A single Epley manoeuvre can improve self-perceptions of disability (quality of life) in patients with cp-BPPV: A randomised controlled trial in primary care.

Background: Posterior canal benign paroxysmal positional vertigo (pc-BPPV) causes physical, functional, and emotional impairment. The treatment of choice is the Epley manoeuvre (EM). The purpose of the study was to compare the impact of the EM and a sham manoeuvre in primary care on self-perceived disability. Method: Randomised, double-blind, sham-controlled clinical trial conducted in primary care with a follow-up of 1 year. Patients aged ≥ 18 years old diagnosed with pc-BPPV according to the Dix-Hallpike test (DHT) were randomised to an intervention (EM) group or a control (sham manoeuvre) group. The main study covariables were age, sex, history of depression and anxiety, presence of nystagmus in the DHT, patient-perceived disability assessed with the Dizziness Handicap Inventory-screening version (DHI-S). Data were analyzed using bivariate and multivariate mixed Tobit analyses. Results: Overall, 134 patients were studied: 66 in the intervention group and 68 in the control group. Median age was 52 years (interquartile range [IQR], 38.25–68.00 years) and 76.12% of the patients were women. The DHT triggered nystagmus in 40.30% of patients. The median total DHI-S score for the overall sample at baseline was 16 (IQR, 8.00–22.00); 16 [IQR, 10.5–24.0] vs 10 [6.0–14.0] for women vs men ( P <0.001) and 16 [IQR, 10.0-24.0] vs 12 [IQR, 8.0–18.0] for patients without nystagmus vs those with nystagmus ( P =0.033).Patients treated with the EM experienced a mean reduction of 2.03 points in DHI-S score over the follow-up period compared with patients in the sham group. Conclusion: Pc-BPPV affects the quality of life of primary care patients. A single EM can improve self-perceptions of disability by around 2 points on the DHI-S scale, Trial registration : ClinicalTrials.gov Identier: training session on diagnosing vertigo and applying the manoeuvre under the supervision of an ENT specialist to ensure consistent execution across patients. Two videos showing an investigator administering the DHT (https://www.youtube.com/watch? v=tJEFi5RFZEM) and the EM (https://www.youtube.com/watch?v=yAFx4-TFcGE) were also recorded.

Perceived disability among patients with BPPV is usually assessed using standardised questionnaires, the most common being the Dizziness Handicap Inventory (DHI) [13], for which several abbreviated versions have been created. One recent study comparing the original 25-item DHI with shorter versions reported that the Dizziness Handicap Inventory -Screening version (DHI-S) was the best option as it shows strong correlation with the original DHI (r=0.86) and has acceptable internal consistency (test-retest r=0.95) [14]. The DHI-S was designed by Jacobson et al. [15] and consists of 10 questions with the same "yes, "sometimes" and "no" answer options as the original questionnaire. It is a self-administered questionnaire that can be completed in 4 to 5 minutes, making it suitable for use in centres that have to deal with large numbers of patients such as primary care practices. It has been validated for use in Spain [16].
The treatment of choice for BPPV is the Epley manoeuvre (EM), whose effectiveness has been demonstrated in numerous studies and systematic reviews [1] [17][18] [19]. The EM is a canalith repositioning manoeuvre that has been associated with improved self-perceptions of disability among patients with BPPV [16] [20]. It has also proven effective in elderly patients [21] and in the long term, even after a single treatment [22].
Although performance of the EM is feasible in primary care [23], most of the studies that have evaluated its impact on perceived disability among patients with pc-BPPV have been performed in specialised clinics. Studies thus are needed to evaluate its impact in patients diagnosed and treated in primary care [1], and it was a secondary outcome of interest from our original clinical trial protocol [24].
Carrillo-Muñoz et al. analyzed quality of life perceived by primary care patients with pc-BBPV using baseline data from the original trial [9], while Ballvé et al measured the effectiveness of the Epley manoeuvre according to Dix-Hallpike test results and perceived vertigo severity assessed on a Likert scale [25]. The current study, by contrast, analyzes the effectiveness of the Epley manoeuvre over a period of a year according to a psychometric scale of perceived disability. This complements clinical measurements by providing insights into patient perceptions of the different dimensions of pc-BPPV.

