Hearing Research 310 (2014) 54e59
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Research paper
Ocular vestibular evoked myogenic potential frequency tuning in certain Menière’s disease Claudia Jerin a, *, Albert Berman a, Eike Krause a, b, Birgit Ertl-Wagner c, Robert Gürkov a, b a
German Center for Vertigo and Balance Disorders, Grosshadern Medical Center, University of Munich, Marchioninistr. 15, 81377 Munich, Germany Department of Otorhinolaryngology e Head and Neck Surgery, Grosshadern Medical Center, University of Munich, Marchioninistr. 15, 81377 Munich, Germany c Institute of Clinical Radiology, Grosshadern Medical Center, University of Munich, Marchioninistr. 15, 81377 Munich, Germany b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 10 December 2013 Received in revised form 27 January 2014 Accepted 4 February 2014 Available online 14 February 2014
Ocular vestibular evoked myogenic potentials (oVEMP) represent extraocular muscle activity in response to vestibular stimulation. To specify the value of oVEMP in the diagnostics of Menière’s disease, the amplitude ratio between 500 and 1000 Hz stimuli was investigated. Thirty-nine patients with certain Menière’s disease, i.e. definite Menière’s disease with visualization of endolymphatic hydrops by magnetic resonance imaging and 19 age-matched healthy controls were enrolled in this study. oVEMP were recorded using 500 and 1000 Hz air-conducted tone bursts. For Menière’s ears, the 500/1000 Hz amplitude ratio (mean ratio ¼ 1.20) was significantly smaller when compared to unaffected ears of Menière’s patients (mean ratio ¼ 1.80; p ¼ 0.008) or healthy controls (mean ratio ¼ 1.81; p ¼ 0.011). The amplitude ratio was neither correlated with the degree of endolymphatic hydrops nor with the duration of disease. While an older age was associated with a diminished amplitude ratio in healthy controls, there was no correlation between the amplitude ratio and age in Menière’s ears. Hence, the calculation of the oVEMP 500/1000 Hz amplitude ratio may be a valuable diagnostic tool for Menière’s disease. Ó 2014 Elsevier B.V. All rights reserved.
Keywords: Vestibular evoked myogenic potential oVEMP Frequency tuning Menière’s disease
1. Introduction Menière’s disease (MD) is a disorder of the inner ear which is characterized by attacks of vertigo, tinnitus and cochlear hearing loss. The pathological hallmark of MD is endolymphatic hydrops (ELH) (Hallpike and Cairns, 1938), even though its role in the pathophysiology of the disease remains unclear. Recently, MR imaging has been used to visualize endolymphatic hydrops in MD patients in vivo, using the intratympanic (Nakashima et al., 2007; Gürkov et al., 2012) or the intravenous (Naganawa et al., 2010) route of contrast agent application. This method enables diagnostic certainty which hitherto could only be achieved by histological post-mortem examination (AAO-HNS, 1995).
Abbreviations: ACS, Air-conducted sound; BCV, Bone-conducted vibration; cVEMP, Cervical vestibular evoked myogenic potentials; ELH, Endolymphatic hydrops; LEIM, Locally enhanced inner ear MR imaging; MD, Menière’s disease; oVEMP, Ocular vestibular evoked myogenic potentials * Corresponding author. Tel.: þ49 89 7095 0; fax: þ49 89 7095 6869. E-mail address: [email protected] (C. Jerin). http://dx.doi.org/10.1016/j.heares.2014.02.001 0378-5955/Ó 2014 Elsevier B.V. All rights reserved.
Ocular vestibular evoked myogenic potentials (oVEMP) are short-latency myogenic potentials which can be elicited in response to vestibular stimulation, e.g. by air-conducted sound (ACS) or bone-conducted vibration (BCV) (Kantner and Gürkov, 2012). Otolithic afferent neurons trigger reflexive electromyographic activity of the extraocular muscles which can be recorded beneath the eye contralateral to the stimulated ear by use of surface electrodes. The pathway from the human otolith organs to the extraocular muscles reflects the vestibulo-ocular reflex (Iwasaki et al., 2007; Rosengren et al., 2010). The oVEMP waveform begins with a negative peak with a latency of about 10 ms (n1), followed by a positive peak at about 15 ms (p1). oVEMP can be applied in the diagnostic work-up of vestibular disorders like Menière’s disease. In contrast to BCV oVEMP, ACS oVEMP can be elicited by audiological equipment approved for routine clinical use. However, the published literature shows wide variation in oVEMP results in MD. While some studies reported a declined response prevalence, decreased oVEMP amplitudes and increased thresholds (Huang et al., 2011; Winters et al., 2011), other studies observed enhanced amplitudes in early stages of MD and
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during acute attacks (Manzari et al., 2010). The value of oVEMP in the diagnostics of MD thus still needs to be specified. We recorded ACS oVEMP in response to the most commonly used frequencies of 500 and 1000 Hz with a standard clinical VEMP equipment in order to investigate oVEMP frequency tuning characteristics in certain Menière’s disease. 2. Methods 2.1. Patients The study was conducted at a large tertiary referral centre for vestibular disorders. Thirty-nine consecutive patients with ascertained unilateral Menière’s disease, i.e. patients with definite Menière’s disease according to the AAO-HNS guidelines (AAO-HNS, 1995) and visualization of endolymphatic hydrops by locally enhanced inner ear MR imaging (LEIM), participated in this study (mean age ¼ 53.0 years; range ¼ 18e71 years). These patients represented an average population of Menière’s patients including different MD stages. Clinical characteristics of the study population are summarized in Table 1. MR imaging and oVEMP recording were performed during a quiescent interval between vertigo attacks. Furthermore, 19 healthy subjects without any history of vertigo or hearing loss were enrolled. The control group was representative of the experimental group in terms of mean age and age range (mean age ¼ 52.2 years; range ¼ 18e73 years). The study protocol was approved by the institutional review board (Protocol No. 210-12) and all subjects gave written informed consent prior to participation in the study.
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sequence was performed to evaluate the anatomy of the whole fluid-filled labyrinth spaces, with the following parameters: TR 6.24 ms, TE 2.87 ms, flip angle of 70 , field of view of 160 mm, matrix size of 320 320, average of 1, and slice thickness of 0.4 mm. ELH was observed as enlarged spaces with hypointense signal inside the labyrinth, as opposed to the contrast-enhanced perilymphatic space, which has a high signal intensity on the T1weighted sequence. Grading of ELH severity on a scale of 0e3 was performed as described previously (Gürkov et al., 2012): 0: no hydrops, 1: mild hydrops, 2: marked hydrops, 3: extreme hydrops. Examples of different grades of endolymphatic hydrops are shown in Fig. 1. Vestibular ELH severity was quantified by measuring the areas occupied by endolymph and perilymph space, respectively, and calculating the endolymph/perilymph space ratio as described previously (Gürkov et al., 2012). The slice for measurement of vestibular ELH was chosen at the level of the horizontal semicircular canal, as previously described (Naganawa et al., 2013). LEIM
2.2. Locally enhanced inner ear MR imaging (LEIM) A Gadolinium-based contrast medium, Gadopentetatedimuglumine (Magnograf, Marotrast, Jena, Germany), was diluted 8-fold in saline solution and injected intratympanically (0.4 ml) under microscopic control, as described previously (Gürkov et al., 2012). The patients remained in a supine position for further 30 min with the head turned 45 toward the contralateral side, instructed not to speak or chew during this period. MRI scans were performed 24 h after application of the contrast agent on a 3T MR scanner (Magnetom Verio; Siemens Healthcare, Erlangen, Germany) using a commercially available 32-channel head coil. A 3D-IR-TSE sequence was acquired with the following parameters: TR 7000 ms, TE 128 ms, TI 1700 m, constant flip angle of 180 , echo train length of 23, matrix size of 384 384, at 0.6 mm slice thickness, and number of excitations 1. The labyrinth was scanned with a square field of view of 16 cm, parallel imaging with a factor of 2 was used using GRAPPA reconstruction. Total scan time for this sequence was 14 min. In addition, a high-resolution strongly T2-weighted CISS
Table 1 Characteristics of the study population (n ¼ 39). Male/female Age (years) Disease duration (months) Pure tone average 0.5e3 kHz (dB) Canal paresis (%) Degree of cochlear hydrops Degree of vestibular hydrops Endolymph/perilymph space ratio (%) Stage: 1 2 3 4
19/20 53.0 13.6 (range 18e71) 109 100 (range 9e420) 50 23 (range 16e130) 34 21 (range 2e83) 1.9 0.7 (range 0e3) 2.1 1.0 (range 0e3) 50 18 (range 18e83) n¼6 n¼8 n ¼ 19 n¼6
Staging was based on the pure-tone average at 0.5e3 kHz (AAO-HNS, 1995). Values are expressed as mean SD.
