Acta Oto-Laryngologica. 2015; 135: 111–118

ORIGINAL ARTICLE

Glycerol affects vestibular-evoked myogenic potentials and pure-tone hearing in patients with Ménière’s disease

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ISILAY OZ, SEYRA HATICE ERBEK, GULFEM ALP, EVREN HIZAL & LEVENT NACI OZLUOGLU Department of Otolaryngology, Faculty of Medicine, Baskent University, Ankara, Turkey

Abstract Conclusion: The pure-tone audiometry results following glycerol administration indicated a positive effect on cochlear endolymphatic hydrops. Glycerol cervical vestibular-evoked myogenic potential (cVEMP) tests are a useful means of diagnosing saccular hydrops. There was no correlation between cVEMP and audiological results. Objective: To document the changes in pure-tone hearing outcomes and cVEMPs in patients with Ménière’s disease (MD) and 10 healthy volunteers before and after oral administration of glycerol. Methods: Twenty-nine study group subjects were chosen with complaints of vertigo. cVEMP testing and pure-tone hearing level testing were performed before and at 1, 2, and 3 h after administration of glycerol. Results: The means of the latencies, amplitudes, and difference ratio in 20 normal subject ears were determined. Based on these values, 9/29 MD-affected (MDA) ears (31%) had a unilaterally absent cVEMP. Compared with difference ratio values of the control groups there were significant differences in both latencies and amplitudes in MDA ears after glycerol administration. Before glycerol administration, there were significant differences between control and MDA ears on mean values of pure-tone hearing outcomes. Twenty patients in the MDA group showed significant pure-tone hearing outcomes after glycerol administration.

Keywords: Glycerol test, hearing outcome, vertigo, endolymphatic hydrops

Introduction Ménière’s disease (MD) can affect hearing and balance to varying degrees [1]. MD represents one of the most common vestibular diseases, and it is well documented in the literature that the typical pathological finding in MD is idiopathic endolymphatic hydrops (EH). EH can affect several structures in the inner ear, and in a study of the temporal bones affected by MD, EH was most often observed in the cochlea, followed by the saccule, utricule, and semicircular canals [2,3]. However, severe hydrops is more common in the saccule, and saccular hydrops may occur in 50% of MD cases. Therefore, more effective methods of detecting saccular hydrops are a key element in improving the diagnosis of MD [4,5].

The diagnosis of MD is made based on clinical symptoms and several clinical tests. Objective diagnostic tests, such as the caloric test, furosemide test, glycerol test, and electrocochleography, are generally accepted techniques for detecting cochlear EH. However, these widely used diagnostic techniques are unreliable for the detection of saccular EH, and it was not until the introduction of cervical vestibularevoked myogenic potential (cVEMP) testing that physicians were able to evaluate saccule function electrophysiologically [4,6–8]. c-VEMP, an electromyographic response of the sternocleidomastoid muscle (SCM) to intense sound, is a new test of the vestibular system that was first described by Colebatch and Halmagyi in 1992 [9]. c-VEMP may reflect the sacculocollic reflex and is mediated by a pathway that includes the saccule

Correspondence: Isilay Oz MD, Department of Otorhinolaryngology, Baskent University, 6. Sokak No: 72/2 Bahçelievler, Ankara, Turkey. Tel: +90 312 223 85 34. Fax: +90 312 215 75 97. E-mail: [email protected]

(Received 12 June 2014; accepted 30 July 2014) ISSN 0001-6489 print/ISSN 1651-2251 online  2015 Informa Healthcare DOI: 10.3109/00016489.2014.952045

