Original Research—Otology and Neurotology

Vestibular Dysfunction in Patients with Enlarged Vestibular Aqueduct Chris K. Zalewski, PhD1,*, Wade W. Chien, MD1,2,*, Kelly A. King, PhD1, Julie A. Muskett, MS1, Rachel E. Baron1, John A. Butman, MD, PhD3, Andrew J. Griffith, MD, PhD1, and Carmen C. Brewer, PhD1

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Abstract Objective. Enlarged vestibular aqueduct (EVA) is the most common inner ear malformation. While a strong correlative relationship between EVA and hearing loss is well established, its association with vestibular dysfunction is less well understood. In this study, we examine the effects of EVA on the vestibular system in patients with EVA. Study Design. Prospective, cross-sectional study of a cohort ascertained between 1999 and 2013. Setting. National Institutes of Health Clinical Center, a federal biomedical research facility. Subjects and Methods. In total, 106 patients with unilateral or bilateral EVA, defined as a midpoint diameter greater than 1.5 mm, were referred or self-referred to participate in a study of the clinical and molecular aspects of EVA. Clinical history was ascertained with respect to the presence or absence of various vestibular signs and symptoms and history of head trauma. Videonystagmography (VNG), cervical vestibular evoked myogenic potential (cVEMP), and rotational vestibular testing (RVT) were performed to assess the vestibular function. Results. Of the patients with EVA, 45% had vestibular signs and symptoms, and 44% of tested patients had abnormal VNG test results. An increased number of vestibular signs and symptoms was correlated with the presence of bilateral EVA (P = .008) and a history of head injury (P \ .001). Abnormal VNG results also correlated with a history of head injury (P = .018). Conclusion. Vestibular dysfunction is common in patients with EVA. However, not all patients with vestibular signs and symptoms have abnormal vestibular test results. Clinicians should be aware of the high prevalence of vestibular dysfunction in patients with EVA. Keywords enlarged vestibular aqueduct, EVA, hearing loss, dizziness, vestibular dysfunction, LVAS, vertigo, VEMP, VNG, RVT

Otolaryngology– Head and Neck Surgery 2015, Vol. 153(2) 257–262 Ó American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0194599815585098 http://otojournal.org

Received September 3, 2014; revised April 1, 2015; accepted April 13, 2015.

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nlarged vestibular aqueduct (EVA) is the most common inner ear malformation associated with earlyonset sensorineural hearing loss.1 It was first described by Mondini2 in 1791, when it was found in conjunction with cochlear malformation in human temporal bone specimens. While EVA is most often associated with Pendred syndrome, it has been associated with multiple other syndromes, including Waardenburg syndrome, branchio-oto-renal syndrome, Noonan syndrome, and oto-facial-cervical syndrome, as well as nonsyndromic hearing loss.3 Pendred syndrome and many cases of nonsyndromic EVA are associated with mutations of the SLC26A4 gene on chromosome 7.4 SLC26A4 encodes an anion-base exchanger called pendrin that is expressed in nonsensory epithelial cells of the cochlea, vestibular end organs, and endolymphatic sac. Slc26a4-deficient mice have acidic endolymph, enlargement of all endolymphcontaining spaces, loss of the endocochlear potential, and elevated auditory brainstem response thresholds.5 Enlargement of the endolymph-containing spaces or the vestibular aqueduct does not appear to be the direct cause of hearing loss in these mice. Rather, the gross malformations appear to be epiphenomenal markers for underlying functional abnormalities of the membranous labyrinth.5 Patients with Pendred syndrome have 2 mutant alleles of SLC26A4, whereas nonsyndromic EVA can be associated

1

National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, Maryland, USA 2 Department of Otolaryngology–Head & Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, USA 3 Clinical Center, National Institutes of Health, Bethesda, Maryland, USA *These authors contributed equally to this work. This article was presented at the 2014 AAO-HNSF Annual Meeting & OTO EXPO; September 21-24, 2014; Orlando, Florida. Corresponding Author: Andrew J. Griffith, MD, PhD, NIDCD/NIH, Porter Neuroscience Research Center, 35A Convent Drive, Room GF103, Bethesda, MD 20892-3729, USA. Email: [email protected]

