM sleep.[7 ]
[8 ]
Two different systems mediate motor control during REM sleep. One is responsible for
locomotor drive and is formed by locomotion generators located in the brainstem, which
receive influences from the telencephalon and diencephalon. The other system is responsible
for inhibiting muscle tone in the anterior horn of the spinal cord. It is constituted
by the aforementioned “REM on” cells, primarily the magnocellular reticular formation
located in the medulla oblongata.[7 ] RBD appears to result from a combination of increased locomotor drive associated
with lesions in nuclei responsible for atonia during REM sleep (magnocellular reticular
formation and sublaterodorsal nucleus). Therefore, it involves a complex and multifaceted
neurotransmitter dysfunction[7 ]
[9 ] ([Figure 2 ]).
Abbreviations: EEG, electroencephalography; EMG, electromyography; PSG, polysomnography;
vl PAG, ventrolateral periaqueductal gray matter; VMM, ventral medial medulla. Adapted
from Fraigne et al., 2015.[9 ]
Figure 2 Representation of the regulation of muscle activity during physiologic REM sleep
and REM sleep behavior disorder (RBD). In physiologic conditions, glutamatergic subcoeruleus
neurons regulate REM sleep muscle tonus through the excitation of inhibitory neurons
of the ventromedial medulla (VMM). Those neurons inhibit motoneurons in the anterior
horn of the spinal cord. In REM sleep, physiological transient muscle activity can
be observed, mediated by red nucleus activity. In individuals with RBD, degeneration
of the circuit subcoeruleus-ventromedial medulla releases motoneurons from their physiologic
inhibition, allowing motor behaviors during REM sleep.
EPIDEMIOLOGY
Since diagnostic methods for RBD are not widely available in many centers, epidemiological
data regarding its prevalence is limited. Epidemiological studies based on clinical
interviews and questionnaires, without polysomnographic confirmation, estimated a
prevalence ranging from 3–10%. Prevalence estimated from community-based studies,
with RDB diagnosis based on clinical and polysomnographic data, estimated a prevalence
between 0.74 to 1.15%.[10 ]
Additionally, in regard to alpha-synucleinopathies, the main RBD risk factor involves
age over 50 years old, and perhaps also male gender, although a Swiss study found
an equal male-female RBD ratio in a community-based PSG study of middle-aged and older
adults, as discussed.[10 ] In individuals younger than 50 years old, there is a similar prevalence of RBD in
men and women. In this specific population (those under 50 years old), narcolepsy
type 1 and medication use are important association factors.[10 ]
NEUROIMAGING
Neuroimaging studies using positron emission tomography (PET), single-photon emission
computed tomography (SPECT), and magnetic resonance imaging (MRI) modalities are contributing
to a better neurochemical, structural, and functional understanding of RBD.
Regarding molecular changes, patients with isolated RBD showed intermediate dopamine
transporters (DAT) levels in the striatum, lower than healthy controls but higher
than PD and RBD patients.[11 ] A deficit of dopaminergic markers in patients with isolated RBD was associated with
a greater likelihood of developing an alpha-synucleinopathy over 3 to 5 years of follow-up.[12 ] Cortical levels of acetylcholinesterase were reduced in patients with isolated RBD
compared to controls.[13 ] PD patients with RBD also exhibited a greater loss than PD patients without RBD.
The literature on regional cerebral blood flow was contradictory but suggested abnormal
perfusion throughout the brain in patients with isolated RBD compared to healthy controls.
Glucose metabolism was also dysregulated in patients with isolated RBD, with hypometabolism
in the posterior parts of the brain and hypermetabolism in other regions.[14 ]
As for the structural assessment, MRI literature revealed that abnormal iron deposits
can be found in subcortical nuclei of the brainstem, a pathophysiological hallmark
of iRBD, namely the substantia nigra and locus coeruleus.[15 ] Widespread cortical atrophy occurs in iRBD patients, showing distinct anterior (involving
orbitofrontal cortex) and posterior (including parietal, occipital, and temporal cortices)
patterns. We understand that a continuum links iRBD to more pronounced brain abnormalities
in PD. In PD with RBD, atrophy is observed in limbic and basal ganglia regions compared
to PD without RBD and healthy controls, consistent with iRBD pathology.
The functional studies identified cortico-cortical, nigrostriatal, and striato-cortical
functional connectivity disruptions in iRBD patients correlated with cognitive decline,
autonomic dysregulation, and motor impairment.[16 ] Compensatory mechanisms were observed with varying cognitive loads during motor
tasks, indicating heightened recruitment of functional networks even with low cognitive
demands.[17 ] Frontal connectivity pathways involving somatosensory regions were noted for maintaining
motor function. Like structural MRI findings, a cortical posterior-based functional
connectivity signature, frontostriatal deficits, and insular connectivity dysfunction
were observed in iRBD patients, mirroring those in PD.[18 ] Consistent patterns were also seen in PD patients with RBD, with disruptions in
cortico-cortical and striato-cortical functioning.