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macula, the inferior vestibular nerve, the lateral vestibular nucleus, and the medial vestibulospinal tract, and ultimately reaches the SCM motor neurons [10]. This non-invasive, well-tolerated, and relatively simple technique is still in standard use in neurologic clinics. Studies on the diagnostic utility of cVEMPs for MD are scarce, and the results of these studies are inconsistent [10–12]. Glycerol, an osmotic diuretic, as it dehydrates the EH of the inner ear, reverts the inner ear pressure back to normal and improves inner ear function. However, few studies have examined the effects of glycerol on the vestibular responses. The combination of glycerol test and audiometry has a high sensitivity in the diagnosis of MD [5,13]. The objective of this study was to determine whether audiologic findings and cVEMP results could be altered by glycerol administration in MD patients and volunteers. Material and methods This study consisted of 30 adult patients, who were admitted to the Ear Nose Throat (ENT) Department of Baskent University (Turkey) with a primary complaint of vertigo, and 10 healthy adults. One patient did not follow up regularly; therefore 29 patients completed the study. The study was approved by the ethical committee of Baskent University’s Institutional Review Board (IRB no. KA09/259), and all participants gave informed consent. The study results were reviewed in blinded fashion by the senior author. All patients underwent a standardized intake assessment that included their medical history and a physical examination by an otolaryngologist. The diagnosis of MD was based on the criteria established by the Committee on Hearing and Equilibrium guidelines for the diagnosis and evaluation of therapy for MD of the American Academy of OtolaryngologyHead and Neck Foundation [1]. Subjects with major health diseases, coexisting conductive hearing loss, neurotologic disorders (e.g. vestibular neuronitis, benign positional paroxysmal vertigo (BPPV), chronic otitis media, otosclerosis, vestibular ototoxicity or labyrinthitis) or neurological diseases (e.g. skull fracture, whiplash trauma, multiple sclerosis or history of meningitis) were excluded. Audiologic evaluation Each patient underwent glycerol testing measured with conventional pure-tone audiometry. Audiologic tests were conducted using a Clinical Audiometer AC40 audiometric device (Interacoustics A/S, DK-5610, Assens, Denmark). The air and bone

conduction hearing thresholds were determined by routine audiologic analyses for values between 0.125 and 8 kHz. Hearing thresholds greater than 20 dB at two or more frequencies were accepted as sensorineural hearing loss (SNHL). Also the staging of the pure-tone threshold of hearing was evaluated. The glycerol test was performed as follows: 1 g/kg body weight of orally administered glycerol was given to each patient and control subject. Pure-tone audiometry was performed before and at 1, 2, and 3 h after the administration. A positive pure-tone average after glycerol administration (G-PTA) was defined as an improvement of ‡10 dB at two or more frequencies or improvement in speech discrimination of ‡12% [14]. cVEMPs Each patient underwent glycerol testing measured with cVEMP. The surface electromyographic activity of the SCM muscle was recorded using an EP 25 device (Interacoustics Co., Assens, Denmark). The active electrode was put on the upper half of the ipsilateral SCM muscle, and the reference electrode was put on the suprasternal notch. During the recording, the seated patients were instructed to rotate their heads to the opposite side to the stimulated ear to activate the SCM. Background electromyographic activity was monitored visually for consistent tonic contraction. Short tone bursts (100 dB nHL and 500 Hz each, with a 1 ms risefall time and a 5 ms plateau time) were delivered monaurally via TDH 49P insert earphones. The stimulation rate was 5 Hz, and the analysis time was 60 ms. In total, 128 responses to stimuli were averaged, and the measurements were repeated twice to check test wave reproducibility. The latencies of the first positive peak (p13), the next negative peak (n23), and amplitude difference between the p13 and n23 amplitudes were measured. Two parameters were evaluated for the VEMP test; the absence/presence parameter and the differences between before and after glycerol administration latency and amplitude values. For each side (left and right), comprising of the latencies and amplitudes was accomplished by calculating the difference ratio (DR). The DR was calculated as a percentage of the ratio (A–B)/(A+B), where A and B are the latency and p13-n23 amplitude recorded before and after glycerol administration in parallel with the pure-tone audiometry, respectively (G-VEMP). Upper limits of DR show a positive G-VEMP, when compared with the normal range (mean + 2 SD in healthy volunteers). The normal range (mean ±2 SD) was determined based on the G-VEMP results from the normal controls. However, in cases where there was no biphasic

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GlycerolVEMP in Ménière’s Disease

Table I. The mean values of speech discrimination and pure-tone audiometry for the study group before and after glycerol administration. Speech discrimination (%) Group

Pure-tone average (dB)

