Prevalence of isolated RBD in the city of Catania, Italy: a population-based study
2021; American Academy of Sleep Medicine; Volume: 17; Issue: 11 Linguagem: Inglês
10.5664/jcsm.9416
ISSN1550-9397
AutoresCalogero Edoardo Cicero, Loretta Giuliano, Riccardo Sgroi, Raffaele Squillaci, Claudio Terravecchia, Edoardo Vancheri, Valeria Todaro, Paola Reitano, Sofia Rizzo, Antonina Luca, Giovanni Mostile, Vincenza Paradisi, Mario Zappia, Alessandra Nicoletti, Rosa Arancio, Francesco Belfiore, Marco Ciancio, Carmelo Di Gregorio, Giuseppa Gerbino, Olivia Laganà, Giuseppe Polizza, A Previtera, Maria Rosaria Putrino, Rosaria de Fátima Segger Macri Russo, Anna Salvo, Rosa Sciacca, Giuseppe Sorgi, Antonio Spina, Guglielmo Travaglianti,
Tópico(s)Genetic Neurodegenerative Diseases
ResumoFree AccessScientific InvestigationsPrevalence of isolated RBD in the city of Catania, Italy: a population-based study Calogero Edoardo Cicero, MD, MSc, Loretta Giuliano, MD, MSc, Riccardo Sgroi, MD, Raffaele Squillaci, MD, Claudio Terravecchia, MD, Edoardo Vancheri, MD, Valeria Todaro, MD, Paola Reitano, MD, Sofia Rizzo, MD, Antonina Luca, MD, PhD, Giovanni Mostile, MD, PhD, Vincenza Paradisi, MD, Mario Zappia, MD, Alessandra Nicoletti, MD, MSc, on behalf of the Italian Society of General Medicine of Catania Study Group, Rosa Arancio, Francesco Belfiore, Marco Ciancio, Carmelo Di Gregorio, Giuseppa Gerbino, Olivia Laganà, Giuseppe Polizza, Antonio Previtera, Maria Rosaria Putrino, Rosaria Russo, Anna Salvo, Rosa Sciacca, Giuseppe Sorgi, Antonio Spina, Guglielmo Travaglianti Calogero Edoardo Cicero, MD, MSc Italian Society of General Medicine, Catania, Italy , Loretta Giuliano, MD, MSc Department of Medical, Surgical and Advanced Technologies G.F. Ingrassia, Section of Neurosciences, University of Catania, Italy , Riccardo Sgroi, MD Department of Medical, Surgical and Advanced Technologies G.F. Ingrassia, Section of Neurosciences, University of Catania, Italy , Raffaele Squillaci, MD Department of Medical, Surgical and Advanced Technologies G.F. Ingrassia, Section of Neurosciences, University of Catania, Italy , Claudio Terravecchia, MD Department of Medical, Surgical and Advanced Technologies G.F. Ingrassia, Section of Neurosciences, University of Catania, Italy , Edoardo Vancheri, MD Department of Medical, Surgical and Advanced Technologies G.F. Ingrassia, Section of Neurosciences, University of Catania, Italy , Valeria Todaro, MD Department of Medical, Surgical and Advanced Technologies G.F. Ingrassia, Section of Neurosciences, University of Catania, Italy , Paola Reitano, MD Department of Medical, Surgical and Advanced Technologies G.F. Ingrassia, Section of Neurosciences, University of Catania, Italy , Sofia Rizzo, MD Department of Medical, Surgical and Advanced Technologies G.F. Ingrassia, Section of Neurosciences, University of Catania, Italy , Antonina Luca, MD, PhD Department of Medical, Surgical and Advanced Technologies G.F. Ingrassia, Section of Neurosciences, University of Catania, Italy , Giovanni Mostile, MD, PhD Department of Medical, Surgical and Advanced Technologies G.F. Ingrassia, Section of Neurosciences, University of Catania, Italy Oasi Institute for Research on Mental Retardation and Brain Aging, Troina, Italy , Vincenza Paradisi, MD Italian Society of General Medicine, Catania, Italy , Mario Zappia, MD Department of Medical, Surgical and Advanced Technologies G.F. Ingrassia, Section of Neurosciences, University of Catania, Italy , Alessandra Nicoletti, MD, MSc Address correspondence to: Alessandra Nicoletti, MD, MSc, Department of Medical, Surgical and Advanced Technologies G.F. Ingrassia, Section of Neurosciences, University of Catania, Italy; Tel: +390953782783; Email: E-mail Address: [email protected] Department of Medical, Surgical and Advanced Technologies G.F. Ingrassia, Section of Neurosciences, University of Catania, Italy , on behalf of the Italian Society of General Medicine of Catania Study Group , Rosa Arancio , Francesco Belfiore , Marco Ciancio , Carmelo Di Gregorio , Giuseppa Gerbino , Olivia Laganà , Giuseppe Polizza , Antonio Previtera , Maria Rosaria Putrino , Rosaria Russo , Anna Salvo , Rosa Sciacca , Giuseppe Sorgi , Antonio Spina , Guglielmo Travaglianti Published Online:November 1, 2021https://doi.org/10.5664/jcsm.9416Cited by:2SectionsAbstractEpubPDF ShareShare onFacebookTwitterLinkedInRedditEmail