CLINICAL MANIFESTATIONS AND DIAGNOSIS
CLINICAL MANIFESTATIONS AND DIAGNOSIS
Motor behaviors and vocalizations during REM sleep, associated with dreams and nightmares,
characterize RBD. Such behaviors can cause injuries to the patient and their partners,
commonly observed as pushing, kicking, punching, biting, shouting, cursing, and occasionally
more dangerous acts such as choking.[19 ]
[20 ] Some studies report that patient or partner injuries occur in 48 to 77% of cases.[7 ]
At the end of the episodes, the individual may wake up rapidly, and when asked about
their dreams, they report a story consistent with the behaviors exhibited during sleep.
This phenomenon is known as isomorphism.[7 ] The dreams are often negative, with reports of being attacked, pursued, or assaulted
by strangers or animals and falling from cliffs.[20 ]
[21 ] During the episodes, it is not common for individuals to walk, run, or leave the
room. Additionally, patients typically keep their eyes closed during the events. These
characteristics aid in differentiating RBD from other parasomnias and nocturnal epileptic
seizures.[22 ]
Although less frequent, non-violent behaviors may also occur in these patients, who
often consider it normal.[20 ]
[21 ] Descriptions of these phenomena are wide-ranging. Patients behave as if they were
smoking, giving speeches to an audience, or flying. Vocalizations such as talking,
screaming, crying, laughing, singing, and whispering occur frequently. Other behaviors
like eating and sexual activities could also happen.[23 ] In some patients, a coexistence of violent and non-violent behaviors is present.[20 ]
[21 ]
These behaviors usually begin after 90 minutes of sleep onset, mainly in the second
half of the night when REM sleep is more prevalent. The presence of a witness who
can report abnormal behaviors during sleep is essential since some patients do not
recall the content of their dreams and movements during sleep.[22 ] The RBD behaviors vary from night to night and over time in the same individual
and between patients. Small twitches and brief jerks affecting the extremities are
the most common movements in RBD and may remain unnoticed for years.
Screening instruments, such as scales, can be utilized for screening patients. The
REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ)[24 ] has been translated and validated for Brazilian Portuguese.[25 ] It is a self-administered instrument with ten simple questions, scored from 0 to
13. Cut-off values of more than four have shown good sensitivity for the suspicion
of RBD ([Figure 3 ]).
Figure 3 REM Sleep Behavior Disorder (RDB) Screening Questionnaire - English version (*) and
Brazilian Portuguese version (†). Source: Stiasny-Kolster et al., 2007; Pena-Pereira
et al., 2020.[24 ]
[25 ]
The diagnostic evaluation should begin with a detailed clinical history with the patient
and bed partner and the examination of recorded home videos, if available. After this
initial stage, polysomnography (PSG) is necessary to identify and quantify RWA and
to document sleep behaviors ([Table 1 ]). Additionally, clinical evaluation helps to rule out conditions that may mimic
RBD, such as Obstructive Sleep Apnea, non-REM sleep parasomnias, nocturnal epileptic
seizures, sleep-related movement disorders, and psychiatric disorders (in particular
Post-traumatic stress disorder).[1 ]
Table 1
International Classification of Sleep Disorders 3rd TR Diagnostic Criteria for REM Sleep Behavior Disorder.[1 ]
CRITERIA A-D MUST BE MET
A. Repeated episodes of sleep-related vocalization and/or complex motor behaviors.
B. 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.
C. Polysomnographic recording demonstrates RWA.
D. The disturbance is not better explained by another sleep disorder, mental disorder,
medication, or substance use.
Abbreviations: ICSD, International Classification of Sleep Disorders; RBD, REM sleep
behavior disorder; RWA, REM sleep without atonia.
Notes: To evaluate amplitude, consider the lowest amplitude in NREM if no stage R
atonia is present. If a periodic limb movement is scored as part of a PLMS series,
it should not be counted in determining if an epoch has RWA.
Type 1 PSG is essential for RBD diagnosis. It is necessary to detect RWA, as required
in the International Classification of Sleep Disorders, 3rd edition (ICSD-3).[1 ] Additionally, it allows documentation of complex motor behaviors and vocalizations
during REM sleep.[1 ] SG can also aid in the differential diagnosis of conditions that may mimic or be
comorbid with RBD, such as obstructive sleep apnea (OSA), non-REM parasomnia, sleep-related
hypermotor epilepsy, vigorous periodic leg movements during sleep, trauma-associated
sleep disorder and sleep-related movement disorder.[26 ]
The PSG aimed at evaluating complex nocturnal behaviors should ideally include, in
addition to the routine parameters, a series of additional variables. Therefore, it
is necessary to use equipment with enough monitoring channels. Furthermore, these
exams should always be done in the laboratory (type 1 PSG), with trained technicians
who document and act during sleep movements.
