Sleep Medicine Reviews 13 (2009) 385–401
Contents lists available at ScienceDirect
Sleep Medicine Reviews
journal homepage: www.elsevier.com/locate/smrv
CLINICAL REVIEW
The clinical and pathophysiological relevance of REM sleep behavior disorder
in neurodegenerative diseases
Alex Iranzo*, Joan Santamaria 1, Eduard Tolosa 2
Neurology Service, Hospital Clı́nic and Institut d’Investigació Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red sobre Enfermedades
Neurodegenerativas (CIBERNED), Barcelona, Spain
s u m m a r y
Keywords:
REM sleep
REM sleep behavior disorder
Neurodegenerative diseases
Multiple system atrophy
Dementia with Lewy bodies
Parkinson’s disease
REM sleep behavior disorder (RBD) is characterized by vigorous movements associated with unpleasant
dreams and increased electromyographic activity during REM sleep. Polysomnography with audiovisual
recording is needed to confirm the diagnosis of RBD and to exclude other sleep disorders that can mimic
its symptoms including obstructive sleep apnea, nocturnal hallucinations and confusional awakenings.
RBD may be idiopathic or related to neurodegenerative diseases, particularly multiple system atrophy,
Parkinson’s disease and dementia with Lewy bodies. RBD may be the first manifestation of these
disorders, antedating the onset of parkinsonism, cerebellar syndrome, dysautonomia, and dementia by
several years. RBD should thus be considered an integral part of the disease process. When effective,
neuroprotective strategies should be considered in subjects with idiopathic RBD. Patients with other
neurodegenerative diseases, though, such as spinocerebellar ataxias, may also present with RBD. When
clinically required, clonazepam at bedtime is effective in decreasing the intensity of dream-enacting
behaviors and unpleasant dreams in both the idiopathic and secondary forms. When part of a neurodegenerative disorder the development of RBD is thought to reflect the location and extent of the
underlying lesions involving the REM sleep centers of the brain (e.g., locus subceruleus, amygdala, etc.),
leading to a complex multiple neurotransmitter dysfunction that involves GABAergic, glutamatergic and
monoaminergic systems. RBD is mediated neither by direct abnormal alpha-synuclein inclusions nor by
striatonigral dopaminergic deficiency alone.
Ó 2008 Elsevier Ltd. All rights reserved.
Introduction
REM sleep behavior disorder (RBD) is a parasomnia characterized by vigorous dream-enacting behaviors associated with
nightmares and abnormal increased phasic and/or tonic electromyographic activity during REM sleep.1,2 RBD may be idiopathic
(IRBD) or secondary to neurological diseases, particularly those with
involvement of the brainstem such as multiple system atrophy
Abbreviations: AD, Alzheimer disease; DLB, dementia with Lewy bodies; IRBD,
idiopathic rapid eye movement sleep behavior disorder; MSA, multiple system
atrophy; PD, Parkinson’s disease; PDD, Parkinson’s disease associated with
dementia; PSG, polysomnography; RBD, rapid eye movement sleep behavior
disorder; REM, rapid eye movement; VPSG, videopolysomnography.
* Corresponding author. Neurology Service, Hospital Clı́nic de Barcelona, C/Villarroel
170, Barcelona 08036, Spain. Fax: þ34 932275783.
E-mail address: [email protected] (A. Iranzo).
1
Present address: Neurology Service, Hospital Clı́nic de Barcelona, C/Villarroel
170, Barcelona 08036, Spain. Fax: þ34 932275783. [email protected].
2
Present address: Neurology Service, Hospital Clı́nic de Barcelona, Barcelona
08036, Spain. Fax: þ34 932275783. [email protected].
1087-0792/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.smrv.2008.11.003
(MSA), Parkinson’s disease (PD) and dementia with Lewy bodies
(DLB). In patients with these neurodegenerative disorders, the onset
of RBD may either antedate or follow the onset of parkinsonism,
cerebellar syndrome, dysautonomia, and cognitive impairment.
RBD may also be related to the development of a structural lesion
(e.g., stroke, tumor, demyelinating plaques, etc.) that damages REM
regulating regions of the brain (e.g., lower brainstem, limbic system,
etc.) and with the introduction of certain medications such as
antidepressants and beta-blockers.1,2 For example, we have seen
patients reporting a temporal association between onset of RBD and
the administration of the following antidepressants: sertraline
(n ¼ 8), fluoxetine (n ¼ 4), venlafaxine (n ¼ 3), clomipramine (n ¼ 3),
paroxetine (n ¼ 2), escitalopram (n ¼ 2) and citalopram (n ¼ 2)
(unpublished observations).
In normal animals and humans, there is minimal skeletal muscle
activity in REM sleep. Onset and maintenance of REM sleep atonia
requires active inhibition of sustained muscle tone (tonic activity)
and intermittent muscular twitches (phasic activity). Neural REM
sleep generators for tonic and phasic muscular components are
thought to be different but located in the dorsal mesopontine
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A. Iranzo et al. / Sleep Medicine Reviews 13 (2009) 385–401
tegmentum and ventromedial medulla. Some RBD patients have
both increased tonic and phasic activity in the mentalis muscle and
limbs. Others only exhibit increased phasic electromyographic
activity in the limbs and normal atonia in the mentalis muscle
whereas other groups of RBD patients have only increased tonic
activity in the mentalis muscle and no excessive phasic activity in
the limbs (this is possibly a subclinical or a mild form of RBD). These
different types of electromyographic activity in RBD may underlie
different degrees and extent of dysfunction in the brainstem
structures that modulate REM sleep atonia. In animals, experimental lesions confined to the dorsolateral pontine tegmentum3
and to the ventromedial medulla4 both produce REM sleep without
atonia associated with what looks like dream-enacting behaviors.
These observations indicated that the lower brainstem is a critical
area for inducing muscle atonia during REM sleep and provided an
animal model for RBD.
RBD was first described as a medical entity in humans by Schenck
and colleagues in 1986.5 The same authors were the first group to
report that RBD may occur in subjects with chronic neurological
diseases, including MSA5 and narcolepsy.6 They also first found that
subjects diagnosed with IRBD eventually develop parkinsonism.7
These observations have been confirmed in other prospective
studies. Emerging neurological disorders in IRBD subjects at our
sleep center were MSA, PD, DLB and mild cognitive impairment.8
This has been recently confirmed by another group of investigators.9
Hence, RBD should no longer be considered as a sleep disorder in
isolation, but rather integrated as one component of a neurological
disease. Moreover, it should be regarded as a potential early marker
for MSA, PD and DLB. During the last four years, several aspects of
RBD have been extensively reviewed in more than 15 publications.10–25 In this article we review our current understanding of the
clinical characteristics and significance of RBD pathophysiology in
neurodegenerative diseases and address some controversial issues.
Also, we provide demographical, clinical and polysomnographic
detailed data on 231 patients from our sleep center diagnosed by
clinical history and videopolysomnography (VPSG) with IRBD and
RBD secondary to MSA, PD and DLB (Tables 1–3).
Clinical aspects of RBD
The clinical spectrum of RBD
RBD usually emerges after the age of 50. Its prevalence is estimated to be less than 1% of the population.26 RBD patients display
abnormal motor and vocal behaviors during REM sleep that have
different degrees of severity across different nights. Severity may also
vary through a single night, usually being more intense at the end of
the night. In our experience reviewing VPSG of patients with RBD,
motor behaviors are more frequent than vocal behaviors and range
from mild limb jerking to jumping out of bed. Typical motor and
Table 1
Demographic and clinical findings of 231 RBD patients with MSA, DLB, PD and the
idiopathic form seen at our sleep center. RBD was confirmed by VPSG in all subjects.
Male (%)
MSA
(n ¼ 67)
DLB
(n ¼ 17)
PD
(n ¼ 65)
IRBD
(n ¼ 102)
56.7
94.1
70.8
86.3
Age at diagnosis of RBD (years)
Age at RBD onset (years)
RBD duration (years)
Age at disease onset (years)
Duration of disease (years)
RBD preceding disease onset (%)
61.5 7.9
54.7 10.2
7.3 6.9
57.1 8.2
4.4 2.7
52.2
74.2 6.5
65.3 11.8
8.9 10.4
71.7 8.4
3.2 4.4
100
65.8 7.5
61.0 7.7
4.6 4.0
56.2 9.7
9.6 6.0
18.5
68.4 6.7
61.0 8.8
7.2 7.2
N/A
N/A
N/A
n: number of subjects, RBD: Rapid eye movement sleep behavior disorder, MSA:
Multiple system atrophy, DLB: Dementia with Lewy bodies, PD: Parkinson’s disease,
IRBD: idiopathic RBD, N/A: not applicable, VPSG: video-polysomnography.
Table 2
Findings of reported dream content and witnessed abnormal behaviors in 231 RBD
patients with MSA, DLB, PD and the idiopathic form seen at our sleep center. RBD
was confirmed by VPSG in all subjects.