ToolsAdd to favoritesDownload CitationsTrack Citations AboutABSTRACTStudy Objectives:Few studies have analyzed the prevalence of isolated rapid eye movement sleep behavior disorder (RBD) giving different estimates. Aim of the study was to estimate the prevalence of isolated RBD in the city of Catania.Methods:A 3-stage design was adopted. Participants attending the offices of general practitioners in the city of Catania were screened with the RBD Single Question Screen questionnaire (Stage I). Positive participants were interviewed by phone and, if suspected of RBD, were invited for clinical examination by a movement disorders specialist and a sleep specialist (Stage II). After the clinical examination, patients diagnosed as probable isolated RBD (pRBD) were invited to undergo a video polysomnography (Stage III) to confirm the diagnosis of definite RBD.Results:A total of 1,524 participants were screened. Of these, 220 (14.4%) screened positive. One hundred forty-three of them were further screened by phone, of whom 75 were suspected RBD. Thirty-six patients were diagnosed as pRBD, giving a prevalence of 2.36% (95% confidence interval, 1.71–3.25). Twelve pRBD agreed to a video polysomnography and, of these, 4 were diagnosed as definite RBD, giving a prevalence of 0.26% (95% confidence interval, 0.07–0.67). Prevalence adjusted by nonparticipants was 3.48% (95% confidence interval, 2.67–4.52) and 1.18% (95% confidence interval, 0.45–1.37) for pRBD and definite RBD, respectively.Conclusions:Prevalence of both pRBD and definite RBD in Italy is comparable to the estimates reported in literature, confirming that isolated RBD has a low prevalence in the general population.Citation:Cicero CE, Giuliano L, Sgroi R, et al. Prevalence of isolated RBD in the city of Catania, Italy: a population-based study. J Clin Sleep Med. 2021;17(11):2241–2248.BRIEF SUMMARYCurrent Knowledge/Study Rationale: Prevalence studies of isolated rapid eye movement sleep behavior disorder (RBD) are difficult to perform. In Italy, prevalence of isolated RBD has been studied using only the clinical confirmation.Study Impact: This is the first RBD prevalence study conducted in Italy that employed video polysomnography using a population-based 3-stage design allowing to calculate estimates for both probable and definite RBD. This study also discusses the reasons behind the differences in prevalence rates across different studies and the challenges in epidemiological research on RBD.INTRODUCTIONRapid eye movement (REM) sleep behavior disorder (RBD) is a condition characterized by the presence of abnormal behaviors in the sleep phase, such as sudden movements and vocalizations caused by a dream enactment behavior.1 Definite diagnosis can be made only with a video polysomnographic recording (VPSG) showing the lack of atonia during rapid eye movement sleep and the presence of abnormal behaviors, according to the current diagnostic criteria.2Isolated RBD could be considered as an alpha-synucleinopathy in its earliest stages, conferring a high risk to convert to either Parkinson disease (PD), dementia with Lewy bodies, or multiple system atrophy.3 Indeed, it represents the most specific risk factor for the development of PD being the strongest prodromal marker in the diagnosis of "Prodromal PD"4 and is part of the core criteria for the dementia with Lewy bodies diagnosis.5 For this reason, it is of paramount importance to study the prevalence of the disease in the general population. Nonetheless, data about prevalence of isolated RBD are scarce, with few population-based studies often reporting estimates that differ significantly depending on the diagnostic process employed.6,7According to a recent a recent meta-analysis, to date 5 studies have evaluated the prevalence of isolated definite RBD (dRBD) (confirmed by VPSG), resulting in a pooled prevalence of dRBD of 0.68% (95% confidence interval [CI], 0.38–1.05) while the pooled prevalence of probable RBD (pRBD, not confirmed by VPSG), based on 14 studies, was 5.65% (95% CI, 4.29–7.18).8 In Italy, only 2 studies have been conducted on the prevalence of pRBD.7,9Aim of the current study is to assess the prevalence of both probable and definite isolated RBD in the city of Catania using a population-based 3-stage design.METHODSStudy population and study designThe study has been conducted in the