Before glycerol

After glycerol

Before glycerol

After glycerol

p value

Affected ears

66.2 ± 24.7

71.7 ± 25.4

57.6 ± 22.6

50.5 ± 24.8

0.00*

Unaffected ears

93.5 ± 11.0

92.6 ± 13.0

21.2 ± 13.5

20.4 ± 12.7

0.14

97 ± 2.5

97.2 ± 2.3

13.9 ± 5.9

13.3± 5.6

0.15

Control ears

wave before glycerol administration, the DR could not be calculated. In such a case, if a biphasic wave was observed after glycerol administration the results of the G-VEMP were also considered to be positive (DR = 100), and if there was no biphasic wave, the results were considered to be negative (DR = zero). A difference of more 20% between the values before and after glycerol testing was considered significant for both the latencies and amplitudes [8,10].

The 29 affected ears in the MD group (MDA) included 12 (41.4%) right and 17 (58.6%) left ears. Disease duration was calculated in months, and the mean time for the onset of disease was 15.1 ± 15.9 months.

Audiological examination Statistical analysis Statistical analysis was performed using SPSS Statistics 17.0 software. The data are represented as the means ± standard deviation (SD) or as percentages. Because the data had a normal distribution, the analyses were conducted using parametric tests. An independent sample t test was used for comparison of the means between the groups, whereas a paired sample t test was used for comparison of the means of continuous measurements. Differences were considered statistically significant when the p value was < 0.05. Chi-squared tests were used to determine the relationship between the groups in terms of categorical variables. Because the tests were analyzed with a 5% error margin, the limits were determined by using the mean ±2 SD formula.

The mean duration of hearing loss was 10.7 ± 12.6 months in the affected ears of the MD group (MDA). For the study groups the mean values of PTA and speech discrimnation scores are summarized in Table I and Figure 1, and stages of the pure-tone threshold of hearing are summarized in Table II and Table III before and after glycerol administration. Before glycerol administration, there were significant increases between control and MDA ears in mean values of pure-tone hearing outcomes (p = 0.00). There were no significant differences between affected and unaffected ears (p = 0.12). PTA Before PTA After

60

50

Results The study consisted of a total of 39 individuals, of whom 14 (35.8%) were female and 25 (64.1%) were male. The MD group consisted of 11 (37.9%) females and 18 (62.1%) males, and the control group consisted of 3 (30%) females and 7 (70%) males. The mean age of the 29 patients in the MD group was 46.17 ± 11.56 (range 28–64) years, and the mean age of the 10 patients in the control group was 43.7 ± 8.39 (range 32–56) years. No significant differences were observed between the two groups in terms of age and gender (p = 0.099 and p = 0.652, respectively). The total number of evaluated ears was 58 in the MD group and 20 in the control group. Unaffected ears were also evaluated in the MD group (MDU).

40 Hearing level

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*Significant differences between pre- and post-glycerol administration in affected ears.

30

20

10

0 Healthy ears

Affected ears

Control ears

Figure 1. Pure-tone average (PTA) values before and after glycerol.

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Isilay Oz et al. decreases at more than two frequencies or improvement in speech discrimination ‡12% in MDA and the results were significant. Only one ear showed a positive result in MDU. The difference between the affected and unaffected ears was significant (p = 0.00, c2 = 26.94).

Table II. Effects of glycerol on stage of pure-tone threshold of hearing. Stage

No effect

Decrease

Increase

Total

I

2

0

0

2

II

2

2

0

4

III

10

6

0

16

IV

6

1

0

7

G-VEMP

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Effects of the glycerol test on audiological findings (G-PTA)

VEMP responses were obtained from both ears in all subjects in the control group. The upper limits were determined using the mean ±2 SD formula and were 18.3 ms for p13, 27.56 ms for n23, and 158.74 mV for the p13-n23 amplitude. Also, the mean ±2 SD of DR

Positive results observed in 20 ears (69%) in which pure-tone audiometry revealed 10 dB or higher

Table III. VEMP values and stage of audiologic findings before and after the glycerol test in the affected ears. Audiologic evaluation

Pre-glycerol

Patient no.

