bbpv with uric acid.pdf

Serum uric acid levels correlate with benign paroxysmalpositional vertigo

A. Celikbileka, Z. K. Gencerb, L. Saydamb, G. Zararsizc, N. Tanika and M. OzkirisbaDepartment of Neurology, Medical School, Bozok University, Yozgat; bDepartment of Otolaryngology, Medical School, Bozok Univer-

sity, Yozgat; and cDepartment of Biostatistics, Medical School, Hacettepe University, Ankara, Turkey

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 fre-

quently encountered condition that can severely affect the quality of life. In this

study, we aimed to assess the possible relations between serum uric acid (SUA) lev-

els 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 Dix–Hallpike maneuver and supine roll

test for posterior semicircular canal (PSC) and horizontal semicircular canal, respec-

tively. 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 profiles 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 cutoff value of 4 for SUA level with a sen-

sitivity of 0.72 (0.58–0.84) and a specificity of 0.60 (0.43–0.75) was obtained in the

receiver operating characteristic analyses. There was a significant 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 affected in 26 patients (57.8%) and the left side in 19 patients (42.2%).

SUA levels did not differ 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

efforts 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 5–15% of patients and, more rarely, involvement of

the anterior canal may also be observed [3].

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], cardiovascu-

lar events [7], pre-eclampsia [8], renal failure [9], cere-

brovascular diseases [10] and vascular dementia [11].

Several researchers have suggested that SUA might be

an independent risk factor for all the conditions listed

above [12–14]. A recent Finnish study has demon-

strated 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.

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: [email protected]).

© 2013 The Author(s)European Journal of Neurology © 2013 EFNS 79

European Journal of Neurology 2014, 21: 79–85 doi:10.1111/ene.12248

Methods

Fifty patients with BPPV, and 40 age- and sex-

matched 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 neurotologi-

cal 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 electronystagmogra-

phy or videonystagmography [18]. A diagnosis of PSC

BPPV was based on the torsional paroxysmal position-

ing 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 pro-

voked 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, lim-

ited-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. Sys-

tolic blood pressure (SBP) and diastolic blood pres-

sure (DBP) were measured for each patient. Body

mass index (BMI) was calculated as weight in kilo-

grams divided by the square of height in meters [20].

Fasting venous blood samples were taken from all the

subjects and, thus, routine hematological and bio-

chemical analyses involving SUA were performed in

our laboratory.

Posterior semicircular canal BPPV was treated by

the Epley’s maneuver, whereas HSC BPPV was trea-

ted 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.

Statistical analysis

Shapiro Wilk’s test was used, and histogram and q-q

plots were examined to test the data normality. The

Levene test was used to assess the variance homogene-

ity. Independent samples t-test and Mann–Whitney

U-test were used to compare the differences between

continuous variables, and v2 analysis between categor-

ical 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% confidence inter-

vals (CIs). Variables were considered statistically sig-

nificant at P < 0.10 in univariate logistic regression

analysis, and backward stepwise elimination was per-

formed using the Wald statistic at P < 0.05 stringency

level to determine the independent predictors. Low-

density lipoprotein (LDL) and total cholesterol (TC)

values were included into multiple models separately

due to their strong correlation. Moreover, non-para-

metric receiver operating characteristic (ROC) analy-

ses were applied for uric acid, albumin, LDL and

triglyceride variables; area under curve (AUC) mea-

sures were calculated with 95% CIs and compared

with each other. Cutoff values were calculated for

each factor, and sensitivity, specificity, positive predic-

tive rate, negative predictive rate and accuracy rate

diagnostic measures were calculated with 95% CIs.

Also, the kappa statistic was calculated for each fac-

tor. Analyses were conducted using R 3.0.0 software

[22], with P < 0.05 considered statistically significant.

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 signifi-

cant difference was found between the two groups

(P > 0.05). Similarly, there was no significant associa-

tion 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-stimu-

lating hormone did not significantly differ (P > 0.05),

but the values of creatinine and albumin reached

statistical significance (P < 0.05) in patients with BPPV

compared with controls. Additionally, the increase of

lipid profile and SUA levels were statistically mean-

ingful (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 per-

formed. Due to the strong correlation, LDL and TC

values were included into the multiple model sepa-

rately (r = 0.940, P < 0.001). The variables that were

statistically significant in the univariate model were

used in the multiple model, then albumin (P < 0.05)

© 2013 The Author(s)European Journal of Neurology © 2013 EFNS

80 A. Celikbilek et al.

and SUA (P < 0.001) were found to be independently

associated with BPPV in the multiple logistic regres-

sion model (Table 2). Every 1 unit increase in SUA

value was shown to cause a 3.35- (1.87–5.99) 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 vari-

ables. AUC values were found to be 0.75 (0.65–0.84),0.62 (0.51–0.72), 0.64 (0.53–0.74) and 0.63 (0.52–0.73),respectively, and the differences between these curves

were not found to be statistically significant (P > 0.05;

Fig. 1). A cutoff value of 4 for SUA level was shown

in Fig. 2, with a sensitivity of 0.72 (0.58–0.84) and

a specificity of 0.60 (0.43–0.75), as shown in Table 3

(P < 0.05). There was a significant 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 (cut-

off 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 five patients (10%), while the other rare

involvements were absent. With respect to the most

frequent involvement (PSC), the right side was

affected in 26 patients (57.8%) and the left side in 19

patients (42.2%). SUA levels did not differ statistically

in patients with PSC BPPV for either the right or left

side (P > 0.05).

