Hearing Function After Intratympanic Application of Gadolinium- Based Contrast Agent: A Long-term Evaluation

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1 The Laryngoscope VC 2015 The American Laryngological, Rhinological and Otological Society, Inc. Hearing Function After Intratympanic Application of Gadolinium- Based Contrast Agent: A Long-term Evaluation Julia Louza, MD; Eike Krause, MD; Robert G urkov, MD Objectives/Hypothesis: The aim of this study was to evaluate the long-term influence of intratympanic gadoliniumbased contrast agent on hearing function in patients with possible Menière s disease and normal auditory thresholds who were undergoing locally enhanced magnetic resonance imaging scans. Study Design: Prospective observational cohort study in a tertiary referral university hospital ear, nose, and throat department. Methods: Between 2009 and 2012, 17 patients with possible or probable Menière s disease and a four-tone pure-tone average baseline of <25 db were recruited for our study. Before undergoing intratympanic injection of gadolinium-based contrast agent, all patients underwent a complete audiological evaluation. The study population was then invited back after at least 6 months postinjection for a follow-up auditory evaluation. This consisted of comprehensive clinical and audiological tests on both sides and were evaluated according to the ototoxicity guidelines. Results: A long-term evaluation of our study group revealed no significant difference in the air-conduction pure-tone average. Furthermore, no statistical difference at individual frequencies compared to baseline was found. There was no evidence of ototoxicity in the injected ear. Conclusions: Long-term hearing function assessment after intratympanic application of gadolinium-based agent showed no evidence of ototoxicity. The use of intratympanic gadolinium-based agent in the diagnosis of Menières disease is currently a helpful tool, and seems to be a safe method, especially with regard to auditory function. Key Words: Gadolinium, intratympanic application, hearing function, Menière s disease, long term. Level of Evidence: 4. Laryngoscope, 125: , 2015 INTRODUCTION Until recently, Menière s disease, the idiopathic syndrome of endolymphatic hydrops (ELH), was diagnosed based only on its clinical presentation: aural fullness and/or hearing loss, tinnitus, and recurrent vertigo attacks. The confirmation of the diagnosis was only possible in postmortem investigation. Newer technologies, including magnetic resonance imaging (MRI) and the use of intratympanic gadoliniumbased contrast agent (GBCA), have opened a new era in the diagnosis of ELH and Menière s disease. 1 3 These techniques are particularly important for the differential diagnosis of diseases with similar symptoms, (e.g., vestibular migraine). 4,5 The intravenous use of GBCA in MRI is a very safe method and has been used for more than 20 years. Contraindications are very few: chronic severe kidney disease, acute kidney injury, or history of hypersensibility From the Department of Otorhinolaryngology Head and Neck Surgery, Ludwig-Maximilians University of Munich, Munich, Germany Editor s Note: This Manuscript was accepted for publication February 17, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Julia Louza, MD, Department of Otorhinolaryngology Head and Neck Surgery, Ludwig-Maximilians University of Munich, Marchioninistrasse 15, Munich, Germany. julia. louza@med.uni-muenchen.de DOI: /lary reactions to other GBCAs. Patients with this medical history should avoid GBCA because of the increased risk of nephrogenic systemic fibrosis. 6 Less severe complications include headache, dizziness, and nausea. 7 The intratympanic route of application of GBCA uses the round window transport capacity to access the perilymph system and thus bypasses the cardiovascular system. The result is a stronger signal intensity of relevant structures compared to the intravenous route. 1 The increasing utilization of MRI with intratympanic GBCA injection to evaluate inner ear pathology has raised concerns about the possible side effects of this substance on the function of the inner ear. Experimental studies with animal models have shown that eightfold diluted GBCA did not have any apparent effects on the stria vascularis of guinea pigs. 8 Aprevious clinical study with 21 Menière s disease patients has shown that the intratympanic use of GBCA had no adverse effects on audiological function 1 day after application. 9 Another follow-up study evaluated the hearing function not only directly after application but also 1 week later. The results of this study with 65 patients having possible Menière s disease showed no hearing deterioration. 10 However, the long-term influence of GBCA on hearing function is still unknown. The aim of this study was to evaluate the long-term effects of GBCA on hearing function in patients with normal auditory thresholds.

