Impact of rapid eye movement sleep behavior disorder and autonomic disorders on Parkinson's disease: a review

Oliveira, Pérola de; Cardoso, Francisco

doi:10.1590/0004-282X-anp-2020-0173

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View and Review • Arq. Neuro-Psiquiatr. 79 (2) • Feb 2021 • https://doi.org/10.1590/0004-282X-anp-2020-0173 copy

Impact of rapid eye movement sleep behavior disorder and autonomic disorders on Parkinson's disease: a review

Impacto do transtorno comportamental do sono REM e doenças autonômicas na doença de Parkinson: uma revisão

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Parkinson's disease (PD) has heterogeneous clinical manifestations and prognoses. It is accompanied by a group of motor and non-motor symptoms ranging from independence to total disability, limiting work and personal care activities. Currently, disease subtype markers for informing prognosis remain elusive. However, some studies have reported an association between rapid eye movement (REM) sleep behavior disorder (RBD) and faster motor and non-motor symptom progression, including autonomic dysfunction and cognitive decline. Moreover, since autonomic dysfunction has been described in idiopathic forms of RBD, and they share some central regulatory pathways, it remains unclear whether they have a primary association or if they are more severe in patients with PD and RBD, and thus are a disease subtype marker. This article aimed at critically reviewing the literature on the controversies about the prevalence of RBD in PD, the higher incidence of PD non-motor symptoms associated with RBD, the evidence of faster motor worsening in parkinsonian patients with this parasomnia, and the main pathophysiological hypotheses that support these findings.

Keywords:
Parkinson Disease; REM Sleep Behavior Disorder; Autonomic Nervous System Diseases; Pathology; Epidemiology

Author	Year	Country	iRBD (n)	RBD diagnostic method	Findings
Postuma et al.¹⁴14. Postuma RB, Lanfranchi PA, Blais H, Gagnon JF, Montplaisir JY. Cardiac autonomic dysfunction in idiopathic REM sleep behavior disorder. Mov Disord. 2010 Oct;25(14):2304-10. https://doi.org/10.1002/mds.23347 https://doi.org/10.1002/mds.23347...	2010	Canada	99	Polysomnography	Patients with RBD showed cardiac autonomic dysfunction in both those who developed and did not develop neurodegenerative disease.
Frauscher et al.⁶6. Frauscher B, Nomura T, Duerr S, Ehrmann L, Gschliesser V, Wenning GK, et al. Investigation of autonomic function in idiopathic REM sleep behavior disorder. J Neurol. 2012 Jun;259(6):1056-61. https://doi.org/10.1007/s00415-011-6298-0 https://doi.org/10.1007/s00415-011-6298-...	2012	Austria	15	Polysomnography	Presence of autonomic dysfunction in patients with iRBD.
Sorensen et al.¹⁵15. Sorensen GL, Mehlsen J, Jennum P. Reduced sympathetic activity in idiopathic rapid-eye-movement sleep behavior disorder and Parkinson's disease. Auton Neurosci. 2013 Dec;179(1-2):138-41. https://doi.org/10.1016/j.autneu.2013.08.067 https://doi.org/10.1016/j.autneu.2013.08...	2013	Denmark	11	Polysomnography	Patients with RBD had attenuated sympathetic activity.
Ferini-Strambi et al.⁷7. Ferini-Strambi L, Oertel W, Dauvilliers Y, Postuma RB, Marelli S, Iranzo A, et al. Autonomic symptoms in idiopathic REM behavior disorder: A multicentre case-control study. J Neurol. 2014 Jun;261(6):1112-8. https://doi.org/10.1007/s00415-014-7317-8 https://doi.org/10.1007/s00415-014-7317-...	2014	Multicenter	318	Polysomnography	Patients with iRBD had more gastrointestinal, cardiovascular, and urinary problems.
Lee et al.¹⁶16. Lee H, Cho YW, Kim HA. The severity and pattern of autonomic dysfunction in idiopathic rapid eye movement sleep behavior disorder. Mov Disord. 2015 Nov;30(13):1843-8. https://doi.org/10.1002/mds.26416 https://doi.org/10.1002/mds.26416...	2015	Korea	17	Polysomnography	iRBD was associated with autonomic dysfunction; predominantly, adrenergic and cardiovagal functions.
Aguirre-Mardones et al.¹⁷17. Aguirre-Mardones C, Iranzo A, Vilas D, Serradell M, Gaig C, Santamaria J, et al. Prevalence and timeline of nonmotor symptoms in idiopathic rapid eye movement sleep behavior disorder. J Neurol. 2015 Jun;262(6):1568-78. https://doi.org/10.1007/s00415-015-7742-3 https://doi.org/10.1007/s00415-015-7742-...	2015	Spain	44	Polysomnography	iRBD was associated with hyposmia and constipation.
Bedard et al.¹⁸18. Bedard MA, Aghourian M, Legault-Denis C, Postuma RB, Soucy JP, Gagnon JF, et al. Brain cholinergic alterations in idiopathic REM sleep behaviour disorder: a PET imaging study with (18)F-FEOBV. Sleep Med. 2019 Jun;58:35-41. https://doi.org/10.1016/j.sleep.2018.12.020 https://doi.org/10.1016/j.sleep.2018.12....	2019	Canada	5	Polysomnography	Specific marker on positron emission tomography showed brain cholinergic alterations in patients with iRBD.