Discussion

The main findings of our study show the following. (i)

Lipid profile, albumin and SUA were found to be

significantly 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

cutoff value of 4 for SUA level with a sensitivity of

72% and a specificity of 60% was obtained in the

Table 1 Clinical features and laboratory data of patients with

vertigo and controls

Variables Control (n = 40) Vertigo (n = 50) P

Age (years) 32 � 6.74 33.4 � 6.15 0.306

Gender

(female/male)

23 (57.5)/17 (42.5) 29 (58.0)/21 (42.0) 0.962

BMI (kg/m2) 24.47 � 2.77 25.31 � 2.35 0.120

SBP (mmHg) 110 (100–120) 110 (110–120) 0.122

DBP (mmHg) 70 (65–80) 70 (70–80) 0.142

WBC (103/mm3) 7.42 � 1.48 7.61 � 1.37 0.533

Hemoglobin

(mg/dl)

13.8 (12.7–14.45) 14.25 (13–15.5) 0.266

Platelet (103/mm3) 246 (221.5–289.5) 250.25 (224–307) 0.748

FG (mg/dl) 85.5 (83.5–88) 84 (82–88) 0.135

Creatinine (mg/dl) 0.6 (0.6–0.7) 0.7 (0.6–0.8) 0.034

TC (mg/dl) 185.3 � 35.95 202.42 � 36.29 0.028

TG (mg/dl) 91 (76–132.5) 118 (93–164) 0.038

HDL-C (mg/dl) 43.2 � 7.41 44.36 � 8.27 0.491

LDL-C (mg/dl) 113.73 � 28.3 126.18 � 25.99 0.033

AST (IU/l) 17 (15–19) 17 (15–19) 0.857

ALT (IU/l) 15 (11–18) 16 (13–21) 0.281

Albumin (g/dl) 4.66 � 0.21 4.52 � 0.31 0.018

TSH (uIU/ml) 1.8 � 0.92 1.64 � 0.78 0.390

Uric acid (mg/dl) 3.6 (3.25–4.5) 4.85 (3.9–5.5) < 0.001

Values are expressed as n (%), mean � SD or median (25th–75th

percentiles). ALT, alanine aminotransferase; AST, aspartate amino-

transferase; BMI, body mass index; DBP, diastolic blood pressure;

FG, fasting blood glucose; HDL-C, high-density lipoprotein choles-

terol; LDL-C, low-density lipoprotein cholesterol; SBP, systolic

blood pressure; TC, total cholesterol; TG, triglyceride; TSH, thy-

roid-stimulating hormone; WBC, white blood cells.

Table 2 Univariate and multiple logistic regression analysis to

identify the predictors of vertigo

Variables

Univariate Multipleb

OR

(95% CI) P

OR

(95% CI) P

Age (years) 1.04 (0.97–1.11) 0.303 – –

Gender

(female/male)

1.02 (0.44–2.37) 0.962 – –

BMI (kg/m2) 1.14 (0.97–1.35) 0.123 – –

SBP (mmHg) 1.03 (0.99–1.07) 0.165 – –

DBP (mmHg) 1.04 (0.99–1.10) 0.136 – –

WBC (103/mm3) 1.10 (0.82–1.48) 0.528 – –

Hemoglobin

(mg/dl)

1.19 (0.90–1.57) 0.233 – –

Platelet

(103/mm3)

1.00 (0.99–1.01) 0.955 – –

FG (mg/dl) 0.89 (0.87–1.03) 0.107 – –

z(Creatinine)a 1.54 (0.98–2.42) 0.060 – –

TC (mg/dl) 1.01 (1.00–1.03) 0.032 – –

TG (mg/dl) 1.01 (1.00–1.02) 0.071 – –

HDL-C (mg/dl) 1.02 (0.97–1.08) 0.486 – –

LDL-C (mg/dl) 1.02 (1.00–1.03) 0.037 – –

AST (IU/l) 1.02 (0.90–1.16) 0.752 – –

ALT (IU/l) 1.02 (0.96–1.08) 0.547 – –

Albumin (g/dl) 0.15 (0.03–0.81) 0.028 0.05

(0.01–0.41)

0.005

TSH (uIU/ml) 0.80 (0.49–1.32) 0.386 – –

Uric acid

(mg/dl)

2.85 (1.67–4.86) < 0.001 3.35

(1.87–5.99)

< 0.001

aThe OR for creatinine is calculated based on its z-score value, raw

values were 24.91 (0.87–713.91). 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 (25th–75th percentiles). ALT, alanine aminotransferase;

AST, aspartate aminotransferase; BMI, body mass index; CI,

confidence interval; DBP, diastolic blood pressure; FG, fasting blood

glucose; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-

density lipoprotein cholesterol; OR, odds ratio; SBP, systolic blood

pressure; TC, total cholesterol; TG, triglyceride; TSH, thyroid-

stimulating hormone; WBC, white blood cells.