Fig. 1. Locally enhanced inner ear MR imaging of right ears with evidence of mild (A), moderate (B) and severe (C) vestibular endolymphatic hydrops (arrows point out the vestibulum). Bright areas represent perilymphatic space, dark areas within the inner ear represent endolymphatic space.
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evaluation was performed as a blinded consensus reading by an experienced head and neck radiologist and an experienced neurotologist.
variables. Descriptive statistics are expressed as mean standard error (SE). Statistical significance was determined at the p < 0.05 level.
2.3. oVEMP recording
3. Results
Twenty-four hours prior to MR imaging, 500 Hz and 1000 Hz air-conducted tone bursts were presented monaurally via a pair of calibrated ABR3A insert earphones at an intensity of 100 dB nHL, using the following stimulus profile: 2 ms rise time, 2 ms plateau time and 2 ms fall time. Averaging of the responses to 100e150 stimulus repetitions, presented at a repetition rate of 5.1/s, ensured sufficient reproducibility. oVEMP were recorded using an Eclipse EP 25 VEMP evoked potential system (Interacoustics AS, Assens, Denmark). Surface EMG electrodes were placed on the skin beneath the eye contralateral to the stimulated ear, with the recording electrodes positioned inferior to the lower-lid margin and the reference electrodes 2e3 cm below on the cheek. The ground electrode was placed on the forehead. Impedances were maintained below 3 kU oVEMP were recorded with the subjects lying supine. Prior to the beginning of the recording, subjects were instructed to look upward at a marking on the wall located closely behind their head at a distance of 1 m, corresponding to a 35 upward gaze angle. The EMG was amplified (60 dB), bandpass filtered (10 Hze750 Hz) and recorded from 10 ms before to 70 ms after stimulus onset. From each subject, at least two separate measurements (three measurements, of the first two differed by more than 20%) were performed and mean amplitude and latency values were used for analysis. oVEMP amplitudes were determined as n1-p1 peak-topeak amplitudes. If no reliable oVEMP waveform could be elicited, the amplitude was defined as 1 mV in order to calculate ratios and to avoid division by 0. In cases where the oVEMP was neither elicited by 500 nor by 1000 Hz stimuli, the amplitude ratio was artificially set at 1. In order to exclude the effects of fatigue, the sequence of the 500 Hz stimulus testing and the 1000 Hz stimulus testing was randomized.
Examples of oVEMP waveforms recorded in response to 500 Hz and 1000 Hz are shown in Fig. 2. Descriptive oVEMP statistics recorded from affected Menière’s ears, unaffected ears and healthy controls in response to 500 Hz and 1000 Hz tone bursts are summarized in Table 2.
2.4. Data analysis Data analysis was performed with IBM SPSS Statistics 20 (SPSS Inc., Chicago, IL, USA). Data were analyzed descriptively and by using the non-parametric Kruskal-Wallis-test for comparison between three groups (MD ear, contralateral ear, control ear) and Mann-Whitney-test for comparison between two groups (e.g. MD and control groups). Correlation was calculated using the Spearman’s rank correlation coefficient for non-parametric
3.1. oVEMP amplitudes In response to 500 Hz tone bursts, reproducible oVEMP waveforms could be elicited in 69%, 77% and 76% of Menière’s ears, contralateral ears and healthy controls, respectively. The response prevalence in Menière’s, unaffected and healthy ears for 1000 Hz was 69%, 72% and 61%, respectively. In response to 500 Hz tone bursts, Menière’s ears generated the smallest amplitudes (mean n1ep1 amplitude 2.65 mV), whereas the largest amplitudes were observed for the unaffected ears of Menière’s patients (mean n1e p1 amplitude 3.73 mV) (Fig. 3). However, amplitude differences between groups were not significant (p ¼ 0.117). Regarding oVEMP amplitudes in response to 1000 Hz, healthy controls showed a trend to produce the smallest amplitudes (mean 1.69 mV), while similar oVEMP were measured in affected and unaffected Menière’s ears (mean 2.67 mV each). For amplitudes in response to the 1000 Hz stimulus, group comparison did not reveal statistical significance, either (p ¼ 0.458). 3.2. 500/1000 Hz amplitude ratio The mean 500/1000 Hz amplitude ratios amounted to 1.20, 1.80 and 1.81 for Menière’s ears, unaffected ears and healthy controls, respectively (Fig. 4). The 500/1000 Hz ratio was significantly smaller for affected ears when compared to unaffected ears (p ¼ 0.008) or healthy controls (p ¼ 0.011). 500/1000 Hz ratios in unaffected and healthy ears, however, did not differ from each other (p ¼ 0.951). From MD ears, contralateral ears and healthy controls, 9, 8 and 9 ears showed no reliable oVEMP in response to both 500 and 1000 Hz, so that the ratio in these cases was artificially defined as 1. When considering only those individuals with oVEMP responses, the 500/1000 Hz amplitude ratio amounted to 1.26, 2.01 and 2.06 for MD, unaffected and healthy ears, respectively. Again, the amplitude ratio was significantly smaller for MD ears when
Fig. 2. Examples of oVEMP waveforms recorded in a healthy subject (A) and an MD patient (B) in response to 500 Hz and 1000 Hz.
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Table 2 Amplitudes and latencies in response to 500 Hz and 1000 Hz tone bursts.
500 Hz Response prevalence n1ep1 amplitude (mV) n1 latency (ms) p1 latency (ms) 1000 Hz Response prevalence n1ep1 amplitude (mV) n1 latency (ms) p1 latency (ms) 500/1000 Hz ratio 500/1000 Hz ratio when considering only the individuals with oVEMP responses
Menière’s ears (n ¼ 39)
Unaffected ears (n ¼ 39)
Controls (n ¼ 38)
27 (69%) 2.65 0.39 11.44 0.22 15.70 0.25
30 (77%) 3.73 0.49 11.73 0.38 16.13 0.39
29 (76%) 3.04 0.46 11.26 0.20 16.20 0.23
27 (69%) 2.67 0.43 11.46 0.29 15.81 0.30 1.20 0.14 1.26 0.18 (n ¼ 30)
28 (72%) 2.67 0.48 11.56 0.39 16.24 0.37 1.80 0.23 2.01 0.28 (n ¼ 31)
23 (61%) 1.69 0.13 11.43 0.25 16.15 0.32 1.81 0.31 2.06 0.40 (n ¼ 29)
Values are expressed as mean SE.
compared to contralateral ears (p ¼ 0.009) or healthy controls (p ¼ 0.010), whereas the ratio in contralateral and healthy ears did not differ from each other (p ¼ 0.935). 3.3. oVEMP latencies N1 and p1 latencies in response to both 500 and 1000 Hz were comparable between affected, unaffected and healthy ears, revealing no significant differences (p ¼ 0.815 and p ¼ 0.305 for n1 and p1 to 500 Hz; p ¼ 0.715 and p ¼ 0.770 for n1 and p1 to 1000 Hz). Latency values are summarized in Table 2. 3.4. Correlation of the oVEMP 500/1000 Hz ratio with other audiovestibular function parameters, disease duration and severity of endolymphatic hydrops To investigate whether a diminished 500/1000 Hz oVEMP ratio in Menière’s patients is associated with the extent of endolymphatic hydrops or with other audiovestibular test results, a correlation analysis was performed. A significant correlation was neither
Fig. 4. The 500/1000 Hz amplitude ratio in Menière’s ears, contralateral ears and controls. Error bars represent the SE. Significance levels are indicated by asterisks (*p < 0.05; **p < 0.01).
