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European Journal of Neurology 2014, 21: 7985

doi:10.1111/ene.12248

Serum uric acid levels correlate with benign paroxysmal positional vertigo
A. Celikbileka, Z. K. Gencerb, L. Saydamb, G. Zararsizc, N. Tanika and M. Ozkirisb
Department of Neurology, Medical School, Bozok University, Yozgat; bDepartment of Otolaryngology, Medical School, Bozok University, Yozgat; and cDepartment of Biostatistics, Medical School, Hacettepe University, Ankara, Turkey
a

Keywords:

benign paroxysmal positional vertigo, uric acid


Received 2 May 2013 Accepted 9 July 2013

Background and purpose: Benign paroxysmal positional vertigo (BPPV) is a frequently encountered condition that can severely aect the quality of life. In this study, we aimed to assess the possible relations between serum uric acid (SUA) levels and BPPV. Methods: Fifty patients with BPPV, and 40 age- and sex-matched control subjects were enrolled in the study. All the patients and controls underwent a complete audio-vestibular test battery including the DixHallpike maneuver and supine roll test for posterior semicircular canal (PSC) and horizontal semicircular canal, respectively. Routine hematological and biochemical analyses were performed in both groups. In the BPPV group, measurements of SUA levels were repeated 1 month after the vertigo attack. Results: The lipid proles and SUA levels were higher in patients with BPPV than detected in controls (P < 0.05 and P < 0.001, respectively). Albumin and SUA values were independently associated with BPPV in multiple logistic regression models (P < 0.05 and P < 0.001, respectively). A cuto value of 4 for SUA level with a sensitivity of 0.72 (0.580.84) and a specicity of 0.60 (0.430.75) was obtained in the receiver operating characteristic analyses. There was a signicant decrement in SUA level 1 month after the vertigo attack compared with the values obtained during the attack (P < 0.001). Among the most involved type of BPPV (PSC BPPV), the right side was aected in 26 patients (57.8%) and the left side in 19 patients (42.2%). SUA levels did not dier statistically in patients with PSC BPPV for either the right or left sides (P > 0.05). Conclusions: Elevated SUA is positively correlated with BPPV, requiring further eorts to clarify the exact mechanism.

Background
Benign paroxysmal positional vertigo (BPPV) is one of the most common clinical entities encountered in a neurotology clinic [1]. In association with reduced daily activities, falls and depression, BPPV may cause severe impact on the quality of life, especially in elderly patients [2]. The posterior semicircular canal (PSC) type of BPPV is the most common condition, accounting for up to 90% of the patients, whereas the horizontal semicircular canal (HSC) cases only occur in 515% of patients and, more rarely, involvement of the anterior canal may also be observed [3].
Correspondence: A. Celikbilek, Bozok University, Department of Neurology, 66200, Yozgat, Turkey (tel.: +90 505 653 26 15; fax: +90 354 217 10 72; e-mail: asunebioglu@yahoo.com).

Uric acid is the end product of purine metabolism [4]. Epidemiological studies have reported a relation between increased serum uric acid (SUA) levels and hypertension [5], metabolic syndrome [6], cardiovascular events [7], pre-eclampsia [8], renal failure [9], cerebrovascular diseases [10] and vascular dementia [11]. Several researchers have suggested that SUA might be an independent risk factor for all the conditions listed above [1214]. A recent Finnish study has demonstrated that higher SUA levels, even within the normal range, were associated with negative clinical outcomes in patients with heart failure [15]. There are limited data studying the relation between SUA levels and BPPV in the literature. Adam demonstrated an increase in SUA levels in patients with BPPV [16]. In this study, we aimed to assess the possible relations between SUA levels and BPPV.