2 TABLE I. Time After MRI. Time After MRI (mo) No. 17 Mean 20 Median 20 SD 8 Minimum 7 Maximum 34 MRI 5 magnetic resonance imaging; SD 5 standard deviation. MATERIALS AND METHODS Patients Inclusion criteria were possible or probable Menière s disease, 11 age more than 18 years, and a four-tone pure-tone average (PTA) baseline of <25 db, as well as a speech recognition score at 60 db of at least 85%. Therefore, the study population consisted of patients with largely preserved hearing function. Exclusion criteria were previous otologic surgery, ablative therapy (e.g., gentamicin), presence of ventilation tube, and/or any kind of middle ear disease. Contrast-enhanced T1-weighted MRI was used to rule out vestibular schwannoma. The study was performed in a large tertiary referral neurotology center of a university hospital. The study protocol was approved by the local institutional review board, and patients gave their written informed consent. Between 2009 and 2012, 17 consecutive patients (7 male and 10 female) were included. Four patients were injected on the right side and 13 patients on the left side. The side of injection was chosen according to the laterality of aural symptoms as reported by the patients. The average age at the time of MRI was 41 years (range, years). For evaluation of short-term effects, all patients underwent clinical and audiological testing immediately before and 1 day after injection. At least 6 months after MRI, the study population was invited to have a follow-up evaluation, which again included clinical and audiological tests (in both ears at this time). All hearing thresholds were additionally evaluated according to the American Speech-Language- Hearing Association s ototoxicity guidelines. 12 is regularly recalibrated (every 6 months) according to the local university equipment standard. Data Analysis Patient data were stored and analyzed with SPSS software (IBM SPSS Statistics version 22; IBM, Armonk, NY). The analysis included descriptive statistics and Wilcoxon signed rank tests at the P 5.05 level. For comparison of injected side and noninjected side, PTA and McNemar s test was used with a contingency table with a dichotomous trait (deterioration vs. no deterioration), with a 5-dB increase defined as a clinically significant deterioration. RESULTS Immediately after intratympanic injection of GBCA, no adverse reactions were observed. Otomicroscopic and tympanometric control of the tympanic membrane showed regular function on the day after injection. The perforation site was healed in all patients, and there was no sign of middle ear disease. At long-term evaluation, including otomicroscopy and tympanometry, no adverse reactions were observed. and the tympanic membrane had regular function. The average time of long-term evaluation after MRI is shown in Table I. All subjects had enhancement throughout the cochlea after intratympanic injection of GBCA. In five patients (29%) ELH was detected, and in 12 patients (71%) no ELH was detected on MRI according to previously reported criteria. 5 Patients without ELH had the following diagnoses: vestibular migraine (six patients), fluctuating hearing loss (three patients), initial stage of Menières disease without ELH (two patients), and vestibular paroxysmia (one patient). Injected Ear One day after application of GBCA and at the longterm evaluation, no statistical difference in airconduction PTA was found (P >.05; Figs. 1 and 2). Application of GBCA One day before MRI, GBCA was injected into the middle ear of each patient. The procedure was performed under microscopic control with a 27-gauge needle. The patient was lying in a supine position with the head turned 45 to the opposite side. After local anesthesia of the ear canal with 4% tetracaine, about 0.4 ml of GBCA (gadopentetate dimeglumine) diluted eightfold with saline solution was injected through the tympanic membrane. After injection, the patient remained in the supine position, without speaking and swallowing, for 30 minutes so that the injected solution was able to diffuse into the inner ear. Audiologic Evaluation Before and after injection, the tympanic membrane was checked by otomicroscopy and tympanometry. Audiological tests consisted of pure-tone audiometry by air conduction at the frequencies of 250 Hz to 8.0 khz. PTA was calculated at the frequencies 0.5, 1.0, 2.0, and 3.0 khz. 11 All audiometric equipment Fig. 1. Pure-tone average before and 1 day after gadoliniumbased contrast agent injection. 2367