observed between the oVEMP 500/1000 Hz ratio and the degree of hydrops in the cochlea (rho ¼ 0.210; p ¼ 0.200) nor between the amplitude ratio and the degree of vestibular hydrops (rho ¼ 0.056; p ¼ 0.736). There was no correlation between the oVEMP ratio and the endolymph-to-perilymph-space-ratio, either (rho ¼ 0.093; p ¼ 0.583). Furthermore, there was no significant correlation between the oVEMP amplitude ratio and the pure tone hearing level average at 0.5, 1, 2 and 3 kHz (rho ¼ 0.067; p ¼ 0.684) or between the amplitude ratio and the degree of lateral semicircular canal paresis on caloric irrigation (rho ¼ 0.117; p ¼ 0.479). Disease duration was defined as the time period from the onset of the first audiovestibular symptoms. The oVEMP 500/1000 Hz ratio and disease duration were not significantly correlated (rho ¼ 0.189; p ¼ 0.249). 3.5. Correlation of the oVEMP 500/1000 Hz ratio with age Given that oVEMP are known to be modulated by age, we investigated the relationship between the 500/1000 Hz ratio and the subjects’ age. In healthy controls, an older age was associated with a decreasing oVEMP 500/1000 Hz ratio. This correlation was highly significant (rho ¼ 0.494; p ¼ 0.002). A similar relationship was observed for the unaffected ears of Menière’s patients, albeit the correlation was not as strong as for the control subjects (rho ¼ 0.344; p ¼ 0.032). In the affected ears of Menière’s patients, however, age was not correlated with the oVEMP amplitude ratio (rho ¼ 0.054; p ¼ 0.742). 4. Discussion
Fig. 3. Amplitudes obtained in response to 500 Hz and 1000 Hz in affected and contralateral ears in MD patients and healthy control subjects. Mean values are shown. Error bars represent the SE. There were no significant differences between groups.
The published literature regarding the optimal frequency to elicit air-conducted oVEMP in healthy subjects shows wide variation. Several studies found the largest amplitudes in response to 500 Hz tone bursts (Murnane et al., 2011; Park et al., 2010), whereas others achieved best oVEMP results in response to 1000 Hz tone bursts (Lewis et al., 2010; Taylor et al., 2012a). A recent study observed largest amplitudes in response to 750 Hz, although there were no significant differences in amplitude for 500, 750 and 1000 Hz (Piker et al., 2013). Hence, a variety of frequencies appears to be suitable for evoking oVEMP in healthy subjects. There is, however, strong evidence for the influence of a subject’s age upon the optimal frequency, with the tuning of oVEMP for older adults
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shifting towards higher frequencies (Taylor et al., 2012a; Piker et al., 2013). In Menière’s disease, air-conducted oVEMP are characterized by a declined response prevalence, decreased amplitudes and increased thresholds in the interval between attacks (Huang et al., 2011; Winters et al., 2011). Other studies, in contrast, observed enhanced amplitudes in early stages of MD and during acute attacks (Manzari et al., 2010). oVEMP response rates in MD have been reported variably as well, in a wide range of 10e70% (Taylor et al., 2011; Sandhu et al., 2012; Winters et al., 2011; Taylor et al., 2012b), which may be influenced by different disease stage and disease activity, but also by different stimulus parameters and recording conditions. Furthermore, MD was reported to result in altered frequency tuning characteristics of oVEMP. In MD-affected ears, largest amplitudes and lowest thresholds were achieved using 1000 Hz tone bursts, whereas healthy controls and unaffected MD ears yielded best oVEMP results upon 500 Hz tone bursts (Winters et al., 2012). In the same study, even the unaffected ears of MD patients revealed decreased amplitudes and higher thresholds in response to both 500 Hz and 1000 Hz when compared to healthy subjects, albeit abnormalities in MD-affected ears were more strongly pronounced (Winters et al., 2012). This study, however, did not use age-matched controls. The mean age of Menière’s patients was 56 years, while the healthy control cohort had a mean age of 30 years. In consideration of the well-known effects of age on oVEMP frequency tuning, the observed shift towards higher-frequency tuning in patients when compared to healthy subjects cannot be solely attributed to the diagnosis of MD in their study. Moreover, the difference in terms of age does not permit a comparison of absolute amplitudes between controls and affected or unaffected Menière’s ears, since several studies described decreased oVEMP amplitudes in older individuals (Nguyen et al., 2010; Piker et al., 2011). Similarly, a shift towards higher frequencies in patients with Menière’s disease when compared to healthy subjects and contralateral ears has been reported, with this shift being more pronounced in definite than in probable MD (Sandhu et al., 2012). In this study, however, subjects were not age-matched, either (average age 53 years for the Menière group and 31 years for the control group). Taylor et al. (2012b) reported that both 500 Hz and 1000 Hz were optimal frequencies for controls and unaffected MD ears, whereas the 1000 Hz stimulus produced larger amplitudes than the 500 Hz stimulus in affected MD ears. The authors, however, did not calculate the amplitude ratio and conceded that the low oVEMP response prevalence (45% for MD ears to 500 Hz) in this study limited its clinical utility. Correspondingly, a shift toward higher-frequency tuning has been reported for air-conducted cervical vestibular evoked myogenic potentials (cVEMP) in several studies, with largest amplitudes observed at 500 Hz in healthy controls and at 1000 Hz in Menière’s ears (Rauch et al., 2004; Node et al., 2005; Kim-Lee et al., 2009). In all three studies, however, MD patients had an older age than controls, so that for the lack of age-matching, the results must be interpreted with caution. In our study, age-matched controls were examined to avoid an age-related bias. Moreover, MRI-based visualization of endolymphatic hydrops allowed conducting the study in patients with certain Menière’s disease. In these Menière’s patients, we demonstrated a diminished 500/ 1000 Hz ratio compared to both unaffected Menière’s ears and controls, whereas absolute amplitudes in response to 500 Hz only showed a non-significant trend towards diminished amplitudes. The oVEMP 500/1000 Hz ratio thus seems to better differentiate Menière’s patients from healthy subjects than absolute amplitudes. Particularly in younger subjects, a diminished oVEMP amplitude
ratio may be diagnostically valuable because the physiologically decreasing response prevalence in older subjects reduces the utility of oVEMP results and because age itself has an influence on frequency tuning similar to MD. In our study, we examined patients and controls in a broad age range, with oVEMP response prevalence decreasing with age. In comparison to previous reports, the response prevalence in healthy subjects was slightly lower in our study population, which is most probably due to the relatively old age. In order to be able to calculate ratios and avoid division by zero, amplitudes were defined as 1 mV if no oVEMP could be elicited. This way allowed for calculation of ratios for subjects who had clear oVEMP in response to 500 Hz but lacked oVEMP to 1000 Hz (which was the case in a few healthy subjects) or the other way round (which was the case for several Menière’s patients). In case that oVEMP were absent in response to both 500 and 1000 Hz, the amplitude ratio was defined as 1. A low response prevalence may therefore artificially reduce the amplitude ratio. Absence of oVEMP to both frequencies, however, occurred similarly frequently in all groups. Accordingly, an analysis of only those individuals with detectable oVEMP revealed slightly higher mean values for the amplitude ratio in all groups, while the significant differences between MD and contralateral as well as healthy ears were largely the same as for the original analysis. In contrast to the previous results by Winters et al. (2012), we did not observe any significant differences between unaffected Menière’s ears and healthy controls in terms of amplitudes, which may be due to age-matching. The 500/1000 Hz ratio was not altered in unaffected ears of MD patients, either. Hence, our results do not support previous speculations that oVEMP aberrancy in unaffected ears might indicate asymptomatic endolymphatic hydrops in the contralateral ear. To explain the upward shift in frequency tuning, a massstiffness-model has been proposed (Todd et al., 2000). The mass of the otoconia in otolith organs induces an inertial force, whereas stiffness is provided by the inelastic membranous labyrinth and the viscid mesh-gel layer on the sensory hair cells. These elements have contrary effects in frequency tuning. Mass limits stimulation by high frequencies, whereas stiffness limits responses to low frequencies. Endolymphatic hydrops in Menière’s disease causes increased stiffness which in turn may limit the transmission of low frequencies and cause an upward shift in frequency tuning. In consideration of the influence of age, however, other factors than endolymphatic hydrops must be involved. An age-related loss of hair cells in the otolithic macula as well as a reduction in the number and density of otoconia is likely to contribute to a shift in oVEMP frequency tuning (Taylor et al., 2012a). Reduced otolith mass may result in altered resonance and thus modify frequency tuning. In our patients with certain Menière’s disease, we did not detect any factors which were associated with a diminished oVEMP frequency ratio. Neither the degree of cochlear or vestibular hydrops nor the duration since the onset of audiovestibular symptoms showed a significant correlation with a diminished amplitude ratio. Age is known to strongly influence oVEMP results and was correlated with a decreasing 500/1000 Hz ratio in healthy ears. In Menière’s ears, however, age was not associated with a diminished oVEMP ratio. Hence, it remains unclear why a diminished 500/ 1000 Hz ratio develops in Menière’s patients and by which means it is influenced. In summary, our study confirms altered frequency tuning characteristics of oVEMP in patients with certain MD compared to an age-matched control group, supporting the office-based use of these two stimulus frequencies in the diagnostic work-up of vertigo patients.
