Abstract
Introduction
The aim of this study was to evaluate the consistency of “probable RBD” diagnosis with the RBD screening questionnaire (RBDSQ) assessed 2 years apart in a population‐based study.
Methods
Probable RBD was assessed by RBDSQ in 2008 and in 2010 in the Bruneck Study Cohort, with participants aged ≥60 years.
Results
A total of 437 participants completed the RBDSQ in 2008 and 2010. There were 29 (6.6%) and 23 (5.3%) participants with probable RBD in 2008 and in 2010, respectively. Only eight (1.8%) screened positive on both occasions. RBDSQ values 2 years apart showed low correlation with each other (Spearman rank coefficient r = 0.348, P < 0.001) and low agreement (intraclass correlation coefficient 0.388, P < 0.001).
Conclusions
We found low agreement between the two assessments. Possible explanations are the fluctuation of untreated RBD expression and the poor utility of the RBDSQ to detect RBD in the general population. Until further PSG validation of the RBDSQ in population‐based studies, investigators must be aware of the inherent uncertainty of questionnaire‐based RBD diagnosis.
Keywords: REM‐sleep behavior disorder, Parkinson's disease, Lewy body disease, risk marker, nonmotor symptom
Idiopathic REM‐sleep behavior disorder (iRBD) is a harbinger of neurodegeneration, and as long‐term follow‐up investigations of iRBD cohorts have shown, ≥80% of subjects will eventually develop a synuclein‐mediated neurodegenerative disease.1, 2, 3, 4 Moreover, iRBD is the most specific among the different risk factors for Parkinson's disease (PD).5
The identification of iRBD in the general elderly population would therefore be of utmost importance to identify subjects in an early premotor phase of α‐synucleinopathy, which can precede by >10 years the onset of motor symptoms or dementia.1, 2, 3, 4
Current International Classification of Sleep Disorders (ICSD) criteria require video‐polysomnography for a definite diagnosis of RBD.6 Various questionnaires have been developed and validated in sleep laboratory settings to enable a diagnosis of probable RBD.7 A commonly used instrument is the RBD screening questionnaire (RBDSQ), reported to have excellent sensitivity and specificity for both idiopathic and α‐synuclein‐related RBD.8
The aim of the present study was to evaluate the follow‐up consistency of a diagnosis of “probable RBD” with the RBDSQ assessed at two different time points two years apart in the population‐based Bruneck Study.
Patients and Methods
The Bruneck Study Cohort is representative for the general elderly community (aged ≥60 years) and was used for the present study.9 Patients completed the RBDSQ questionnaire8 after instructions were given by the physician and under the constant presence of the physician to help as needed. The RBDSQ5 was applied to the study cohort in 2008 and after 1.91 ± 0.07 years in 2010. The local ethics committee approved the study protocol and all subjects provided written informed consent in advance of study participation.
Statistics
Because linear variables were not normally distributed, as demonstrated by the Kolmogorov‐Smirnov test, the Wilcoxon signed‐rank test was used for a comparison of RBDSQ scores between the two assessments. Correlations between the two RBDSQ assessments, and with age, were evaluated with the Spearman rank test. Agreement of the two RBDSQ assessments was determined by the intraclass correlation coefficient using a one‐way random‐effects analysis of variance model for scalar variables and by the Cohen's kappa for nominal variables. The significance level was set at P < 0.05. SPSS 22.0 (SPSS, Chicago, IL) was used for all statistical analyses.
Results
A total of 437 participants without Parkinson's disease completed the RBDSQ in 2008 and in 2010 (204 men). Median age at the 2008 assessment was 69.5 (57.9–96.1) years. Median RBDSQ score was 1 (0–8) in 2008 and 2 (0–9) in 2010 (Wilcoxon P < 0.001). There were no gender differences in RBDSQ scores (Wilcoxon P = 0.568 in 2008, P = 0.894 in 2010) and no correlation with age (2008 Spearman r = 0.092, P = 0.054; 2010 Spearman r = 0.077, P = 0.106).
According to the established cut‐off ≥5 points on the RBDSQ, 29 (6.6%; 14 women, 15 men; 95% CI: 4.7%–9.4%) and 23 (5.3%; 14 women, 9 men; 95% CI: 3.4%–7.9%) participants had probable RBD in 2008 and in 2010, respectively. However, only 8 participants screened positive on both occasions (1.8%; 4 women, 4 men; 95% CI: 0.9%–3.7%). None of the patients with “probable RBD” according to the RBDSQ in 2008 received therapy for RBD between the two assessments. RBDSQ values in 2008 and 2010 showed low correlation with each other (Spearman rank coefficient r = 0.348, P < 0.001) and low agreement (intraclass correlation coefficient 0.388, P < 0.001). Among the 44 subjects who screened positive on at least one occasion, the RBDSQ score increased in 43.2%, remained unchanged in 4.5%, and decreased in 52.3% (Fig. 1).