The PSG analysis for diagnosing parasomnias involves a series of considerations related
to the monitored parameters, careful analysis of muscle activity, and detailed examination
of synchronized video. These make PSG analysis for diagnosing complex movements during
sleep more sophisticated than routine sleep lab exams, used, for example, to diagnose
sleep-related breathing disorders.
The American Academy of Sleep Medicine Manual for the Scoring of Sleep and Associated
Events defines technical recommendations for PSG acquisition and analysis. These recommendations
likely pertain to the specific electrode placements, data collection procedures, and
criteria for scoring various sleep stages and events during the PSG ([Table 2 ]) ([Figure 4 ]).[1 ]
Table 2
American Academy of Sleep Medicine specifications for detection of REM Sleep without
atonia.[30 ]
TECHNICAL SPECIFICATIONS FOR MONITORING
1. Time-synchronized, audio-equipped video PSG should be used to document complex
motor behaviors and vocalizations during REM sleep.
2. LMs - surface electrodes placed longitudinally and symmetrically in the middle
of the anterior tibialis muscle so that they are 2-3 cm apart or one-third of the
length of the anterior tibialis muscle, whichever is shorter.
3. For monitoring LMs, the use of 60 Hz (notch) filters should be avoided. Impedances
need to be < 10,000 Ω. 5,000 Ω is preferred but may be difficult to obtain.
4. For monitoring movements of the upper limbs, surface electrodes should be placed
longitudinally and symmetrically, so that they are 2-3 cm apart over the surface of
the flexor digitorum superficialis or the surface of the extensor digitorum communis.
5. Both legs and arms should be monitored. Separate channels for each leg and each
arm are strongly preferred.
DEFINITIONS
1. Excessive sustained muscle activity (tonic activity) in REM: An epoch of stage R with at least 50% of the duration of the epoch having a chin
EMG amplitude at least 2 times greater than the stage R atonia level (or lowest amplitude
in NREM, if no stage R atonia is present). Multiple segments may contribute to the
total duration, but each segment must be > 5 seconds.
2. Excessive transient muscle activity (phasic activity) in REM: In a 30-second epoch of stage R divided into 10 sequential 3-second mini-epochs,
at least 5 (50%) of the mini-epochs contain bursts of transient muscle activity in
the chin or limb EMG. In RWA, excessive transient muscle activity bursts are 0.1-5.0 seconds
in duration and at least 2 times as high in amplitude as the stage R atonia level.
3. Any chin EMG activity . Activity with a minimum amplitude 2 times greater than the stage R atonia level.
CRITERIA
AN EPOCH EXHIBITS RWA WHEN ONE OF THE FOLLOWING IS PRESENT:
a. Excessive sustained muscle activity in REM in the chin EMG.
b. Excessive transient muscle activity during REM in the chin or limb EMG.
c. At least 50% of 3-second mini-epochs contain any chin activity (as defined above)
or limb EMG activity (bursts of EMG activity 0.1-5.0 seconds in duration and at least
2 times as high in amplitude as the stage R atonia level.
SCORE THE RWA INDEX AS THE PERCENT OF STAGE R EPOCHS THAT MEET CRITERIA
Abbreviations: LMs, leg movements; PSG, polysomnography; RWA, REM sleep without atonia.
Notes: To evaluate amplitude, consider the lowest amplitude in NREM if no stage R
atonia is present. If a periodic limb movement is scored as part of a PLMS series,
it should not be counted in determining if an epoch has RWA. Epochs containing RWA
with sustained chin activity as defined above may not meet criteria for stage R, but
in these cases, the epoch can still be scored as stage R if other criteria for stage
R are met, or if the epoch is contiguous with an epoch scored as stage R.
Since the AASM manual lacks a specific quantification of RWA to define clear cutoff
values, other methods have been developed.[27 ] In the 'SINBAR' method, proposed by the Barcelona and Innsbruck group, the combination
of 'any' EMG activity in the mentalis muscle with both phasic flexor digitorum superficialis
muscles yielded a cutoff of 32% (area under the curve [AUC] 0.998) for patients with
RBD.[28 ] The Mayo Clinic method combined visual analysis and a computer-based quantitative
automatic scoring algorithm known as the 'REM sleep Atonia Index' to evaluate EMG
activity in the submental and anterior tibialis muscles, yielding a cutoff of 43.4%
(AUC 0.983).[29 ] In the same study, using the AASM diagnostic standards resulted in a combined submentalis
and anterior tibialis phasic muscle activity cutoff of 34.7% (AUC 0.960).[29 ] Therefore, the polysomnography report should describe the percentage of REM sleep
epochs that meet the criteria for RWA to better distinguish patients with and without
RBD.[30 ]
RBD MIMICS
Some clinical conditions can mimic dream enactment behaviors, making it sometimes
difficult to distinguish solely based on medical history or even homemade videos ([Table 3 ]). OSA, especially in severe cases, can show upon awakening after a breathing event,
particularly during REM sleep, with movements that align with performance during sleep.[31 ] Such behaviors tend to improve after treating the sleep-breathing disorder. Thus,
snoring, feeling of choking, and witnessed apneas during sleep should draw attention
to this differential diagnosis. Distinguishing between these conditions is crucial
as clonazepam, one of the treatments used for RBD can worsen OSA.