municipality of Catania, Italy (population: 314,555 inhabitants; Istituto Nazionale di Statistica, ISTAT 2016) from April 2016 to November 2017.For the first stage (screening phase–Stage I) a sample of general practitioners (GPs) working in the study area was randomly selected from the provincial roster of the Italian Society of General Medicine to participate in the study. Before conducting the survey, several meetings were carried out with the selected GPs to explain the aim of the survey. GPs were given posters to be displayed in their waiting rooms explaining what is RBD.Seven trained medical students visited each of the GPs' offices at least 3 times a week. Participants aged 40 years and above attended by the GPs were interviewed face-to-face by the students who administered the RBD Single Question Screen questionnaire. The RBD Single Question Screen is a screening questionnaire with 94% sensitivity and 87% specificity validated in Italian language10 and consists of the following question: "Have you ever been told, or suspected yourself, that you seem to 'act out your dreams' while asleep (for example, punching, flailing your arms in the air, making running movements, etc.)?"At the second stage (Stage II), participants positive at the screening phase underwent a structured phone interview carried out by a board-certified sleep specialist (LG) to confirm the suspicion of isolated RBD. When the suspicion was confirmed, patients were invited to undergo a clinical evaluation at the neurology clinic of the AOU Policlinico–Vittorio Emanuele of Catania. A board-certified sleep specialist (LG) and a movement disorders expert (CEC) confirmed the presence of pRBD, based on a standardized semistructured interview to exclude other sleep disorders and to evaluate the presence of other neurological disorders, including parkinsonisms. When available, bed partners were contacted to provide information on the sleep behaviors. For all the enrolled patients at Stage II, the presence of extrapyramidal symptoms has been evaluated using the Unified Parkinson's Disease Rating Scale III.11 To exclude patients with dementia at this stage, cognition and activities of daily living were assessed with the Unified Parkinson's Disease Rating Scale sections I and II. Subjects with a suspected cognitive impairment underwent an extensive neuropsychological evaluation. The second stage allowed us to reach the diagnosis of isolated pRBD.Patients considered as pRBD at second stage were invited to undergo a VPSG to confirm the presence of RBD (Stage III). Patients with a VPSG-confirmed RBD were diagnosed as isolated dRBD according to the current diagnostic criteria.2 In the case of patients with a highly suggestive clinical history and presence of VPSG clinical events, but not satisfying the rapid eye movement sleep without atonia (RSWA) cut-off criteria for the diagnosis of RBD, a diagnosis of provisional RBD (provRBD) was proposed.2 The study has been conducted in accordance with the Standards of Reporting of Neurological Disorders guidelines.12Polysomnographic recordingsVPSG was recorded for at least 1 night for each participant. The VPSG recording was carried out using a minimum of 8 electroencephalography channels (placed according to the international 10-20 system), 2 electrocardiographic derivations, submentalis muscle, the bilateral flexor digitorum superficialis muscle, and the bilateral anterior tibialis muscle electrodes, electrooculogram, nasal thermistor, snore monitor, chest and abdominal movements, pulse rate, and oximetry (Micromed SpA, Mogliano Veneto, Italy).The VPSG recordings were scored by 2 investigators (LG, CEC) according to the American Academy of Sleep Medicine criteria13 and, in case of disagreement, the conclusions were sorted out by discussion. RSWA was visually scored.13 RBD was defined according to the International Classification of Sleep Disorders, third edition.2 The presence of periodic limb movements during sleep and sleep apneas was also recorded.13 We considered pathological a periodic limb movements during sleep index > 15 events/h and an apnea-hypopnea index > 5 events/h.2Sample size calculationSample size calculation was based on a previous described prevalence of 0.74%14 in a European country with similar population characteristics to southern Italy. Thus, considering the population of the