3 Fig. 2. Pure-tone average before and long term after gadoliniumbased contrast agent injection. Table II shows the outcome in percentages at 1 day and at long-term evaluation according to the recommendation of outcome evaluation after otologic surgery. In most cases there was a small change in PTA. The individual frequencies were likewise analyzed at 1 day after injection and at long-term evaluation. No statistical difference from baseline was found (P >.05). For better illustration, the difference of the mean values for each frequency was calculated. Positive values indicate deterioration; negative values indicate improvement (Fig. 3). In 16 patients, no evidence of ototoxicity after longterm evaluation was found. One patient (60 years old, female) had a deterioration of 10 to 20 db in the frequencies 3 khz, 4 khz, 6 khz, and 8 khz. However, this deterioration was not related to the GBCA injection, as she had the same deterioration on the contralateral side. Noninjected Ear The results in long-term control were calculated as described above (Fig. 4). Similar to the injected side, there was a very small deterioration in the long-term control. However, this difference was not significant between injected and noninjected ears in McNemar s binominal distribution test (P 5 1.0). Fig. 3. Mean difference in hearing level at each frequency 1 day and long term after gadolinium-based contrast agent injection. For better illustration of the effect of GBCA alone without the physiological effect of aging, the mean values of the difference of the noninjected side were subtracted from those of the injected side. The results are shown in Figure 5. In all frequencies there was no significant deterioration. DISCUSSION The intratympanic application route of GBCA is being increasingly used in the diagnosis of Menières disease. MRI with GBCA is an important tool, not only for diagnosis, but also in the follow-up, 13 and to evaluate the therapeutic results. 14,15 Furthermore, important new insights into the transport mechanisms of substances across the middle ear can be gained, such as the middle ear - inner ear barrier can be obtained from imaging studies after intratympanic GBCA application. Recently, the oval window could be identified as a major transmission route, whereas traditionally, the round window was thought to be the main entry point into the inner ear. 16,17 Therefore, analysis of possible side effects concerning the cochlea and hearing function is important. Our results show no long-term ototoxicity after the intratympanic use of GBCA for MRI. These results TABLE II. Outcome in Percentage Change. Percentage Change db Better db Worse Mean SD < to to 0 1 to to to One day after Long term Air-conduction, four-tone pure-tone average 0.5, 1, 2, and 3 khz; negative values indicate better hearing. SD 5 standard deviation. 2368

4 Fig. 4. Mean difference in hearing level at each frequency at long term on noninjected ear. confirm the observations of previous studies analyzing hearing thresholds after GBCA, which showed no shortterm side effects or ototoxicity. 9,10 Animal studies from Tanaka et al. 18 showed morphological changes such as shape changing, hair cell impairment, and cell shrinkage in vestibular end organs of bullfrogs after application of fourfold diluted GBCA. With the eightfold and sixteenfold dilution, the morphological changes were less frequent. The mode of application in their study, however, differed markedly from the clinical situation, because the vestibular hair cells and the isolated vestibular organs were bathed directly in the diluted GBCA solution. During clinical application, however, diluted GBCA that is applied intratympanically only enters the inner ear in minute amounts, resulting in a further dilution by a factor of about On the other hand, a different animal study from Kakigi et al. 8 showed no effect of an eightfold dilution on the stria vascularis of guinea pigs. Regarding the distribution of GBCA in the inner ear after intratympanic injection, Yoshika et al. 20 showed that 18% of the injected ears had no or poor round window permeability for GBCA. In addition, they found that 2 hours after application of GBCA, the contrast was clearly visible in the scala vestibule on MRI. However, there were no comments about the possible adverse effects on hearing function after the intratympanic application. A similar study by Fukuoka et al. 21 showed that the distribution of GBCA in the perilymphatic space of the inner ear is variable. GBCA penetrates the inner ear through the round window membrane and reaches all perilymphatic spaces after 24 hours. The patterns of distribution differed individually and probably depended on the size of the endolymphatic space. Regarding hearing function, there was no deterioration of the PTA in all 26 examined ears. With this study, we investigated the possibility of long-term changes in hearing function after application of intratympanic GBCA. The results obtained showed no deterioration in PTA in 17 patients after an average of 19 months postinjection. The minimum observation time was 7 months and the maximum was 34 months. At long-term evaluation, none of the patients reported the subjective feeling of fluctuating hearing loss. The