Figure 1.
RBDSQ values (2008 and 2010) of the 44 subjects positive in at least one occasion. The horizontal dotted line represents the cut‐off for probable RBD with the RBDSQ, corresponding to 5 points. On the left side the 2008 scores are represented, and on the right side the 2010 scores. Grey lines represent subjects who screened positive (RBDSQ ≥5) on one of two occasions; red lines represent subjects who screened positive both times (n = 8). Each line reflects either one subject or more subjects showing the same RBDSQ on both occasions. The lines without asterisks represent one subject; for lines with asterisks, the number of asterisks reflects the number of subjects represented by the specific line. RBDSQ, REM sleep behavior disorder (RBD) screening questionnaire.
When individual questions of the RBDSQ were analysed, only item 5, “it thereby happened that I (almost) hurt my bed partner or myself,” showed moderate agreement between the two assessments (Cohen's kappa 0.546, P < 0.001), whereas there was little or no agreement between the two assessments for all other questions (Cohen's kappa between 0.116 and 0.308).
Discussion
This study evaluated the consistency of a “probable RBD” diagnosis based on the RBDSQ administered twice, two years apart, in a prospective cohort study of the general elderly population. Low agreement between the two assessments was found.
The RBDSQ was the first validated questionnaire for RBD and asks for present—and in some questions additionally for past—behaviors and events. As one of the control groups, the original publication included patients with other neurological disorders, and the specificity of the RBDSQ was low in this population (0.56).8 Interestingly, a Japanese study aiming to evaluate the validity of the RBDSQ in the general population included detailed telephone interviews with the subjects with “probable RBD.”10 Only 5% (9/179) were determined to have probable RBD after the telephone interview. One reason could be that the response type is a forced choice, yes/no only, so ambiguous responses cannot be reflected.
A study demonstrated that the diagnostic value of RBDSQ depends on the circumstances and setting.11 Because the RBDSQ in the present study was administered in the exactly same way at both assessments, the low consistency of our results is not easily explained by such factors.
We previously reported in this population an association of probable RBD diagnosis with biomarkers for α‐synucleinopathy at the 2010 assessment.9
It is well known that RBD clinical expression can fluctuate with time, and violent movements represent only a small fraction of motor events even in severe RBD.12 In addition, patients may not always be aware of movements occurring during sleep. As a time frame is not specified in the RBDSQ, this might explain the low consistency of the diagnosis of “probable RBD” observed in this study. More likely, the RBDSQ is not the appropriate questionnaire to assess RBD in the general population.
A limitation of this study is that we did not perform video‐polysomnography in the subjects with “probable RBD” according to the RBDSQ.
Until further PSG validation of the RBDSQ in population‐based studies is performed, investigators must be aware of the inherent uncertainty of a questionnaire‐based RBD diagnosis.
Roles: 1. Research Project: A. Conception, B. Acquisition of Data, C. Organization, D. Execution, E. Obtaining Funding; 2. Statistical Analysis: A. Design, B. Interpretation of Data, C. Execution, D. Review and Critique, E. Designing the Bruneck Study; 3. Manuscript Preparation: A. Writing the First Draft, B. Manuscript Revision, C. Review and Critique.
A. S.: 2A, 2B, 2C, 3A, 3B
P. M.: 1A, 1B, 1C, 2B, 3B
K.S.: 1A, 1C, 1D, 1E, 2E, 3B
M.N.: 1B, 3B
K.J.M.: 1B, 3B
A.H.: 1B, 3B
H.S.: 1B, 3B
J.W.: 1E, 2E, 3B
S.K.: 1E, 2E, 3B
G.R.: 1B, 3B
A.G.: 1B, 2E, 3B
W.P.: 1A, 1E, 2B, 2E, 3B
B.H.: 1A, 2B, 2D, 3B, 3C
Disclosures
Ethical Compliance Statement: The local ethics committee approved the study protocol and all subjects provided written informed consent before study participation. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflicts of Interest: There was no specific funding for this study. Philipp Mahlknecht was supported by a grant from the Austrian Society of Neurology (ÖGN). The Bruneck Study was supported by the “Pustertaler Verein zur Prävention von Herz–und Hirngefaesserkrankungen,” the Gesundheitsbezirk Bruneck, the mayor of Bruneck, and the “Assessorat fuer Gesundheit,” Province of Bolzano, Italy. The authors report no conflicts of interest.
