Quantifying the risk of neurodegenerative
disease in idiopathic REM sleep
R.B. Postuma, MD
J.F. Gagnon, PhD
M. Vendette, BSc
M.L. Fantini, MD
J. Montplaisir, MD,
Objective: Idiopathic REM sleep behavior disorder (RBD) is a potential preclinical marker for the
development of neurodegenerative diseases, particularly Parkinson disease (PD) and Lewy
body dementia. However, the long-term risk of developing neurodegeneration in patients with
idiopathic RBD has not been established. Obtaining an accurate picture of this risk is essential
for counseling patients and for development of potential neuroprotective therapies.
Methods: We conducted a follow-up study of all patients seen at the sleep disorders laboratory at
the Ho ˆpital du Sacre ´ Coeur with a diagnosis of idiopathic RBD. Diagnoses of parkinsonism and
dementia were defined according to standard criteria. Survival curves were constructed to esti-
mate the 5-, 10-, and 12-year risk of developing neurodegenerative disease.
Results: Of 113 patients, 93 (82%) met inclusion criteria. The mean age of participants was 65.4
years and 75 patients (80.4%) were men. Over the follow-up period, 26/93 patients developed a
tia, 4 developed dementia that met clinical criteria for AD, and 1 developed multiple system atro-
phy. The estimated 5-year risk of neurodegenerative disease was 17.7%, the 10-year risk was
40.6%, and the 12-year risk was 52.4%.
Conclusions: Although we have found a slightly lower risk than other reports, the risk of devel-
oping neurodegenerative disease in idiopathic REM sleep behavior disorder is substantial,
with the majority of patients developing Parkinson disease and Lewy body dementia.
DSM-IV ? Diagnostic and Statistical Manual of Mental Disorders, 4th edition; LBD ? Lewy body dementia; MMSE ? Mini-
Mental State Examination; MSA ? multiple system atrophy; PD ? Parkinson disease; PSG ? polysomnogram; RBD ? REM
sleep behavior disorder; UPDRS ? Unified Parkinson’s Disease Rating Scale.
REM sleep behavior disorder (RBD) is characterized by a loss of the normal muscle atonia that
accompanies REM sleep.1,2Affected patients have excessive motor activity such as punching,
kicking, or crying out in association with dream content. RBD is commonly associated with
neurodegenerative disorders characterized by ?-synuclein deposition, including PD, multiple
system atrophy (MSA), and Lewy body dementia (LBD).2-5Recent studies have suggested that
it may be related to ?-synuclein-mediated degeneration of sleep-regulating nuclei in the brain-
stem, especially in the pontine tegmentum.6,7
In a substantial proportion of cases, RBD can occur before the development of dementia or
parkinsonism.5,8,9This has major implications in the understanding of the pathophysiology of
PD and LBD, and suggests that an opportunity exists for neuroprotective measures in the
Address correspondence and
reprint requests to Dr. Ronald B.
Postuma, Department of
Neurology, L7-305 Montreal
General Hospital, 1650 Cedar
Ave., Montreal, Quebec, Canada
Editorial, page 1294
e-Pub ahead of print on December 24, 2008, at www.neurology.org.
From the Centre d’etude du sommeil (J.F.G., M.V., J.M.-M., J.M., R.B.P.), Hopital du Sacre-Coeur, Montreal; Department of Neurology (R.B.P.),
McGill University, Montreal General Hospital, Montreal, Quebec; De ´partement de psychiatrie (J.F.G., J.M.), Universite ´ de Montre ´al, Canada; and
Sleep Disorders Center (M.L.F.), Department of Neurology, Universita ` Vita-Salute San Raffaele, Milan, Italy.
Supported by a Canadian Institutes of Health Research grant to J.M. and J.F.G., and by a grant from the Fonds de la recherche en sante ´ du Que ´bec to
Disclosure: J.Y. Montplaisir received personal compensation as consultant (Boehringer Ingelheim, Servier, Shire Biochem), speaker (Boehringer, Shire),
and received financial support for research activities from Sanofi Synthelabo, GlaxoSmithKline. R.B. Postuma, J.F. Gagnon, M. Vendette, M.L.
Fantini, and J. Massicotte-Marquez have nothing to disclose.
Copyright © 2009 by AAN Enterprises, Inc.
preclinical stage of disease. However, the risk
of developing neurodegenerative disease in
patients with idiopathic RBD has not been
fully defined. To assess this risk, we con-
ducted a clinical follow-up study of 93 pa-
tients seen at the Ho ˆpital du Sacre ´-Coeur
sleep disorders center, using life-table analysis
to define disease risk over 5, 10, and 12 years.
METHODS Subjects. All procedures were carried out at the
sleep disorders laboratory at the Ho ˆpital du Sacre ´ Coeur, Mon-
treal, Quebec, Canada, and ethics approval was obtained from
the REB of the hospital. All patients with idiopathic RBD diag-
nosed between 1989 and 2006 were potential candidates for this
study—these patients were identified from a computerized data-
base that tracks all diagnoses of patients seen at the sleep disor-
ders center since 1989. Patients were generally referred from
general practitioners or neurologists to evaluate abnormal sleep
behaviors, although some patients were referred from other sleep
specialists and neurologists in the province of Quebec specifically
for inclusion into ongoing prospective research protocols (which
have been continuing in our clinic since 1999). To mitigate im-
portant selection bias created by selective participation in re-
search protocols, the inclusion criteria were set as broad as
possible. Therefore the minimal criteria for inclusion were as
1. Polysomnogram (PSG)-confirmed RBD, as defined by
standard criteria as REM sleep without atonia,10and at
least one of a) history of harmful or potentially harmful
motor manifestations or b) complex motor behaviors
during REM sleep on PSG-synchronized videotape re-
cording.11Note that patients were withdrawn from any
medication known to affect sleep or motor behavior for at
least 2 weeks prior to PSG. RBD symptom onset was
defined by patient self-report.
2. Absence of signs of neurodegenerative disease confirmed
on a baseline neurologic examination.
3. At least one follow-up examination ?1 year after the
baseline examination. If distance or inability to travel pre-
vented an in-person examination, telephone follow-up
could be offered.
Given concerns that telephone or clinic-based follow-up
could inaccurately assess the presence of disease, a subcohort of
patients was defined according to stricter inclusion criteria,
namely that all patients must have had a systematic research-
based in-person follow-up examination, as described below.
Follow-up protocol. In-person research-based examination
protocols have been conducted since 1999 in our clinic. Al-
though specific aspects of the examination varied, each in-person
examination protocol included, at minimum, a complete medi-
cal history and neurologic examination, assessment of the Uni-
fied Parkinson’s Disease Rating Scale Part III (UPDRS), and
cognitive testing (at minimum, the Folstein Mini-Mental State
Examination [MMSE]). The clinical examination was con-
ducted by a movement disorders specialist (R.P. or M.L.F.).
Neuropsychological evaluation12and extensive evaluation of
nonmotor symptoms13was offered to all patients, but was not
required for inclusion.
To prevent bias due to selective attendance in clinic, a sys-
tematic telephone interview was conducted by a neurologist
(R.P.) for the subset of patients who were unable to attend an
in-person evaluation. This interview consisted of a clinical his-
tory of current RBD status and symptoms, medications used,
family history, past medical history review, and review of diag-
noses of parkinsonism or dementia. Undiagnosed parkinsonism
was screened for using the Tanner questionnaire (a nine-item
interview with a sensitivity and specificity of over 90%14). All
components of the UPDRS Parts I and II were assessed. As a
screen for dementia, the Telephone Interview for Cognitive Sta-
tus was administered. This is a mental status test adapted for the
telephone, with reported sensitivity of 83–100%.15-17A score of
?26/39 was considered suggestive of cognitive impairment.
Diagnosis of disease. At the conclusion of the study, all data
on each patient were collected in a centralized database. Parkin-
sonism was diagnosed according to UK brain bank criteria as
bradykinesia in association with rest tremor, rigidity, or postural
instability. The most likely cause for the parkinsonism was delin-
eated based on standard criteria.18Dementia was diagnosed as
the presence of cognitive impairment (MMSE ?24) in associa-
tion with impairment of activities of daily living. Probable LBD
was defined according to McKeith criteria19as cognitive decline,
the presence of RBD (present in all patients), in association with
at least one of parkinsonism, visual hallucinations, or fluctua-
tions. Possible LBD was not included as a diagnostic category,
since all RBD patients with dementia would, by definition, carry
this diagnosis. The diagnosis of Alzheimer dementia was defined
according to DSM-IV criteria as the presence of progressive im-
pairment of memory and at least one other cognitive domain of
sufficient severity to impact social or occupation functioning,
without alternate explanation.20To ensure reliability of disease
assessment, and given the very high prevalence of subtle signs in
idiopathic RBD,13parkinsonism and dementia were strictly de-
fined; therefore, possible parkinsonism (i.e., one cardinal feature
only) or mild cognitive impairment were not considered disease
Statistical analysis. Statistical analysis was performed by R.P.
The primary outcome measure was defined as the risk of devel-
oping parkinsonism or dementia. This was calculated using a life
table (Kaplan-Meier) survival analysis. For this analysis, Time ?
0 was set at the year that PSG confirmed the diagnosis of idio-
pathic RBD (year of self-reported symptom onset was not cho-
sen as Time ? 0 because of concerns about reliability of
symptom onset reports, and because patients who developed dis-
ease before PSG diagnosis would be systematically excluded from
these calculations). For parkinsonism, time of disease onset was
the first of 1) the first self-reported symptom of parkinsonism,21
or 2) if asymptomatic, the demonstration of parkinsonism on
examination. For dementia, time of disease onset was set as the
time of onset of cognitive impairment severe enough to affect
activities of daily living (by report of either the patient or care-
giver). Linear regression of disease risk over time was performed
to ensure no violation of the proportional hazards assumption.
Analysis of categorical variables was conducted with the Fisher
exact test, and continuous variables were analyzed with the two-
sided t test.
RESULTS A total of 113 patients were diagnosed
with idiopathic RBD at the Ho ˆpital du Sacre ´ Coeur
from 1989 to 2006. Of these patients, 93 (82.3%)
met inclusion criteria. Of the 20 not participating,
13 patients could not be contacted, 6 had died with-
out clinical follow-up (2 within the first year), and 1
refused further follow-up. Of the 93 patients in-
Neurology 72 April 14, 2009
cluded, 78 (83.9%) met the strictest inclusion crite-
examination. Of the remaining 15 patients, 6 had an
in-person follow-up supplemented by a more recent
telephone follow-up, 3 had in-person clinical
follow-up only (with J.M.), and 6 had telephone
The mean age of participants was 65.4 years and
75 patients (80.4%) were men (table). The mean du-
ration of disease from PSG diagnosis to last evalua-
tion was 5.2 years. The mean duration between RBD
symptom onset and PSG diagnosis was 7.2 years.
Of the 93 patients included, 26 developed neuro-
degenerative disease, 15 developed parkinsonism,
and 11 developed dementia. Of the patients with
parkinsonism, 14 had a diagnosis of idiopathic PD,
and 1 was diagnosed with MSA. Of the patients with
dementia, 7 met clinical criteria for LBD, and 4 had
no clinical hallmarks of LBD and met clinical criteria
for AD. There were no significant differences in age
or sex between those who did or did not develop
disease, although there may have been a tendency
toward decreased risk of dementia in women (0/11
dementia patients, p ? 0.11). There was no differ-
ence in RBD duration between those who did or did
not develop disease.
The life table survival curve is presented in figure
1. The estimated 5-year risk of developing neurode-
generative disease (parkinsonism or dementia) was
17.7%. The estimated 10-year risk of disease was
40.6%, and the 12-year risk was 52.4%. Linear re-
gression of the disease risk vs time suggested that
the risk of developing disease remained constant over
the follow-up period (R2? 0.038, p ? 0.54). In the
strict-inclusion cohort (n ? 78), the estimated risk
was similar; 5-year risk was 19.5%, 10-year risk was
38.0%, and 12-year risk was 55.0%.
DISCUSSION It has been commonly noted that
RBD often precedes the development of parkinson-
ism and dementia.2,8Obtaining an accurate picture
of the risk of developing a neurodegenerative disor-
der is essential for accurate counseling of patients and
for planning of any potential neuroprotective trials.
However, definition of the risk of developing a neu-
rodegenerative condition has been published only in
Table Patient demographics
9367 26 1511
Mean age at
65.4 ? 9.364.5 ? 9.967.6 ? 7.3 p?0.1567.0 ? 8.1 p?0.37 68.1 ? 6.8 p?0.25
Men/women (% female)
75/18 (19.6)52/15 (22.4) 23/3 (11.6) p? 0.3812/3 (20.0) p? 1.0 11/0 (0) p? 0.11
polysomnogram to last visit
well or disease onset
(mean ? SD)
4.8 ? 3.6 4.5 ? 3.5 5.5 ? 3.9 p?0.23 4.6 ? 3.3 p?0.926.7 ? 4.6 p?0.20
Duration since symptom
onset to last visit well or
disease (mean ? SD)
12.0 ? 9.612.2 ? 10.4 11.5 ? 6.6 p?0.75 11.1 ? 5.6 p?0.73 12.5 ? 8.7 p?0.93
All p values refer to the comparison to the disease-free group.
Disease outcome is defined as the development of parkin-
sonism or dementia.
Neurology 72 April 14, 2009
two relatively small-scale studies.5,9The initial report
of RBD as a predictor of neurodegenerative disease
found that 38% of 29 male patients had developed a
parkinsonian disorder 5 years after the diagnosis of
idiopathic RBD. More recently, a study of 44 pa-
tients with an initial diagnosis of idiopathic REM
sleep behavior disorder found that after a median of
5 years of follow-up, 20 of 44 patients (45%) went
on to develop a neurodegenerative condition; the
commonest diagnoses were PD,9LBD,6and mild
cognitive impairment.4Two case series, reported in
abstract form only, have suggested that at a mean
follow-up of 10 years, 65% of patients had developed
neurodegenerative disease.22,23No published studies
have described 10- and 12-year follow-up of idio-
We have demonstrated a risk of disease that is
somewhat lower than found in the two previous case
series. Some of this variation may be due to differ-
ences in disease definition—mild cognitive impair-
ment was not considered a disease outcome in our
study, and we used a systematic strict definition of
parkinsonism which excluded those with mild par-
kinsonian signs or a single cardinal manifestation of
parkinsonism. It is also possible that disease risk can
be changing with time, perhaps related to earlier di-
agnosis and recognition of milder cases. In support of
this notion, the interval between RBD symptom on-
set and diagnosis in those patients diagnosed between
1989 and 1996 was 10.3 ? 9.2 years (n ? 18) com-
pared to an interval of 5.7 ? 5.0 years in those diag-
nosed from 2004 to 2006 (n ? 22, p ? 0.052).
Therefore symptom to diagnosis latency seems to be
changing in time, which no doubt reflects increased
awareness and recognition of the disorder. Finally,
differences in analytic method between studies can
result in important differences in estimation of dis-
ease risk. Whereas our method of analysis was a life
table analysis, the two previous case series estimating
risk of disease in RBD described the proportion de-
veloping disease, with mean follow-up duration. If
we analyze our results in the same way, we find a
similar, although slightly lower proportion develop-
ing neurodegenerative disease (i.e., 27.9% over a
mean of 5.2 years follow-up [to last clinical visit]).
An important advantage of the life table method is
that it utilizes censored data—that is, patients, who
are censored because of death, loss to follow-up, or
recent diagnoses, can contribute in a systematic man-
ner to estimation of risk at later time points. Because
of this method and the size of the cohort, we were
able to estimate disease risk at 10- and 12-year time
Some limitations of this study should be noted.
Because persons who agree to participate in prospec-
tive annual protocols may have important differences
in disease risk between those who refuse or who are
unable to participate, we felt that it was essential to
include all patients for whom follow-up information
was available. This warranted the inclusion of 15 (of
93) patients for whom at least some information was
collected from clinical records or telephone follow-
up. This information is probably less reliable than
that gleaned from a systematic research-based in-
person examination—in particular, subtle parkin-
sonism is often missed by patients, and can be picked
up only on examination. However, the large majority
of patients had a thorough standardized examination
by a movement disorders specialist, and a second
analysis that included only these individuals did not
find differences in disease risk. All diagnoses were
clinical, without autopsy confirmation; inevitably,
some patients may have been misdiagnosed. In par-
ticular, the diagnosis of LBD requires the presence of
clinical hallmarks which may not be apparent early in
disease. Given that pathologic studies have found
Lewy bodies in all cases of RBD with dementia,24it
will be of exceptional interest to see if the four pa-
tients diagnosed with clinical AD will eventually de-
velop hallmarks of LBD. Preliminary analysis of our
patients with dementia (presently in progress) has
suggested that our patients with clinical diagnosis of
AD are indistinguishable from our LBD patients,
suggesting that our clinical AD patients in fact have
LBD (data not shown). Finally, although this study
is the largest study following patients with idiopathic
RBD, sample size restrictions prevented analysis of
subgroups—in particular, it would be of interest to
assess whether risk of developing dementia may be
lower in women with idiopathic RBD.
Received May 21, 2008. Accepted in final form September 18, 2008.
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