Non-REM sleep parasomnias such as sleepwalking, night terrors, confusional arousal,
and sleep-related eating disorders typically occur in younger individuals compared
to RBD. Additionally, unlike RBD, where the patient exhibits behavior with closed
eyes and in the final third of the night, in these parasomnias, the patient experiences
symptoms in the early third of the night with eyes open. Since the occurrence during
the polysomnography examination night is rare, the absence of REM sleep without atonia
and multiple awakenings during slow wave sleep are hallmarks of non-REM sleep parasomnias.[26 ]
Nocturnal epileptic seizures can also simulate RBD. Seizures originating in the frontal
lobe can exhibit hyperkinetic motor manifestations, with abrupt, violent movements
and intense limb activity, often confused with the aggressive behaviors of RBD. Furthermore,
temporal lobe seizures can involve motor and verbal automatisms that may resemble
the sleep talking observed in RBD. The stereotyped movements of epileptic seizures
can help differentiate them, as their occurrence predominantly during non-REM sleep,
the electroencephalographic changes such as epileptic discharges, and the response
to anti-seizure medications.[32 ]
Other less common clinical conditions can mimic RBD. Periodic limb movements during
sleep (PLMS) are characterized by repetitive movements involving toe extension, ankle
dorsiflexion, and sometimes knee flexion during sleep. Several cases of vigorous PLMS
were mistakenly diagnosed as RBD during clinical evaluation.[33 ] Trauma-associated sleep disorder presents with trauma-related nightmares, autonomic
hyper-arousal, and excessive movements, which can be confused with RBD-like symptoms.
Another rare RBD mimic is Rhythmic Movement Disorders during sleep, involving repetitive,
stereotyped, and rhythmic movements of large muscle groups. These movements occur
during quiet wakefulness, drowsiness, or sleep.[26 ]
ASSOCIATED CONDITIONS
A strong association of RBD with diseases caused by the deposition of alpha-synuclein
in neurons, such as Parkinson's disease (PD), Multiple System Atrophy (MSA), and Dementia
with Lewy Bodies (DLB), is well-established.[34 ]
[35 ]
[36 ] The abnormal deposition of this protein in brainstem structures, particularly in
the medulla oblongata and pontine transition, leads to the formation of intraneuronal
inclusion bodies called Lewy bodies and the RBD clinical manifestations.[37 ] A prospective multicenter study involving 24 centers documented an annual phenoconversion
rate of 6.3%, with a 73.5% phenoconversion rate after 12 years of follow-up. The majority
of individuals developed PD (56.5%), followed by DLB (43.5%) and MSA (4.5%).[38 ]
In cases where no association with another condition exists, we refer to it as isolated
RBD. There is an increasing body of evidence that suggests that most cases of isolated
RBD are associated with asymptomatic alpha-synucleinopathies[3 ]
[39 ]
[40 ] ([Figure 5 ]). Several studies have already demonstrated that patients with isolated RBD more
frequently exhibit cognitive deficits, particularly in executive function, visuospatial
attention, processing speed, short-term memory, and pareidolias (tendency to perceive
a meaningful image in an ambiguous visual pattern). Almost a third of RBD patients
met the diagnostic criteria for mild cognitive impairment (MCI), which serves as a
predictive biomarker for DLB.[41 ]
[42 ] Other symptoms observed in RBD patients include hyposmia, constipation, orthostatic
hypotension, and gait abnormalities, also linked to a higher risk of phenoconversion.[42 ]
Abbreviations: EKG, electrocardiogram; EMG, electromyography; L, left; O2, oxygen;
R, right.
Figure 4 (A ) REM sleep without atonia findings in polysomnography. It shows a 30 seconds epoch
with excessive sustained tonic muscle activity observed in the chin electromyography
derivation. (B ) shows a 30 seconds epoch with excessive phasic muscle activity on the lower (anterior
tibialis muscle) and upper (flexor digitorum superficialis muscle) limbs electromyography
derivations.
Abbreviations: FDS, flexor digitalis superficialis; RBE, REM sleep behavioral events.
Figure 5 Concept of prodromal REM Sleep Behavior Disorder (RBD). Clinical and neurophysiological
findings on type I video-polysomnography and electromyography (EMG) progress along
a continuum over disease evolution. Individuals progress from isolated RBD into RBD in the context
of overt alpha-synucleinopathy. Source: Högl et al, 2017.[3 ]
Besides the association with synucleinopathies, RBD may be related to medications,
most frequently antidepressants, and substance withdrawal. Other neurologic conditions
were associated with RBD, such as narcolepsy type 1. RBD can also manifest as a consequence
of a neurological lesion affecting structures related to REM sleep atonia control,
in the brainstem. Such conditions are relatively rare, but secondary RDB can occur
in the context of meningiomas or, even more rarely, pontine cavernomas or lymphomas,
multiple sclerosis, and stroke. RBD can also be associated with posttraumatic stress
disorder[43 ]
[44 ] ([Table 4 ]).
Table 3
Main clinical differential diagnosis of REM Sleep Behavior Disorder.
Sleep disorders
Obstructive sleep apnea
Non-REM parasomnias
• Sleepwalking
• Sleep terrors
• Confusional arousals, with aggressive/violent behaviors
Parasomnia overlap disorder (RBD + Non-REM parasomnia)
Periodic leg movements during sleep
Sleep Related rhythmic movement disorder
Status dissociatus (aggressive/violent behavior during ambiguous sleep)
Neurological disorders
Nocturnal epileptic seizures
o Sleep-related hypermotor epilepsy
Anti-IgLON5 disease
Psychiatric disorders
Post-traumatic stress disorder
Sleep-related dissociative disorder
Other clinical disorders
Nocturnal (severe) hypoglicemia (insulinoma)
Sources: Antelmi E, et al. 2021 and Baltzan M, et al., 2020.[26 ]
[43 ]
Table 4
Conditions and substances associated with REM Sleep Behavior Disorder and REM sleep
without atonia.
Conditions
1) Alpha-synucleinopathy:
○ Dementia with Lewy bodies (prevalence of RBD: 68–90%)
○ Parkinson's disease (prevalence of RBD: 15–65%)
○ Multiple system atrophy (prevalence of RBD: 60–90%)
2) Sleep disorders:
○ Narcolepsy type 1 (prevalence of RBD: up to 60%)
3) Paraneoplastic and autoimmune encephalitis:
○ Voltage-gated potassium channel complex (contactin-associated protein 2 [CASPR2],
leucine-rich glioma-inactivated protein 1 [LGI1])
○ Ma1 and Ma2 autoantibody-related encephalopathies· Anti-IgLON5 disease
4) Other neurologic diseases:
○ Machado-Joseph disease (spinocerebellar atrophy type 3)
○ Adult-onset autosomal dominant leukodystrophy
○ Myotonic dystrophy type 2
○ Autism
○ Gilles de la Tourette syndrome
○ Möbius syndrome
○ Smith-Magenis syndrome
○ Amyotrophic lateral sclerosis
○ Progressive supranuclear palsy
○ Huntington's disease
○ Wilson's disease
○ Creutzfeldt-Jakob disease
○ Multiple sclerosis
○ Astrocytomas
○ Acoustic neuroma
○ Vascular malformations
○ Central nervous system vasculitis
○ Cerebral infarcts
○ Guadeloupean atypical parkinsonism
Medications
1) Antidepressants
1.a. Selective serotonin reuptake inhibitor:
○ Citalopram
○ Fluoxetine
○ Paroxetine
○ Sertraline
1.b. Serotonin-norepinephrine reuptake inhibitor:
○ Duloxetine
○ Venlafaxine
○ Mirtazapine*
* (atypical mechanism of action)
1.c. Selective norepinephrine reuptake inhibitor:
o Reboxetine
1.c. Tricyclic antidepressant:
○ Amitriptyline
○ Clomipramine
○ Imipramine
○ Nortriptyline
2) Lithium
3) Monoamine oxidase inhibitor:
○ Phenelzine
○ Selegiline
4) Beta blocker:
○ Bisoprolol
○ Propranolol
5) Caffeine abuse
6) Withdrawal from substances:
○ Barbiturates
○ Benzodiazepines (nitrazepam)
○ Ethanol
○ Amphetamines
○ Cocaine
Adapted from Hoque & Chesson, 2010; Baltzan et al., 2020; AASM, 2023.
TREATMENT
The treatment of RBD involves safety orientation to protect the environment and avoid
injuries to the patient and the sleep partner. Sharp and puncture-prone objects, weapons,
and any objects on the nightstand that could lead to safety issues should be removed
from the bedroom. Additional safety measures include safety bars and nets on windows
and balconies, padded corners and edges of furniture, placement of the mattress on
the floor, or use of side safety rails to prevent falls from the bed. Protecting the
sleep partner requires protective barriers, such as the placement of pillows between
the patient and the sleep partner or else sleeping in separate beds with a safe distance
between them.[45 ]
In individuals with drug-induced or drug-exacerbated RBD, drug discontinuation is
only recommended if clinically safe for the patient, particularly in the context of
psychiatric disorders when the psychiatrist should be consulted. For example, dream
enactment may improve after decreasing or discontinuing an antidepressant, but clinicians
should remember that this may take several months. If antidepressant discontinuation
is not psychiatrically safe, bupropion, a drug with a lower serotoninergic profile,
may be an option, especially since no case of bupropion-induced or exacerbated RBD
has been reported.[45 ]
Until now, few double-blind randomized trials have evaluated medication use for RBD.
Most of the published papers on the subject had an observational design. ([Table 5 ]) Recently, a recommendation from the American Academy of Sleep Medicine was published,
summarizing the selection of the main medications used.[45 ]
Melatonin
Two double-blind randomized trials evaluated immediate-release melatonin in RBD with
positive results in reducing the dream-acting frequency and REM sleep without atonia.
The evaluation used the Global Clinical Impression Scale and specific RBD scales,
besides PSG.[46 ]
[47 ] Other observational studies have also documented the effectiveness of this medication.
The dosage ranged from 3 to 15 mg per day at bedtime. Higher dosages were not recorded.[45 ]
Extended-release melatonin for RBD treatment was evaluated in two double-blind randomized
trials. There was no difference in the frequency of acting-out episodes in either.[48 ]
[49 ] Therefore, there is no evidence for the recommendation of extended-release melatonin
for RBD treatment.
In Brazil, melatonin is considered a dietary supplement and is available for sale
in pharmacies at low doses. Therefore, higher dosages, such as the recommended RBD
treatment, require handling the active ingredient in compounding pharmacies or importing
from other countries. Its main adverse effects include headache, excessive drowsiness,
nausea, and mental confusion.
Clonazepam
Clonazepam was the first medication used in RBD patients since its description in
1986.[2 ] Several observational studies have documented improvements in RBD symptoms.[50 ]
[51 ] A single double-blind, randomized trial did not show a difference between patients
who used clonazepam from those who received a placebo. However, RBD diagnosis relied
on a simple question, as this study did not use PSG as a diagnostic method.[52 ]
Clonazepam is a long-acting benzodiazepine with GABAergic action, increasing inhibition
by stimulating chloride channels in the central nervous system. The doses should be
low, between 0.25 and 1 mg at bedtime. Higher doses can be used if the patient tolerates
it. The main side effects include excessive drowsiness, cognitive impairment, imbalance,
risk of dependence, and withdrawal. Therefore, clonazepam should be prescribed with
caution for elderly patients with neurodegenerative diseases.[45 ]
Although no study has investigated this specific combination, empiric use of melatonin
with clonazepam can be considered for some patients, particularly in refractory cases.
The action of different mechanisms and pathways in the central nervous system may
help to control dream enactment manifestations.
Rivastigmine
Transdermal rivastigmine for RBD treatment in patients with PD and MCI has been documented
in clinical trials.[53 ]
[54 ] Its use for isolated RBD has yet to be evaluated. Rivastigmine is an acetylcholinesterase
inhibitor, leading to increased acetylcholine in the central nervous system by inhibiting
the enzyme responsible for its breakdown. The dosage varies from 4.6 to 13.3 mg in
a transdermal patch, with replacement every 24 hours. The main adverse effects are
nausea, vomiting, anorexia, skin irritation, headache, and bradycardia.[45 ]
[53 ]
[54 ]
Dopaminergic agonists
Two studies showed divergent results on the effectiveness of pramipexole in RBD. An
open-label study with 15 patients with isolated RBD showed improvement with doses
of 0.125 to 0.375 mg/ day after a four-week trial.[55 ] Another study in patients with PD and RBD did not show a difference after three
months of medication use.[56 ] A recent recommendation from AASM, from observational studies, suggests its use
in patients with RBD and elevated periodic limb movement.[45 ]
Pramipexole is a dopaminergic agonist medication used for motor symptoms of PD, restless
legs syndrome (RLS), and periodic limb movement disorder. Adverse effects include
nausea, headache, excessive sleepiness, impulse control disorder, and augmentation
in patients with RLS.
A recent open clinical trial with rotigotine enrolling 11 patients over 20 weeks demonstrated
improvement in acting behaviors and bed fall frequency but with persistent RWA.[57 ] Further studies are needed to confirm these findings.
Yokukansan (Yi-Gan San)
Yokukansan (YKS) is an herbal treatment (known as Yi-Gan San in Chinese) made up of
seven herbal ingredients: Japanese Angelica root, Uncaria hook, Cnidium rhizome, Atractylodes lancea rhizome, Poria sclerotium , Bupleurum root, and Glycyrrhiza. Two retrospective observational studies demonstrated
an improvement in the frequency of acting out during sleep episodes.[58 ]
[59 ]
Safinamide
Safinamide is an α-aminoamide that has both dopaminergic and non-dopaminergic mechanisms
of action, including inhibition of monoamine oxidase-B (MAO-B) sodium (Na + ) channel
blockade and modulation of stimulated release of glutamate. A longitudinal, cross-over
study registered a significant reduction of RBD symptoms in PD patients by questionnaire-Hong
Kong-score (RBDQ-HS), mainly for two individual RBDQ-HK-items (dream-related movements
and failing out of bed), and in REM sleep atonia, evaluated by PSG.[60 ]
Ramelteon
Ramelteon is a melatoninergic agonist acting on MT1 and MT2 receptors. Two separate
studies evaluated the effect of this medication on RBD. In one multicenter, open-label
study conducted on patients with PD, there was a reduction in the frequency of RBD
symptoms, as assessed by scales. On the other hand, the other open-labeled trial involving
patients with isolated RBD did not show any difference in symptoms or REM sleep atonia.[61 ]
[62 ]
Drugs with negative effects on trials
A double-blind, randomized trial evaluating cannabidiol in 33 patients with Parkinson's
disease and RBD did not show a difference between the evaluated groups, using 75 and
300 mg/ day for 14 weeks.[63 ]
Nelotanserin, a selective 5-HT (2A) inverse agonist, was evaluated in a multicenter,
double-blind, randomized trial for RBD associated with DLB (n = 33). The study showed
no difference in RBD symptom control between groups.[64 ]
5-hydroxytryptophan was evaluated in a double-blind, randomized study for RBD in PD.