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Acknowledgements The Eclipse VEMP recording system was provided by Interacoustics for the duration of the study. This study was supported by the Federal German Ministry of Education and Research (grant No. 01EO0901). References AAO-HNS guidelines, 1995. Committee on hearing and equilibrium guidelines for the diagnosis and evaluation of therapy in Menière’s disease. American Academy of Otolaryngology-Head and Neck Foundation, Inc Otolaryngol. Head Neck Surg. 113, 181e185. Gürkov, R., Flatz, W., Louza, J., Strupp, M., Ertl-Wagner, B., Krause, E., 2012. In vivo visualized endolymphatic hydrops and inner ear functions in patients with electrocochleographically confirmed Ménière’s disease. Otol. Neurotol. 33, 1040e1045. Hallpike, C.S., Cairns, H., 1938. Observations on the pathology of Meniere’s syndrome: (section of otology). Proc. R. Soc. Med. 31, 1317e1336. Huang, C.H., Wang, S.J., Young, Y.H., 2011. Localization and prevalence of hydrops formation in Meniere’s disease using a test battery. Audiol. Neurootol. 16, 41e48. Iwasaki, S., McGarvie, L.A., Halmagyi, G.M., Burgess, A.M., Kim, J., Colebatch, J.G., Curthoys, I.S., 2007. Head taps evoke a crossed vestibulo-ocular reflex. Neurology 68, 1227e1229. Kantner, C., Gürkov, R., 2012. Characteristics and clinical applications of ocular vestibular evoked myogenic potentials. Hear Res. 294, 55e63. Kim-Lee, Y., Ahn, J.H., Kim, Y.K., Yoon, T.H., 2009. Tone burst vestibular evoked myogenic potentials: diagnostic criteria in patients with Ménière’s disease. Acta Otolaryngol. 129, 924e928. Lewis, A., Mustain, W., Xu, Y., Eby, T., Zhou, W., 2010. Frequency tuning in the tone burst-evoked myogenic potentials in extraocular muscles in normal human subjects. Otolaryngol. Head Neck Surg. 39, 491e497. Manzari, L., Tedesco, A.R., Burgess, A.M., Curthoys, I.S., 2010. Ocular and cervical vestibular evoked myogenic potentials to bone conducted vibration in Meniere’s disease during quiescence vs during acute attacks. Clin. Neurophysiol. 121, 1092e1101. Murnane, O.D., Akin, F.W., Kelly, K.J., Byrd, S., 2011. Effects of stimulus and recording parameters on the air conduction ocular vestibular evoked myogenic potential. J. Am. Acad. Audiol. 22, 469e480. Naganawa, S., Yamazaki, M., Kawai, H., Bokura, K., Sone, M., Nakashima, T., 2010. Visualization of endolymphatic hydrops in Ménière’s disease with single-dose intravenous gadolinium-based contrast media using heavily T(2)-weighted 3D-FLAIR. Magn. Reson Med. Sci. 9, 237e242. Naganawa, S., Suzuki, K., Nakamichi, R., Bokura, K., Yoshida, T., Sone, M., Homann, G., Nakashima, T., Ikeda, M., 2013. Semi-quantification of
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endolymphatic size on MR imaging after intravenous injection of single-dose gadodiamide: comparison between two types of processing strategies. Magn. Reson Med. Sci. 25, 261e269. Nakashima, T., Naganawa, S., Sugiura, M., Teranishi, M., Sone, M., Hayashi, H., Nakata, S., Katayama, N., Ishida, I.M., 2007. Visualization of endolymphatic hydrops in patients with Meniere’s disease. Laryngoscope 117, 415e420. Nguyen, K.D., Welgampola, M.S., Carey, J.P., 2010. Test-retest reliability and age related characteristics of the ocular and cervical vestibular evoked myogenic potential tests. Otol. Neurotol. 31, 793e802. Node, M., Seo, T., Miyamoto, A., Adachi, A., Hashimoto, M., Sakagami, M., 2005. Frequency dynamic shifts of vestibular evoked myogenic potentials in patients with endolymphatic hydrops. Otol. Neurotol. 26, 1208e1213. Park, H.J., Lee, I.S., Shin, J.E., Lee, Y.J., Park, M.S., 2010. Frequency-tuning characteristics of cervical and ocular vestibular evoked myogenic potentials induced by air-conducted tone bursts. Clin. Neurophysiol. 121, 85e89. Piker, E.G., Jacobson, G.P., McCaslin, D.L., Hood, L.J., 2011. Normal characteristics of the ocular vestibular evoked myogenic potential. J. Am. Acad. Audiol. 22, 222e230. Piker, E.G., Jacobson, G.P., Burkard, R.F., McCaslin, D.L., Hood, L.J., 2013. Effects of age on the tuning of the cVEMP and oVEMP. Ear Hear 34, e65e73. Rauch, S.D., Zhou, G., Kujawa, S.G., Guinan, J.J., Herrmann, B.S., 2004. Vestibular evoked myogenic potentials show altered tuning in patients with Meniere’s disease. Otol. Neurotol. 25, 333e338. Rosengren, S.M., Welgampola, M.S., Colebatch, J.G., 2010. Vestibular evoked myogenic potentials: past, present and future. Clin. Neurophysiol. 121, 636e651. Sandhu, J.S., Low, R., Rea, P.A., Saunders, N.C., 2012. Altered frequency dynamics of cervical and ocular vestibular evoked myogenic potentials in patients with Ménière’s disease. Otol. Neurotol. 33, 444e449. Taylor, R.L., Wijewardene, A.A., Gibson, W.P., Black, D.A., Halmagyi, G.M., Welgampola, M.S., 2011. The vestibular evoked-potential profile of Ménière’s disease. Clin. Neurophysiol. 122, 1256e1263. Taylor, R.L., Bradshaw, A.P., Halmagyi, G.M., Welgampola, M.S., 2012a. Tuning characteristics of ocular and cervical vestibular evoked myogenic potentials in intact and dehiscent ears. Audiol. Neurootol. 17, 207e218. Taylor, R.L., Zagami, A.S., Gibson, W.P., Black, D.A., Watson, S.R., Halmagyi, M.G., Welgampola, M.S., 2012b. Vestibular evoked myogenic potentials to sound and vibration: characteristics in vestibular migraine that enable separation from Meniere’s disease. Cephalalgia 32, 213e225. Todd, N.P., Cody, F.W., Banks, J.R., 2000. A saccular origin of frequency tuning in myogenic vestibular evoked potentials? Implications for human responses to loud sounds. Hear Res. 141, 180e188. Winters, S.M., Campschroer, T., Grolman, W., Klis, S.F., 2011. Ocular vestibular evoked myogenic potentials in response to air-conducted sound in Meniere’s disease. Otol. Neurotol. 32, 1273e1280. Winters, S.M., Berg, I.T., Grolman, W., Klis, S.F., 2012. Ocular vestibular evoked myogenic potentials: frequency tuning to air-conducted acoustic stimuli in healthy subjects and Meniere’s disease. Audiol. Neurootol. 17, 12e19.