city of Catania in 2016, a 0.5 precision interval, and 95% CIs, a minimum number of 1,122 participants was calculated. Moreover, to account for an estimated proportion of 20% of nonparticipants, minimum sample size was increased to 1,346.Statistical analysisDemographic, clinical, and instrumental data were double entered in an ad hoc created database. Before analysis, a range and consistency check has been conducted on the variables considered for the study. Missing data were identified and cross-referenced with the original documents. Qualitative variables have been described as frequencies, while quantitative variables as means and standard deviations. Differences of demographic and clinical qualitative data were analyzed with the chi-squared test and quantitative data with the t-test. When not normally distributed, appropriate nonparametric test was used. Data have been analyzed with STATA 16.0 software. Lifetime prevalence and the 95% CI were calculated for isolated pRBD and dRBD. Moreover, the combined prevalence of provRBD and dRBD were calculated. For pRBD, age and sex specific prevalences were also measured. Prevalence estimates considering only the population ≥ 50 years and ≥ 60 years were also calculated. Prevalence rates for both isolated pRBD and dRBD were adjusted, projecting the obtained rates to the nonparticipants (both at Stage I and Stage II).EthicsThe study was approved by the Ethical Committee of the AOU Policlinico-Vittorio Emanuele. All the patients were given a paper briefly explaining the reasons of the study containing a written informed consent model to be signed.RESULTSStage I: screening phaseIn the offices of 22 GPs who participated in the study, a total of 1,524 participants (642 [42.1%] men; mean age 62.2 ± 11.7 years) were screened. Of these, 220 (14.4%) were positive at the screening questionnaire (mean age 63.8 ± 11.6; 119 [54.1%] men). Flowchart of the participants at each of the study stages is reported in Figure 1. Participants who screened positive were older (P = .03) and with a higher prevalence of men (P < .001). Demographic characteristics of the entire sample are reported in Table 1.Figure 1: Flowchart of the study.dRBD = definite rapid eye movement sleep behavior disorder, pRBD = probable RBD, provRBD = provisional RBD, RBD = rapid eye movement sleep behavior disorder, RBD1Q = rapid eye movement sleep behavior disorder single-question screen, VPSG = video polysomnography.Download FigureTable 1 Characteristics of the screened sample.Total (n = 1,524)Negative RBD1Q (n = 1,304)Positive RBD1Q (n = 220)PAge, y (mean ± SD)62.2 ± 11.761.9 ± 11.763.8 ± 11.6.03Sex (male), n (%)642 (42.1)523 (40.1)119 (54.1)< .001Marital status, n (%).225 Not married141 (9.3)122 (9.4)19 (8.6) Married1,111 (72.9)958 (73.5)153 (69.6) Widow138 (9.1)110 (8.4)28 (12.7) Other134 (8.8)114 (8.7)20 (9.1)Educational level, n (%).086 Primary school380 (24.9)324 (24.9)56 (25.5) Secondary school544 (35.7)461 (35.4)83 (37.7) High school370 (24.3)327 (25.1)43 (19.6) University137 (9.0)120 (9.2)17 (7.7) Other93 (6.1)72 (5.5)21 (9.6)Occupation, n (%).021 Unemployed121 (7.9)100 (7.7)21 (9.6) Employee255 (16.7)218 (16.7)37 (16.8) Housewife442 (29.0)400 (30.7)42 (19.1) Professional87 (5.7)72 (5.5)15 (6.8) Retired515 (33.8)428 (32.8)87 (39.6) Other104 (6.8)86 (6.6)18 (8.2)Familial history of Parkinson disease, n (%)51 (3.4)39 (3.0)12 (5.5).06Significant P values are in bold. RBD1Q = rapid eye movement sleep behavior disorder single-question screen, SD = standard deviation.Stage II: prevalence of isolated pRBDOf the 220 who screened positive, 10 (4.5%) were excluded because they were either deceased (n = 6) or did not meet inclusion criteria (3 had a neurodegenerative disease and 1 a demyelinating disease). Sixty-seven (31.9%) of the 210 screened positive did not participate at Stage II (29 [43.2%] could not be traced and 38 [56.7%] refused to participate in the study). Finally, 143 participants were further evaluated, leading to a participation rate at Stage II of 68.1% (Figure 1). Compared to nonparticipants, those who have been evaluated were younger (mean age 61.9 ± 11.4 years vs 66.3 ± 11.0 years; P = .01) and with a higher educational level (high school graduated 23.8% vs 10.5%; P = .02).Sixty-eight of the 143 (47.5%) screened positive were excluded because the suspicion of RBD was not confirmed at the