MSA
(n ¼ 67)
Self-awareness of behaviors (%) 23.9
Unpleasant dream recall (%)
65.7
Most frequent unpleasant dreams
Attacked by someone (%)
38.8
Arguing with someone (%)
35.8
Chased by someone (%)
35.8
Falling from a cliff (%)
29.9
Attacked by animals (%)
26.9
Most frequent abnormal behaviors
Talking (%)
89.6
Shouting (%)
79.1
Swearing (%)
26.9
Crying (%)
52.2
Laughing (%)
61.2
Singing (%)
13.4
Punching (%)
73.1
Kicking (%)
56.7
Falling out of bed (%)
46.3
Patients injured (%)
13.4
Bed partners injured (%)
6.0
Treatment with clonazepam (%) 29.9
Dose of clonazepam (mg/day)
0.58 0.20
DLB
(n ¼ 17)
PD
(n ¼ 65)
IRBD
(n ¼ 102)
29.4
82.4
35.4
86.2
53.9
92.1
64.7
41.2
47.1
11.8
29.4
67.7
53.1
53.8
44.6
32.3
84.3
58.8
52.9
48.0
42.2
94.1
82.4
23.5
41.2
52.9
0
64.7
41.2
82.4
41.2
5.9
35.3
0.90 0.65
95.4
89.2
29.2
49.2
47.7
13.8
69.2
66.2
38.5
15.4
10.8
46.2
0.66 0.35
96.1
89.2
33.3
42.2
54.9
17.6
83.3
78.4
77.5
55.9
23.5
65.7
0.94 0.93
n: number of subjects, RBD: Rapid eye movement sleep behavior disorder, MSA:
Multiple system atrophy, DLB: Dementia with Lewy bodies, PD: Parkinson’s disease,
IRBD: idiopathic RBD, VPSG: video-polysomnography.
vocal behaviors include punching, kicking, beating, biting, knocking
off the nightstand, sitting on the bed, jumping out of bed, whispering, talking, shouting, swearing, crying, laughing and singing.
Consequently, patients and bed partners may suffer lacerations,
contusions and fractures. In some patients, non-violent behaviors
(e.g., gesturing, elaborated pseudo-purposeful behaviors, whistling)
may occasionally coexist with the typical violent behaviors.26
Recalled dreams commonly have a negative emotional content and
include being attacked, robbed, or chased by unfamiliar people for
known or unknown reasons. In these dreams patients are threatened
and react verbally or physically against the offender being rarely the
primary aggressor. Other common nightmares include being frightened or attacked by animals (snakes, bulls, lions, donkeys, etc.) and
falling off a cliff. A few patients recall funny dreams, which may be
associated with smiling and laughing during sleep (Table 2). Type of
unpleasant dreams and motor and vocal expressions of RBD are
similar between subjects with IRBD and secondary RBD to MSA and
PD.27 In contrast to somnambulism and frontal lobe nocturnal
seizures, RBD patients usually have their eyes closed, and it is very
uncommon for them to get out of bed and walk or run. The clinical
and pathophysiological significance of the coexistence of RBD with
epileptic discharges28 and epilepsy29 in the elderly without neurodegenerative diseases is unknown.
The presence of a bed partner or anyone who can witness the
patient’s sleep is crucial in RBD detection, as many patients are
unaware of their abnormal sleep behaviors and may mistakenly
report undisturbed sleep.30 Behaviors of mild intensity, such as
jerking (the most common abnormal motor finding in VPSG
studies), may easily be undetected by bed partners. Alternatively,
they may be considered to be non-pathological and thus unreported to the physician. Consequently, it is important that the
physician inquires about these symptoms. It is possible that only
the patients with the most severe form of RBD seek medical
attention while those with milder intensity remain underdiagnosed. It is unknown if the clinical severity of RBD is associated
with a higher risk for developing a neurodegenerative disease. The
natural course of RBD symptomatology is unknown since most of
A. Iranzo et al. / Sleep Medicine Reviews 13 (2009) 385–401
387
Table 3
Polysomnographic findings in 211 RBD patients with MSA, DLB, PD and the idiopathic form seen at our sleep centre. RBD was confirmed by VPSG in all subjects.
Sleep efficiency (%)
Total sleep time (min)
Sleep onset latency (min)
Arousal index
Stage I (%)
Stage II (%)
Stage III–IV (%)
REM (%)
REM sleep latency (min)
REM sleep stages (n)
PLMS index
Apnoea-hypopnea index
MSA (n ¼ 67)
DLB (n ¼ 17)
PD (n ¼ 45)
IRBD (n ¼ 102)
64.2 16.0
285.4 74.0
34.3 33.4
22.1 13.3
17.2 11.4
44.8 12.6
21.8 14.7
16.0 9.3
140.0 85.9
2.4 1.3
27.9 36.8
10.5 11.4
74.9 10.8
346.5 52.5
36.6 40.0
27.7 20.5
24.2 18.2
46.6 14.9
17.3 13.4
11.8 7.5
195.5 109.3
1.9 0.8
21.5 34.6
14.1 17.3
65.9 17.0
309 91.8
21.7 21.4
25.4 17.6
19.0 14.1
47.2 14.6
16.3 9.8
17.5 8.0
134.0 86.2
2.6 1.4
10.4 17.9
13.9 19.3
73.9 12.8
340.5 68.4
25.5 21.5
23.3 13.9
22.2 12.6
46.3 11.4
14.2 9.1
17.6 7.3
131.2 6.3
2.8 1.1
12.8 22.3
13.4 16.4
n, number of subjects; RBD, Rapid eye movement sleep behaviour disorder; MSA, multiple system atrophy; DLB, dementia with Lewy bodies; PD, Parkinson’s disease; IRBD,
idiopathic RBD; PLMS, periodic leg movements in sleep.
the patients are effectively treated with clonazepam. Some patients
report long periods of remission while others report a gradual
worsening of symptoms. Effective clonazepam treatment, however,
does not prevent development of a neurodegenerative disease in
subjects initially diagnosed as having IRBD.8
RBD manifestations depend of the amount of time spent in REM
sleep. The use of antidepressants may be related to a subjective
improvement in RBD symptomatology because these medications
decrease REM sleep time. Paradoxically, the use of antidepressants
has been associated with development of RBD, likely due to their
ability to increase muscular activity during REM sleep.31–33
The male predominance in RBD
More than 80% of the patients presenting to sleep centers with
IRBD are men.9,27,34,35 In our experience, a strong male predominance is also observed in DLB patients with RBD (unpublished
data). In PD, the male predominance has been observed in most but
not all series.36 Interestingly, the male predominance is not evident
in MSA, probably because RBD occurs in most, if not all, patients
with MSA, and this disease has no gender predominance.27,37
The origin of the male preponderance in RBD is unknown. It has
been hypothesized that sex hormone abnormalities might account
for this male predominance and for the violent nature of the RBDassociated behaviors.2 However, two studies in male patients with
IRBD38 and RBD linked to PD39 showed no differences in morning
circulating sex hormone levels between patients and controls.
Aside from hormonal issues, there are other possible explanations for the male predominance of patients with RBD presenting at
sleep centers. First, RBD may be milder in female and produce less
vigorous and disruptive behaviors, thereby making female patients
less prone to seek medical help. This hypothesis is supported by 1)
the finding that in PD the mildest form of RBD (subclinical
increased submental tonic electromyographic activity in REM
sleep) is equally frequent in men and women, whereas clinically
evident RBD is more common in men,40 2) the result of an epidemiological study showing that subjects with a milder clinical form
of RBD do not seek medical attention41 and by 3) the fact that
unpleasant dream content in RBD is somewhat different between
males and females.42 RBD-related dream content in men usually
compromise physical and vocal self-defense against unknown
attackers. In contrast, dream content in women includes sensation
of threat and fear and being chased, while physical aggression
against someone is rarely reported.42 A different explanation for
the male predominance is a referral bias. RBD may manifest
similarly in women and men, but women may be more embarrassed by their condition and ashamed to seek medical consultation. It is also possible that women are more capable than men in
detecting sleep disorders of their bed partners (such as snoring,
apneas, and abnormal sleep behaviors) and are more prompt to
seek medical attention for them.
Polysomnography in the diagnosis of RBD
In 2005, the International Classification of Sleep Disorders
(ICSD-2) established that the diagnosis of RBD should be based on
both clinical and PSG criteria.1 Demonstration of increased electromyographic activity during REM sleep by PSG is required mainly
because RBD-like behaviors may occur in people with and without
neurodegenerative disorders who are affected by obstructive sleep
apnea,43 somnambulism,44,45 nocturnal epilepsy, hallucinations,
confusional states and patients with unusually prominent periodic
leg movements of sleep also involving the head, trunk and
upper limbs (personal observations). In these situations, termed
as pseudo-RBD, only VPSG can diagnose these disorders and
exclude RBD (Figs. 1–4). Alternatively, RBD may incidentally
coexist with obstructive sleep apnea, somnambulism, epileptiform
activity28,29,46 and confusional awakenings. Only VPSG can detect
these conditions occurring in the same patient. Furthermore, VPSG
increases the sensitivity of diagnosing RBD because a proportion of
patients are unaware of their abnormal behaviors during the
night.27 Therefore, the presence of RBD may be either overestimated or underestimated when based only on clinical history.