noninjected ear was also analyzed long term to eliminate confounding factors such as the effects of time, age, and an independent bilateral cochlear degeneration (e.g., presbycusis). In one patient, a detailed analysis was performed, as some deterioration appeared 30 months postinjection. She was 60 years old at the time of the MRI. An effect of GBCA could be excluded, as she had a symmetrical deterioration in the noninjected ear. In the higher frequencies only, a slight deterioration after long-term evaluation could be observed. This tendency is probably due to the normal ageing process, as both ears showed the same trend. Limitations of the study were the small study population and the absence of different age cohorts. Particularly for higher frequencies, pure-tone audiometry with frequencies more than 8,000 Hz are needed. CONCLUSION The application of intratympanic GBCA seems to be a safe method, particularly with regard to the hearing function. No long-term effects on hearing threshold could be found. Acknowledgments The authors are grateful to Professor Eva Grill, Department of Epidemiology and German Centre for Vertigo and Balance Disorders, for the discussion of statistical test applications. BIBLIOGRAPHY Fig. 5. Mean difference of the noninjected side subtracted from the injected side at each frequency. 1. Nakashima T, Naganawa S, Sugiura M, et al. Visualization of endolymphatic hydrops in patients with Menières disease. Laryngoscope 2007; 117:

5 2. Pyykk o I, Zou J, Poe D, et al. Magnetic resonance imaging of the inner ear in Menière s disease. Otolaryngol Clin North Am 2010;15: G urkov R, Flatz W, Louza J, et al. In vivo visualized endolymphatic hydrops and inner ear functions in patients with electrocochleographically confirmed Menière s disease. Otol Neurotol 2012;33: Nakada T, Yoshida T, Suga K et al. Endolymphatic space size in patients with vestibular migraine and Menières disease. J Neurol 2014;261: G urkov R, Kantner C, Strupp M, et al. Endolymphatic hydrops in patients with vestibular migraine and auditory symptoms. Eur Arch Otorhinolaryngol 2014;271: Hao D, Ai T, Goerner F, et al. MRI contrast agents: basic chemistry and safety. J Magn Reson Imaging 2012;36: Magnevist injection [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; Kakigi A, Nishimura M, Takeda T, et al. Effects of gadolinium injected into the middle ear on the stria vascularis. Acta Otolaryngol 2008;128: Louza JP, Flatz W, Krause E, et al. Short-term audiologic effect of intratympanic gadolinium contrast agent application in patients with Menières disease. Am J Otolaryngol 2012;33: Louza J, Krause E, G urkov R. Audiologic evaluation of Menière s disease patients one day and one week after intratympanic application of gadolinium contrast agent: our experience in sixty-five patients. Clin Otolaryngol 2013;38: American Academy of Otolaryngology-Head and Neck Foundation, Inc. Committee on Hearing and Equilibrium guidelines for the diagnosis and evaluation of therapy in Menières disease. Otolaryngol Head and Neck Surg 1995;113: American Speech-Language-Hearing Association Audiologic management of individuals receiving cochleotoxic drug therapy [guidelines]. Available at: ASHA 2002 Desk Reference Volume Jerin C, Krause E, Ertl-Wagner B, et al. Longitudinal assessment of endolymphatic hydrops with contrast-enhanced magnetic resonance imaging of the labyrinth. Otol Neurotol 2014;35: G urkov R, Flatz W, Keeser D, et al. Effect of standard-dose Betahistine on endolymphatic hydrops: an MRI pilot study. Eur Arch Otorhinolaryngol 2013;270: G urkov R, Berman A, Dietrich O, et al. MR volumetric assessment of endolymphatic hydrops. Eur Radiol 2015;25: King EB, Salt AN, Eastwood HT, et al. Direct entry of gadolinium into the vestibule following intratympanic applications in Guinea pigs and the influence of cochlear implantation. J Assoc Res Otolaryngol 2011;12: Zou, J, Pyyk o I. Enhanced oval window and block round window passages for middle-inner ear transportation of gadolinium in guinea pigs with a perforated round window membrane. Eur Arch Otorhinolaryngol 2015; 272: Tanaka F, Tanigawa T, Suzuki M, et al. Effects of MRI contrast agents (Omniscan) on vestibular end organs. Acta Otolaryngol 2010;130: Naganawa S, Nakashima T. Visualization of endolymphatic hydrops with MR imaging in patients with Menières disease and related pathologies: current status of its methods and clinical significance. Jpn J Radiol 2014;32: Yoshika M, Naganawa S, Sone M, et al. Individual differences in the permeability of the round window: evaluating the movement of intratympanic gadolinium into the inner ear. Otol Neurotol 2009;30: Fukuoka H, Tsukada K, Miyagawa M, et al. Semi-quantitative evaluation of endolymphatic hydrops by bilateral intratympanic gadolinium-based contrast agent (GBCA) administration with MRI for Menières disease. Acta Otolaryngol 2010;130: