Introduction: The underlying pathophysiology of idiopathic REM sleep behavior disorder (iRBD) is not fully understood, although the condition is currently recognized as an early-stage alpha-synuclein disorder. We evaluated the morbidity, mortality, and rate of conversion to a neurodegenerative disorder in a national group of patients. Methods: All patients in Denmark with a diagnosis of RBD between 2006 and 2013 were identified from the Danish National Patient Registry (NPR) records. We excluded patients who had received a diagnosis of narcolepsy or any of the following neurodegenerative diseases before their diagnosis of RBD: Parkinson’s disease, multiple system atrophy, progressive supranuclear paralysis, Alzheimer’s, and Lewy body dementia. We used randomly chosen controls matched for age, gender, and municipality. Results: In total, 246 iRBD patients and 982 matched controls were analyzed. The mortality rate was the same in both groups. The morbidity rate was significantly higher in the years before and after an RBD diagnosis, due to a wide variety of disorders in the following major disease groups: mental/behavioral disorders; endocrine/metabolic diseases; diseases of the eye; diseases of the nervous, digestive, musculoskeletal, circulatory, and respiratory systems; abnormal findings not classified elsewhere; external causes; and factors influencing health status. The conversion rate from RBD to a neurodegenerative disease was 13% over the 8 years after a diagnosis of RBD. Conclusions: A diagnosis of RBD is associated with increased morbidity several years before and after a diagnosis is made. Patients have a higher risk of converting to a neurodegenerative disorder than matched controls. Mortality rates are unchanged.

1.
Iranzo
A
,
Santamaria
J
,
Tolosa
E
.
Idiopathic rapid eye movement sleep behaviour disorder: diagnosis, management, and the need for neuroprotective interventions
.
Lancet Neurol
.
2016 Apr 1
[cited 2019 Apr 25];
15
(
4
):
405
19
. Available from: https://www.sciencedirect.com/science/article/pii/S1474442216000570.
2.
Dauvilliers
Y
,
Schenck
CH
,
Postuma
RB
,
Iranzo
A
,
Luppi
PH
,
Plazzi
G
, et al
REM sleep behaviour disorder
.
Nat Rev Dis Primers
.
2018
;
4
(
1
):
19
.
3.
Haba-Rubio
J
,
Frauscher
B
,
Marques-Vidal
P
,
Toriel
J
,
Tobback
N
,
Andries
D
, et al
Prevalence and determinants of rapid eye movement sleep behavior disorder in the general population
.
Sleep
.
2018
;
41
(
2
):
1
8
. .
4.
Schenck
CH
,
Boeve
BF
,
Mahowald
MW
.
Delayed emergence of a parkinsonian disorder or dementia in 81% of older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder: a 16-year update on a previously reported series
.
Sleep Med
.
2013
;
14
(
8
):
744
8
. .
5.
Iranzo
A
,
Fernández-Arcos
A
,
Tolosa
E
,
Serradell
M
,
Molinuevo
JL
,
Valldeoriola
F
, et al
Neurodegenerative disorder risk in idiopathic REM sleep behavior disorder: study in 174 patients
.
PLoS One
.
2014
;
9
(
2
):
e89741
. .
6.
Iranzo
A
,
Lomeña
F
,
Stockner
H
,
Valldeoriola
F
,
Vilaseca
I
,
Salamero
M
, et al
Parkinson risk in idiopathic REM sleep behavior disorder
.
Lancet Neurol
.
2016 Mar 1
[cited 2019 Apr 25];
12
(
5
):
215
27
.
7.
Postuma
RB
,
Berg
D
.
Advances in markers of prodromal Parkinson disease
.
Nat Rev Neurol
.
2016
;
12
(
11
):
622
34
.
8.
Galbiati
A
,
Verga
L
,
Giora
E
,
Zucconi
M
,
Ferini-Strambi
L
.
The risk of neurodegeneration in REM sleep behavior disorder: a systematic review and meta-analysis of longitudinal studies
.
Sleep Med Rev
.
2019
;
43
:
37
46
. .
9.
Postuma
RB
,
Gagnon
JF
,
Vendette
M
,
Fantini
ML
,
Massicotte-Marquez
J
,
Montplaisir
J
.
Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder
.
Neurology
.
2009
;
72
(
15
):
1296
300
. .
10.
Iranzo
A
,
Molinuevo
JL
,
Santamaría
J
,
Serradell
M
,
Martí
MJ
,
Valldeoriola
F
, et al
Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study
.
Lancet Neurol
.
2006
;
5
(
7
):
572
7
. .
11.
Kim
Y
,
Kim
YE
,
Park
EO
,
Shin
CW
,
Kim
HJ
,
Jeon
B
.
REM sleep behavior disorder portends poor prognosis in Parkinson’s disease: a systematic review
.
J Clin Neurosci
.
2018 Jan 1
[cited 2019 Sep 3];
47
:
6
13
Available from: https://www-sciencedirect-com.ep.fjernadgang.kb.dk/science/article/pii/S0967586817316946.
12.
Jacobs
ML
,
Dauvilliers
Y
,
St Louis
EKEK
,
McCarter
SJ
,
Romenets
SR
,
Pelletier
A
, et al
Risk factor profile in Parkinson’s disease subtype with REM sleep behavior disorder
.
J Parkinsons Dis
.
2016
;
6
(
1
):
231
7
. .
13.
Yao
C
,
Fereshtehnejad
SM
,
Keezer
MR
,
Wolfson
C
,
Pelletier
A
,
Postuma
RB
.
Risk factors for possible rem sleep behavior disorder: a clsa population-based cohort study
.
Neurology
.
2019
;
92
(
5
):
E475
85
.
14.
Frandsen
R
,
Kjellberg
J
,
Ibsen
R
,
Jennum
P
.
Morbidity in early Parkinson’s disease and prior to diagnosis
.
Brain Behav
.
2014 May
;
4
(
3
):
446
52
. .
15.
Jennum
P
,
Zoetmulder
M
,
Korbo
L
,
Kjellberg
J
.
The health-related, social, and economic consequences of parkinsonism: a controlled national study
.
J Neurol
.
2011 Aug
;
258
(
8
):
1497
506
. .
16.
Frandsen
R
,
Baandrup
L
,
Kjellberg
J
,
Ibsen
R
,
Jennum
P
.
Increased all-cause mortality with psychotropic medication in Parkinson’s disease and controls: a national register-based study
.
Park Relat Disord
.
2014 Nov
;
20
(
11
):
1124
8
.
17.
Jennum
P
,
Sabers
A
,
Christensen
J
,
Ibsen
R
,
Kjellberg
J
.
Welfare consequences for people with epilepsy and their partners: a matched nationwide study in Denmark
.
Seizure
.
2017 Jul
;
49
:
17
24
. .
18.
Jennum
P
,
Thorstensen
EW
,
Pickering
L
,
Ibsen
R
,
Kjellberg
J
.
Morbidity and mortality of middle-aged and elderly narcoleptics
.
Sleep Med
.
2017 Aug
;
36
:
23
8
. .
19.
Braak
H
,
Ghebremedhin
E
,
Rüb
U
,
Bratzke
H
,
Del Tredici
K
.
Stages in the development of Parkinson’s disease-related pathology
.
Cell Tissue Res
.
2004
;
318
(
1
):
121
34
.
20.
Vgontzas
A
,
Pavlović
JM
.
Sleep disorders and migraine: review of literature and potential pathophysiology mechanisms
.
Headache
.
2018
;
58
(
7
):
1030
9
. .
21.
Manni
R
,
Terzaghi
M
,
Zambrelli
E
.
REM sleep behavior disorder and epileptic phenomena: clinical aspects of the comorbidity
.
Epilepsia
.
2006
;
47
(
Suppl 5
):
78
81
. .
22.
Pajediene
E
,
Pajeda
A
,
Urnieziute
G
,
Paulekas
E
,
Liesiene
V
,
Bileviciute-Ljungar
I
, et al
Subjective and objective features of sleep disorders in patients with acute ischemic or haemorrhagic stroke: it is not only sleep apnoea which is important
.
Med Hypotheses
.
2020
;
136
(
November 2019
):
109512
.
23.
Fantini
ML
,
Michaud
M
,
Gosselin
N
,
Lavigne
G
,
Montplaisir
J
.
Periodic leg movements in REM sleep behavior disorder and related autonomic and EEG activation
.
Neurology
.
2002
;
59
(
12
):
1889
94
. .
24.
Postuma
RB
,
Gagnon
JF
,
Pelletier
A
,
Montplaisir
JY
.
Insomnia and somnolence in idiopathic RBD: a prospective cohort study
.
NPJ Parkinsons Dis
.
2017
;
3
(
1
):
9
5
. Available from: .
25.
Weissová
K
,
Škrabalová
J
,
Skálová
K
,
Červená
K
,
Bendová
Z
,
Miletínová
E
, et al
Circadian rhythms of melatonin and peripheral clock gene expression in idiopathic REM sleep behavior disorder
.
Sleep Med
.
2018
;
52
:
1
6
. .
26.
Howell
MJ
,
Arneson
PA
,
Schenck
CH
.
A novel therapy for REM sleep behavior disorder (RBD)
.
J Clin Sleep Med
.
2011
;
7
(
6
):
639
44A
. .
27.
Schenck
CH
,
Lee
SA
,
Bornemann
MA
,
Mahowald
MW
.
Potentially lethal behaviors associated with rapid eye movement sleep behavior disorder: review of the literature and forensic implications
.
J Forensic Sci
.
2009
;
54
(
6
):
1475
84
. .
28.
Buckley
E
,
Siddique
A
,
McNeill
A
.
Hyposmia, symptoms of REM sleep behavior disorder and Parkinsonian motor signs suggests prodromal neurodegeneration in 22q11 deletion white rose research online URL for this paper: version: submitted version article: buckl
.
2017
.
29.
Henriques-Filho
PS
,
Pratesi
R
.
Sleep apnea and REM sleep behavior disorder in patients with Chiari malformations
.
Arq Neuropsiquiatr
.
2008
;
66
(
2B
):
344
9
. .
30.
Ju
YE
,
Larson-Prior
L
,
Duntley
S
.
Changing demographics in REM sleep behavior disorder: possible effect of autoimmunity and antidepressants
.
Sleep Med
.
2011
;
12
(
3
):
278
83
. .
31.
Chang
CC
,
Lin
TM
,
Chang
YS
,
Chen
WS
,
Sheu
JJ
,
Chen
YH
, et al
Autoimmune rheumatic diseases and the risk of Parkinson disease: a nationwide population-based cohort study in Taiwan
.
Ann Med
.
2018
;
50
(
1
):
83
90
.
32.
Witoelar
A
,
Jansen
IE
,
Wang
Y
,
Desikan
RS
,
Gibbs
JR
,
Blauwendraat
C
, et al
Genome-wide pleiotropy between Parkinson disease and autoimmune diseases
.
JAMA Neurol
.
2017 Jul
;
74
(
7
):
780
92
. .
33.
Archibald
NK
,
Clarke
MP
,
Mosimann
UP
,
Burn
DJ
.
Visual symptoms in Parkinson’s disease and Parkinson’s disease dementia
.
Mov Disord
.
2011
;
26
(
13
):
2387
95
. .
34.
Satue
M
,
Garcia-Martin
E
,
Fuertes
I
,
Otin
S
,
Alarcia
R
,
Herrero
R
, et al
Use of Fourier-domain OCT to detect retinal nerve fiber layer degeneration in Parkinson’s disease patients
.
Eye
.
2013
;
27
(
4
):
507
14
. .
35.
Nowacka
B
,
Lubinski
W
,
Honczarenko
K
,
Potemkowski
A
,
Safranow
K
.
Ophthalmological features of Parkinson disease
.
Med Sci Monit
.
2014
;
20
:
2243
9
. .
36.
Lai
SW
,
Lin
CL
,
Liao
KF
,
Chang-Ou
KC
.
Increased risk of Parkinson’s disease in cataract patients: a population-based cohort study
.
Parkinsonism Relat Disord
.
2015 Jan
;
21
(
1
):
68
71
.
37.
Caggiu
E
,
Arru
G
,
Hosseini
S
,
Niegowska
M
,
Sechi
G
,
Zarbo
IR
, et al
Inflammation, infectious triggers, and Parkinson’s disease
.
Front Neurol
.
2019 Feb 19
;
10
:
122
. Available from: https://pubmed.ncbi.nlm.nih.gov/30837941. .
38.
Cryan
JF
,
O’Riordan
KJ
,
Cowan
CSM
,
Sandhu
KV
,
Bastiaanssen
TFS
,
Boehme
M
, et al
The microbiota-gut-brain axis
.
Physiol Rev
.
2019
;
99
(
4
):
1877
2013
. .
39.
Heintz-Buschart
A
,
Pandey
U
,
Wicke
T
,
Sixel-Döring
F
,
Janzen
A
,
Sittig-Wiegand
E
, et al
The nasal and gut microbiome in Parkinson’s disease and idiopathic rapid eye movement sleep behavior disorder
.
Mov Disord
.
2018
;
33
(
1
):
88
98
. .
40.
Matheoud
D
,
Cannon
T
,
Voisin
A
,
Penttinen
AM
,
Ramet
L
,
Fahmy
AM
, et al
Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1
.
Nature
.
2019
;
571
(
7766
):
565
9
.
41.
Marras
C
,
Canning
CG
,
Goldman
SM
.
Environment, lifestyle, and Parkinson’s disease: implications for prevention in the next decade
.
Mov Disord
.
2019
;
34
(
6
):
801
11
.
42.
Wong
JC
,
Li
J
,
Pavlova
M
,
Chen
S
,
Wu
A
,
Wu
S
, et al
Risk factors for probable REM sleep behavior disorder: a community-based study
.
Neurology
.
2016
;
86
(
14
):
1306
12
. .
43.
Postuma
RB
,
Montplaisir
JY
,
. Pelletier
A
,
. Dauvilliers
Y
,
. Oertel
W
,
. Iranzo
A
, et al
Environmental risk factors for REM sleep behavior disorder
.
Neurology
.
2012
;
79
:
248
434
.
44.
Barber
TR
,
Lawton
M
,
Rolinski
M
,
Evetts
S
,
Baig
F
,
Ruffmann
C
, et al
Prodromal Parkinsonism and neurodegenerative risk stratification in REM sleep behavior disorder
.
Sleep
.
2017
;
40
(
8
):
11
3
. .
45.
Pagano
G
,
Polychronis
S
,
Wilson
H
,
Giordano
B
,
Ferrara
N
,
Niccolini
F
, et al
Diabetes mellitus and Parkinson disease
.
Neurology
.
2018
;
90
(
19
):
E1654
62
. .
46.
De Pablo-Fernandez
E
,
Goldacre
R
,
Pakpoor
J
,
Noyce
AJ
,
Warner
TT
.
Association between diabetes and subsequent Parkinson disease: a record-linkage cohort study
.
Neurology
.
2018
;
91
(
2
):
e139
42
. .
47.
Cereda
E
,
Barichella
M
,
Pedrolli
C
,
Klersy
C
,
Cassani
E
,
Caccialanza
R
, et al
Diabetes and risk of Parkinson’s disease: a systematic review and meta-analysis
.
Diabetes Care
.
2011
;
34
(
12
):
2614
23
.
48.
Xu
Q
,
Park
Y
,
Huang
X
,
Hollenbeck
A
,
Blair
A
,
Schatzkin
A
, et al
Diabetes and risk of Parkinson’s disease
.
Diabetes Care
.
2011
;
34
(
4
):
910
5
. .
49.
Hawkes
CH
,
Del Tredici
K
,
Braak
H
.
Parkinson’s disease: a dual-hit hypothesis
.
Neuropathol Appl Neurobiol
.
2007 Dec
;
33
(
6
):
599
614
.
50.
Borghammer
P
,
Van Den Berge
N
.
Brain-first versus gut-first Parkinson’s disease: a hypothesis
.
J Parkinsons Dis
.
2019
;
9
(
s2
):
S281
95
. Available from: https://pubmed.ncbi.nlm.nih.gov/31498132.
51.
Fereshtehnejad
SM
,
Romenets
SR
,
Anang
JBM
,
Latreille
V
,
Gagnon
JF
,
Postuma
RB
.