Correct diagnosis of RBD is particularly important in subjects
without evidence of an underlying neurological disease because
this parasomnia may be its initial manifestation.7,8,29 Misdiagnosis
of RBD may carry unnecessary emotional consequences and
medical practice liability. Moreover, correct diagnosis of RBD is
important because patients with RBD may injure themselves and
their bed partners, and because this parasomnia can be treated
effectively with clonazepam.15 It is not recommended, however, to
prescribe clonazepam before ruling out other conditions that may
mimic RBD symptomatology47 such as obstructive sleep apnea.43,48
We think that when either IRBD is suspected or the intensity of
the sleep behaviors requires initiation of clonazepam, VPSG is
required to diagnose this parasomnia. In contrast, if sleep behaviors
are clinically mild, appear in the setting of a known neurodegenerative disease such as PD, and sleep apnea is unlikely by clinical
history, the need for a sleep study is debatable. In some instances
like in PD, clinical interview with both the patient and bed partner
may show a high specificity and sensitivity.36 However, it should be
noted that obstructive sleep apnea is common in patients with PD
and normal body mass index.38 Unpleasant dreams and vigorous
sleep behaviors may be present in patients with severe obstructive
sleep apnea.43 In RBD subjects with comorbid severe obstructive
sleep apnea, treatment with continuous positive airway pressure
388
A. Iranzo et al. / Sleep Medicine Reviews 13 (2009) 385–401
Fig. 1. A) A normal REM sleep episode in a healthy subject showing muscle atonia in the chin, upper and lower limbs. B) Sustained tonic electromyographic activity in the chin with
normal atonia in the limbs during REM sleep in a patient with RBD. EOG: electrooculogram. C3, C4, O1, O2: electrode positions according to the 10/20 International system,
referenced to combined ears (Ac). Chin: electromyography of the mentalis muscle. L and R Bic: electromyography of the left and right biceps brachii. L and R TA: electromyography
of the left and right tibialis anterior. Nasal: nasal air flow. Oral: oral air flow. Tho: thoracic respiratory movements. Abd: abdominal respiratory movements. EKG: electrocardiogram.
Note the time calibration mark.
alone decreases the frequency and intensity of unpleasant dream
recall and abnormal sleep behaviors but RBD persists. This occurs in
patients with IRBD43 and PD patients with RBD (unpublished
observation).
Clinical, electromyographic and video-classification of RBD
Measuring the characteristics and severity of RBD is important
when monitoring the efficacy of medications. It is also of interest
because it is thought that RBD frequency and intensity may vary
over time, although this has never been assessed. It should be
noted, though, that RBD occurs every night but with a high internight variability in its intensity. A recent study showed that a single
night of PSG with synchronized audiovisual monitoring was
adequate in the diagnosis of RBD in most patients.49 The following
attempts have been made to classify RBD by clinical history, REM
sleep electromyographic features and the abnormal behaviors seen
in audiovisual recordings.
Fig. 2. A) Excessive phasic electromyographic activity and intermittent increased tonic electromyographic activity in the chin with normal atonia in the limbs during REM sleep in
a patient with RBD. B) Abnormal phasic electromyographic burst of all the muscles recorded associated with a sudden body jerk during REM sleep in a patient with RBD.
(Abbreviations as in Fig. 1).
A. Iranzo et al. / Sleep Medicine Reviews 13 (2009) 385–401
389
Fig. 3. A) Increased phasic electromyographic activity during REM sleep only in the lower limbs with muscle atonia in the chin and upper limbs in a patient with RBD. B) Increased
phasic electromyographic activity during REM sleep only in the upper limbs with muscle atonia in the chin and lower limbs in a patient with RBD. (Abbreviations as in Fig. 1).
Clinical history
In the first edition of the International Classification of Sleep
Disorders (ICSD-1) severity of RBD was classified in mild, moderate
and severe.50 These categories were defined according to the
intensity and frequency of the witnessed behaviors as follows:
Mild: RBD that occurs less than once per month; only mild
discomfort for the patient or bed partner.
Moderate: RBD that occurs more than once per month but less
than once per week; usually associated with physical discomfort to
the patient or bed partner.
Fig. 4. Electromyographic activity from multiple muscles during REM sleep in a patient with RBD. A) Lack of atonia only in the chin. B) Atonia in the chin and increased phasic
electromyographic activity in the upper limbs starting in both biceps brachii and spreading to the deltoid and sternocleidomastoid. C) Increased phasic electromyographic activity
mainly in the upper limbs. EOG: electrooculogram. Cz, O2: electrode position according to the 10/20 International system, referenced to combined ears (Ac). Chin: electromyography
of the mentalis muscle. Ster: sternocleidomastoid. Delt: deltoides. Bic: biceps brachii. Flex: flexor digitorum superficialis. Abd: abductor pollicis brevis. Pasp: thoracolumbar paraspinal. Fem: rectus femoris. TA: tibialis anterior. Gast: gastrocnemius; Ext: extensor digitorum brevis. L: left, R: Right.
390
A. Iranzo et al. / Sleep Medicine Reviews 13 (2009) 385–401
Severe: RBD that occurs more than once per week; associated
with physical injury to patient or bed partner.
This classification was not validated by any study. Despite its
potential interest and use in some studies27 the classification was
removed from the second edition of the International Classification
of Sleep Disorders in 2005.1 We think that this system, in the
absence of any other clinical classification could be a reasonable
way of classifying RBD intensity and frequency by clinical history.
However, its main limitation is that it is totally dependent on the
patient and bed partner ability to detect the behaviors occurring at
night. Its use is very limited in RBD patients that sleep alone
because many are unaware of their nocturnal behaviors.27
Electromyographic analysis
No accepted methodology exists to measure the excessive electromyographic activity occurring in REM sleep, and cut-off values that
can distinguish normality from RBD are lacking. Several systems have
been proposed to quantify the electromyographic activity, either
visually51–53 or based on computerized systems.54–56 There is a lot of
variability among the different proposed systems, with different
duration of epochs (7.5, 10, 20 or 30 s) and mini-epochs (2, 3 or 7.5 s).
Some authors have evaluated only the tonic activity,40 only the phasic
activity,53,57 or both the tonic and phasic activities.27 Others have used
a different approach defining short and long lasting electromyographic activity.58 There is also variability in the muscles used for
analysis with several combinations including 1) exclusively the
mentalis or the submentalis, 2) the mentalis or submentalis plus left
and right anterior tibialis and 3) the mentalis or submentalis plus
right and left anterior tibialis, and either the brachioradialis, biceps
brachii, extensor digitorum or carpi radialis. The SINBAR (SleepInnsbruck-Barcelona) group found that simultaneous recording of the
mentalis, flexor digitorum superficialis and extensor digitorum brevis
muscles detects the highest rate of phasic EMG activity during REM
sleep in subjects with RBD.53
Video analysis
It should be noted that minor distal limb movements in REM
sleep occur in normal people. Motor and vocal behaviors displayed
by RBD patients are variable. Four different classification systems
have been proposed. The first three classify the behaviors according
to their nature into simple and complex59,60 or into elementary and
complex.61 A fourth classification system classifies the behaviors
severity into mild, moderate and severe.62
Overall, there is a clear need for a consensus classification of the
clinical, electromyographic and video aspects of RBD. This could
produce progress in our understanding of this sleep disorder.
Treatment of RBD
tolerance is rarely seen.27 However, some patients may require up
to 4 mg to achieve some clinical benefit. For unknown reasons a few
patients do not respond to clonazepam, particularly those with
IRBD (personal observations). Side effects of clonazepam include
dizziness, somnolence, impotence and urinary incontinence at
night.27 One study involving 5 IRBD patients showed that clonazepam decreases the phasic, but no the tonic, electromyographic
activity in the submentalis muscle during REM sleep.51 The beneficial effect of clonazepam might be related to its GABAergic activity
depressing motor reflexes at the spinal cord level, promoting glycinergic activity and thereby reducing muscular activity.63
However, this does not explain why other benzodiazepines have
been found not to ameliorate RBD symptoms.35
Melatonin (3–12 mg at bedtime or 30 min before bedtime) is also
effective in patients with idiopathic64 and secondary RBD.64,65 Its
beneficial effect occurs within the first week of treatment. Unlike
clonazepam, melatonin decreases the tonic, but not the phasic,
electromyographic activity in the submentalis muscle in subjects
with RBD.64 It has been speculated that melatonin improves RBD due
to restoration of the REM sleep circadian rhythm.64 Melatonin can be
useful in refractory cases to clonazepam, when clonazepam is
associated with side effects, and when clonazepam is not indicated
due to the presence of obstructive sleep apnea and severe dementia.
The co-administration of small doses of clonazepam and melatonin
may also be effective in some patients (personal observations).
Methods of self-protection from injury, such as placing a mattress on
the floor or removal of furniture from the room, may be necessary. It
is recommended to minimize the use of antidepressants and lipophilic beta-blockers such as bisoprolol because these medications
may induce or aggravate RBD.31,33,66
RBD in the setting of neurodegenerative diseases
RBD often antedates the full-blown clinical presentation of
several neurodegenerative diseases, suggesting that this sleep
disorder should be considered part of the neurodegenerative
process rather than a predisposing factor. Therefore, it can be argued
whether the idiopathic form of RBD really exists.13 On the other
hand, neurologists should be aware that their patients with established MSA, PD and DLB may present with RBD. These three diseases
have several molecular, clinical and morphologic abnormalities in
common, such as substantia nigra cell loss resulting in parkinsonism
that responds to dopaminergic agents to a variable extent. However,
like other non-motor symptoms, the presence of RBD in these
diseases is mainly explained by the intrinsic neurodegenerative
process beyond the substantia nigra. In this section we review the
relevance and characteristics of RBD in the setting of some neurodegenerative diseases. In Tables 1–3 we present clinical, demographical and PSG characteristics of 231 RBD patients confirmed by
PSG with IRBD, MSA, PD and DLB seen at our sleep center.
Treatment of RBD may be required in the following situations:
The natural history of idiopathic RBD
1) To prevent injuries in patients with violent dream-enacting
behaviors.
2) To decrease the intensity of unpleasant dreams in those
subjects disturbed by this uncomfortable experience.
3) To avoid disturbing the bed partner’s quality of sleep.
No prospective placebo-controlled trials have been performed
for any therapy of RBD.15 In idiopathic and secondary RBD, symptoms usually respond dramatically to small doses of clonazepam
(0.25–4 mg) at bedtime.27,34,35 Clonazepam decreases the
frequency and severity of both dream-enacting behaviors and
unpleasant dream recall in the first week of treatment. In our
experience, the mean effective dose of clonazepam is 1 mg and
Idiopathic RBD is diagnosed when a patient with VPSG confirmation of RBD has no evidence of a neurological disease or other
possible causes. In many IRBD patients, though, subclinical abnormalities can be detected, such as olfactory deficits,67 color vision
impairment,68 cognitive deficits on neuropsychological tests,69
subtle cortical electroencephalographic slowing,70 dysautonomic
abnormalities,71 reduced cardiac 123-I Metaiodobenzylguanidine
(MBIG) scintigraphy,72 decreased dopamine transporter imaging,73
and increased substantia nigra echogenicity.74,75 All these features
have also been described in patients with the established classic
motor and cognitive features of MSA, PD and DLB. Furthermore,
neuropathological examination in two IRBD patients showed the
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hallmarks of PD, namely neuronal cell loss and Lewy bodies in the
brainstem.76,77
It has been shown that neurodegenerative diseases frequently
develop in IRBD patients followed at sleep centers. Schenck et al. first
reported development of parkinsonism in 11 of 29 (38%) men at
a mean interval of 12.7 years after RBD onset and 3.7 years after the
diagnosis of RBD.7 After an additional seven years of follow-up, the
proportion of subjects that developed parkinsonism and/or
dementia increased to 65%.78 In a second series, we showed that 20
of 44 (45%) IRBD patients developed a neurological disorder after
a mean interval of 11.5 years from RBD onset and after a mean followup of 5.1 years from the diagnosis of IRBD. Emerging disorders were
PD in nine patients (two with associated dementia), DLB in six, MSA
with predominant cerebellar syndrome in one, and mild cognitive
impairment in four in whom visuospatial dysfunction was prominent. The finding that patients who developed a disorder were
those with longer follow-up suggested that conversion rate (45%)
could increase with the passage of time.8 This was confirmed after
two years of follow-up when one patient with IRBD developed PD,
two patients with mild cognitive impairment converted into DLB,
and seven subjects with IRBD developed mild cognitive impairment.
Also, two PD patients developed mild cognitive impairment. Overall,
in our center 64% of IRBD patients have developed a neurological
disorder after a mean clinical follow-up of 7 years.79 An additional
patient with IRBD and mild cognitive impairment who was lost to
follow-up for four years recently presented with marked dementia,
rigid-akinetic parkinsonism and recurrent paranoid delusions. In
another study, 26 of 93 (27%) IRBD patients seen at a sleep center
developed PD in 14 cases, DLB in 7 cases, MSA in 1 case and dementia
of unknown origin in 4 cases. Diagnosis of these diseases was based
on clinical examination or telephone interviews. The estimated 5year risk of neurodegenerative disease was 17.7%, the 10-year risk
was 40.6% and the 12-year risk was 52.4%.9
RBD in multiple system atrophy (MSA)
MSA is a progressive, sporadic, adult-onset neurodegenerative
disorder characterized by a combination of parkinsonism, cerebellar syndrome and autonomic failure. Neuropathology shows
neuronal loss, astrogliosis and alpha-synuclein positive glial cytoplasmic inclusions in many brain structures, including the striatum,
amygdala, cerebellum and brainstem nuclei (e.g., substantia nigra,
locus ceruleus and pedunculopontine nucleus). Multiple central
neurotransmitter systems are impaired including dopaminergic,
cholinergic, serotonergic, adrenergic, noradrenergic and glutamatergic.80–82
Prevalence of RBD in MSA
A majority of patients with MSA have RBD with a prevalence of
90.5–100%.27,37,83 In one study, 21 consecutive MSA patients
without sleep behavioral complaints underwent VPSG that
demonstrated typical RBD features in 19 (90.5%).83 In another study,
VPSG showed RBD in 35 out of 37 (95%) consecutive patients.37 In
our experience, all 73 MSA patients who were referred to our sleep
center from April 1997 to December 2008 for different reasons
(suspected RBD, stridor or sleep fragmentation) had RBD on VPSG.
Taken together, we think that in a patient with suspected MSA, the
absence of RBD (particularly if it is formally excluded by VPSG)
should seriously question the diagnosis of this disease. RBD is
currently considered a red flag for the diagnosis of MSA.84
Clinical characteristics of RBD in MSA
Self-awareness of abnormal sleep behaviors and unpleasant
dream recall is variable among MSA subjects with RBD. In one
study, 27 of 39 (69%) consecutive MSA patients with RBD or their
391
relatives reported dream-enacting behaviors. Interestingly, most of
the 12 that did not report dream-enacting behaviors were sleeping
alone at their home.37 In another study, only seven of 21 (33%) MSA
patients with RBD recalled vivid dreams.83 In our first published
case series comprising 26 consecutive MSA cases with RBD free of
psychoactive drugs, 77% of the patients were unaware of their
abnormal behaviors, which were only noticed by bed partners.
Recall of unpleasant dreams was absent in 35% of the patients.27 In
our experience involving 67 MSA patients with RBD, 51 (46%) were
not aware of their abnormal behaviors and 24 (33%) did not recall
unpleasant dreams (Table 1).
The strong male predominance seen in the idiopathic form of
RBD, and in those RBD forms associated with PD and DLB is much
less evident in MSA, where 33–61% of the patients are men.27,37,85
This may be explained by the simple fact that most, if not all,
patients with MSA have RBD. The male/female ratio of RBD in MSA
reflects the roughly 1:1 male/female ratio of the disease.80
RBD in MSA is unrelated to age, disease severity, disease duration, clinical subtype (parkinsonian or cerebellar), or to any other
demographic or clinical feature.27
Onset of RBD in MSA
RBD may be the first symptom of MSA. In one study of 27 RBD
patients aware of their dream-enacting behaviors, RBD preceded the
waking motor symptoms in 12 (44%).37 In another study with 19
patients, RBD features were reported by the patients or their relatives as the first manifestation of the disease in 3, concomitant with
other symptoms in 9, and developed after the onset of waking
symptoms in the remaining 7.85 In our series, RBD onset antedated
parkinsonian, cerebellar and dysautonomic onset in 35 of 67 (52%)
patients by a mean of 7.0 7.2 years (range, 1–38 years). In our sleep
center two patients with IRBD developed the dysautonomic and
motor features of cerebellar subtype of MSA, two and four years after
the diagnosis of IRBD. We have recently reported a patient presenting with dysautonomia, stridor during sleep and RBD without
parkinsonism or cerebellar syndrome in whom brain pathology
disclosed MSA after sudden death during wakefulness.86
Polysomnography of RBD in MSA
Typically, VPSG shows marked increase of submental tonic
electromyographic activity during REM sleep which is greater than
in IRBD and PD.27 Also, phasic electromyography activity is usually
excessive in REM sleep.
In a few MSA subjects with RBD, we have observed brief
episodes of sudden trunk and limb jerks during non-REM sleep
similar to, but less complex than, those occurring in the same
patient during REM sleep (Fig. 5). Also, aperiodic limb movements
are frequent in non-REM sleep. These non-REM sleep motor
abnormalities in MSA patients with RBD are indicators of dissociate states of sleep. Intrusion of components of one state into
another has been reported in patients with RBD associated to
neurodegenerative dementia (complex motor behaviors in nonREM sleep stages 1–2),87 narcolepsy (muscle atonia during
wakefulness),6 antidepressant treatment (e.g., rapid eye movements in non-REM sleep) and in a patient with a mesopontine
cavernoma that evolved towards a status dissociatus (an indeterminate state where wakefulness and sleep stages cannot be
distinguished by PSG means) after surgery.88
Pathophysiology of RBD in MSA
The finding that in MSA brainstem cell loss is consistently
widespread and severe82 may explain the high prevalence of RBD in
this disease. It was first reported that cell loss in the cholinergic
pedunculopontine and laterodorsal nuclei was the cause of RBD in
MSA.89 The same authors, however, reported later that the severity
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A. Iranzo et al. / Sleep Medicine Reviews 13 (2009) 385–401
Fig. 5. A patient with multiple system atrophy and RBD presents during non-REM sleep a brief episode of major (A) and moderate (B) sudden body/limb jerk similar to those
occurring in REM sleep but somewhat shorter. (Abbreviations as in Fig. 1).
of cholinergic neuronal loss in these nuclei was not different
between 8 MSA patients with clinical history suggestive of RBD and
3 without suspected RBD by history and concluded that damage of
these cholinergic nuclei was probably not the primary mechanism
of RBD.90 However, this conclusion may be invalid since those 3
patients with history not suggestive of RBD did not undergo VPSG.
Correct diagnosis or exclusion of RBD in MSA can only be disclosed
when VPSG is performed.27,37,83
Treatment of RBD in MSA
Severity of RBD in MSA ranges from mild in asymptomatic
patients to severe with some patients suffering rib fractures after
falling out of the bed. Clonazepam is effective to treat RBD in MSA.
Before prescribing clonazepam, it is desirable to rule out stridor and
obstructive sleep apnea by VSPG, since this medication may worsen
existing apneas by aggravating upper airway obstruction at the
level of the larynx and the pharynx, a common feature in MSA.91
Melatonin could be used to treat RBD in MSA patients with upper
airway obstruction.
RBD in Parkinson’s disease (PD)
PD is clinically characterized by levodopa responsive parkinsonism. PD is associated with other features such as depression,
dementia, hyposmia and several sleep disorders including RBD.92
PD is morphologically characterized by progressive neuronal loss
and Lewy bodies in the substantia nigra pars compacta and other
brainstem structures, including dorsal vagal nucleus, gigantocellular reticular nucleus, locus ceruleus, locus subceruleus,
pedunculopontine nucleus, dorsal raphe and nucleus of the solitary
tract. Neurodegeneration may involve the amygdala, nucleus
basalis of Meynert, limbic cortex, hippocampus, the posterior
hypothalamus and neocortex.93
Prevalence of RBD in PD
PD may occur in patients with idiopathic PD and PD secondary
to genetic mutations.62 RBD occurs in PD patients untreated or
treated with dopaminergic agents.27,36,40,94,95 When diagnosis is
based solely on clinical history, the prevalence of RBD in idiopathic
PD varies from 15% to 46%.96–100 These figures are somewhat lower
than the ones reported when diagnosis of RBD is performed using
clinical and VPSG criteria,1 which range between 46 and
58%.36,40,94,95 This is because some PD patients are not aware of the
abnormal sleep behaviors that can only be disclosed by VPSG.27
Most of the studies have evaluated RBD in nondemented and
non-hallucinator idiopathic PD subjects. One study in 45 nondemented patients found that 18 (40%) showed either clinical RBD
(16%) or subclinical REM sleep without atonia (24%).94 In another
study, nineteen out of 33 patients with mild to moderate idiopathic
PD had REM sleep without submental atonia. Of these, 11 reported
clinical RBD, whereas the remaining 8 either were unaware of sleep
behaviors or REM sleep without atonia was not associated with
abnormal motor manifestations on their VPSG.40 One study evaluating 10 Park2 patients by clinical history and VPSG found RBD in 6
(60%).62
Clinical characteristics of RBD in PD
Sixty-five percent of the PD patients with RBD are unaware of
their RBD-related symptoms and 24% do not recall frightening
dreams.27 Sixty-five to seventy-five percent of the PD patients
with RBD are men,27,94 a figure similar to the frequency of men
in PD.92
The presence of RBD in PD has been associated with longer
parkinsonism duration,36,94 orthostatic hypotension,101 and treatment of parkinsonism with a higher dose of dopaminergic agents.94
RBD is more common in the rigid-akinetic clinical subtype of the
disease than in the tremoric subtype.102,103
It has not been studied if RBD is more common in demented
than in nondemented PD patients. It has been suggested, though,
that RBD may be a marker for the development of dementia in PD
because nondemented PD patients with RBD are more likely to
show electroencephalographic slowing during wakefulness104 and
poorer performance in executive function, verbal memory and
visuospatial abilities in neuropsychological test.105 However, it has
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been argued that these findings may simply reflect a more widespread neurodegenerative disease affecting the brainstem causing
RBD and the cortex causing cognitive abnormalities.106 Moreover,
longer duration of PD is linked to the development of both
dementia92 and RBD.36,94
The relationship between visual hallucinations and RBD remains
controversial.99 RBD in PD is not associated with age,36,94,103 disease
severity,36,103 motor fluctuations,103 dyskinesias,103 depression,101
hyposmia,103 hypersomnia,36 sleep benefit,36 sleep architecture
36,94,103
or lower daily doses of levodopa equivalent.36,94,103
Onset of RBD in PD
When idiopathic PD patients exhibit RBD, this parasomnia
precedes the onset of parkinsonism in 18–22% of the cases.27,94
Unlike MSA, RBD rarely precedes parkinsonism when parkinsonian
signs develop before the age of 50.102 In patients initially diagnosed
with IRBD who later develop PD 1) the age at parkinsonism onset
(mean of 72 years) is older than reported for PD patients in the
community (mean of 62 years), and 2) the most frequent parkinsonism subtype is the rigid-akinetic which responds to levodopa.8
In subjects with Parkin mutations RBD develops after parkinsonism
onset.62
Polysomnography of RBD in PD
Most of the studies evaluating RBD in PD have been based on
clinical history only. We here emphasize again the need to perform
VPSG in PD subjects in order to assess the occurrence of RBD and to
exclude other sleep disorders that present with similar symptoms.
On one hand, many of the PD patients with RBD are unaware of
their RBD-related symptoms and do not recall frightening
dreams.27 On the other hand, somnambulism,36,44,45 confusional
awakenings and sleep apnea107 may mimic RBD symptoms in PD.
The sensitivity of specialized interviews for identifying RBD in
patients with PD varies from 33%108 to 95%.36
Interestingly, VPSG analysis in PD with RBD shows that movements seen in REM sleep are faster and smoother than those
occurring during wakefulness.36
Pathophysiology of RBD in PD
In PD, the brain structures that modulate REM sleep such as the
gigantocellularis reticular nucleus, subceruleus region and amygdala are damaged93 reflecting the high prevalence of RBD in this
disease. The finding that RBD frequently occurs in the rigid-akinetic
subtype of the disease102,103 may suggest that in these patients the
ventrolateral region of the substantia nigra pars compacta is more
severely damaged.93
Treatment of RBD in PD
In idiopathic PD, severity of the RBD symptoms ranges from
mild to severe.27 In patients with Park2 mutations RBD severity is
usually mild.62 Most of the cases respond to clonazepam.27 There is
no clear evidence that dopaminergic agents influence the development, evolution and severity of RBD. Pramipexole,109 pallidotomy27 and subthalamic deep brain stimulation110,111 do not
improve RBD symptoms and RBD-related PSG measures.
RBD in dementia with Lewy bodies (DLB)
DLB is the second most common cause of neurodegenerative
dementia after Alzheimer’s disease (AD). DLB is clinically characterized by dementia, parkinsonism, recurrent visual hallucinations
and fluctuations in cognition and alertness. DLB is diagnosed if
dementia precedes or appears within one year before onset of
parkinsonism, whereas PD later complicated with dementia (PDD)
is diagnosed if dementia occurs more than one year after onset of
393
parkinsonism.112–115 The cognitive pattern in DLB is characterized
by deficits of visuospatial ability, attention and executive frontal
function. Memory is also impaired. The cognitive profile in DLB is
similar to that reported in PDD115 and different from that reported
in AD.116
Neuronal loss, gliosis and Lewy neurites and Lewy bodies are
found in the brainstem (substantia nigra, locus ceruleus, etc.),
limbic system (amygdala, transentorhinal cortex and cingulate) and
neocortex (frontal, temporal and parietal). The combination of
brainstem and cortical Lewy bodies is necessary for the pathological diagnosis of DLB. There are no striking neuropathological
differences in the brain between DLB and PDD. The neurodegenerative process in DLB involves widespread central cholinergic,
histaminergic, noradrenergic and dopaminergic deficiency.112–114
Characteristics of RBD in DLB
The literature on RBD in DLB is limited, and, to the best of our
knowledge, no published studies exist that address the prevalence
and demographic, clinical, therapeutical and VPSG characteristics
of RBD in consecutive patients with DLB. Available data, though,
seems to reflect that RBD is very frequent among patients with DLB,
predominates in men and usually precedes the onset of dementia.