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Hearing Research journal homepage: www.elsevier.com/locate/heares
Research paper
Ocular vestibular evoked myogenic potential frequency tuning in certain Menière’s disease Claudia Jerin a, *, Albert Berman a, Eike Krause a, b, Birgit Ertl-Wagner c, Robert Gürkov a, b a
German Center for Vertigo and Balance Disorders, Grosshadern Medical Center, University of Munich, Marchioninistr. 15, 81377 Munich, Germany Department of Otorhinolaryngology e Head and Neck Surgery, Grosshadern Medical Center, University of Munich, Marchioninistr. 15, 81377 Munich, Germany c Institute of Clinical Radiology, Grosshadern Medical Center, University of Munich, Marchioninistr. 15, 81377 Munich, Germany b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 10 December 2013 Received in revised form 27 January 2014 Accepted 4 February 2014 Available online 14 February 2014
Ocular vestibular evoked myogenic potentials (oVEMP) represent extraocular muscle activity in response to vestibular stimulation. To specify the value of oVEMP in the diagnostics of Menière’s disease, the amplitude ratio between 500 and 1000 Hz stimuli was investigated. Thirty-nine patients with certain Menière’s disease, i.e. definite Menière’s disease with visualization of endolymphatic hydrops by magnetic resonance imaging and 19 age-matched healthy controls were enrolled in this study. oVEMP were recorded using 500 and 1000 Hz air-conducted tone bursts. For Menière’s ears, the 500/1000 Hz amplitude ratio (mean ratio ¼ 1.20) was significantly smaller when compared to unaffected ears of Menière’s patients (mean ratio ¼ 1.80; p ¼ 0.008) or healthy controls (mean ratio ¼ 1.81; p ¼ 0.011). The amplitude ratio was neither correlated with the degree of endolymphatic hydrops nor with the duration of disease. While an older age was associated with a diminished amplitude ratio in healthy controls, there was no correlation between the amplitude ratio and age in Menière’s ears. Hence, the calculation of the oVEMP 500/1000 Hz amplitude ratio may be a valuable diagnostic tool for Menière’s disease. Ó 2014 Elsevier B.V. All rights reserved.
Keywords: Vestibular evoked myogenic potential oVEMP Frequency tuning Menière’s disease
1. Introduction Menière’s disease (MD) is a disorder of the inner ear which is characterized by attacks of vertigo, tinnitus and cochlear hearing loss. The pathological hallmark of MD is endolymphatic hydrops (ELH) (Hallpike and Cairns, 1938), even though its role in the pathophysiology of the disease remains unclear. Recently, MR imaging has been used to visualize endolymphatic hydrops in MD patients in vivo, using the intratympanic (Nakashima et al., 2007; Gürkov et al., 2012) or the intravenous (Naganawa et al., 2010) route of contrast agent application. This method enables diagnostic certainty which hitherto could only be achieved by histological post-mortem examination (AAO-HNS, 1995).
Abbreviations: ACS, Air-conducted sound; BCV, Bone-conducted vibration; cVEMP, Cervical vestibular evoked myogenic potentials; ELH, Endolymphatic hydrops; LEIM, Locally enhanced inner ear MR imaging; MD, Menière’s disease; oVEMP, Ocular vestibular evoked myogenic potentials * Corresponding author. Tel.: þ49 89 7095 0; fax: þ49 89 7095 6869. E-mail address: [email protected] (C. Jerin). http://dx.doi.org/10.1016/j.heares.2014.02.001 0378-5955/Ó 2014 Elsevier B.V. All rights reserved.
Ocular vestibular evoked myogenic potentials (oVEMP) are short-latency myogenic potentials which can be elicited in response to vestibular stimulation, e.g. by air-conducted sound (ACS) or bone-conducted vibration (BCV) (Kantner and Gürkov, 2012). Otolithic afferent neurons trigger reflexive electromyographic activity of the extraocular muscles which can be recorded beneath the eye contralateral to the stimulated ear by use of surface electrodes. The pathway from the human otolith organs to the extraocular muscles reflects the vestibulo-ocular reflex (Iwasaki et al., 2007; Rosengren et al., 2010). The oVEMP waveform begins with a negative peak with a latency of about 10 ms (n1), followed by a positive peak at about 15 ms (p1). oVEMP can be applied in the diagnostic work-up of vestibular disorders like Menière’s disease. In contrast to BCV oVEMP, ACS oVEMP can be elicited by audiological equipment approved for routine clinical use. However, the published literature shows wide variation in oVEMP results in MD. While some studies reported a declined response prevalence, decreased oVEMP amplitudes and increased thresholds (Huang et al., 2011; Winters et al., 2011), other studies observed enhanced amplitudes in early stages of MD and
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during acute attacks (Manzari et al., 2010). The value of oVEMP in the diagnostics of MD thus still needs to be specified. We recorded ACS oVEMP in response to the most commonly used frequencies of 500 and 1000 Hz with a standard clinical VEMP equipment in order to investigate oVEMP frequency tuning characteristics in certain Menière’s disease. 2. Methods 2.1. Patients The study was conducted at a large tertiary referral centre for vestibular disorders. Thirty-nine consecutive patients with ascertained unilateral Menière’s disease, i.e. patients with definite Menière’s disease according to the AAO-HNS guidelines (AAO-HNS, 1995) and visualization of endolymphatic hydrops by locally enhanced inner ear MR imaging (LEIM), participated in this study (mean age ¼ 53.0 years; range ¼ 18e71 years). These patients represented an average population of Menière’s patients including different MD stages. Clinical characteristics of the study population are summarized in Table 1. MR imaging and oVEMP recording were performed during a quiescent interval between vertigo attacks. Furthermore, 19 healthy subjects without any history of vertigo or hearing loss were enrolled. The control group was representative of the experimental group in terms of mean age and age range (mean age ¼ 52.2 years; range ¼ 18e73 years). The study protocol was approved by the institutional review board (Protocol No. 210-12) and all subjects gave written informed consent prior to participation in the study.
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sequence was performed to evaluate the anatomy of the whole fluid-filled labyrinth spaces, with the following parameters: TR 6.24 ms, TE 2.87 ms, flip angle of 70 , field of view of 160 mm, matrix size of 320 320, average of 1, and slice thickness of 0.4 mm. ELH was observed as enlarged spaces with hypointense signal inside the labyrinth, as opposed to the contrast-enhanced perilymphatic space, which has a high signal intensity on the T1weighted sequence. Grading of ELH severity on a scale of 0e3 was performed as described previously (Gürkov et al., 2012): 0: no hydrops, 1: mild hydrops, 2: marked hydrops, 3: extreme hydrops. Examples of different grades of endolymphatic hydrops are shown in Fig. 1. Vestibular ELH severity was quantified by measuring the areas occupied by endolymph and perilymph space, respectively, and calculating the endolymph/perilymph space ratio as described previously (Gürkov et al., 2012). The slice for measurement of vestibular ELH was chosen at the level of the horizontal semicircular canal, as previously described (Naganawa et al., 2013). LEIM
2.2. Locally enhanced inner ear MR imaging (LEIM) A Gadolinium-based contrast medium, Gadopentetatedimuglumine (Magnograf, Marotrast, Jena, Germany), was diluted 8-fold in saline solution and injected intratympanically (0.4 ml) under microscopic control, as described previously (Gürkov et al., 2012). The patients remained in a supine position for further 30 min with the head turned 45 toward the contralateral side, instructed not to speak or chew during this period. MRI scans were performed 24 h after application of the contrast agent on a 3T MR scanner (Magnetom Verio; Siemens Healthcare, Erlangen, Germany) using a commercially available 32-channel head coil. A 3D-IR-TSE sequence was acquired with the following parameters: TR 7000 ms, TE 128 ms, TI 1700 m, constant flip angle of 180 , echo train length of 23, matrix size of 384 384, at 0.6 mm slice thickness, and number of excitations 1. The labyrinth was scanned with a square field of view of 16 cm, parallel imaging with a factor of 2 was used using GRAPPA reconstruction. Total scan time for this sequence was 14 min. In addition, a high-resolution strongly T2-weighted CISS
Table 1 Characteristics of the study population (n ¼ 39). Male/female Age (years) Disease duration (months) Pure tone average 0.5e3 kHz (dB) Canal paresis (%) Degree of cochlear hydrops Degree of vestibular hydrops Endolymph/perilymph space ratio (%) Stage: 1 2 3 4
19/20 53.0 13.6 (range 18e71) 109 100 (range 9e420) 50 23 (range 16e130) 34 21 (range 2e83) 1.9 0.7 (range 0e3) 2.1 1.0 (range 0e3) 50 18 (range 18e83) n¼6 n¼8 n ¼ 19 n¼6
Staging was based on the pure-tone average at 0.5e3 kHz (AAO-HNS, 1995). Values are expressed as mean SD.