The study included eighteen patients with a crossover design. There was no difference
in RBD symptoms frequency nor the REM sleep atonia indices.[65 ]
PERSPECTIVES
RBD may precede the onset of cognitive and motor symptoms related to synucleinopathies.
Future studies should define clinical, radiological, laboratory, and neurophysiological
variables (“biomarkers) that can be used, individually or in combination, to predict
the risk of developing synucleinopathies, and the associated timelines, ideally forecasting
the type of future pathology.[42 ] These biomarkers could potentially become the targets of neuroprotective strategies
that could prevent the emergence, or slow down the progression, of neurodegenerative
diseases. Currently, a clinical study registered in Clinical Trials is investigating
the potential neuroprotective effect of idebenone in these patients.[66 ]
Many studies tried to develop time-saving computerized methods for quantifying and
detecting RWA. The advent of artificial intelligence, with techniques of deep learning
and machine learning, has been used in recent studies with patients with RBD.[67 ]
[68 ] Shortly, these technologies may assist us in the polysomnography analysis (evaluation
of muscular activity, subtle movements in the video, or even electroencephalographic
activity), neuroimaging assessment, and screening of homemade videos.
Furthermore, RBD may change the global neurochemical balance in areas of the central
nervous system broader than the specific atonia-generating brainstem circuitry, which
can provide a dynamic model of interaction between the brainstem and other CNS structures.
Thus, integrated with clinical and neuroimaging findings, neurophysiological studies
will provide novel insights into mechanisms underlying cortical and brainstem dysfunction
in RBD and probably offer additional future therapeutic opportunities.
PROGNOSTIC COUNSELING AND ETHICAL IMPLICATIONS REGARDING IRBD LONG-TERM PROGNOSIS
PROGNOSTIC COUNSELING AND ETHICAL IMPLICATIONS REGARDING IRBD LONG-TERM PROGNOSIS
Since it is now well-established by multiple studies published in the medical literature
that up to 90% of patients ≥ 50 years old with iRBD will eventually develop an alpha-synucleinopathy,
the important issues of prognostic counseling and ethical implications must be considered.
A comprehensive review by experts on this topic (including one of the authors, CHS)
has recently been published,[69 ] and will now be summarized. The most common ethical model for the physician-patient
relationship is “shared decision-making”. In this context, disclosure of the high
risk of iRBD for the future emergence of a synucleinopathy is almost always indicated.
The physician should exercise appropriate sensitivity in this process, as a worrisome
medical prognosis will be shared, and with no neuroprotective (“disease-modifying”)
agent currently available to slow down or halt the progression from iRBD to overt
synucleinopathy. Disclosure in this context will enable patients and their families
to suitably prepare, in multiple ways, for the future.
Also, appropriate information should be given about the signs and symptoms of each
synucleinopathy. A healthy lifestyle, including regular exercise, should be encouraged.
Additionally, enrollment in longitudinal cohort studies, currently available in North
America (NAPS2),[70 ] Italy (FARPRESTO),[71 ] and across other countries (International RBD Study Group)[72 ] can help empower patients by participating in studies to both learn more about the
progression of iRBD to overt synucleinopathy and to also participate in future studies
testing promising neuroprotective agents.
Furthermore, shared decision-making is a mode of communication between the physician
and patient that focuses on understanding the patient's values and preferences, and
then customizing the sharing of sensitive and serious information with these values
in mind. In this context, the patient is given the opportunity for complete respect
of their preferences as the physician attempts to understand the extent to which the
patient understands the nature of their prodromal disease (i.e. iRBD) and their high
risk for developing parkinsonism or dementia. Shared decision-making is a process
that often requires sequential conversations during multiple clinical visits. This
process can evolve naturally as information about the patient's individual case and
disease course is continuously assessed and updated in the clinical setting. Importantly,
a foundation of mutual trust is built gradually that will enable more detailed conversations
and information sharing to take place over time.