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Methods
Fifty patients with BPPV, and 40 age- and sexmatched control subjects of Caucasian origin ranging in age from 25 to 40 years were enrolled in this clinical prospective study. Patients with malignant, chronic renal, hepatic, cardiovascular or autoimmune diseases, gout, diabetes mellitus, hypo- or hyperthyroidism, pregnancy, morbid obesity, the use of any drug, in particular allopurinol and/or diuretics, and a history of concomitant vestibular or neurological diseases were excluded from the study. All patients and control subjects received a complete physical and neurotological examination. A typical history of brief attacks of positional vertigo was obtained from all patients with BPPV in whom the apparent etiology was absent and described as idiopathic [17]. Patients with BPPV underwent a complete audio-vestibular test in which eye movements were recorded by electronystagmography or videonystagmography [18]. A diagnosis of PSC BPPV was based on the torsional paroxysmal positioning nystagmus that was typically induced by the Dix Hallpike maneuver in the direction of the involved canal [19]. HSC BPPV was diagnosed by the presence of a purely horizontal paroxysmal nystagmus provoked during the supine roll test in which the head was turned by about 90 to each side while supine [19]. The additional characteristics of a short-latency, limited-duration intensity characterized by crescendo and decrescendo elements were also noted in conjunction with this pattern of nystagmus of intense vertigo [19]. The study protocol was approved by the Bozok University Research Ethics Committee, and written informed consent was obtained from all patients. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured for each patient. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters [20]. Fasting venous blood samples were taken from all the subjects and, thus, routine hematological and biochemical analyses involving SUA were performed in our laboratory. Posterior semicircular canal BPPV was treated by the Epleys maneuver, whereas HSC BPPV was treated by the Barbecue maneuver, and these maneuvers had to be repeated in 10 cases [21]. Measurements of SUA levels were repeated 1 month after the successful treatment with positioning maneuvers in patients with BPPV.

Levene test was used to assess the variance homogeneity. Independent samples t-test and MannWhitney U-test were used to compare the dierences between continuous variables, and v2 analysis between categorical variables. The Wilcoxon t-test was used for between time comparisons. To identify the predictors of BPPV, univariate and multiple binary logistic regression analyses were performed. For each factor, odds ratios were calculated with 95% condence intervals (CIs). Variables were considered statistically signicant at P < 0.10 in univariate logistic regression analysis, and backward stepwise elimination was performed using the Wald statistic at P < 0.05 stringency level to determine the independent predictors. Lowdensity lipoprotein (LDL) and total cholesterol (TC) values were included into multiple models separately due to their strong correlation. Moreover, non-parametric receiver operating characteristic (ROC) analyses were applied for uric acid, albumin, LDL and triglyceride variables; area under curve (AUC) measures were calculated with 95% CIs and compared with each other. Cuto values were calculated for each factor, and sensitivity, specicity, positive predictive rate, negative predictive rate and accuracy rate diagnostic measures were calculated with 95% CIs. Also, the kappa statistic was calculated for each factor. Analyses were conducted using R 3.0.0 software [22], with P < 0.05 considered statistically signicant.

Results
Clinical features and laboratory data of the patients with BPPV and control patients were summarized in Table 1. With respect to age and gender, no signicant dierence was found between the two groups (P > 0.05). Similarly, there was no signicant association between the parameters of BMI, SBP and DBP in patients with BPPV compared with controls (P > 0.05). The laboratory results revealed that whole blood count, liver function tests, fasting glucose and thyroid-stimulating hormone did not signicantly dier (P > 0.05), but the values of creatinine and albumin reached statistical signicance (P < 0.05) in patients with BPPV compared with controls. Additionally, the increase of lipid prole and SUA levels were statistically meaningful (P < 0.05 and P < 0.001, respectively) in patients with BPPV. To identify the predictors of BPPV, univariate and multiple binary logistic regression analyses were performed. Due to the strong correlation, LDL and TC values were included into the multiple model separately (r = 0.940, P < 0.001). The variables that were statistically signicant in the univariate model were used in the multiple model, then albumin (P < 0.05)
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Statistical analysis
Shapiro Wilks test was used, and histogram and q-q plots were examined to test the data normality. The

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Table 1 Clinical features and laboratory data of patients with vertigo and controls Variables Age (years) Gender (female/male) BMI (kg/m2) SBP (mmHg) DBP (mmHg) WBC (103/mm3) Hemoglobin (mg/dl) Platelet (103/mm3) FG (mg/dl) Creatinine (mg/dl) TC (mg/dl) TG (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) AST (IU/l) ALT (IU/l) Albumin (g/dl) TSH (uIU/ml) Uric acid (mg/dl) Control (n = 40) 32 6.74 23 (57.5)/17 (42.5) 24.47 2.77 110 (100120) 70 (6580) 7.42 1.48 13.8 (12.714.45) 246 (221.5289.5) 85.5 (83.588) 0.6 (0.60.7) 185.3 35.95 91 (76132.5) 43.2 7.41 113.73 28.3 17 (1519) 15 (1118) 4.66 0.21 1.8 0.92 3.6 (3.254.5) Vertigo (n = 50) 33.4 6.15 29 (58.0)/21 (42.0) 25.31 2.35 110 (110120) 70 (7080) 7.61 1.37 14.25 (1315.5) 250.25 (224307) 84 (8288) 0.7 (0.60.8) 202.42 36.29 118 (93164) 44.36 8.27 126.18 25.99 17 (1519) 16 (1321) 4.52 0.31 1.64 0.78 4.85 (3.95.5) P 0.306 0.962 0.120 0.122 0.142 0.533 0.266 0.748 0.135 0.034 0.028 0.038 0.491 0.033 0.857 0.281 0.018 0.390 < 0.001

Table 2 Univariate and multiple logistic regression analysis to identify the predictors of vertigo Univariate OR (95% CI) 1.04 (0.971.11) 1.02 (0.442.37) 1.14 1.03 1.04 1.10 1.19 (0.971.35) (0.991.07) (0.991.10) (0.821.48) (0.901.57) Multipleb OR (95% CI) 0.05 (0.010.41) 3.35 (1.875.99)

Variables Age (years) Gender (female/male) BMI (kg/m2) SBP (mmHg) DBP (mmHg) WBC (103/mm3) Hemoglobin (mg/dl) Platelet (103/mm3) FG (mg/dl) z(Creatinine)a TC (mg/dl) TG (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) AST (IU/l) ALT (IU/l) Albumin (g/dl) TSH (uIU/ml) Uric acid (mg/dl)
a

P 0.303 0.962 0.123 0.165 0.136 0.528 0.233 0.955 0.107 0.060 0.032 0.071 0.486 0.037 0.752 0.547 0.028 0.386 < 0.001

P 0.005 < 0.001

1.00 (0.991.01) 0.89 1.54 1.01 1.01 1.02 1.02 1.02 1.02 0.15 (0.871.03) (0.982.42) (1.001.03) (1.001.02) (0.971.08) (1.001.03) (0.901.16) (0.961.08) (0.030.81)

Values are expressed as n (%), mean SD or median (25th75th percentiles). ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; DBP, diastolic blood pressure; FG, fasting blood glucose; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride; TSH, thyroid-stimulating hormone; WBC, white blood cells.

0.80 (0.491.32) 2.85 (1.674.86)

and SUA (P < 0.001) were found to be independently associated with BPPV in the multiple logistic regression model (Table 2). Every 1 unit increase in SUA value was shown to cause a 3.35- (1.875.99) fold increase in predicting the risk of BPPV (odds ratio, 95% CI, P < 0.001). Receiver operating characteristic analyses were applied for SUA, albumin, LDL and triglyceride variables. AUC values were found to be 0.75 (0.650.84), 0.62 (0.510.72), 0.64 (0.530.74) and 0.63 (0.520.73), respectively, and the dierences between these curves were not found to be statistically signicant (P > 0.05; Fig. 1). A cuto value of 4 for SUA level was shown in Fig. 2, with a sensitivity of 0.72 (0.580.84) and a specicity of 0.60 (0.430.75), as shown in Table 3 (P < 0.05). There was a signicant decrement in SUA level 1 month after the vertigo attack compared with its values during the attack (P < 0.001; Fig. 3). We found a weak but noteworthy relation between the results of the gold standard test and uric acid test (cuto value = 4, j = 0.322, P = 0.002). The kappa statistic for the uric acid test was found to be higher than the test statistics of albumin, LDL and triglyceride. The PSC was involved in 45 patients (90%) and the HSC in ve patients (10%), while the other rare
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The OR for creatinine is calculated based on its z-score value, raw values were 24.91 (0.87713.91). bLDL and TC values were included into the multiple model separately due to their strong correlation (r = 0.940, P < 0.001). Values are expressed as n (%), mean SD or median (25th75th percentiles). ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CI, condence interval; DBP, diastolic blood pressure; FG, fasting blood glucose; HDL-C, high-density lipoprotein cholesterol; LDL-C, lowdensity lipoprotein cholesterol; OR, odds ratio; SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride; TSH, thyroidstimulating hormone; WBC, white blood cells.

involvements were absent. With respect to the most frequent involvement (PSC), the right side was aected in 26 patients (57.8%) and the left side in 19 patients (42.2%). SUA levels did not dier statistically in patients with PSC BPPV for either the right or left side (P > 0.05).

Discussion
The main ndings of our study show the following. (i) Lipid prole, albumin and SUA were found to be signicantly higher in patients with BPPV than in controls. (ii) SUA was independently associated with BPPV (causing a 3.3-fold risk increase for every 1 unit increase in SUA value) in the multiple model. (iii) A cuto value of 4 for SUA level with a sensitivity of 72% and a specicity of 60% was obtained in the

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Figure 1 Comparison of ROC curves of uric acid, albumin, lowdensity lipoprotein (LDL) cholesterol and triglyceride in identifying BPPV. AUCs were 0.75 (0.650.84), 0.62 (0.510.72), 0.64 (0.530.74) and 0.63 (0.520.73), respectively, and the dierences between these curves were not found to be statistically signicant (P > 0.05).

Figure 2 Dot diagram that displays the uric acid distribution around the 4.0 mg/dl cuto value.

ROC analyses. (iv) SUA level was detected to increase during the vertigo attack, while it decreased after the attack in patients with BPPV. A number of epidemiological studies have shown a connection between SUA levels and a wide variety of cardiovascular conditions, including hypertension [5], metabolic syndrome [6], congestive heart failure [7], cerebrovascular disease [10], vascular dementia [11], pre-eclampsia [8] and kidney disease [9]. Also, there has been increasing evidence suggesting that SUA

might be an independent risk factor for cardiovascular disease [12], renal failure [13] and acute stroke [14]. A recent Finnish study has demonstrated that higher SUA levels, even within the normal range, were associated with negative clinical outcomes in patients with heart failure [15]. Uric acid is the end product of purine metabolism [4]. It is formed by catalysis of xanthine oxidase (XO) enzyme from the xanthine molecule. Women tend to have lower levels than men, probably because of the uricosuric eect of estrogens [23]. SUA levels also vary signicantly within humans as the result of factors that increase generation (such as high-purine or protein diets, alcohol consumption, conditions with high cell turnover, or enzymatic defects in purine metabolism) or decrease excretion (such as diuretics, especially thiazides) [4]. SUA has potentially protective eects as a strong antioxidant. Urate (the soluble form of SUA) can scavenge superoxide, hydroxyl radical and singlet oxygen, and can chelate transition metals [4]. It has been suggested that the antioxidant eects of SUA were protective in several neurological diseases, including multiple sclerosis and Parkinsons disease [24,25]. In contrast, an elevated SUA was also found to increase the risk for stroke [26]. Also, in patients who have already had a stroke, elevated SUA was dened as a strong predictor of poor prognosis and recurrent events [14]. While many prospective studies have suggested an independent association between SUA levels and the future risk of cardiovascularmetabolic morbidities and mortality, only a limited number of randomized clinical trials and observational studies have examined the association between SUA and BPPV. In an observational study reported by Adam [16], the vast majority of patients were male African patients with BPPV showing an increase in SUA levels in a signicant proportion of the study group. On the contrary, a study by Ziavra and Bronstein [27] reported that 20 patients who were predominately European females failed to conrm any relation between hyperuricemia and BPPV. This discrepancy may be attributed to the differences in ethnic background and gender. A prospective case-controlled study by Adam [28] found SUA levels (within the normal range) to be higher in patients with BPPV than in controls. These ndings support a possible role for SUA in BPPV. Our results were also comparable to those of earlier reports [16,28]. In addition to the studied parameters in the previous reports, we repeated SUA measurements in order to accurately explain that elevated SUA levels were primarily related to BPPV attack itself rather than a component of the cardiometabolic conditions. The statistical analysis of the results in the multivariate
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Table 3 Diagnostic measures and kappa test results of parameters in the detection of BPPV Diagnostic measures Parameters Uric acid (> 4 mg/dl) Albumin ( 4.6 g/dl) LDL (> 122 mg/dl) Triglyceride (> 110 mg/dl) SEN (95% CI) 0.72 0.64 0.62 0.59 (0.580.84) (0.490.77) (0.470.75) (0.430.73) SPE (95% CI) 0.60 0.45 0.55 0.70 (0.430.75) (0.290.62) (0.390.71) (0.550.83) PPR (95% CI) 0.69 0.59 0.63 0.68 (0.550.81) (0.450.72) (0.480.77) (0.510.81) NPR (95% CI) 0.63 0.50 0.54 0.62 (0.460.78) (0.330.67) (0.370.69) (0.470.75) AR (95% CI) 0.67 0.56 0.59 0.64 (0.560.76) (0.450.66) (0.480.69) (0.540.74) Kappa test j 0.322 0.091 0.170 0.291 P 0.002 0.386 0.108 0.005

AR, accuracy rate; CI, condence interval; LDL, low-density lipoprotein; NPR, negative predictive rate; PPR, positive predictive rate; SEN, sensitivity; SPE, specicity.

Figure 3 Clustered box-plots of uric acid during and after the vertigo attack in patients with BPPV and controls.

model demonstrated a statistically meaningful increase of uric acid levels during the vertigo attack and a tendency to decrease after the attack resolved, which supported this hypothesis. Currently, little is known about the true metabolism of calcite particles (otoconia) and what causes their dislodgement from the gelatinous matrix of the utricular macula and their precipitation, which is the prerequisite for BPPV. BPPV is frequently preceded by head trauma, vestibular neuritis or other inner ear diseases that may lead to detachment of otoconia from the utricle [29]. Migraine is another factor that predisposes to BPPV, possibly on the basis of recurrent damage to the otoliths because of vasospasm or other migraine-related mechanisms [30]. In our study population none of the subjects had taken alcohol or any drug that might be ototoxic or could aect SUA levels. Considered together with the patient selection criteria, these abovementioned predisposing factors
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could easily be excluded in our patients. Another possibility was that the hormonal factors might play a role in the development of BPPV due to the high prevalence of BPPV in middle-aged women [31]. Because the groups were similar in age and gender, we could also rule out this possibility. Alternatively, we postulated that idiopathic BPPV was linked to an underlying condition that causes detachment of a large amount of otoconia, possibly due to a decit in the structure of the interotoconial lament matrix that embeds the otoconia on the supporting gelatinous matrix [32]. The otoconia were interconnected and secured to the gelatinous matrix by surface adhesion and by connement within a loose interotoconial lament matrix [33]. Increased SUA levels might elicit an inammatory response in this matrix by the activated immunopathological mechanism, which is similar to that in gout joints, and then provoke the damage gradually in proportion to the exposure to high SUA levels throughout adult life [34]. Experimental animal and in vitro studies have already suggested that uric acid was a biologically active compound that could increase inammatory mediators known to lead to vascular damage either by the generation of reactive oxygen species and subsequent endothelial dysfunction or the induced endothelin-1 secretion in vitro [35,36]. The data revealing that these eects were reversed by the treatment with allopurinol (an XO inhibitor) also proved this inammatory theory [3739]. More recently, Lin et al. [40] found a positive association between gout and peripheral vertigo in an Asian population-based study. The hypothesis in this paper suggested that the chemical composition of the otoconia as a build-up of purine crystal deposits within the semicircular canals could be responsible for BPPV in patients with gout [40]. Despite many recently reported neurotological research studies, currently we do not have access to the inner ear in order to uncover the actual chemistry of the endolymph in real time, which represents the greatest limitation of these studies. The other drawbacks that may be attributed to our research are listed below.

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(i) Despite the fact that the groups were identical for age and gender, it is clearly unrealistic to homogenize all environmental and demographic factors for all enrolled subjects, such as nutritional and physical exercise habits, which have a signicant impact on uric acid metabolism. (ii) Our results with repeated measurements of SUA levels revealed a strongly positive correlation between increased SUA levels and BPPV, but it is still dicult to explain an accurate pathophysiological pathway for this condition. (iii) Our study population represented only PSC and HSC BPPV cases, thus lacking data from other rare involvements, such as anterior, multiple and/ or bilateral canal BPPV that might aect the results. In conclusion, this study provides evidence that suggests that exposure to increased SUA levels in endolymph may be a causative pathological process in the origin of BPPV. As these data are scarce, the potential role of SUA on this subject should be claried with further studies.

Disclosure of conicts of interest


The authors declare no nancial or other conicts of interest.

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