Fig. 1. Locally enhanced inner ear MR imaging of right ears with evidence of mild (A), moderate (B) and severe (C) vestibular endolymphatic hydrops (arrows point out the vestibulum). Bright areas represent perilymphatic space, dark areas within the inner ear represent endolymphatic space.
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evaluation was performed as a blinded consensus reading by an experienced head and neck radiologist and an experienced neurotologist.
variables. Descriptive statistics are expressed as mean standard error (SE). Statistical significance was determined at the p < 0.05 level.
2.3. oVEMP recording
3. Results
Twenty-four hours prior to MR imaging, 500 Hz and 1000 Hz air-conducted tone bursts were presented monaurally via a pair of calibrated ABR3A insert earphones at an intensity of 100 dB nHL, using the following stimulus profile: 2 ms rise time, 2 ms plateau time and 2 ms fall time. Averaging of the responses to 100e150 stimulus repetitions, presented at a repetition rate of 5.1/s, ensured sufficient reproducibility. oVEMP were recorded using an Eclipse EP 25 VEMP evoked potential system (Interacoustics AS, Assens, Denmark). Surface EMG electrodes were placed on the skin beneath the eye contralateral to the stimulated ear, with the recording electrodes positioned inferior to the lower-lid margin and the reference electrodes 2e3 cm below on the cheek. The ground electrode was placed on the forehead. Impedances were maintained below 3 kU oVEMP were recorded with the subjects lying supine. Prior to the beginning of the recording, subjects were instructed to look upward at a marking on the wall located closely behind their head at a distance of 1 m, corresponding to a 35 upward gaze angle. The EMG was amplified (60 dB), bandpass filtered (10 Hze750 Hz) and recorded from 10 ms before to 70 ms after stimulus onset. From each subject, at least two separate measurements (three measurements, of the first two differed by more than 20%) were performed and mean amplitude and latency values were used for analysis. oVEMP amplitudes were determined as n1-p1 peak-topeak amplitudes. If no reliable oVEMP waveform could be elicited, the amplitude was defined as 1 mV in order to calculate ratios and to avoid division by 0. In cases where the oVEMP was neither elicited by 500 nor by 1000 Hz stimuli, the amplitude ratio was artificially set at 1. In order to exclude the effects of fatigue, the sequence of the 500 Hz stimulus testing and the 1000 Hz stimulus testing was randomized.
Examples of oVEMP waveforms recorded in response to 500 Hz and 1000 Hz are shown in Fig. 2. Descriptive oVEMP statistics recorded from affected Menière’s ears, unaffected ears and healthy controls in response to 500 Hz and 1000 Hz tone bursts are summarized in Table 2.
2.4. Data analysis Data analysis was performed with IBM SPSS Statistics 20 (SPSS Inc., Chicago, IL, USA). Data were analyzed descriptively and by using the non-parametric Kruskal-Wallis-test for comparison between three groups (MD ear, contralateral ear, control ear) and Mann-Whitney-test for comparison between two groups (e.g. MD and control groups). Correlation was calculated using the Spearman’s rank correlation coefficient for non-parametric
3.1. oVEMP amplitudes In response to 500 Hz tone bursts, reproducible oVEMP waveforms could be elicited in 69%, 77% and 76% of Menière’s ears, contralateral ears and healthy controls, respectively. The response prevalence in Menière’s, unaffected and healthy ears for 1000 Hz was 69%, 72% and 61%, respectively. In response to 500 Hz tone bursts, Menière’s ears generated the smallest amplitudes (mean n1ep1 amplitude 2.65 mV), whereas the largest amplitudes were observed for the unaffected ears of Menière’s patients (mean n1e p1 amplitude 3.73 mV) (Fig. 3). However, amplitude differences between groups were not significant (p ¼ 0.117). Regarding oVEMP amplitudes in response to 1000 Hz, healthy controls showed a trend to produce the smallest amplitudes (mean 1.69 mV), while similar oVEMP were measured in affected and unaffected Menière’s ears (mean 2.67 mV each). For amplitudes in response to the 1000 Hz stimulus, group comparison did not reveal statistical significance, either (p ¼ 0.458). 3.2. 500/1000 Hz amplitude ratio The mean 500/1000 Hz amplitude ratios amounted to 1.20, 1.80 and 1.81 for Menière’s ears, unaffected ears and healthy controls, respectively (Fig. 4). The 500/1000 Hz ratio was significantly smaller for affected ears when compared to unaffected ears (p ¼ 0.008) or healthy controls (p ¼ 0.011). 500/1000 Hz ratios in unaffected and healthy ears, however, did not differ from each other (p ¼ 0.951). From MD ears, contralateral ears and healthy controls, 9, 8 and 9 ears showed no reliable oVEMP in response to both 500 and 1000 Hz, so that the ratio in these cases was artificially defined as 1. When considering only those individuals with oVEMP responses, the 500/1000 Hz amplitude ratio amounted to 1.26, 2.01 and 2.06 for MD, unaffected and healthy ears, respectively. Again, the amplitude ratio was significantly smaller for MD ears when
Fig. 2. Examples of oVEMP waveforms recorded in a healthy subject (A) and an MD patient (B) in response to 500 Hz and 1000 Hz.
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Table 2 Amplitudes and latencies in response to 500 Hz and 1000 Hz tone bursts.
500 Hz Response prevalence n1ep1 amplitude (mV) n1 latency (ms) p1 latency (ms) 1000 Hz Response prevalence n1ep1 amplitude (mV) n1 latency (ms) p1 latency (ms) 500/1000 Hz ratio 500/1000 Hz ratio when considering only the individuals with oVEMP responses
Menière’s ears (n ¼ 39)
Unaffected ears (n ¼ 39)
Controls (n ¼ 38)
27 (69%) 2.65 0.39 11.44 0.22 15.70 0.25
30 (77%) 3.73 0.49 11.73 0.38 16.13 0.39
29 (76%) 3.04 0.46 11.26 0.20 16.20 0.23
27 (69%) 2.67 0.43 11.46 0.29 15.81 0.30 1.20 0.14 1.26 0.18 (n ¼ 30)
28 (72%) 2.67 0.48 11.56 0.39 16.24 0.37 1.80 0.23 2.01 0.28 (n ¼ 31)
23 (61%) 1.69 0.13 11.43 0.25 16.15 0.32 1.81 0.31 2.06 0.40 (n ¼ 29)
Values are expressed as mean SE.
compared to contralateral ears (p ¼ 0.009) or healthy controls (p ¼ 0.010), whereas the ratio in contralateral and healthy ears did not differ from each other (p ¼ 0.935). 3.3. oVEMP latencies N1 and p1 latencies in response to both 500 and 1000 Hz were comparable between affected, unaffected and healthy ears, revealing no significant differences (p ¼ 0.815 and p ¼ 0.305 for n1 and p1 to 500 Hz; p ¼ 0.715 and p ¼ 0.770 for n1 and p1 to 1000 Hz). Latency values are summarized in Table 2. 3.4. Correlation of the oVEMP 500/1000 Hz ratio with other audiovestibular function parameters, disease duration and severity of endolymphatic hydrops To investigate whether a diminished 500/1000 Hz oVEMP ratio in Menière’s patients is associated with the extent of endolymphatic hydrops or with other audiovestibular test results, a correlation analysis was performed. A significant correlation was neither
Fig. 4. The 500/1000 Hz amplitude ratio in Menière’s ears, contralateral ears and controls. Error bars represent the SE. Significance levels are indicated by asterisks (*p < 0.05; **p < 0.01).