Pre-glycerol

Post-glycerol

Side

p13 (ms)

n23 (ms)

1

I

I

R

0.0

0.0

2

IV

IV

L

20.4

29.8

3

III

III

R

0.0

0.0

4

III

III

L

9.0

28.7

5

II

I

R

20.9

28.7

6

III

III

L

14.9

24.3

7

III

II

L

0.0

8

II

I

L

17.9

9

III

III

L

15.9

10

III

II

R

20.2

11

IV

IV

L

12

II

II

L

13

I

I

14

IV

15

IV

16 17

Post-glycerol

Amplitude (mv)

% change

p13 (ms)

n23 (ms)

Amplitude (mv)

Amplitude (mv)

0.0

20.7

28.2

38.0

17.9

28.7

0.0

14.4

89.2

15.3

31.8

19.1

90.9

14.7

0.0

0.0

23.8

74.9

23.2 29.7

0.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

19.0

26.0

37.6

100.0

100.0

100.0

R

13.1

21.2

58.0

12.8

21.0

37.9

–1.2

–0.4

–20.9

IV

L

19.3

29.9

122.0

19.1

29.3

47.4

–0.5

–0.9

–44.8

IV

L

14.5

24.7

65.8

13.5

24.2

42.3

–3.5

–1.0

–21.7

III

III

R

0.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

III

II

R

18.9

26.3

178.8

15.4

23.1

74.2

–7.5

–6.4

–41.1

18

IV

IV

L

16.9

27.8

94.5

15.9

24.9

85.9

–3.0

–5.5

–4.8

19

III

III

R

13.4

24.5

57.9

17.2

28.1

76.8

12.4

6.7

14.3

p13

n23

52.1

100.0

100.0

100.0

7.5

–9.8

–1.8

–67.0

26.6

37.0

100.0

100.0

100.0

24.8

98.7

–12.0

–7.2

5.1

26.5

31.2

–4.5

–3.9

–0.9

24.5

106.7

–0.6

0.4

7.9

17.1

22.9

37.7

100.0

100.0

100.0

16.2

24.5

57.2

–4.9

1.5

–13.3

16.0

14.8

24.1

39.6

–3.5

1.9

42.4

60.3

19.1

28.5

33.3

–2.7

–2.1

–28.8

20

III

II

L

17.7

29.4

130.5

15.7

25.9

50.8

–5.9

–6.2

–43.9

21

III

II

R

16.7

23.3

49.0

15.9

22.9

71.5

–2.4

–1.4

18.6

22

IV

III

L

16.8

28.0

97.2

15.4

22.7

106.7

–4.3

–10.5

4.6

23

III

III

L

0.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

24

III

III

R

0.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

25

III

III

L

15.4

23.7

138.7

14.9

23.7

77.7

–1.6

0.0

–28.2

26

IV

IV

R

14.8

22.4

46.7

14.8

23.8

39.6

0.0

3.0

–8.2

27

III

II

L

15.8

25.0

218.6

16.7

21.7

200.5

2.7

–7.1

–4.3

28

III

III

L

0.0

0.0

0.0

14.7

24.1

136.7

100.0

100.0

100.0

29

II

II

R

15.7

26.2

38.4

13.5

23.7

12.7

–7.5

–4.9

–50.4

GlycerolVEMP in Ménière’s Disease Table IV. Normal range of difference ratio (DR) in G-VEMP. Measured parameters of DR of VEMP

Normal range of DR

Amplitude

–18.06 < DR < 46.97%

p13 latency

–4.76 < DR < 10.99%

n23 latency

–1.95 < DR < 5.71%

G-VEMP, glycerol cervical vestibular-evoked myogenic potential.