The presence of RBD in DLB has mostly been addressed by a single
group of investigators from the Mayo Clinic in Rochester, Minnesota.112,117–123 In one study, it was noted that at least 50% of patients
with DLB have RBD but no further details were given.121 The same
group presented in abstract form that REM sleep without atonia
was found in 65 of 78 (83%) DLB patients who underwent sleep
medicine consultations.122 Another study evaluated whether some
clinical aspects of fluctuations could distinguish DLB from AD and
found that 50 of 70 (72%) DLB patients reported symptoms
suggestive of RBD.123
We have identified 17 consecutive DLB patients with RBD
confirmed by VPSG who were referred to our sleep center
(unpublished data). Sixteen patients were male and the mean age
of RBD onset was 65 years. In all instances RBD preceded the onset
of cognitive complaints. Unpleasant dream recall was absent in 3
(17.6%) patients and 10 (58.8%) were unaware of their nocturnal
behaviors. Post mortem neuropathological examination in three
patients confirmed the diagnosis of DLB. On the other hand, 12
other patients diagnosed with IRBD in our center have subsequently developed DLB after several years of close clinical followup. Post mortem examination in one of them confirmed the diagnosis of DLB. Furthermore, 15 additional patients diagnosed with
IRBD in our center have developed mild cognitive impairment that
was mainly characterized by the same neuropsychological pattern
seen in DLB.124 It is our experience in some IRBD patients that
cognitive and motor symptoms may appear in tandem or separated
just by a few months.
RBD as a diagnostic feature of DLB
Established in 2005, current consensus criteria for DLB state that
diagnosis of probable DLB can be made in subjects with dementia
plus RBD and at least one of the three core features (parkinsonism,
visual hallucinations and fluctuations).113 The diagnosis of possible
DLB can be established in a patient with dementia plus RBD in the
absence of any of the three core features. The current criteria
consider RBD as a suggestive feature of the disease because ‘‘it has
been demonstrated to be more frequent in DLB than in other
dementing disorders’’.113 This statement is based on a single
retrospective study published in 1998 involving 37 consecutive
patients with dementia plus RBD.117 Thirty-four of these patients
(92%) were male. In 35 (96%) RBD symptoms preceded or occurred
simultaneously with the cognitive complaints. Of the 37 patients,
23 fulfilled the 1996-consensus criteria for probable DLB (dementia
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plus at least two of the following: parkinsonism, visual hallucinations and fluctuations), and all fulfilled criteria for possible DLB
(dementia plus one of the following: parkinsonism, visual hallucinations and fluctuations).125 The diagnosis of DLB was confirmed in
the three patients that underwent autopsy and supported the
contention that the combination of dementia and RBD most often
reflects DLB.125 The same group of authors observed that when
patients with dementia plus RBD are compared with a group of
patients with neuropathological confirmed AD, neurocognitive
testing shows poorer performance in visuospatial abilities, attention and letter fluency.118 This neurocognitive profile is found in
autopsy proven DLB patients112,113 and subjects with PDD.115 Taken
together, the clinical combination of dementia and RBD indicates
underlying Lewy body disease, namely DLB and PDD. This is in
agreement with neuropathological studies in patients with ante
mortem diagnosis of DLB plus RBD showing cell loss and Lewy
bodies in the brainstem (locus ceruleus and substantia nigra),
limbic system (amygdala and enthorinal) and neocortex.119,126,127
RBD in Alzheimer’s disease
Alzheimer’s disease (AD) is the most common cause of
dementia and is characterized by tau deposits, amyloidal plaques
and neurofibrillary tangles in the hippocampus, limbic system and
cortex. Only one study has evaluated the occurrence of RBD in AD
using PSG.128 In this study, 15 patients with mild to moderate
dementia underwent VPSG. None of the patients had a clinical
history of RBD. One patient had increased submental tonic electromyographic in REM sleep and abnormal behaviors, supporting
the diagnosis of subclinical RBD. Three patients had REM sleep
with increased muscle tone but without abnormal behaviors on
VPSG. The finding that neuronal damage in the brainstem is less
prominent129 may explain why RBD is not frequent in patients
with AD.
RBD in progressive supranuclear palsy and related disorders
Progressive supranuclear palsy is a taupathy involving the
brainstem, basal ganglia, and many other brain areas. It is characterized by dementia, poor levodopa responsive parkinsonism,
vertical gaze palsy and falls.130 The first reported case of RBD
linked to progressive supranuclear palsy was a 70-year-old
woman presenting with inhibition of speech during wakefulness
and intelligible somniloquy at night due to RBD. Parkinsonism
developed one year before the onset of RBD.131 In a series of 15
progressive supranuclear palsy patients who underwent PSG, 2
had clinical RBD and 4 exhibited REM sleep with increased tonic
electromyographic activity.132 Clinical manifestations of RBD were
severe in one patient, but none of the patients were aware of
their abnormal sleep behaviors (Isabelle Arnulf, personal
communication). In a recent study, 7 of 20 (35%) patients had
clinical RBD.133 In our sleep center, we have identified five
progressive supranuclear palsy patients with RBD confirmed by
PSG (unpublished data).
Guadeloupean parkinsonism is a progressive supranuclear
palsy-like syndrome related to the ingestion of a toxic ingredient
found in a tropical plant called sour sop. Pathology reveals tau
protein deposits in the brainstem and basal ganglia.134 One study
involving 9 patients undergoing VPSG showed that seven (78%)
had RBD.135 These patients were five men and two women, and in
three (43%) RBD antedated parkinsonism onset. Intensity of RBD
was severe. All seven patients recalled nightmares and were
aware of their abnormal behaviors (Isabelle Arnulf, personal
communication).
The finding that RBD may be found in two taupathies such as
progressive supranuclear palsy and Guadeloupean parkinsonism
argues against RBD as an exclusive feature of the synucleinopathies
(MSA, PD and DLB).
RBD in Huntington disease
Huntington disease is a genetic neurological disorder characterized by progressive dementia, chorea and psychiatric disturbances linked to expanded CAG repeats in the Huntington gene.
Pathological studies demonstrate severe atrophy of the putamen
and caudate, and, to a lesser extent, of the cortex.136 In one study,
three of 25 (12%) patients had VPSG confirmed RBD.137 Two were
aware of their abnormal behaviors at night, but these behaviors
were considered clinically mild (Isabelle Arnulf, personal
communication).
RBD in spinocerebellar ataxias
Spinocerebellar ataxias are inherited neurodegenerative disorders that result from mutations in different genes. These diseases
affect the spinocerebellar tracts, cerebellum, brainstem and many
other structures in the brain. They are clinically characterized by
progressive ataxia and a wide variety of other neurological symptoms and signs such as polyneuropathy and parkinsonsim.138
Spinocerebellar ataxia type 3 (Machado Joseph disease) is an
autosomal dominant disorder linked to CAG-trinucleotide repeat
expansions in the ataxin-3 gene. It is characterized by progressive
cerebellar syndrome associated with ophtalmoplegia and extrapyramidal signs. Neurodegeneration involves the cerebellum, spinocerebellar tracts and brainstem.138 One study described the presence
of symptoms suggestive of RBD in 12 of 22 (56%) patients but VPSG
was not performed.139 Another study reported RBD confirmed by
PSG in a 61-year-old man. Duration of the cerebellar syndrome was
40 years and RBD duration was one year, consisting of at least five
dream-enactment episodes that resulted in falling out of bed.140 We
described the presence of VPSG confirmed RBD in 5 of 9 (55%)
patients, 4 men and 1 woman, with a mean age of 48 years and
a mean ataxia duration of 14 years. In two patients RBD preceded the
ataxia onset by 10 and 8 years.141 After this publication from our
group we have identified another three spinocerebellar ataxia type 3
patients with RBD. RBD has also been described in spinocerebellar
ataxia type 1,142 type 2142,143 and type 8 (personal observation). We
saw a 22-year-old man with Friedreich ataxia and severe RBD where
VPSG showed abnormal behaviors that mainly affected the head and
trunk in REM sleep (personal observation).
The pathophysiology of RBD
The finding that RBD is frequent in subjects with MSA, PD and
DLB led to the speculation that the pathogenesis of this parasomnia
could be linked to synuclein pathology144 or dopamine deficiency
alone.58,73,145 There are several questions that need to be answered
regarding the pathophysiology of RBD.
Does alpha-synuclein pathology cause RBD?