Author	Year	Country	Total of PD patients	Diagnostic method	PD prevalence (%)
Mahajan et al.⁵5. Mahajan A, Rosenthal LS, Gamaldo C, Salas RE, Pontone GM, McCoy A, et al. REM sleep behavior and motor findings in Parkinson's disease: a cross-sectional analysis. Tremor Other Hyperkinet Mov (N Y). 2014 Jun;4:245. https://doi.org/10.7916/D84B2ZDF https://doi.org/10.7916/D84B2ZDF...	2014	USA	418	RBDSQ	27.0
Munhoz et al.²³23. Munhoz RP, Teive HA. REM sleep behaviour disorder: how useful is it for the differential diagnosis of parkinsonism? Clin Neurol Neurosurg. 2014 Dec;127:71-4. https://doi.org/10.1016/j.clineuro.2014.09.014 https://doi.org/10.1016/j.clineuro.2014....	2014	Brazil	100	ICSD-RBD	58.0
Kim et al.²⁴24. Kim YE, Yang HJ, Yun JY, Kim HJ, Lee JY, Jeon BS. REM sleep behavior disorder in Parkinson disease: association with abnormal ocular motor findings. Parkinsonism Relat Disord. 2014 Apr;20(4):444-6. https://doi.org/10.1016/j.parkreldis.2013.12.003 https://doi.org/10.1016/j.parkreldis.201...	2014	Korea	202	ICSD-RBD	57.4
Aygun et al.¹1. Aygun D, Turkel Y, Onar MK, Sunter T. Clinical REM sleep behavior disorder and motor subtypes in Parkinson's disease: a questionnaire-based study. Clin Neurol Neurosurg. 2014 Apr;119:54-8. https://doi.org/10.1016/j.clineuro.2014.01.011 https://doi.org/10.1016/j.clineuro.2014....	2014	Turkey	104	ICSD-RBD	NT	T
	2014	Turkey	104	ICSD-RBD	45.2	54.8
Janković et al.⁸8. Janković M, Svetel M, Kostić V. Frequency of REM sleep behavior disorders in patients with Parkinson's disease. Vojnosanit Pregl. 2015 May;72(5):442-6. https://doi.org/10.2298/vsp130501006j https://doi.org/10.2298/vsp130501006j...	2015	Serbia	97	RBDQ-HK	15.5
Alatriste-Booth et al.²⁵25. Alatriste-Booth V, Rodríguez-Violante M, Camacho-Ordoñez A, Cervantes-Arriaga A. Prevalence and correlates of sleep disorders in Parkinson's disease: a polysomnographic study. Arq Neuropsiquiatr. 2015 Mar;73(3):241-5. https://doi.org/10.1590/0004-282X20140228 https://doi.org/10.1590/0004-282X2014022...	2015	Brazil	120	Polysomnography	35.1
Swallow et al.²⁶26. Swallow DM, Lawton MA, Grosset KA, Malek N, Smith CR, Bajaj NP, et al. Variation in recent onset parkinson's disease: implications for prodromal detection. J Parkinsons Dis. 2016 Mar;6(2):289-300. https://doi.org/10.3233/JPD-150741 https://doi.org/10.3233/JPD-150741...	2016	UK	1,719	RBDSQ	43.3
Chahine et al.²⁷27. Chahine LM, Xie SX, Simuni T, Tran B, Postuma R, Amara A, et al. Longitudinal changes in cognition in early Parkinson's disease patients with REM sleep behavior disorder. Parkinsonism Relat Disord. 2016 Jun;27:102-6. https://doi.org/10.1016/j.parkreldis.2016.03.006 https://doi.org/10.1016/j.parkreldis.201...	2016	Multicenter	423	RBDSQ	25.5
Suzuki et al.²⁸28. Suzuki K, Okuma Y, Uchiyama T, Miyamoto M, Sakakibara R, Shimo Y, et al. Impact of sleep-related symptoms on clinical motor subtypes and disability in Parkinson's disease: a multicentre cross-sectional study. J Neurol Neurosurg Psychiatry. 2017 Nov;88(11):953-9. https://doi.org/10.1136/jnnp-2017-316136 https://doi.org/10.1136/jnnp-2017-316136...	2017	Multicenter	436	RBDSQ	35.1