Financial Disclosures for the previous 12 months: Ambra Stefani received travel support from Habel Medizintechnik, Inspire Medical Systems, OSG. Klaus Seppi reported grants from Medical University Innsbruck, grants from Oesterreichische Nationalbank, grants from FWF Austrian Science Fund, grants from the Michael J. Fox Foundation, grants and personal fees from the International Parkinson and Movement Disorder Society, personal fees from Teva, personal fees from UCB, personal fees from Lundbeck, and personal fees from AOP Orphan Pharmaceuticals AG. Werner Poewe reports personal fees from AbbVie, Allergan, AstraZeneca, Boehringer‐Ingelheim, Boston Scientific, GlaxoSmithKline, Ipsen, Lundbeck, Medtronic, MDS, Merk‐Serono, Merz Pharmaceuticals, Novartis, Orion Pharma, Teva, UCB and Zambon (consultancy and lecture fees related to clinical drug development programs for PD), and Royalties from Thieme, Wiley Blackwell, Oxford University Press, and Cambridge University Press. Birgit Högl reports consulting, advisory board, and/or speaker's honoraria from UCB, Otsuka, Lilly, AbbVie, Axovant, Lundbeck, Mundipharma, and travel support from Habel Medizintechnik, Austria. Philipp Mahlknecht, Michael Nocker, Katherina J. Mair, Anna Hotter, Heike Stockner, Johann Willeit, Stefan Kiechl, Gregor Rungger, and Arno Gasperi have nothing to disclose.
Relevant disclosures and conflicts of interest are listed at the end of this article.
References
- 1. Högl B, Stefani A. REM sleep behaviour disorder (RBD): update on diagnosis and treatment. Somnologie (in press). 2016. doi: 10.1007/s11818-016-0048-6 [DOI] [PMC free article] [PubMed]
- 2. 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;14:744–748. [DOI] [PubMed] [Google Scholar]
- 3. Iranzo A, Tolosa E, Gelpi E, et al. Neurodegenerative disease status and post‐mortem pathology in idiopathic rapid‐eye‐movement sleep behavior disorder: an observational cohort study. Lancet Neurol 2013;12:443–453. [DOI] [PubMed] [Google Scholar]
- 4. Postuma RB, Gagnon JF, Bertrand JA, Génier Marchand D, Montplaisir JY. Parkinson risk in idiopathic REM sleep behavior disorder: preparing for neuroprotective trials. Neurology 2015;84:1104–1113. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Mahlknecht P, Seppi K, Poewe W. The concept of prodromal Parkinson's disease. J Parkinsons Dis 2015;5:681–697. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. American Academy of Sleep Medicine . International classification of sleep disorders, 3rd ed Darien, IL: American Academy of Sleep Medicine; 2014. [Google Scholar]
- 7. Iranzo A, Santamaria J, Tolosa E. Idiopathic rapid eye movement sleep behavior disorder: diagnosis, management, and the need for neuroprotective interventions. Lancet Neurol 2016;15:405–419. [DOI] [PubMed] [Google Scholar]
- 8. Stiasny‐Kolster K, Mayer G, Schäfer S, et al. The REM sleep behavior disorder screening questionnaire—a new diagnostic instrument. Mov Disord 2007;22:2386–2393. [DOI] [PubMed] [Google Scholar]
- 9. Mahlknecht P, Seppi K, Frauscher B, et al. Probable RBD and association with neurodegenerative disease markers: a population‐based study. Mov Disord 2015;30:1417–1421. [DOI] [PubMed] [Google Scholar]
- 10. Nomura T, Inoue Y, Kagimura T, Kusumi M, Nakashima K. Validity of the Japanese version of the REM sleep behavior disorder (RBD) screening questionnaire for detecting probable RBD in the general population. Psychiatry Clin Neurosci 2015;69:477–482. [DOI] [PubMed] [Google Scholar]
- 11. Stiasny‐Kolster K, Sixel‐Döring F, Trenkwalder C, et al. Diagnostic value of the REM sleep behavior disorder screening questionnaire in Parkinson's disease. Sleep Med 2015;16:186–189. [DOI] [PubMed] [Google Scholar]
- 12. Frauscher B, Gschliesser V, Brandauer E, et al. Video analysis of motor events in REM sleep behavior disorder. Mov Disord 2007;22:1464–1470. [DOI] [PubMed] [Google Scholar]