New clinical subtypes of Parkinson disease and their longitudinal progression a prospective cohort comparison with other phenotypes
.
JAMA Neurol
.
2015
;
72
(
8
):
863
73
. .
52.
Bonanni
L
,
Franciotti
R
,
Pizzi
SD
,
Thomas
A
,
Onofrj
M
.
Lewy body dementia
.
Neurodegener Dis Clin Asp Mol Genet Biomarkers
.
2018
:
297
312
. .
53.
Jellinger
KA
,
Korczyn
AD
.
Are dementia with lewy bodies and Parkinson’s disease dementia the same disease?
BMC Med
.
2018
;
16
(
1
):
1
16
. .
54.
Postuma
RB
,
Gagnon
JF
,
Tuineaig
M
,
Bertrand
JA
,
Latreille
V
,
Desjardins
C
, et al
Antidepressants and REM sleep behavior disorder: isolated side effect or neurodegenerative signal?
Sleep
.
2013
;
36
(
11
):
1579
85
. .
55.
Jennum
P
,
Frandsen
R
,
Knudsen
S
.
Characteristics of rapid eye movement sleep behavior disorder in narcolepsy
.
Sleep Biol Rhythms
.
2013 Jun
;
11
(
Suppl 1
):
65
74
. Available from: http://doi.wiley.com/10.1111/j.1479--8425.2012.00556.x. .
56.
Gustafsson
H
,
Nordström
A
,
Nordström
P
.
Depression and subsequent risk of Parkinson disease
.
Neurology
.
2015 Jun 16
;
84
(
24
):
2422 LP
2429
. Available from: http://n.neurology.org/content/84/24/2422.abstract. .
57.
Schuurman
AG
,
Van den Akker
M
,
Ensinck
KTJL
,
Metsemakers
JFM
,
Knottnerus
JA
,
Leentjens
AFG
, et al
Increased risk of Parkinson’s disease after depression: a retrospective cohort study
.
Neurology
.
2002
;
58
(
10
):
1501
4
.
58.
Dede
,
Benbir Senel
G
,
Karadeniz
D
.
Rapid eye movement sleep without atonia constitutes increased risk for neurodegenerative disorders
.
Acta Neurol Scand
.
2019 Dec
;
140
(
6
):
399
404
.
59.
Stefani
A
,
Gabelia
D
,
Högl
B
,
Mitterling
T
,
Mahlknecht
P
,
Stockner
H
, et al
Long-term follow-up investigation of isolated rapid eye movement sleep without atonia without rapid eye movement sleep behavior disorder: a pilot study
.
J Clin Sleep Med
.
2015 Nov 15
;
11
(
11
):
1273
9
. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26156949. .
60.
Frauscher
B
,
Gabelia
D
,
Mitterling
T
,
Biermayr
M
,
Bregler
D
,
Ehrmann
L
, et al
Motor events during healthy sleep: a quantitative polysomnographic study
.
Sleep
.
2014
;
37
(
4
):
763
73
. .
61.
Feemster
JC
,
Jung
Y
,
Timm
PC
,
Westerland
SM
,
Gossard
TR
,
Teigen
LN
, et al
Normative and isolated rapid eye movement sleep without atonia in adults without REM sleep behavior disorder
.
Sleep
.
2019
;
42
(
10
):
1
13
. .
62.
McCarter
SJ
,
Tabatabai
GM
,
Jong
HY
,
Sandness
DJ
,
Timm
PC
,
Johnson
KL
, et al
REM sleep atonia loss distinguishes synucleinopathy in older adults with cognitive impairment
.
Neurology
.
2020
;
94
(
1
):
e15
29
. .
63.
Schenck
CH
,
Mahowald
MW
.
Subclinical REM sleep behavior disorder and its clinical and research implications
.
Sleep
.
2008
;
31
(
12
):
1627
. .
64.
Wermuth
L
,
Lassen
CF
,
Himmerslev
L
,
Olsen
J
,
Ritz
B
.
Validation of hospital register-based diagnosis of Parkinson’s disease
.
Dan Med J
.
2012
;
59
(
3
):
A4391
.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.