phone interview. Out of the 75 suspected RBD, 73 were in-person evaluated at the neurologic clinic while 2 were unable to come to the hospital and the diagnosis of pRBD was confirmed just by an accurate phone interview.Of the 75 suspected RBD, 53 (70.7%) had a bed partner who shared information on the nocturnal behaviors of the patients. Thirty-nine (52%) were excluded, because 7 (18.0%) had a suspicion of non-rapid eye movement parasomnia, 6 (15.4%) of restless legs syndrome, 10 (25.6%) of insomnia, 6 (15.4%) of obstructive sleep apnea, while 3 (7.7%) presented with other alternative diagnoses, such as posttraumatic stress disorder, epileptic seizures, and laryngospasm, and 4 (10.2%) had sleep complaints of uncertain clinical significance. An additional 3 patients (7.7%) were excluded because they presented with other associated disorders, thus leading to a diagnosis of secondary RBD (2 PD and 1 dementia with Lewy bodies).Finally, 36 patients (20 men [55.6%]; mean age 62.5 ± 10.8 years) fulfilled the diagnosis of isolated pRBD, giving a prevalence of 2.36% (95% CI, 1.71–3.25); a similar prevalence of 2.45% (95% CI, 1.73–3.46) was obtained for the population aged ≥ 50 years, and 2.53% (95% CI, 1.66–3.84) for those aged ≥ 60 years. Prevalence was higher among men (3.10%; 95% CI, 2.01–4.74) than women (1.82%; 95% CI, 1.12–2.93) and steeply increased with age starting from 1.91% (95% CI, 0.82–4.40) in the population aged 40–49 years to reach a peak of 3.38% (95% CI, 1.98–5.70) in the group aged 60–69 years and to slowly decline soon after (Table 2). Baseline characteristics of pRBD are reported in Table 3.Table 2 Age- and sex-specific prevalence of pRBD.Age Classes, yMenWomenAllSampleCasesPrevalence (95% CI)SampleCasesPrevalence (95% CI)SampleCasesPrevalence (95% CI)40–499322.15% (0.60–7.50)16831.78% (0.61–5.11)26151.91% (0.82–4.40)50–5914653.42% (1.47–7.76)26251.91% (0.82–4.38)408102.45% (1.33–4.45)60–6917752.82% (1.21–6.44)20783.86% (1.97–7.43)384133.38% (1.98–5.70)70–7916563.63% (1.67–7.70)2000036561.64% (0.75–3.53)80–896123.27% (0.90–11.19)420010321.94% (0.53–6.80)90–99300000300Total645203.10% (2.01–4.74)879161.82% (1.12–2.93)1,524362.36% (1.71–3.25)CI = confidence interval, pRBD = probable rapid eye movement sleep behavior disorder.Table 3 Clinical and demographic characteristics of patients with pRBD, dRBD, and provRBD.pRBD (n = 36)dRBD (n = 4)provRBD (n = 5)Age, y (mean ± SD)62.5 ± 10.865.2 ± 12.552.5 ± 8.5Age, y (median and range)63 (42–86)64 (52–81)54 (42–62)Sex (men), n (%)20 (55.6)2 (50)2 (40)UPDRS-III5.7 ± 5.14.5 ± 4.54 ± 2.3Sleep macrostructure Total sleep time, min (mean ± SD)—323.7 ± 71.9314.2 ± 114.2 Sleep latency, min (mean ± SD)—34 ± 19.27.4 ± 7.3 Sleep efficiency, % (mean ± SD)—77 ± 7.283.8 ± 8.6 Wake after sleep onset, min (mean ± SD)—84 ± 23.359.2 ± 30.3 N1 sleep, % (mean ± SD)—8 ± 4.32.6 ± 3.2 N2 sleep, % (mean ± SD)—52 ± 11.052 ± 9.9 N3 sleep, % (mean ± SD)—24.8 ± 7.424.6 ± 12.5 REM sleep, % (mean ± SD)—16.3 ± 3.419.2 ± 7.5dRBD = definite rapid eye movement sleep behavior disorder, pRBD = probable RBD, provRBD = provisional RBD, REM = rapid eye movement, SD = standard deviation, UPDRS-III = Unified Parkinson's Disease Rating Scale-III.Stage III: prevalence of isolated dRBDOut of the 36 patients with pRBD, only 12 (33.3%) agreed to spend a night in the clinic to undergo a VPSG. The 24 (66.7%) pRBD who refused the VPSG were slightly older (65.8 ± 9.4 years vs 56.4 ± 11.3 years; P = .01), but apart from age, no significant differences were found. Considering the 12 patients who underwent VPSG, 4 (33.3%) were diagnosed as isolated dRBD, while 5 (41.7%) were diagnosed as provRBD, reaching a confirmation rate of 75% (Figure 1). For the other 3 patients, diagnoses of obstructive sleep apnea, restless legs syndrome, and fragmented sleep were made. Among the dRBD cases, 2 also presented with a periodic limb movements during sleep index > 15 events/h, while 1 showed an apnea-hypopnea index higher than 5 events/h. Sleep comorbidities for provRBD were periodic limb movements during sleep in 2 and sleep apnea in 1. Participants with provRBD were slightly younger compared to those with dRBD (Table 3).Considering the 4 patients with isolated dRBD, the prevalence was 0.26% (95% CI, 0.07–0.67) with a slightly higher prevalence among men (0.31% [95% CI, 0.04–1.0] vs 0.23% [95% CI, 0.006–0.8]). Prevalence of dRBD was slightly higher both in the population aged ≥ 50 years (0.31% [95% CI, 0.12–0.81]) and in the population aged ≥ 60 years (0.36% [95% CI, 0.12–1.06]). Prevalence reached 0.59% (95% CI, 0.27–1.12) when provRBD cases were also considered. Clinical, demographic, and polysomnographic characteristics of patients with dRBD and provRBD are reported in Table 3.Adjusted prevalence of isolated pRBD and dRBDWhen prevalence rates obtained for participants were applied to nonparticipants, prevalence of pRBD was 3.48% (95% CI, 2.67–4.52) while prevalence of dRBD was 1.18% (95% CI, 0.45–1.37). Considering both, dRBD and provRBD prevalence adjusted by nonparticipants was 2.62% (95% CI, 1.93–3.55).DISCUSSIONCompared to other neurologic diseases, there is still a paucity of information on the epidemiology of RBD. According to a recent meta-analysis, the pooled prevalence of dRBD is 0.68% and 5.65% for pRBD.8 However, prevalence estimates vary widely across the studies due to the different methodological approaches, study designs, diagnostic criteria, screening questionnaires adopted, age structure of the selected populations, and participation rate.8In our study, using a 3-stage design we found a prevalence of isolated pRBD of 2.36% and 0.26% for dRBD that rose to 0.59% when patients with provRBD were considered. Our prevalence estimates are lower than those reported in the meta-analysis on isolated RBD, albeit within the observed range for both dRBD and pRBD diagnosis.8 Nonetheless, they get closer to those reported in literature when adjusted by the participation rate.Prevalence of isolated pRBD: stage IIIn our study, at stage II, we found a prevalence of pRBD of 2.36%. However, 30.5% of the screened population did not participate at the second stage, and when prevalence rate was adjusted projecting the observed rate to the nonparticipants, an adjusted prevalence rate of 3.48% was obtained.To date, 14 studies have evaluated the prevalence of pRBD and rates reported ranges from 0.6% to 13.6%.8 Although our prevalence is in the range of those reported in literature it is lower than the average pooled prevalence (5.65%). However, the majority of these studies adopted a 1-stage design, thus the diagnosis of pRBD was not confirmed through a clinical interview but was only based on the screening questionnaires. Comparison with these studies is, in general, difficult, because 1-stage studies tend to overestimate the prevalence of RBD (pooled prevalence 6.40%),8 that in this case depends on the sensitivity and specificity of the adopted questionnaires. Indeed, sensitivity and specificity of RBD screening questionnaires depend on the studied population,15 clinical setting,16 and might not be consistent across repeated evaluations.17 Except for the Mayo Sleep Questionnaire,18 the majority of these tools have been validated in just a hospital setting. Nonetheless, it is well known that hospital validations tend to overestimate both sensitivity and specificity levels.19 Furthermore, the 1-stage design does not allow for exclusion of the presence of secondary RBD, such as RBD associated with alpha-synucleinopathies.Only 2 studies adopted a 2-stage design in which participants who screened positive were confirmed by a clinical evaluation (Stage II).7,20 Prevalence rates reported in these latter studies were on average lower with respect to the 1-stage studies (pooled prevalence 2.1%)8 and closer to our estimates.To the best of our knowledge only 2 small studies involving about 400 participants aged 60 years and above evaluated the prevalence of pRBD in Italy.7,9 In particular a 2-stage study was carried out in the Trentino-Alto Adige region7 and reported a prevalence of 4.6%, while a 1-stage survey focused on the mild parkinsonian signs was carried out in the Emilia Romagna region9 and reported a prevalence of 4.3%. These estimates are higher with respect to the rate reported in our study (2.36%), but close if we consider the adjusted rate (3.48%). The participation rate at Stage II (68.1%) in our study could, in fact, in part explain such a difference, but we strongly believe that the confirmation of the pRBD at Stage II by an expert on sleep disorders has played an important role in lowering the number of false positives. As a matter of fact, only 16.4% of those screened positive at Stage I were confirmed at Stage II. In agreement with other studies, prevalence of pRBD was higher among men.20–22Prevalence of isolated dRBD: stage IIIOur study is the first VPSG-based study on the prevalence of isolated RBD in Italy. Prevalence of isolated dRBD in our study was 0.26% but reached 0.59% when provRBD were also considered. These rates are close to those reported in literature.8 Only 5 studies aimed to determine the prevalence of isolated dRBD have been carried out, reporting rates ranging from 0.29% to 1.15% (pooled 0.68%),8 and of these, 3 adopted a similar 3-stage design and reported on average a low prevalence rate ranging from 0.29% to 0.74%.14,23,24In particular, our prevalence for dRBD (0.26%) is lower than that reported by a European 3-stage study performed in Spain14 where prevalence of dRBD was 0.74%. However, the participation rate in our study at both stage II (68.1%) and Stage III (33.3%) was lower than that reported in the Spanish study. Indeed, when adjusting for the nonparticipants, prevalence of dRBD in our sample was closer to the Spanish one (1.18%). Another similar 3-stage survey has been carried out in Japan, where a prevalence of dRBD of 0.54% was reported.23 In this latter study, prevalence rose up to 1.23% when provisional RBD was also considered. This estimate is close to that obtained in our survey when patients with provRBD were included. Interestingly, the adjusted prevalence rates of dRBD (1.18%) and dRBD plus provRBD (2.62%) in our study were almost double when compared to this study where the participation rate was slightly above 50%.23Finally, a third 3-stage survey was carried out in China where, considering only isolated dRBD, prevalence was 0.29%.24 Comparison with the other 2 studies is limited because of different inclusion criteria and procedures.6,25Weaknesses and strengthsOur survey confirms that isolated RBD is a disease with a very low prevalence rate in the general population, considering both pRBD and dRBD, and underlines the difficulties in carrying out population-based surveys above all for dRBD.One of the main pitfalls in conducting a prevalence survey to estimate RBD prevalence is related to the participation rate, especially for the diagnosis of dRBD that requires the VPSG recording.Participation rates, across the different stages, vary widely between studies, with some having low participation rates20,23 and others higher.14,24,25 In our survey, the participation rate was good (almost 70%) for the Stage II (clinical evaluation), but very low (33%) at Stage III (VPSG examination). In particular, participation rate at Stage III was lower than that recorded in the Spanish study,14 but higher compared to a Japanese study where none of the participants agreed to a VPSG.20 The issue of participation rate has a relevant impact in interpreting prevalence estimates, since the low participation rate can lead to an underestimation of the true prevalence when rates are not adjusted by the number of nonparticipants and can also lead to a selection bias limiting the generalizability of the results.There are different factors that might have contributed to the low participation rate at the VPSG examination. First, patients affected by RBD are often not aware of their disorder, which is usually considered as a paraphysiological behavior. For this reason they often do not agree to spend a night at the hospital to undergo VPSG. Another cause for refusal reported by the enrolled participants was related to the fact that they had been informed about the possible association between RBD and PD and, for this reason, preferred to avoid further investigations. Indeed, ethical issues in RBD epidemiological studies are a delicate matter balancing between advantages and disadvantages of disclosing alpha-synucleinopathy risk information in such research settings.26 In our study we chose an approach based on full disclosure of the scope of the study, explaining also the associated risk of developing an alpha-synucleinopathy, albeit underlining that the real extent of the risk is not well understood.A further important limit in interpreting the estimates of dRBD reported in literature is related to the VPSG procedure. The rate of pRBD confirmed by VPSG is generally very low.14 Indeed, if the diagnosis based on clinical grounds (pRBD) tends to be
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