For patients who appear excessively apprehensive or distressed at the time of iRBD
diagnosis, a “watchful waiting” approach for prognostic counseling should be considered,
in which the physician repeatedly assesses the patient for the best timing and the
best means of delivering this critical information. This approach in this scenario
may offer some advantages, such as building a deeper mutual rapport and trust with
the patient over time, and serial exams may reveal important symptoms or signs signaling
the patients' own individual course, enabling an appropriately tailored prognostic
discussion.
Another important consideration must be acknowledged in this process, as most patients
with iRBD, along with their family and friends, will likely learn about the strong
neurodegenerative risk with iRBD through the internet or other widely available sources.
Therefore, without prompt physician discussion on this topic, not only might learning
such information on one's own as a patient be alarming, it might also undermine trust
in the physician if this risk had not been previously brought up as a topic for discussion.
The proposed approach favors prognostic counseling for most patients following an
initial PSG-confirmed iRBD diagnosis.
LEGAL IMPLICATIONS OF AGGRESSIVE AND VIOLENT RBD BEHAVIORS
LEGAL IMPLICATIONS OF AGGRESSIVE AND VIOLENT RBD BEHAVIORS
The typical clinical profile of chronic RBD consists of a middle-aged or older man
with aggressive dream-enacting behaviors that cause repeated injury to himself and/or
his wife. This profile was revealed in the first two large published series on RBD,
involving 96 and 93 patients, respectively.[23 ]
[73 ] In these two series, male predominance was 87.5% and 87%, mean age at RBD onset
was 52 years and 61 years, dream-enacting behaviors were reported in 87% and 93% of
patients, and sleep-related injury as the chief complaint was reported in 79% and
97% of patients. Injuries included ecchymoses, subdural hematomas, lacerations (arteries,
nerves, tendons), fractures (including high cervical—C2), dislocations, and other
injuries.
A review of published cases of RBD that were associated with potentially lethal behaviors
identified choking/headlock in 22–24 patients, diving from bed in 10 patients, defenestration/near-defenestration
in 7 patients, and punching a pregnant bed partner in 2 patients.[74 ] A remarkable case of repeated RBD injury involved a 63-year-old man from China whose
four consecutive wives had divorced him because of his aggressive and violent dream-enacting
behaviors, including repeated biting.[75 ] With his first wife, one night he dreamed that he was eating an apple, but instead
he was biting her ear. On subsequent nights, during similar dreams, he would bite
her ears, nose, and face, which culminated in his wife divorcing him after four years
of marriage. His 3 next marriages were also terminated by the wives on account of
his repeated RBD-related sleep violence, including aggressive biting during dreams.
In addition, three brief relationships with girlfriends were also terminated for the
same RBD-related reasons. Also, in a series of 203 consecutive idiopathic RBD patients,
the prevalence of biting in RBD was 8.4%, which usually involved bed partners.[76 ] Nevertheless, a recent comprehensive review of sleep-related homicide and attempted
homicide did not find any case involving RBD, only NREM parasomnias.[77 ]
Mahowald et al. have developed the following guidelines to assist in the evaluation
of forensic cases involving sleep-related violence[78 ]
[79 ]:
There should be a reason to suspect a genuine sleep disorder, either based on historical
evidence or formal evaluation in a sleep laboratory. Previous episodes, with either
benign or harmful outcomes, should have occurred before;
The duration of the action is typically brief, lasting only a few minutes;
The behavior is sudden, immediate, impulsive, and appears to lack any logical motivation.
It is completely inappropriate considering the overall situation and is uncharacteristic
of the individual when awake. There is no evidence of premeditation;
The person affected is usually someone who happened to be present at the time and
may have triggered the arousal;
There is no attempt to escape, hide, or cover up the actions. It is evident that the
person was unaware during the event;
There is usually some level of amnesia for the event, although it may not be complete.
Comment on Guideline 6: In the largest series on iRBD published to date on 203 patients,
40% of patients were not aware of their dream-enacting behaviors (DEB), which their
spouses clearly observed as DEB.[76 ] The abnormal dreams were often recalled by this subgroup of RBD patients, but not
the DEB.
Table 5
Medications used in REM sleep behavior disorder with positive trial results.
Medication
Dose
Study type
Population
Clonazepam
0.25 - 2 mg
One open, randomized trial and observational studies (2,17,18)
Isolated RBD
PD
Melatonin (immediate release)
1 - 15 mg
Two double-blind, placebo-controlled, trials (47,48)
Isolated RBD; PD; Narcolepsy
Rivastigmine
4.6–13.3 mg
Two placebo-controlled, cross-over, open trial (54,55)
PD; MCI
Pramipexole
0.125 - 0.375 mg
One open-label trial (56)
Isolated RBD
Safinamide
50 mg
One double-blind, randomized trial (61)
PD
Rotigotine
2–16 mg
Prospective open-label, trial (58)
PD
Abbreviations: PD, Parkinson's disease; MCI, Mild cognitive impairment; RBD, REM sleep
behavior disorder.