observed between the oVEMP 500/1000 Hz ratio and the degree of hydrops in the cochlea (rho ¼ 0.210; p ¼ 0.200) nor between the amplitude ratio and the degree of vestibular hydrops (rho ¼ 0.056; p ¼ 0.736). There was no correlation between the oVEMP ratio and the endolymph-to-perilymph-space-ratio, either (rho ¼ 0.093; p ¼ 0.583). Furthermore, there was no significant correlation between the oVEMP amplitude ratio and the pure tone hearing level average at 0.5, 1, 2 and 3 kHz (rho ¼ 0.067; p ¼ 0.684) or between the amplitude ratio and the degree of lateral semicircular canal paresis on caloric irrigation (rho ¼ 0.117; p ¼ 0.479). Disease duration was defined as the time period from the onset of the first audiovestibular symptoms. The oVEMP 500/1000 Hz ratio and disease duration were not significantly correlated (rho ¼ 0.189; p ¼ 0.249). 3.5. Correlation of the oVEMP 500/1000 Hz ratio with age Given that oVEMP are known to be modulated by age, we investigated the relationship between the 500/1000 Hz ratio and the subjects’ age. In healthy controls, an older age was associated with a decreasing oVEMP 500/1000 Hz ratio. This correlation was highly significant (rho ¼ 0.494; p ¼ 0.002). A similar relationship was observed for the unaffected ears of Menière’s patients, albeit the correlation was not as strong as for the control subjects (rho ¼ 0.344; p ¼ 0.032). In the affected ears of Menière’s patients, however, age was not correlated with the oVEMP amplitude ratio (rho ¼ 0.054; p ¼ 0.742). 4. Discussion
Fig. 3. Amplitudes obtained in response to 500 Hz and 1000 Hz in affected and contralateral ears in MD patients and healthy control subjects. Mean values are shown. Error bars represent the SE. There were no significant differences between groups.
The published literature regarding the optimal frequency to elicit air-conducted oVEMP in healthy subjects shows wide variation. Several studies found the largest amplitudes in response to 500 Hz tone bursts (Murnane et al., 2011; Park et al., 2010), whereas others achieved best oVEMP results in response to 1000 Hz tone bursts (Lewis et al., 2010; Taylor et al., 2012a). A recent study observed largest amplitudes in response to 750 Hz, although there were no significant differences in amplitude for 500, 750 and 1000 Hz (Piker et al., 2013). Hence, a variety of frequencies appears to be suitable for evoking oVEMP in healthy subjects. There is, however, strong evidence for the influence of a subject’s age upon the optimal frequency, with the tuning of oVEMP for older adults
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shifting towards higher frequencies (Taylor et al., 2012a; Piker et al., 2013). In Menière’s disease, air-conducted oVEMP are characterized by a declined response prevalence, decreased amplitudes and increased thresholds in the interval between attacks (Huang et al., 2011; Winters et al., 2011). Other studies, in contrast, observed enhanced amplitudes in early stages of MD and during acute attacks (Manzari et al., 2010). oVEMP response rates in MD have been reported variably as well, in a wide range of 10e70% (Taylor et al., 2011; Sandhu et al., 2012; Winters et al., 2011; Taylor et al., 2012b), which may be influenced by different disease stage and disease activity, but also by different stimulus parameters and recording conditions. Furthermore, MD was reported to result in altered frequency tuning characteristics of oVEMP. In MD-affected ears, largest amplitudes and lowest thresholds were achieved using 1000 Hz tone bursts, whereas healthy controls and unaffected MD ears yielded best oVEMP results upon 500 Hz tone bursts (Winters et al., 2012). In the same study, even the unaffected ears of MD patients revealed decreased amplitudes and higher thresholds in response to both 500 Hz and 1000 Hz when compared to healthy subjects, albeit abnormalities in MD-affected ears were more strongly pronounced (Winters et al., 2012). This study, however, did not use age-matched controls. The mean age of Menière’s patients was 56 years, while the healthy control cohort had a mean age of 30 years. In consideration of the well-known effects of age on oVEMP frequency tuning, the observed shift towards higher-frequency tuning in patients when compared to healthy subjects cannot be solely attributed to the diagnosis of MD in their study. Moreover, the difference in terms of age does not permit a comparison of absolute amplitudes between controls and affected or unaffected Menière’s ears, since several studies described decreased oVEMP amplitudes in older individuals (Nguyen et al., 2010; Piker et al., 2011). Similarly, a shift towards higher frequencies in patients with Menière’s disease when compared to healthy subjects and contralateral ears has been reported, with this shift being more pronounced in definite than in probable MD (Sandhu et al., 2012). In this study, however, subjects were not age-matched, either (average age 53 years for the Menière group and 31 years for the control group). Taylor et al. (2012b) reported that both 500 Hz and 1000 Hz were optimal frequencies for controls and unaffected MD ears, whereas the 1000 Hz stimulus produced larger amplitudes than the 500 Hz stimulus in affected MD ears. The authors, however, did not calculate the amplitude ratio and conceded that the low oVEMP response prevalence (45% for MD ears to 500 Hz) in this study limited its clinical utility. Correspondingly, a shift toward higher-frequency tuning has been reported for air-conducted cervical vestibular evoked myogenic potentials (cVEMP) in several studies, with largest amplitudes observed at 500 Hz in healthy controls and at 1000 Hz in Menière’s ears (Rauch et al., 2004; Node et al., 2005; Kim-Lee et al., 2009). In all three studies, however, MD patients had an older age than controls, so that for the lack of age-matching, the results must be interpreted with caution. In our study, age-matched controls were examined to avoid an age-related bias. Moreover, MRI-based visualization of endolymphatic hydrops allowed conducting the study in patients with certain Menière’s disease. In these Menière’s patients, we demonstrated a diminished 500/ 1000 Hz ratio compared to both unaffected Menière’s ears and controls, whereas absolute amplitudes in response to 500 Hz only showed a non-significant trend towards diminished amplitudes. The oVEMP 500/1000 Hz ratio thus seems to better differentiate Menière’s patients from healthy subjects than absolute amplitudes. Particularly in younger subjects, a diminished oVEMP amplitude
ratio may be diagnostically valuable because the physiologically decreasing response prevalence in older subjects reduces the utility of oVEMP results and because age itself has an influence on frequency tuning similar to MD. In our study, we examined patients and controls in a broad age range, with oVEMP response prevalence decreasing with age. In comparison to previous reports, the response prevalence in healthy subjects was slightly lower in our study population, which is most probably due to the relatively old age. In order to be able to calculate ratios and avoid division by zero, amplitudes were defined as 1 mV if no oVEMP could be elicited. This way allowed for calculation of ratios for subjects who had clear oVEMP in response to 500 Hz but lacked oVEMP to 1000 Hz (which was the case in a few healthy subjects) or the other way round (which was the case for several Menière’s patients). In case that oVEMP were absent in response to both 500 and 1000 Hz, the amplitude ratio was defined as 1. A low response prevalence may therefore artificially reduce the amplitude ratio. Absence of oVEMP to both frequencies, however, occurred similarly frequently in all groups. Accordingly, an analysis of only those individuals with detectable oVEMP revealed slightly higher mean values for the amplitude ratio in all groups, while the significant differences between MD and contralateral as well as healthy ears were largely the same as for the original analysis. In contrast to the previous results by Winters et al. (2012), we did not observe any significant differences between unaffected Menière’s ears and healthy controls in terms of amplitudes, which may be due to age-matching. The 500/1000 Hz ratio was not altered in unaffected ears of MD patients, either. Hence, our results do not support previous speculations that oVEMP aberrancy in unaffected ears might indicate asymptomatic endolymphatic hydrops in the contralateral ear. To explain the upward shift in frequency tuning, a massstiffness-model has been proposed (Todd et al., 2000). The mass of the otoconia in otolith organs induces an inertial force, whereas stiffness is provided by the inelastic membranous labyrinth and the viscid mesh-gel layer on the sensory hair cells. These elements have contrary effects in frequency tuning. Mass limits stimulation by high frequencies, whereas stiffness limits responses to low frequencies. Endolymphatic hydrops in Menière’s disease causes increased stiffness which in turn may limit the transmission of low frequencies and cause an upward shift in frequency tuning. In consideration of the influence of age, however, other factors than endolymphatic hydrops must be involved. An age-related loss of hair cells in the otolithic macula as well as a reduction in the number and density of otoconia is likely to contribute to a shift in oVEMP frequency tuning (Taylor et al., 2012a). Reduced otolith mass may result in altered resonance and thus modify frequency tuning. In our patients with certain Menière’s disease, we did not detect any factors which were associated with a diminished oVEMP frequency ratio. Neither the degree of cochlear or vestibular hydrops nor the duration since the onset of audiovestibular symptoms showed a significant correlation with a diminished amplitude ratio. Age is known to strongly influence oVEMP results and was correlated with a decreasing 500/1000 Hz ratio in healthy ears. In Menière’s ears, however, age was not associated with a diminished oVEMP ratio. Hence, it remains unclear why a diminished 500/ 1000 Hz ratio develops in Menière’s patients and by which means it is influenced. In summary, our study confirms altered frequency tuning characteristics of oVEMP in patients with certain MD compared to an age-matched control group, supporting the office-based use of these two stimulus frequencies in the diagnostic work-up of vertigo patients.