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with 0, 1, or 2 mutant alleles of SLC26A4. Enlarged vestibular aqueduct can be unilateral or bilateral. It can be detected by computed tomography (CT) or magnetic resonance imaging (MRI). Hearing loss associated with EVA typically has a pre- or perilingual onset. It can be sensorineural or mixed and can fluctuate or progress in an incremental manner. In some patients, sudden declines in hearing can be precipitated by minor head trauma or barotrauma. Such declines may be unilateral, which can account for the observation of unilateral or asymmetric bilateral hearing loss in many patients with EVA. Many studies have sought to identify phenotypicphenotypic and genotypic-phenotypic correlations in patients with EVA. Although some studies have reported that EVA size is correlated with the severity of hearing loss,6,7 many other studies have concluded that EVA size has no effect on the severity of hearing loss.8-10 These disparities may arise from differences in how EVA is measured, how EVA is defined, subject recruitment, or etiologic differences between individual patients or between cohorts. In our National Institutes of Health (NIH) cohort and others, the number of mutant alleles of SLC26A4 is correlated most consistently with auditory and thyroid phenotypes, as well as familial recurrence in siblings.8-10 There are comparatively few published descriptions of vestibular signs and symptoms and objective vestibular test results in patients with EVA. Moreover, these reports have been retrospective and limited to small cohorts or case reports.11,12 The reported percentages of patients with EVA with vestibular signs and symptoms vary from 0% to 100%.6,11,13-28 Commonly reported signs and symptoms include episodic vertigo, imbalance, and motor developmental delay. In this prospective study, we evaluate the vestibular phenotype of patients with EVA to identify correlations of objective vestibular findings with symptomatology, clinical phenotype, the number of SLC26A4 mutant alleles, and the results of imaging studies.

Materials and Methods This study was approved by the Combined Neuroscience (CNS) Institutional Review Board, NIH, Bethesda, Maryland. We obtained written, informed consent from adult subjects and parents of minor subjects. Vestibular data were available for 106 patients with unilateral or bilateral EVA seen at the NIH between 1999 and 2013. For most of these patients, their SLC26A4 genotypes and auditory phenotypes were described previously.8 Vestibular signs and symptoms were ascertained from patient/parent interview by an otolaryngologist. These included late independent ambulation (.18 months), rotatory vertigo, clumsiness, and head tilt with associated vomiting. Rotatory vertigo was defined as at least 1 episode of rotatory dizziness. Clumsiness was defined as imbalance and incoordination. A history of head trauma was ascertained in these patients. This was defined as trauma to the head resulting in dizziness, hearing loss, loss of consciousness, formal medical evaluation, or any combination of the above.