Alpha-synuclein is a normal brain protein that is thought to be
involved in synaptic vesicle transport.132 Diseases characterized by
abnormal alpha-synuclein aggregates in the nervous system
include MSA, PD, DLB and pure autonomic failure, which are
sometimes termed synucleinopathies.146 Glial cytoplasmic inclusions of abnormal alpha-synuclein are the characteristic pathological finding in MSA.80 Lewy bodies are not found in MSA.80 The
A. Iranzo et al. / Sleep Medicine Reviews 13 (2009) 385–401
main component of Lewy bodies, the histological hallmark of DLB
and PD, is alpha-synuclein.93
It has been speculated that RBD is linked to accumulation of
alpha-synuclein aggregates.141,147 This conclusion is based on the
following observations. First, Lewy bodies were found in the
autopsied brains of the two published IRBD patients with no clinical evidence of a neurodegenerative disease.76,77 Second,
pathology in RBD subjects with comorbid parkinsonism and/or
dementia demonstrates widespread Lewy bodies in the
brain.120,126,127,148 Third, RBD is very frequent in those neurodegenerative disorders characterized by deposition of alpha-synuclein, such as MSA, PD and DLB.16 Conversely, RBD is not described,
absent or uncommon in several neurodegenerative disorders
lacking alpha-synuclein inclusions including pallido-ponto-nigral
degeneration,149 AD,128 frontotemporal dementia, corticobasal
degeneration, Wilson disease and amyotrophic lateral sclerosis.16,22
Available data, though, indicate that RBD in the setting of
a neurodegenerative disease is not an exclusive finding of a synucleinopathy. RBD occurs in several disorders involving intracellular
accumulation of other abnormal proteins such as ataxins, parkin
and tau. RBD has been found in disorders in which synuclein
pathology is generally lacking such as spinocerebellar ataxias,139–
143
parkinsonism with Parkin mutations,62 progressive supranuclear palsy,131–133 Guadeloupean parkinsonism135 and Huntington disease.137 Conversely, RBD is uncommon in patients with pure
autonomic failure, a disorder where Lewy bodies are found in the
central and autonomic nervous systems.150,151 Taken together, we
believe that there is no strong evidence indicating that RBD is
caused by the abnormal deposition of a single protein like alphasynuclein. Moreover, it is unclear whether Lewy bodies are a toxic
aggregation contributing to neuronal death or have a neuroprotective role.152
Does nigrostriatal dopaminergic deficiency play
a central role in RBD?
It has been hypothesized that dysfunction of the dopaminergic
nigrostriatal system plays an important role in the pathogenesis of
RBD.58,73,145 It occurs frequently in MSA, PD, and DLB, three
neurodegenerative diseases where substantia nigra neuronal loss
is prominent.16 There are published reports of a few patients who
experienced subjective improvement of RBD symptoms after the
administration of dopaminergic agents.70,153,154 A unique episode
of RBD was triggered during PD surgery after unilateral microlesion in or near the substantia nigra pars compacta.155 A PET
study showed that in MSA patients with RBD the tonic electromyographic activity during REM sleep is correlated to decreased
nigrostriatal dopamine projections.156 In some patients with IRBD,
FP-CIT-SPECT (I-N-fluoropropyl-2-b-carbomethoxy-3- b-iodophenylnortophane single photon emission computed tomography)
shows reduced striatal dopamine transporters.73 However, this
observation may alternatively represent a comorbid finding and
not the primary pathogenic determinant of RBD, as subjects with
IRBD frequently develop a neurodegenerative disorder associated
with substantia nigra cell loss (e.g., MSA, PD and DLB).8,9 In PD,
parkinsonism only manifests when the substantia nigra pars
compacta reaches a 60–70% of cell loss. Thus, it is possible that FPCIT-SPECT in IRBD is detecting subjects close to 60–70% substantia
nigra neuronal loss at a high risk for developing parkinsonism,
rather than explaining the pathophysiology of RBD. Moreover,
dopamine transporter FP-CIT-SPECT is abnormal in idiopathic PD
regardless of the presence or absence of RBD.
Besides, there are many lines of evidence suggesting that
dopaminergic deficiency is not directly responsible for RBD
pathogenesis:
395
1) RBD or REM sleep without atonia does not occur in about half
of the PD patients.40
2) In some PD patients with RBD, the parasomnia onset clearly
antedates the onset of parkinsonism.27
3) Total levodopa equivalent dose and the use of dopamine
agonists are not different between PD patients with and
without RBD.27,36
4) In PD patients with RBD, total levodopa equivalent dose is not
associated with measures of RBD severity, such as submental
tonic electromyographic percentage, submental and limb
phasic electromyographic percentage, self-reported severity of
the RBD symptoms, and severity of the behaviors detected on
VPSG.27
5) The use of dopaminergic agents usually does not improve RBD.
In PD, pramipexole, a dopamine agonist, does not improve RBD
symptoms and VPSG RBD-related measures.109 Dopaminergic
agents in subjects with IRBD60 and RBD secondary to PD 157
increase the tonic electromyographic activity during REM
sleep. Moreover, in some PD patients, RBD onset was temporarily associated with the initiation of levodopa,157 dopamine
agonists,158 and selegiline.159
6) In PD, surgical techniques (e.g., deep brain subthalamic stimulation) do not ameliorate RBD while provide effective control
of the parkinsonian dopaminergic motor symptoms.110,111,160
7) In RBD cases secondary to structural brainstem lesions (stroke,
tumors, etc.) the substantia nigra is habitually spared88,161–169
8) Two conditions that respond to dopaminergic agents, restless
legs syndrome and periodic leg movements in sleep, are not
more common in PD patients with RBD than without RBD.36
9) REM sleep without atonia and abnormal behaviors during REM
sleep do not occur in the chronic MPTP-treated primate, an
animal model of parkinsonism due to severe selective nigrostriatal deficiency (David Rye, personal communication).
10) Although not systematically studied, there are neither published reports of RBD precipitated by antipsychotic drugs
blocking dopaminergic receptors nor descriptions of RBD
occurring in subjects with drug-induced parkinsonism.
Based on the available data, we think that dopamine does not
play a central role in the pathogenesis of RBD even though dopaminergic mechanisms may have some role in the modulation of
REM sleep. The neural mechanisms generating and regulating REM
sleep are complex and only partially known. Recent studies suggest
that GABAergic and glutamatergic systems may be directly involved
in the physiology of REM sleep onset, maintenance and atonia
modulating the REM-on and REM-off structures in the brainstem.170–174 Serotonin, hypocretin, histamine, dopamine,
noradrenaline and acetylcholine are also modulators of the REM-on
and REM-off structures.170–174 This would explain why some antidepressants with serotonergic, noradrenergic and anti-cholinergic
activity31–33 may induce or aggravate RBD. It should be noted that
degenerative changes in MSA, PD and DLB are not restricted to the
nigrostriatal pathway also involving many nondopaminergic cell
groups,
including
GABAergic,
glutamatergic
and
monoaminergic.81,82,93
The mechanisms causing muscle atonia during REM sleep are
complex. It has long been believed that muscle suppression in REM
sleep is ultimately modulated by glycinergic inhibition of the
motoneurons in the ventral horn of the spinal cord and in the
cranial nerve nuclei.175 A recent provocative study in rats showed
that blockade of glycinergic and GABAA transmission at the
trigeminal nucleus did not prevent or reverse REM sleep atonia in
the masseter muscle.176 The authors of this study suggested that
the mechanism mediating REM sleep atonia required reevaluation
in order to find an unknown non-glycinergic biochemical
396
A. Iranzo et al. / Sleep Medicine Reviews 13 (2009) 385–401
substrate. This controversial study led to strong criticisms due to
limitations of the techniques that were employed (lack of intracellular data, continuous drug delivery for 2–4 h, low concentrations of the substances that were delivered, possible diffusion of
drugs in other surrounding nuclei in the brainstem, and the neural
diversity and complexity of the trigeminal nucleus).177–179 These
criticisms were elegantly defended by the authors.180 Other experts
in the field have been less poignant stating that ‘‘is needed an open
view of a number of simultaneous possibilities that can cause
atonia and not a single holy grail’’ (e.g., glycine).181 The debate is
still open.
What does anatomy tell us?
REM sleep is a complex state characterized by rapid eye
movements, striated muscle atonia and desynchronized electroencephalographic activity. Dreams with emotional content occur
predominantly in REM sleep. The precise anatomic network and
biochemical mechanisms of REM sleep are still unclear. A large
number of anatomic structures, however, are known to be directly
or indirectly implicated in the generation of REM sleep. These
structures include the magnocellularis reticular nucleus, locus
subceruleus, locus ceruleus, dorsal raphe, pedunculopontine
nucleus, lateral dorsal tegmentum, periaqueductal grey matter,
lateral pontine tegmentum, substantia nigra, hypothalamus, thalamus, amygdala, striatum, subthalamus, basal forebrain and
neocortex.170–174
Although initially it was thought that the central mechanisms
regulating REM sleep were cholinergic and monoaminergic in
nature, recent evidence indicates that the system responsible for
REM sleep is more complex, involving critical GABAergic and glutamatergic neurotransmission.170–174 Recent studies in rodents
suggest that REM sleep is mainly generated by GABAergic and nonGABAergic projections to the locus subceruleus in the brainstem,
which then project through direct and indirect glutamatergic
pathways to the cortex, thalamus, basal forebrain, amygdala,
ventromedial medulla and spinal cord.170–174 The pontine
tegmentum and medial medulla are critical areas for muscle atonia
generation in REM sleep. In animals, experimental lesions in the
dorsolateral pontine tegmentum eliminate muscle atonia and
induce abnormal behaviors during REM sleep.3 The site and extent
of the lesions in the pons determine the severity of the behaviors
that the animal releases, ranging from prominent limb twitches to
locomotion and attack behaviors.182 Selective experimental lesions
in the ventromedial medulla also produce REM sleep without
atonia associated with abnormal behaviors.4 On the other hand, the
amygdala is connected with the brainstem nuclei that regulate
muscle tone and probably modulates the emotional component of
dreams occurring in REM sleep. Cats with unilateral damage to the
central nucleus of the amygdala preceded by bilateral pontine
lesions exhibit attack behaviors associated with increased electromyography activity during REM sleep.183 Also, cats with brainstem
lesions and normal limbic system exhibit REM sleep without atonia
and abnormal behaviors.183 It should be noted that results in
animals may depend on the species studied (rodents, felines, dogs,
non human primates and humans).