Author	Year	Country	Total number of PD patients	RBD (% of total)	Findings related to PD motor symptoms	Findings related to PD non-motor symptoms
Postuma et al.³¹31. Postuma RB, Montplaisir J, Lanfranchi P, Blais H, Rompre S, Colombo R, et al. Cardiac autonomic denervation in Parkinson's disease is linked to REM sleep behavior disorder. Mov Disord. 2011 Jul;26(8):1529-33. https://doi.org/10.1002/mds.23677 https://doi.org/10.1002/mds.23677...	2011	Canada	53	60		Cardiac autonomic denervation was not associated with PD; rather, it was associated with RBD.
Kim et al.²¹21. Kim YE, Jeon BS. Clinical implication of REM sleep behavior disorder in Parkinson's disease. J Parkinsons Dis. 2014;4(2):237-44. https://doi.org/10.3233/JPD-130293 https://doi.org/10.3233/JPD-130293...	2014	Review	4,089	20–72		RBD was associated with hallucinations and dementia.
Mahajan et al.⁵5. Mahajan A, Rosenthal LS, Gamaldo C, Salas RE, Pontone GM, McCoy A, et al. REM sleep behavior and motor findings in Parkinson's disease: a cross-sectional analysis. Tremor Other Hyperkinet Mov (N Y). 2014 Jun;4:245. https://doi.org/10.7916/D84B2ZDF https://doi.org/10.7916/D84B2ZDF...	2014	USA	418	27	Patients with RBD were 1.66 times more likely to present worse motor symptoms.	No depression differences between patients with and without RBD.
Fantini et al.³²32. Fantini ML, Macedo L, Zibetti M, Sarchioto M, Vidal T, Pereira B, et al. Increased risk of impulse control symptoms in Parkinson's disease with REM sleep behaviour disorder. J Neurol Neurosurg Psychiatry. 2015 Feb;86(2):174-9. https://doi.org/10.1136/jnnp-2014-307904 https://doi.org/10.1136/jnnp-2014-307904...	2015	Multicenter	216	53.0		RBD was associated with an increased risk of developing impulse control disorders.
Cui et al.³³33. Cui SS, Du JJ, Fu R, Lin YQ, Huang P, He YC, et al. Prevalence and risk factors for depression and anxiety in Chinese patients with Parkinson disease. BMC Geriatr. 2017 Nov;17:270. https://doi.org/10.1186/s12877-017-0666-2 https://doi.org/10.1186/s12877-017-0666-...	2017	China	403			RBD was a risk factor for anxiety development (OR: 1.029 and p-value: 0.037).
Liu et al.⁴4. Liu Y, Zhu XY, Zhang XJ, Kuo SH, Ondo WG, Wu YC. Clinical features of Parkinson's disease with and without rapid eye movement sleep behavior disorder. Transl Neurodegener. 2017 Dec;6:35. https://doi.org/10.1186/s40035-017-0105-5 https://doi.org/10.1186/s40035-017-0105-...	2017	China	141	21.3		Patients with RBD had more anxiety, depression, constipation, hallucinations, and a higher prevalence of orthostatic hypotension.
Jozwiak et al.³⁴34. Jozwiak N, Postuma RB, Montplaisir J, Latreille V, Panisset M, Chouinard S, et al. REM sleep behavior disorder and cognitive impairment in Parkinson's disease. Sleep. 2017 Aug;40(8):zsx101. https://doi.org/10.1093/sleep/zsx101 https://doi.org/10.1093/sleep/zsx101...	2017	Canada	93	56.9		RBD was associated with greater cognitive impairment and a higher diagnosis frequency of mild cognitive impairment.