VEMP values before glycerol test VEMP responses could not be obtained in nine (29%) MDA ears. The p13 latency was prolonged in five (17.2%) patients and the n23 latency was prolonged

in eight (27.5%) patients; increased amplitudes were detected in two (6.8%) patients (Table III). Compared with the control group, there were significant increases in the p13 and n23 latencies (p = 0.00 and p = 0.002, respectively), and no significant differences in the amplitudes (p = 0.37). For the MDU group, the p13 latency was prolonged in two (6.89%) patients, and the n23 latency was prolonged in two patients; increased amplitudes were detected in one (3.44%) patient. Comparing the MDA and MDU ears, there were significant increases in the p13 and n23 latencies (p = 0.00 and p = 0.006, respectively), but no significant differences in the amplitudes (p = 0.39). Comparing the control and MDU ears, there were significant differences in the p13 and n23 latencies (p = 0.02 and p = 0.01, respectively), but no significant differences in the amplitudes (p = 0.99).

A

10 µV

P1 15.7

N1 21.3

5

10

15

20 ms

25

30

35

30

35

B P1 16.7

50 µV

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was –4.76 to 10.99% for p13 latency, –1.95 to 5.71% for n23 latency, –18.06 to 46.97% for amplitude (Table IV, Figure 2).

115

N1 24.0

5

10

15

20 ms

25

Figure 2. Normal VEMP of control patient (a 42-year-old man) recorded before glycerol administration. (A) p13, 15.7 ms; n23, 21.3 ms; and amplitude, 29.22 mV for right. (B) p13, 16.67 ms; n23, 24.0 ms; and amplitude, 74.13 mV.

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Isilay Oz et al.

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Effects of glycerol administration on the VEMP No prolongations were detected in the p13 and n23 latencies of the control group, and no significant differences were observed. Appearance of the VEMP waves was obtained in five (55.5%) of nine patients after the glycerol test. In MDA ears, one showed improvement in VEMP amplitudes. Latency was within the normal ranges in two of five patients with prolonged p13 latency and in five of eight patients with prolonged n23 latency. In MDA ears, there were positive results in six ears (20.6%) in the G-VEMP p13 latency, five ears (17.2%) in the n23 latency and five ears (17.2%) in the amplitudes (Table III). Compared with the DR values of the control groups there were significant changes in p13 and n23 latencies and amplitudes in MDA ears. In three ears both of the latencies and the amplitude were changed. There were no significant changes in the latency and amplitude in the unaffected side. Between MDA and MDU ears, there were significant DR changes in values for p13 and n23 latencies and amplitudes. However, between MDU and control ears, there were no significant changes in DR values in p13 and n23 latencies and amplitudes. Outcome between G-VEMP and G-PTA Only 5/29 (17.2%) patients had positive results in both of the tests. Before glycerol administration, VEMP wave was not detected in these patients. The incidence of positive findings when evaluating the same patients with both G-VEMP and G-PTA increased to 75%, suggesting a synergistic effect when compared with either of the tests performed alone (GPTA 69%, G-VEMP 20.6% for p13 latency, 17.2% for n23 latency and amplitude). Discussion MD is an idiopathic disease of the inner ear, and EH is the most important histological sign of the disease. In the early stage, the disease appears as the enlargement of the apical turn of the cochlea and saccule in the inferior part of the membranous labyrinth, whereas further stages may involve the entire endolymphatic system, and the saccule may lean against the horizontal channel and the base of the stapes [15,16]. Thus, VEMP responses may exhibit variations in MD. Several authors recorded VEMPs of the patients at the different stages of MD with varying degrees of changes [17,18]. Some studies showed that low amplitude of VEMPs may be found in the affected ear in MD [4,6]. They