Aim
The aim of the study was to compare the effect of the EM and a sham manoeuvre on self-perceived disability assessed using the DHI-S at 1 week, 1 month, and 1 year in primary care patients with pc-BPPV.

Trial design
Randomised, double-blind, sham-controlled clinical trial with an allocation ratio of 1:1 conducted in two primary care practices.
Changes to trial design Although vestibular migraine was not an exclusion criterion for the trial [24], emerging evidence on the high prevalence of this condition [26] and its overlapping symptoms with pc-BPPV suggested that patients with vestibular migraine might have been recruited for the trial. It was therefore decided to re-assess all patients after completion of the follow-up phase and to remove those who met the 2013 criteria for probable vestibular migraine [27]. Results following the original trial design, including patients with probable vestibular migraine, are presented as supplementary material Participants Patients were recruited between November 2012 and January 2015, and three follow-up visits, held a week, a month, and a year after the intervention, were performed by six general practitioners (GPs) blinded to treatment allocation working at two primary care practices, which employ 26 GPs and offer care for 38 305 people in L'Hospitalet de Llobregat (Barcelona, Spain).
Eligible participants included all adults (≥18 years) with symptoms of vertigo seen at the primary care practices, and patients clinically suspected to have pc-BPPV were systematically recruited by the GPs involved in the study. Patients who agreed to participate were referred for baseline evaluation by one of six GPs on the research team. Those who provided written informed consent and had a positive DHT, with or without nystagmus (O-BPPV or S-BPPV, respectively), were included. Patients with purely vertical nystagmus, nystagmus lasting >1 minute, or vertical or alternating nystagmus were excluded and referred to an ear, nose, and throat (ENT) specialist. This was done because it was suspected that their nystagmus was caused by a condition other than pc-BPPV (possibly even central nystagmus). They would therefore have required further investigation (e.g., magnetic resonance imaging, computed tomography, referral to an ENT specialist) and this would have affected our results. The full list of exclusion criteria is available in the study protocol [24].

Interventions and comparisons
At the baseline visit, the patients underwent a full physical examination and a complete medical history, including review of electronic medical records.
Patients in the intervention group were treated with a single EM. They were prescribed betahistine 8 mg/8h and instructed to use the medication as required (maximum 3 times a day) until their symptoms improved.
Patients in the control group were prescribed betahistine as the same dosage. Instead of the EM, however, they received a sham manoeuvre consisting of laying the patient with his/her head turned towards the affected side for 5 minutes [28].
The GPs who administered the EM took part in a 2-hour practical training session on diagnosing vertigo and applying the manoeuvre under the supervision of an ENT specialist to ensure consistent execution across patients. Two videos showing an investigator administering the DHT (https://www.youtube.com/watch? v=tJEFi5RFZEM) and the EM (https://www.youtube.com/watch?v=yAFx4-TFcGE) were also recorded.

Variables
Patient-perceived disability assessed using the total score on the DHI-S was used as the main outcome variable. The 10 items on the DHI-S are scored with 0 for "no", 2 for "sometimes", and 4 for "yes". The total possible score therefore ranges from 0 (no self-perceived disability) to 40 (worst possible self-perceived disability).
The independent variables were age, sex, DHT result (O-BPPV or S-BPPV), history of anxiety and/or depression (Yes/No) and treatment with benzodiazepines, antidepressants, and/or vertigo drugs (Yes/No) at the time of the baseline visit.

Sample size
The sample size was calculated for outcomes not analyzed in this study. Based on a sample size of 65 and 61 patients in the study arms at week 1, the study had a power of 80% to detect a statistically signi cant difference (alpha = 0.05) of 5.16 in DHI-S scores between groups (assuming a standard deviation of 10 [16] in a Wilcoxon test [power estimated by bootstrap]).

Randomisation and allocation
Patients were assigned to the intervention and control groups using a list of randomisation sequences prepared in advance by the study statistician. The randomisation sequences were generated in 'R: A language and environment for statistical computing', version 2.14.2 (R Foundation for Statistical Computing, Vienna, Austria).
Two members of staff from the participating primary care practices not involved in the clinical trial were responsible for safeguarding the randomisation list. On completion of the baseline visit activities, the recruiting GPs contacted one of these members of staff to nd out the randomisation number and arm to which the patient was to be assigned.