In humans, RBD can be caused by a structural unilateral or
bilateral focal lesion (e.g., stroke, tumor, demyelinating plaque)
confined to the brainstem.88,161–169 Also, RBD can be produced by
direct damage of those supratentorial structures anatomically
connected with the brainstem nuclei modulating REM sleep. For
example, RBD has been described in neurological disorders sparing
the brainstem but damaging either the limbic system (limbic
encephalitis associated with antibodies to voltage-gated potassium
channels),184 anterior thalamus (familial fatal insomnia)185 or
posterior hypothalamus (narcolepsy).6 In these disorders, RBD is
probably caused by functional dysregulation of the brainstem REM
sleep related structures rather than by their primary damage.
Narcolepsy is believed to be an autoimmune disorder which is
characterized by loss of hypocretin-producing neurons in the
posterior hypothalamus. The occurrence of RBD in narcolepsy may
be explained by hypocretin deficiency since hypocretin neurons
have wide projections to several brainstem nuclei which regulate
REM sleep atonia.
In neurodegenerative diseases where RBD is frequent, such as
MSA, PD and DLB, pathological changes are common in the
Fig. 6. Patient with idiopathic RBD who 5 years later developed PD that was confirmed at autopsy. While the patient is talking and waving his arms against an imaginary offender,
there is excessive tonic and phasic electromyographic activity first in the chin and upper limbs spreading to the lower limbs. Movement artifacts are seen in the EEG leads, EKG and
respiratory bands. Without looking at the video it is very difficult to distinguish here if the patient is awake or asleep. EOG: electrooculogram. C3, C4, O1, O2: electrode positions
according to the 10/20 International system, referenced to combined ears (Ac). Chin: electromyography of the mentalis muscle. L and R Bic: electromyography of the left and right
biceps brachii. L and R TA: electromyography of the left and right tibialis anterior. Nasal: nasal air flow. Oral: oral air flow. Tho: thoracic respiratory movements. Abd: abdominal
respiratory movements. EKG: electrocardiogram.
A. Iranzo et al. / Sleep Medicine Reviews 13 (2009) 385–401
brainstem structures modulating REM sleep (e.g., locus subceruleus, pedunculopontine nucleus, gigantocellularis reticular
nucleus) and amygdala.93,186–189 In contrast, full-blown expression
of RBD is uncommon in diseases associated with widespread
brainstem cell loss and little limbic system damage, such as
progressive supranuclear palsy,132 as well as in diseases with no
marked brainstem cell loss (e.g., AD).128 It is tempting to speculate
that in RBD motor behaviors reflect brainstem impairment while
RBD frightening dreams reflect amygdalar dysfunction. Cortical
areas may also be involved in the pathogenesis of RBD, since
patients sometimes display purposeful long motor elaborated and
complex behaviors, sing, and give long speeches 36 (Fig. 6).
However, these elaborated behaviors may alternatively represent
a dissociated sleep/wake phenomena rather than REM sleep with
increased motor and vocal activity.190 Taken together, we think that
RBD is the result of a dysfunction in the brainstem nuclei that
modulate REM sleep and their anatomical inputs from other
regions.
Does the Braak et al. ascending hypothesis for Parkinson’s disease fit
with the time of appearance of RBD?
Braak et al.191,192 postulated that in sporadic PD, Lewy pathology
(Lewy bodies and Lewy neurites) begins in the dorsal motor nucleus
of the vagus nerve in the medulla (stage 1) and advances
upwards through the magnocellularis reticular nucleus and the
subceruleus-ceruleus complex (stage 2), the substantia nigra,
the pedunculopontine nucleus and the amygdala (stage 3), the
temporal mesocortex (stage 4), and finally reaches the neocortex
(stages 5 and 6). Braak et al. suggested that stages 1 and 2 correspond
to a pre-parkinsonian motor state of PD, stages 3 and 4 to the
development of parkinsonism, and stages 5 and 6 to parkinsonism
associated with cognitive impairment.191,192 This temporal sequence
of Lewy pathology in PD may account for the finding that in some
patients RBD (stage 2) antedates the onset of parkinsonism (stage
3).7–9,27 This temporal sequence, however, does not explain why
some PD patients do not develop RBD40 and why parkinsonism
precedes RBD onset in most PD subjects.27 One possible explanation
is that in these situations severity of neuronal dysfunction in the
brainstem structures modulating REM sleep does not reach a critical
threshold for the clinical expression of RBD. Alternatively, it is
possible that Braak et al. staging system in sporadic PD may not be
valid in all instances. A recent study evaluating 71 PD cases showed
that the caudo-rostral spreading described by Braak et al. did not
occur in 47% of the cases.193 The clinical significance of Braak et al.
staging system in PD is debatable because 1) the patients that based
the Braak et al. original hypothesis were not clinically phenotyped,
2) inclusion criteria may have biased the results since only cases with
Lewy pathology in the medulla were studied, 3) cell loss was not
assessed, and 4) it is unknown if Lewy pathology is directly
responsible for neurological symptoms. Several studies have shown
that in PD and DLB, Lewy pathology may be found in multiple sites
sparing the medulla.194–196 Moreover, Lewy pathology is found in 2–
20% of the normal aged population,197 and 10% of the healthy aged
people exhibit Lewy bodies in the substantia nigra.198 It may be that
the severity of cell loss in the nuclei that modulate REM sleep, rather
than the presence of Lewy bodies in surviving neurons, is necessary
for the development of RBD.
The caudo-rostral topographical sequence for PD described by
Braak et al.191,192 has not been found in DLB, a neurodegenerative
disorder commonly associated with RBD where dementia antedates parkinsonism onset. It has been suggested that in DLB
a neuropathological regional pattern of Lewy pathology exists that
progresses downwards from the neocortex to the amygdala, diencephalon and finally reaches the brainstem (substantia nigra, locus
397
ceruleus, reticular formation and dorsal vagal nucleus).199 This
stage system does not fit with the common observation that RBD
precedes dementia in DLB.
A grading system similar to that for PD has not been proposed in
MSA yet. Grading neuropathology on MSA is currently based in the
presence of neuropathological changes in the nigrostriatal and
olivopontocerebellar systems. The state of the brainstem and limbic
structures that modulate REM sleep is not evaluated in the current
proposed morphological MSA grading system.200
In summary, based on the available evidence we think that RBD
when occurring in neurodegenerative diseases is probably
explained by regional distribution and severity of neuronal
dysfunction in the brainstem structures that regulate REM sleep
and their anatomic connections. Subjects without RBD are probably
those in whom neuronal dysfunction does not occur in these
regions or in whom the threshold for clinical symptomatology is
not exceeded. RBD is not mediated by either abnormal alpha-synuclein inclusions or striatonigral dopaminergic deficiency alone.
The Braak et al. staging system in sporadic PD only fits with the
observation of RBD preceding parkinsonism.
Practice points
1. A significant proportion of patients (8–35%) with RBD is
not aware of having dream-enacting behaviors.
2. A significant proportion of patients (50–75%) with RBD
do not recall unpleasant dreams.
3. Clinical history with the bed partner is essential to
suspect RBD.
4. Videopolysomnography is needed to confirm the diagnosis of RBD and exclude other conditions presenting
with similar symptoms.
5. Clinical follow-up of patients with the idiopathic form of
RBD is necessary for early detection of the development
of multiple system atrophy, Parkinson’s disease and
dementia with Lewy bodies.
6. RBD is frequent in the setting of multiple system atrophy
(90–100%), Parkinson’s disease (46–58%) and dementia
with Lewy bodies (approximately 70%).
7. In a patient with parkinsonism or cerebellar syndrome
the absence of RBD confirmed by VPSG argues against
multiple system atrophy
8. RBD is rare in patients with Alzheimer’s disease.
9. In a patient with dementia the presence of RBD supports
the diagnosis of dementia with Lewy bodies against
Alzheimer disease and other forms of cognitive
impairment.
10. Clinical symptoms of RBD may be mild, moderate or
severe. When needed, clonazepam is effective to treat
RBD symptoms. Melatonin may also be effective.
Research agenda
1. To find biomarkers for identifying those patients with
idiopathic RBD who are at a high risk for developing the
characteristic motor, autonomic and cognitive symptoms of multiple system atrophy, Parkinson’s disease
and dementia with Lewy bodies.
2. To evaluate the effect of neuroprotective strategies in
patients with idiopathic RBD.
3. To find effective drugs for treating RBD symptoms when
clonazepam fails or causes side effects.
4. To elucidate the precise physiopathology of RBD.
398
A. Iranzo et al. / Sleep Medicine Reviews 13 (2009) 385–401
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