suggested that amplitudes are more useful than latencies. They used click stimulus and click stimulus produces longer and more variable latencies because of requiring loud stimuli. But a substantial proportion of subjects shows no VEMP, or a higher threshold. Rauch et al. supposed that thresholds are more reliable than amplitude. They suggested that the 500 Hz tone burst VEMP has the lowest threshold, and that altered frequency tuning observed in MD subjects was due to hydropic structural distortion of the saccule [12]. In the present study, VEMPs of the MDA group were absent in nine ears. Compared with the control group, significant prolongations were observed in the p13 and n23 latencies of the initial VEMP response of the affected ears. Increased amplitudes were detected in two patients. Audiological tests are used for the diagnosis of MD. Whereas hearing loss is higher at low frequencies in the early stages of the disease, a linear loss may appear in later stages. The most commonly seen audiogram is the ‘peak’ type (seen in up to 51% of patients). With regard to audiological tests, peak audiometric testing is encountered most commonly. On peak audiograms, hearing losses at low frequencies are observed with 2000 Hz increments and re-decrements. Savastano et al. emphasized that hearing loss at high frequencies is directly associated with disease duration [19]. In the present study, the audiometric analysis of patients with MD revealed that hearing loss was greater at low frequencies, where 69% of hearing loss occurred compared with a 31% linear loss. The glycerol test temporarily improves the hearing threshold in the majority of the patients; alternatively, the threshold remains the same. Murofushi et al. detected improvement in the PTAs of 6 (35.29%) of 17 patients with MD and proposed that hair cells in the cochlea might have been permanently injured in the ears that experienced no hearing improvement [4]. In another study, Magliulo et al. evaluated audiological data from 22 patients with unilateral MD and obtained positive results in 8 (36.4%) patients [13]. Ohki et al. conducted a study in nine patients with contralateral delayed EH and detected no changes in the PTAs of any of the patients after the glycerol test [10]. A few studies have shown a significant improvement of 10 or 15% of speech discrimination [12,13]. In the present study, positive G-PTA results were obtained in 20 (69%) of 29 patients at 3 h after the glycerol test. Improvements were detected in nine (31%) patients in stages II and III. Compared with the results of previous studies, the rate of positive hearing results was higher in the present study. We believe that the positive results obtained using glycerol testing support a diagnosis of EH that has not caused permanent injury in the cochlea.

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GlycerolVEMP in Ménière’s Disease Magliulo et al. remarked that the VEMP test performed with glycerol provides an advantage for the diagnosis of cases with unilateral hydrops. In addition, they emphasized the importance of VEMP as a new test parameter to detect saccular hydrops [13]. Murofushi et al. and Shojaku et al. separately observed elevations in the amplitudes of VEMP responses following oral glycerol intake in patients with MD [4,20]. They suggested that the values detected before glycerol administration favor EH and that the change in VEMP responses indicates the presence of saccular hydrops. The saccule is the second most common site of hydrops, after the cochlea, in patients with MD [8]. There are studies suggesting that audiologic evaluation using the glycerol test together with the VEMP test should not be used as a routine diagnostic method and that the glycerol test is more sensitive in patients suspected to be in the beginning stage of MD [8,13]. In 2008, Magliulo et al. conducted a study in 22 patients with unilateral MD and observed increasing in the amplitudes of 10 of 22 patients; however, they observed no changes in latencies. They also observed significant changes in the pure-tone audiometry values of 12 patients [8]. Osei-Lah et al. reported that the mean interaural amplitude DR is significantly higher in stable MD as compared with acute MD. Thresholds and latencies were not useful [21]. However, the results of the present study revealed significant DRs in both latencies and amplitudes after glycerol administration in affected ears but not in unaffected ears. Although VEMP responses could not be obtained in nine patients in the MD group, the responses were obtained in five patients after the glycerol test, but there was no correlation between G-VEMP and G-PTA. We observed that amplitude values of VEMP were quite variable in the literature. In the present study there are small SDs of p13 and n23, but there is a large SD outcome for the amplitude. In this case, we thought that latencies were more determinant than the amplitudes. Also variable amplitudes of p13-n23 may be related to muscular effort in the head rotation method and the amount of SCM muscle fiber. It is also well known that head position on body can change VEMP responses. Based on the results of the present study, the positive data obtained via glycerol testing performed in patients with MD are helpful for verifying a diagnosis of EH. It would be convenient for clinics to evaluate the results by their own specified normative data for VEMP testing performed together with glycerol testing. In this study, obtaining a VEMP response after glycerol testing in patients with no previous

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VEMP responses and in the presence of significant changes in latencies supports a diagnosis of saccular hydrops and this should be confirmed by further studies, even though these results are consistent with previous studies. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Glycerol affects vestibular-evoked myogenic potentials and pure-tone hearing in patients with Ménière's disease.

The pure-tone audiometry results following glycerol administration indicated a positive effect on cochlear endolymphatic hydrops. Glycerol cervical ve...
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