Pagano et al.²2. Pagano G, De Micco R, Yousaf T, Wilson H, Chandra A, Politis M. REM behavior disorder predicts motor progression and cognitive decline in Parkinson disease. Neurology. 2018 Sep;91(10):e894-e905. https://doi.org/10.1212/WNL.0000000000006134 https://doi.org/10.1212/WNL.000000000000...	2018	Multicenter	421	37.5	RBD was associated with a faster progression of PD motor symptoms.	RBD was associated with a greater risk of cognitive decline and a higher number of non-motor symptoms associated with PD, including hallucinations, pain, fatigue, constipation, and urinary problems.
Kang et al.³⁵35. Kang SH, Yoon IY, Lee SD, Han JW, Kim TH, Kim KW. REM sleep behavior disorder in the Korean elderly population: prevalence and clinical characteristics. Sleep. 2013 Aug;36(8):1147-52. https://doi.org/10.5665/sleep.2874 https://doi.org/10.5665/sleep.2874...	2013	Systematic review			Higher frequency of RBD in the predominant non-tremor PD phenotype.	RBD was a risk factor for the development of dementia and hallucinations.
Kim et al.³⁶36. 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;47:6-13. https://doi.org/10.1016/j.jocn.2017.09.019 https://doi.org/10.1016/j.jocn.2017.09.0...	2018	Systematic review				RBD in PD patients was associated with greater disease severity and increased mortality risk; further, the authors suggested that RBD could be a PD subtype marker.
Liu et al.³⁷37. Liu H, Ou R, Wei Q, Hou Y, Cao B, Zhao B, et al. Rapid eye movement behavior disorder in drug-naive patients with Parkinson's disease. J Clin Neurosci. 2019 Jan;59:254-8. https://doi.org/10.1016/j.jocn.2018.07.007 https://doi.org/10.1016/j.jocn.2018.07.0...	2019	China	158	19.6		RBD was associated with cognitive decline, other sleep disorders, and anxiety.
Banks et al.³⁸38. Banks SJ, Bayram E, Shan G, LaBelle DR, Bluett B. Non-motor predictors of freezing of gait in Parkinson's disease. Gait Posture. 2019 Feb;68:311-6. https://doi.org/10.1016/j.gaitpost.2018.12.009 https://doi.org/10.1016/j.gaitpost.2018....	2019	USA	100			RBD was associated with gait motor complications.
Baig et al.³3. Baig F, Kelly MJ, Lawton MA, Ruffmann C, Rolinski M, Klein JC, et al. Impulse control disorders in Parkinson and RBD: A longitudinal study of severity. Neurology. 2019 Aug;93(7):e675-e687. https://doi.org/10.1212/WNL.0000000000007942 https://doi.org/10.1212/WNL.000000000000...	2019	UK	921 (in the first assessment)			RBD was not associated with an increased risk of developing impulse control disorders.
Bargiotas et al.³⁹39. Bargiotas P, Ntafouli M, Lachenmayer ML, Krack P, Schupbach WMM, Bassetti CLA. Apathy in Parkinson's disease with REM sleep behavior disorder. J Neurol Sci. 2019 Apr;399:194-8. https://doi.org/10.1016/j.jns.2019.02.028 https://doi.org/10.1016/j.jns.2019.02.02...	2019	Switzerland	64	40.0		RBD was associated with apathy and increased depressive symptom severity.
Pilotto et al.⁴⁰40. Pilotto A, Romagnolo A, Tuazon JA, Vizcarra JA, Marsili L, Zibetti M, et al. Orthostatic hypotension and REM sleep behaviour disorder: impact on clinical outcomes in alpha-synucleinopathies. J Neurol Neurosurg Psychiatry. 2019 Nov;90(11):1257-63. https://doi.org/10.1136/jnnp-2019-320846 https://doi.org/10.1136/jnnp-2019-320846...	2019	Systematic review				Patients with PD and RBD had an increased risk of cognitive decline. The authors proposed the existence of a malignant PD phenotype associated with RBD and orthostatic hypotension, which could be characterized by faster progression of cognitive decline and postural instability.