Blinding
The study was double blind. The GPs who performed the baseline visits did not participate in the follow-up visits, and vice-versa. GPs responsible for follow-up were therefore unaware of allocation. Randomisation data were not recorded in the data collection notebooks or database. Only the study statistician had access to this information.

Statistics
Continuous variables (e.g., DHI-S scores) were expressed as median and interquartile range (IQR), while categorical variables (e.g., anxiety) were expressed as absolute and relative frequencies. For the between-group comparisons at each time point, the distribution of DHI-S answers were compared using the Chi-square test, while DHI-S scores were compared using the Wilcoxon test. These bivariate analyses were performed for the overall samples and strati ed by sex and presence or absence of nystagmus at baseline.
A longitudinal multivariate regression model was built using DHI-S scores. Given the considerable proportion of 0 scores, a full mixed-effects multivariate Tobit regression model was adjusted to explain DHI-S scores by intervention, baseline DHI-S score, sex, baseline diagnosis (O-BPPV vs S-BPPV), and three-way interactions between all these variables and the treatment group, with adjustment for correlated intraindividual observations. Stepwise backward variable selection using the Akaike information criterion (AIC) was applied to obtain the nal model. This reduced Tobit model contained all relevant variables and interactions; results are presented as marginal effects (medians of individual effects [29] [30]) and statistical signi cance (p-value) of the associated coe cients.

Results
Of the 330 patients with suspected pc-BPPV analyzed, 134 (40.6%) were included in the trial: 66 were randomised to the intervention group and 68 to the sham group. The reasons for exclusion are summarised in the study owchart ( Figure 1). The main reason for exclusion was a negative DHT at baseline (n=123). Nineteen patients were removed retrospectively because they had criteria compatible with vestibular migraine. Their results, however, can be consulted in the supplementary material. The respective number of patients lost to follow-up at the three time points (week, month, and year) was 7, 17, and 21. The baseline characteristics for the overall sample and the intervention and control groups are shown in Table 1. The median age was 52 years (IQR, 38.25-68.00, standard deviation, 16.98) and 76.12% of the patients were women. The DHT triggered nystagmus in 40.30% of patients (O-BPPV). The proportion of patients with anxiety and depression was 25.38% and 23.08%, respectively. In total, 17.91% of patients were being treated with benzodiazepines, 20.15% with antidepressants, and 58.21% with vertigo drugs at the baseline visit. No signi cant differences were observed between the intervention and control group for any of the study variables. The median duration between symptom onset and visit (EM application) was 10.52 days [IQR= 5,31]. The rate of subjects who referred having suffered at least a previous BPPV episode similar to the presenting one was 52.38%.
Patient-perceived disability during the follow-up period (week, month, year) was not in uenced by a history of anxiety or depression or treatment with anxiolytics. The nal multivariate model (the model with the best performance according to the AIC) showed that variations in DHI-S scores were explained by treatment group, baseline DHI-S score, follow-up (time point), and interaction between DHI-S score and time. Baseline DHI-S score was positively associated with DHI-S score during follow-up, with an initial marginal effect of 0.37 at week 1. The respective effects at 1 month and 1 year were 0.3 and 0.32 (signi cant decrease). According to the selection process, the interaction treatment × time did not provide the model with su cient predictive accuracy for these coe cients to be retained. In the nal model thus, the treatment effect did not vary signi cantly over time, showing a stable marginal effect of -2.03 (-4.59, -0.06) points ( Table 3). The expected DHI values estimated by the multivariate model in Table 3 are shown in Figure 2 according to the different exposure characteristics.
No statistically signi cant differences in DHI-S scores were observed between the intervention and control group at baseline or during follow-up according to sex or presence or absence of nystagmus at baseline (Tables 2a, 2b, 2c and 2d).

Summary
Patients' perceptions of pc-BPPV-associated disability assessed by the DHI-S improved after treatment with a single EM performed by GPs, with a signi cant difference in DHI-S scores of -2.03 points compared with the sham group over the follow-up period; no signi cant variations were observed during this period.
Although the difference of -2.03 points was signi cant, it may not have been clinically relevant, as the minimal detectable difference for the long version of the DHI is 17.68 points in the 0 -100 theoretical range [31]. Our results should, therefore, be interpreted with caution and it is important to consider the theoretical score ranges of the different versions of the DHI. We might also have observed greater differences if we had treated certain patients with more than one EM (the recommended number is up to four) [32].
The median age of the patients in our series is similar to that observed in other studies at specialised clinics [16] [31] and primary care practices [23].
Also supporting previous ndings [2] [20] [33] [34], women outnumbered men in our study, which is consistent with the higher prevalence of pc-BPPV in women [35] [36][37] [38]. No signi cant differences between men and women were found in terms of response to the EM during follow-up, even though baseline DHI-S scores were higher among women. Sex was not a signi cant factor in the multivariate model. Pereira et al [20] also reported similar responses to the EM in men and women.
The main strength of our study is that it was conducted under typical conditions encountered in primary care practices, which is where most patients with BPPV are seen.
The higher proportion of patients with S-BPPV detected in our series compared with earlier series [14] [40] indicates that we may have underestimated the prevalence of O-BPPV. Patients seen in primary care often have early-stage nystagmus, which is more di cult to diagnosis, particularly if special tools such as Frenzel goggles or videonystagmography are not used [41]. The gold standard diagnostic work-up for pc-BPPV does not include these tools [1], but they can increase the number of O-BPPV cases diagnosed. Testing primary care patients with S-BPPV in addition to those with O-BBPV (greater diagnostic sensitivity at the expense of speci city) in primary care may improve early diagnosis and treatment rates, and such an approach has been suggested by other authors [40]. The decision not to use Frenzel goggles or videonystagmography in our study was deliberate as we wished to reproduce the conditions faced by GPs in routine practice. Response to the EM in terms of perceived disability was not in uenced by the presence or absence of nystagmus at baseline, supporting previous ndings by Huebner et al [40] and Marques et al [42]. Nonetheless, we cannot completely rule out the possibility that some of the patients in the S-BPPV group may have had vestibular neuritis or vestibular migraine.
Our ndings for perceived disability contrast with previous ndings for the same series of patients showing that the EM reversed positive DHTs and resulted in less severe vertigo in patients with O-BPPV but not S-BPPV [25].

Implications for research and/or practice
The DHI-S is a simple tool that can be administered in a matter of minutes. It would therefore be interesting to determine cut-off points for different levels of perceived disability (none, mild, moderate, and severe).
It would also be interesting to calculate the minimal detectable change and minimal clinically important difference for the DHI-S in order to determine the relevance of changes over time.
BPPV can cause considerable disability. Early treatment of pc-BPPV using repositioning manoeuvres can result in signi cant improvements, highlighting the importance of prompt treatment in all patients, including those seen in primary care. It would be very interesting to determine whether performance of more than one EM would improve the outcomes observed in this study.

Conclusions
Pc-BPPV affects the quality of life of primary care patients. A single EM can improve self-perceptions of disability by around 2 points on the DHI-S scale. Nonetheless, although this difference is statistically signi cant, it may have little clinical relevance.

Declarations ETHICS APPROVAL AND CONSENT TO PARTICIPATE
The study protocol was approved by the CEIC (Clinical Research Ethics Committee) of IDIAP Jordi Gol (P12/69). As stated in the written consent form, the study was conducted in accordance with the principles of the Declaration of Helsinki and the Royal Spanish Decree 561/1993 of 16 April 1993 (Title I, Article 12). Data were processed in accordance with the Spanish Organic Law on the con dentiality of computerised data (Organic law 5/1992).

CONSENT FOR PUBLICATION
Not applicable

AVAILABILITY OF DATA AND MATERIALS
The original dataset is available upon request from the corresponding author: E-mail address: ballvejl@gmail.com.

COMPETING INTERESTS
The authors declare that they have no competing interests.      Criterion from an initial model featuring treatment adjusted for follow-up, baseline DHI-S score, sex, nystagmus at baseline, and three-way interactions between these factors and treatment and follow-up. DHI-S =Dizziness Handicap Inventory -Screening version.