Uric acid in positional vertigo 81

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 asso-

ciated 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 effect of estrogens [23]. SUA levels also

vary significantly within humans as the result of fac-

tors 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 protec-

tive effects as a strong antioxidant. Urate (the soluble

form of SUA) can scavenge superoxide, hydroxyl rad-

ical and singlet oxygen, and can chelate transition

metals [4]. It has been suggested that the antioxidant

effects of SUA were protective in several neurological

diseases, including multiple sclerosis and Parkinson’s

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 defined 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 cardiovascular–metabolic morbidities

and mortality, only a limited number of randomized

clinical trials and observational studies have examined

the association between SUA and BPPV. In an obser-

vational study reported by Adam [16], the vast major-

ity of patients were male African patients with BPPV

showing an increase in SUA levels in a significant pro-

portion 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

confirm any relation between hyperuricemia and

BPPV. This discrepancy may be attributed to the dif-

ferences in ethnic background and gender. A prospec-

tive case-controlled study by Adam [28] found SUA

levels (within the normal range) to be higher in

patients with BPPV than in controls. These findings

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

Figure 1 Comparison of ROC curves of uric acid, albumin, low-

density lipoprotein (LDL) cholesterol and triglyceride in identi-

fying BPPV. AUCs were 0.75 (0.65–0.84), 0.62 (0.51–0.72), 0.64(0.53–0.74) and 0.63 (0.52–0.73), respectively, and the differences

between these curves were not found to be statistically significant

(P > 0.05).

Figure 2 Dot diagram that displays the uric acid distribution

around the 4.0 mg/dl cutoff value.



model demonstrated a statistically meaningful increase

of uric acid levels during the vertigo attack and a ten-

dency to decrease after the attack resolved, which sup-

ported 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 utricu-

lar macula and their precipitation, which is the prere-

quisite for BPPV. BPPV is frequently preceded by

head trauma, vestibular neuritis or other inner ear dis-

eases that may lead to detachment of otoconia from

the utricle [29]. Migraine is another factor that predis-

poses to BPPV, possibly on the basis of recurrent

damage to the otoliths because of vasospasm or other

migraine-related mechanisms [30]. In our study popu-

lation none of the subjects had taken alcohol or any

drug that might be ototoxic or could affect SUA lev-

els. Considered together with the patient selection cri-

teria, these abovementioned predisposing factors

could easily be excluded in our patients. Another pos-

sibility 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 deficit in

the structure of the interotoconial filament 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 confinement within a loose interotoconial fila-

ment matrix [33]. Increased SUA levels might elicit an

inflammatory 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 inflammatory 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 effects were reversed by

the treatment with allopurinol (an XO inhibitor) also

proved this inflammatory theory [37–39]. More

recently, Lin et al. [40] found a positive association

between gout and peripheral vertigo in an Asian pop-

ulation-based study. The hypothesis in this paper sug-

gested 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.

Figure 3 Clustered box-plots of uric acid during and after the

vertigo attack in patients with BPPV and controls.

Table 3 Diagnostic measures and kappa test results of parameters in the detection of BPPV

Parameters

Diagnostic measures Kappa test

SEN (95% CI) SPE (95% CI) PPR (95% CI) NPR (95% CI) AR (95% CI) j P

Uric acid (> 4 mg/dl) 0.72 (0.58–0.84) 0.60 (0.43–0.75) 0.69 (0.55–0.81) 0.63 (0.46–0.78) 0.67 (0.56–0.76) 0.322 0.002

Albumin (≤ 4.6 g/dl) 0.64 (0.49–0.77) 0.45 (0.29–0.62) 0.59 (0.45–0.72) 0.50 (0.33–0.67) 0.56 (0.45–0.66) 0.091 0.386

LDL (> 122 mg/dl) 0.62 (0.47–0.75) 0.55 (0.39–0.71) 0.63 (0.48–0.77) 0.54 (0.37–0.69) 0.59 (0.48–0.69) 0.170 0.108

Triglyceride (> 110 mg/dl) 0.59 (0.43–0.73) 0.70 (0.55–0.83) 0.68 (0.51–0.81) 0.62 (0.47–0.75) 0.64 (0.54–0.74) 0.291 0.005

AR, accuracy rate; CI, confidence interval; LDL, low-density lipoprotein; NPR, negative predictive rate; PPR, positive predictive rate; SEN,

sensitivity; SPE, specificity.



(i) Despite the fact that the groups were identical for

age and gender, it is clearly unrealistic to homo-

genize all environmental and demographic factors

for all enrolled subjects, such as nutritional and

physical exercise habits, which have a significant

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 difficult to explain an accurate pathophysio-

logical 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 affect the

results.

In conclusion, this study provides evidence that sug-

gests that exposure to increased SUA levels in endo-

lymph 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 clarified with

further studies.

Disclosure of conflicts of interest

The authors declare no financial or other conflicts of

interest.

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