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Acknowledgements The Eclipse VEMP recording system was provided by Interacoustics for the duration of the study. This study was supported by the Federal German Ministry of Education and Research (grant No. 01EO0901). References AAO-HNS guidelines, 1995. Committee on hearing and equilibrium guidelines for the diagnosis and evaluation of therapy in Menière’s disease. American Academy of Otolaryngology-Head and Neck Foundation, Inc Otolaryngol. Head Neck Surg. 113, 181e185. Gürkov, R., Flatz, W., Louza, J., Strupp, M., Ertl-Wagner, B., Krause, E., 2012. In vivo visualized endolymphatic hydrops and inner ear functions in patients with electrocochleographically confirmed Ménière’s disease. Otol. Neurotol. 33, 1040e1045. Hallpike, C.S., Cairns, H., 1938. Observations on the pathology of Meniere’s syndrome: (section of otology). Proc. R. Soc. Med. 31, 1317e1336. Huang, C.H., Wang, S.J., Young, Y.H., 2011. Localization and prevalence of hydrops formation in Meniere’s disease using a test battery. Audiol. Neurootol. 16, 41e48. Iwasaki, S., McGarvie, L.A., Halmagyi, G.M., Burgess, A.M., Kim, J., Colebatch, J.G., Curthoys, I.S., 2007. Head taps evoke a crossed vestibulo-ocular reflex. Neurology 68, 1227e1229. Kantner, C., Gürkov, R., 2012. Characteristics and clinical applications of ocular vestibular evoked myogenic potentials. Hear Res. 294, 55e63. Kim-Lee, Y., Ahn, J.H., Kim, Y.K., Yoon, T.H., 2009. Tone burst vestibular evoked myogenic potentials: diagnostic criteria in patients with Ménière’s disease. Acta Otolaryngol. 129, 924e928. Lewis, A., Mustain, W., Xu, Y., Eby, T., Zhou, W., 2010. Frequency tuning in the tone burst-evoked myogenic potentials in extraocular muscles in normal human subjects. Otolaryngol. Head Neck Surg. 39, 491e497. Manzari, L., Tedesco, A.R., Burgess, A.M., Curthoys, I.S., 2010. Ocular and cervical vestibular evoked myogenic potentials to bone conducted vibration in Meniere’s disease during quiescence vs during acute attacks. Clin. Neurophysiol. 121, 1092e1101. Murnane, O.D., Akin, F.W., Kelly, K.J., Byrd, S., 2011. Effects of stimulus and recording parameters on the air conduction ocular vestibular evoked myogenic potential. J. Am. Acad. Audiol. 22, 469e480. Naganawa, S., Yamazaki, M., Kawai, H., Bokura, K., Sone, M., Nakashima, T., 2010. Visualization of endolymphatic hydrops in Ménière’s disease with single-dose intravenous gadolinium-based contrast media using heavily T(2)-weighted 3D-FLAIR. Magn. Reson Med. Sci. 9, 237e242. Naganawa, S., Suzuki, K., Nakamichi, R., Bokura, K., Yoshida, T., Sone, M., Homann, G., Nakashima, T., Ikeda, M., 2013. Semi-quantification of
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endolymphatic size on MR imaging after intravenous injection of single-dose gadodiamide: comparison between two types of processing strategies. Magn. Reson Med. Sci. 25, 261e269. Nakashima, T., Naganawa, S., Sugiura, M., Teranishi, M., Sone, M., Hayashi, H., Nakata, S., Katayama, N., Ishida, I.M., 2007. Visualization of endolymphatic hydrops in patients with Meniere’s disease. Laryngoscope 117, 415e420. Nguyen, K.D., Welgampola, M.S., Carey, J.P., 2010. Test-retest reliability and age related characteristics of the ocular and cervical vestibular evoked myogenic potential tests. Otol. Neurotol. 31, 793e802. Node, M., Seo, T., Miyamoto, A., Adachi, A., Hashimoto, M., Sakagami, M., 2005. Frequency dynamic shifts of vestibular evoked myogenic potentials in patients with endolymphatic hydrops. Otol. Neurotol. 26, 1208e1213. Park, H.J., Lee, I.S., Shin, J.E., Lee, Y.J., Park, M.S., 2010. Frequency-tuning characteristics of cervical and ocular vestibular evoked myogenic potentials induced by air-conducted tone bursts. Clin. Neurophysiol. 121, 85e89. Piker, E.G., Jacobson, G.P., McCaslin, D.L., Hood, L.J., 2011. Normal characteristics of the ocular vestibular evoked myogenic potential. J. Am. Acad. Audiol. 22, 222e230. Piker, E.G., Jacobson, G.P., Burkard, R.F., McCaslin, D.L., Hood, L.J., 2013. Effects of age on the tuning of the cVEMP and oVEMP. Ear Hear 34, e65e73. Rauch, S.D., Zhou, G., Kujawa, S.G., Guinan, J.J., Herrmann, B.S., 2004. Vestibular evoked myogenic potentials show altered tuning in patients with Meniere’s disease. Otol. Neurotol. 25, 333e338. Rosengren, S.M., Welgampola, M.S., Colebatch, J.G., 2010. Vestibular evoked myogenic potentials: past, present and future. Clin. Neurophysiol. 121, 636e651. Sandhu, J.S., Low, R., Rea, P.A., Saunders, N.C., 2012. Altered frequency dynamics of cervical and ocular vestibular evoked myogenic potentials in patients with Ménière’s disease. Otol. Neurotol. 33, 444e449. Taylor, R.L., Wijewardene, A.A., Gibson, W.P., Black, D.A., Halmagyi, G.M., Welgampola, M.S., 2011. The vestibular evoked-potential profile of Ménière’s disease. Clin. Neurophysiol. 122, 1256e1263. Taylor, R.L., Bradshaw, A.P., Halmagyi, G.M., Welgampola, M.S., 2012a. Tuning characteristics of ocular and cervical vestibular evoked myogenic potentials in intact and dehiscent ears. Audiol. Neurootol. 17, 207e218. Taylor, R.L., Zagami, A.S., Gibson, W.P., Black, D.A., Watson, S.R., Halmagyi, M.G., Welgampola, M.S., 2012b. Vestibular evoked myogenic potentials to sound and vibration: characteristics in vestibular migraine that enable separation from Meniere’s disease. Cephalalgia 32, 213e225. Todd, N.P., Cody, F.W., Banks, J.R., 2000. A saccular origin of frequency tuning in myogenic vestibular evoked potentials? Implications for human responses to loud sounds. Hear Res. 141, 180e188. Winters, S.M., Campschroer, T., Grolman, W., Klis, S.F., 2011. Ocular vestibular evoked myogenic potentials in response to air-conducted sound in Meniere’s disease. Otol. Neurotol. 32, 1273e1280. Winters, S.M., Berg, I.T., Grolman, W., Klis, S.F., 2012. Ocular vestibular evoked myogenic potentials: frequency tuning to air-conducted acoustic stimuli in healthy subjects and Meniere’s disease. Audiol. Neurootol. 17, 12e19.
