European Journal of Neurology 2014, 21: 79–85 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
a
Department 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.

Uric acid is the end product of purine metabolism

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].
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).
[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.

© 2013 The Author(s)

European Journal of Neurology © 2013 EFNS 79
80 A. Celikbilek et al.
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
 Uric acid in positional vertigo 81

Table 1 Clinical features and laboratory data of patients with Table 2 Univariate and multiple logistic regression analysis to
vertigo and controls identify the predictors of vertigo

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

Age (years) 32  6.74 33.4  6.15 0.306 OR OR

Gender 23 (57.5)/17 (42.5) 29 (58.0)/21 (42.0) 0.962 Variables (95% CI) P (95% CI) P
(female/male)
BMI (kg/m2) 24.47  2.77 25.31  2.35 0.120 Age (years) 1.04 (0.97–1.11) 0.303 – –
SBP (mmHg) 110 (100–120) 110 (110–120) 0.122 Gender 1.02 (0.44–2.37) 0.962 – –
DBP (mmHg) 70 (65–80) 70 (70–80) 0.142 (female/male)
WBC (103/mm3) 7.42  1.48 7.61  1.37 0.533 BMI (kg/m2) 1.14 (0.97–1.35) 0.123 – –
Hemoglobin 13.8 (12.7–14.45) 14.25 (13–15.5) 0.266 SBP (mmHg) 1.03 (0.99–1.07) 0.165 – –
(mg/dl) DBP (mmHg) 1.04 (0.99–1.10) 0.136 – –
Platelet (103/mm3) 246 (221.5–289.5) 250.25 (224–307) 0.748 WBC (103/mm3) 1.10 (0.82–1.48) 0.528 – –
FG (mg/dl) 85.5 (83.5–88) 84 (82–88) 0.135 Hemoglobin 1.19 (0.90–1.57) 0.233 – –
Creatinine (mg/dl) 0.6 (0.6–0.7) 0.7 (0.6–0.8) 0.034 (mg/dl)
TC (mg/dl) 185.3  35.95 202.42  36.29 0.028 Platelet 1.00 (0.99–1.01) 0.955 – –
TG (mg/dl) 91 (76–132.5) 118 (93–164) 0.038 (103/mm3)
HDL-C (mg/dl) 43.2  7.41 44.36  8.27 0.491 FG (mg/dl) 0.89 (0.87–1.03) 0.107 – –
LDL-C (mg/dl) 113.73  28.3 126.18  25.99 0.033 z(Creatinine)a 1.54 (0.98–2.42) 0.060 – –
AST (IU/l) 17 (15–19) 17 (15–19) 0.857 TC (mg/dl) 1.01 (1.00–1.03) 0.032 – –
ALT (IU/l) 15 (11–18) 16 (13–21) 0.281 TG (mg/dl) 1.01 (1.00–1.02) 0.071 – –
Albumin (g/dl) 4.66  0.21 4.52  0.31 0.018 HDL-C (mg/dl) 1.02 (0.97–1.08) 0.486 – –
TSH (uIU/ml) 1.8  0.92 1.64  0.78 0.390 LDL-C (mg/dl) 1.02 (1.00–1.03) 0.037 – –
Uric acid (mg/dl) 3.6 (3.25–4.5) 4.85 (3.9–5.5) < 0.001 AST (IU/l) 1.02 (0.90–1.16) 0.752 – –
ALT (IU/l) 1.02 (0.96–1.08) 0.547 – –
Values are expressed as n (%), mean  SD or median (25th–75th Albumin (g/dl) 0.15 (0.03–0.81) 0.028 0.05 0.005
percentiles). ALT, alanine aminotransferase; AST, aspartate amino- (0.01–0.41)
transferase; BMI, body mass index; DBP, diastolic blood pressure; TSH (uIU/ml) 0.80 (0.49–1.32) 0.386 – –
FG, fasting blood glucose; HDL-C, high-density lipoprotein choles- Uric acid 2.85 (1.67–4.86) < 0.001 3.35 < 0.001
terol; LDL-C, low-density lipoprotein cholesterol; SBP, systolic (mg/dl) (1.87–5.99)
blood pressure; TC, total cholesterol; TG, triglyceride; TSH, thy-
a
roid-stimulating hormone; WBC, white blood cells. The 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
and SUA (P < 0.001) were found to be independently (r = 0.940, P < 0.001). Values are expressed as n (%), mean  SD
associated with BPPV in the multiple logistic regres- or median (25th–75th percentiles). ALT, alanine aminotransferase;
sion model (Table 2). Every 1 unit increase in SUA AST, aspartate aminotransferase; BMI, body mass index; CI,
confidence interval; DBP, diastolic blood pressure; FG, fasting blood
value was shown to cause a 3.35- (1.87–5.99) fold glucose; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-
increase in predicting the risk of BPPV (odds ratio, density lipoprotein cholesterol; OR, odds ratio; SBP, systolic blood
95% CI, P < 0.001). pressure; TC, total cholesterol; TG, triglyceride; TSH, thyroid-
Receiver operating characteristic analyses were stimulating hormone; WBC, white blood cells.
applied for SUA, albumin, LDL and triglyceride vari-
ables. AUC values were found to be 0.75 (0.65–0.84), involvements were absent. With respect to the most
0.62 (0.51–0.72), 0.64 (0.53–0.74) and 0.63 (0.52–0.73), frequent involvement (PSC), the right side was
respectively, and the differences between these curves affected in 26 patients (57.8%) and the left side in 19
were not found to be statistically significant (P > 0.05; patients (42.2%). SUA levels did not differ statistically
Fig. 1). A cutoff value of 4 for SUA level was shown in patients with PSC BPPV for either the right or left
in Fig. 2, with a sensitivity of 0.72 (0.58–0.84) and side (P > 0.05).
a specificity of 0.60 (0.43–0.75), as shown in Table 3
(P < 0.05). There was a significant decrement in SUA
Discussion
level 1 month after the vertigo attack compared with
its values during the attack (P < 0.001; Fig. 3). We The main findings of our study show the following. (i)
found a weak but noteworthy relation between the Lipid profile, albumin and SUA were found to be
results of the gold standard test and uric acid test (cut- significantly higher in patients with BPPV than in
off value = 4, j = 0.322, P = 0.002). The kappa statistic controls. (ii) SUA was independently associated with
for the uric acid test was found to be higher than the BPPV (causing a 3.3-fold risk increase for every 1 unit
test statistics of albumin, LDL and triglyceride. increase in SUA value) in the multiple model. (iii) A
The PSC was involved in 45 patients (90%) and the cutoff value of 4 for SUA level with a sensitivity of
HSC in five patients (10%), while the other rare 72% and a specificity of 60% was obtained in the

© 2013 The Author(s)

European Journal of Neurology © 2013 EFNS
82 A. Celikbilek et al.
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.
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
© 2013 The Author(s)
European Journal of Neurology © 2013 EFNS
 Uric acid in positional vertigo 83

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

Diagnostic measures Kappa test

Parameters 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.

could easily be excluded in our patients. Another pos-

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 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
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.

© 2013 The Author(s)

European Journal of Neurology © 2013 EFNS
84 A. Celikbilek et al.
(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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