Author	Year	Country	Sample	Findings
Nomura et al.⁵¹51. Nomura T, Inoue Y, Kagimura T, Nakashima K. Clinical significance of REM sleep behavior disorder in Parkinson's disease. Sleep Med. 2013 Feb;14(2):131-5. https://doi.org/10.1016/j.sleep.2012.10.011 https://doi.org/10.1016/j.sleep.2012.10....	2013	Japan	82 PD patients	RBD was associated with orthostatic hypotension in PD patients.
Anang et al.⁵²52. Anang JB, Gagnon JF, Bertrand JA, Romenets SR, Latreille V, Panisset M, et al. Predictors of dementia in Parkinson disease: a prospective cohort study. Neurology. 2014 Sep;83(14):1253-60. https://doi.org/10.1212/WNL.0000000000000842 https://doi.org/10.1212/WNL.000000000000...	2014	Canada	80 PD patients	Cardiovascular autonomic dysfunction, RBD, gait disturbances, and color discrimination ability were strong predictors of dementia development in PD patients.
Kim et al.⁵³53. Kim JS, Park HE, Oh YS, Lee SH, Park JW, Son BC, et al. Orthostatic hypotension and cardiac sympathetic denervation in Parkinson disease patients with REM sleep behavioral disorder. J Neurol Sci. 2016 Mar 15;362:59-63. https://doi.org/10.1016/j.jns.2016.01.020 https://doi.org/10.1016/j.jns.2016.01.02...	2016	Korea	94 PD patients; among them, 53 had RBD	RBD in PD patients was associated with orthostatic hypotension.
Jin et al.⁵⁴54. Jin H, Zhang JR, Shen Y, Liu CF. Clinical significance of REM sleep behavior disorders and other non-motor symptoms of Parkinsonism. Neurosci Bull. 2017 Oct;33(5):576-84. https://doi.org/10.1007/s12264-017-0164-8 https://doi.org/10.1007/s12264-017-0164-...	2017	Review		The authors suggested an association of autonomic dysfunctions with RBD; moreover, this association could be a PD sign. However, they emphasize the importance of further studies to prove this hypothesis.
Kim et al.⁵⁵55. Kim JS, Park HE, Park IS, Oh YS, Ryu DW, Song IU, et al. Normal ‘heart’ in Parkinson's disease: is this a distinct clinical phenotype? Eur J Neurol. 2017 Feb;24(2):349-56. https://doi.org/10.1111/ene.13206 https://doi.org/10.1111/ene.13206...	2017	Korea	160 PD patients	Patients with PD and low MIBG* uptake had a higher prevalence of RBD, orthostatic hypotension, constipation, and cognitive decline compared to those with normal uptake.
Fereshtehnejad et al.⁵⁶56. Fereshtehnejad SM, Postuma RB. Subtypes of Parkinson's disease: what do they tell us about disease progression? Curr Neurol Neurosci Rep. 2017 Apr;17(4):34. https://doi.org/10.1007/s11910-017-0738-x https://doi.org/10.1007/s11910-017-0738-...	2017	Review		Patients with PD associated with RBD and autonomic dysfunction presented faster disease progression with more prominent motor symptoms in the early PD stages.
Al-Qassabi et al.⁵⁷57. Al-Qassabi A, Pelletier A, Fereshtehnejad SM, Postuma RB. Autonomic sweat responses in REM sleep behavior disorder and Parkinsonism. J Parkinsons Dis. 2018;8(3):463-8. https://doi.org/10.3233/JPD-181357 https://doi.org/10.3233/JPD-181357...	2018	Canada	150 patients (49 with iRBD, 40 with PD, 20 with atypical parkinsonism, and 41 controls)	Patients with PD and concomitant RBD had significantly lower skin sweat measurements than those with PD without RBD and controls. This finding suggests a between-subgroup difference in the peripheral alpha-synuclein deposition.
Zitser et al.¹⁹19. Zitser J, During EH, Chiaro G, Miglis MG. Autonomic impairment as a potential biomarker in idiopathic REM-sleep-behavior disorder. Auton Neurosci. 2019 Sep;220:102553. https://doi.org/10.1016/j.autneu.2019.05.005 https://doi.org/10.1016/j.autneu.2019.05...	2019	Review		Autonomic symptoms were common in patients with RBD and reported in up to 94% of patients. The presence and severity of autonomic dysfunction symptoms in patients with RBD were associated with the risk of progression to PD. Moreover, it suggests an association of autonomic dysfunctions and RBD with a malignant PD subtype.

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[1] Correspondence: Francisco Cardoso; E-mail: fecardosoc@gmail.com