Vestibular function was assessed by videonystagmography (VNG), cervical vestibular evoked myogenic potential (cVEMP), and/or rotational vestibular testing (RVT). Not every patient was available for or tolerant of all the vestibular tests, and cVEMP testing was performed only in later stages of the study. Abnormal VNG is defined as abnormalities in ocular motor tests (smooth pursuit, saccadic tracking, optokinetic testing, and gaze testing) and/or reduced caloric response (unilateral or bilateral) as measured by VNG (unilateral weakness was defined as .20% difference between ears for the caloric response and bilateral weakness as a total bilateral, bithermal caloric response \22°/s). The relative caloric percent-response was calculated for each ear (eg, [RC 1 RW]/[RC 1 RW 1 LC 1 LW] for the right ear, where RC = right cold, RW = right warm, LC = left cold, and LW = left warm) to assess the vestibular function in each individual ear. Abnormal RVT was defined as reduced gain and/or increased phase of the vestibulo-ocular reflex (VOR) for 2 or more consecutive octave frequencies between 0.01 and 0.64 Hz as measured during sinusoidal harmonic acceleration (defined by VOR gain \0.11, 0.20, 0.29, 0.33, 0.31, 0.34, and 0.34 and/or VOR phase .51.9, 32.9, 19.7, 11.5, 6.9, 8.0, and 4.0 degrees for octave frequencies between 0.01 and 0.64 Hz, respectively). The cVEMP results were obtained by using a 500-Hz rarefaction tone-burst with Blackman gating and a 2-ms rise/fall time with a 0-ms plateau. Responses were recorded from the contracted ipsilateral sternocleidomastoid muscle only when monitored electromyography activity was between 50 and 100 mV. Abnormal cVEMP was defined as between-ear P1 to N1 amplitude ratio .40%, an absent response to a stimulus level 100 to 107 dB normal hearing level (nHL), or a present response to a stimulus level 75 dB nHL. Audiometric evaluation included pure-tone threshold testing. The 4-frequency (.5, 1, 2, 4 kHz) pure-tone average (4FPTA) was used for statistical analysis. SLC26A4 genotypes were determined by nucleotide sequence analysis of all 21 exons and flanking intronic sequences of SLC26A4 amplified by polymerase chain reaction from genomic DNA samples.29 Participants were classified as having 0, 1, or 2 mutant alleles of this gene. Radiologic phenotype was based on MRI, CT, or both and reviewed by an otolaryngologist (A.J.G.) and neuroradiologist (J.A.B.). Enlarged vestibular aqueduct was defined as a vestibular aqueduct diameter .1.5 mm at the midpoint between the posterior cranial fossa and the vestibule of the inner ear, or otherwise grossly malformed morphology of the vestibular aqueduct.30 Images were also reviewed for abnormalities of the cochlea, vestibule, and semicircular canals as described previously.8

Statistics For count variables such as the number of vestibular signs and symptoms, Poisson regression was used to analyze their association with other aspects of EVA. For continuous variables such as caloric response, linear regression was used. For categorical variables such as the presence/absence of

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Figure 1. Rotational vestibular testing results in patients with enlarged vestibular aqueduct (EVA). The average gain (left panel) and phase (right panel) are shown in heavy black lines. The black dashed lines represent 62 standard deviations from healthy subjects. VOR, vestibulo-ocular reflex.

VNG and RVT abnormalities, logistic regression was used. For group comparisons such as RVT VOR gain from unilateral vs bilateral EVA ears and cVEMP amplitudes of EVA vs non-EVA ears, Kruskal-Wallis and Mann-Whitney tests were used, respectively. Statistical significance was set at P \ .05.

Results Patient Demographics A total of 106 patients were enrolled in this study. There were 60 women and 46 men in the cohort. The age of the patients ranged from 11 months to 59 years, with a mean (SD) age of 12 (11.5) years. Twenty-six patients had unilateral EVA, and 80 patients had bilateral EVA. We categorized self-reported race and ethnicity according to our institutional review board reporting guidelines: 98 white, 2 African American, 3 ‘‘more-than-one-race,’’ and 3 unknown. One patient was Hispanic in ethnicity, and the rest were not.

Subjective Vestibular Phenotype Among 106 patients with EVA, 24 reported a prior experience of rotary vertigo (23%), 19 reported clumsiness (18%), 21 had a history of head tilting and vomiting at a prelingual age (20%), and 11 had a delayed onset (.18 months of age) of independent ambulation (10%). Twenty-seven (25%) patients had 1 of 4 vestibular signs and symptoms, 15 (14%) had 2, 5 (5%) had 3, and 1 patient (1%) had all 4 vestibular signs and symptoms. In total, 45% of patients had at least 1 vestibular sign or symptom. Poisson regression was used to evaluate the correlation between the number of vestibular signs and symptoms and other aspects of EVA, adjusting for patient’s age and sex. An increased number of vestibular signs and symptoms correlated with the presence of bilateral EVA (coefficient, 0.91; P = .008; n = 104) and a history of head trauma (coefficient, 1.08; P \ .001; n = 92). The number of vestibular signs and symptoms was not correlated with the severity of hearing loss (coefficient,

0.0050; P = .28; n = 100), the number of mutant alleles of SLC26A4 (coefficient, 0.046; P = .76; n = 96), or EVA size (coefficient, –0.17; P = .20; n = 93).

Objective Vestibular Phenotype Sixty-four patients had VNG testing, 9 underwent cVEMP testing, and 24 patients received RVT. Twenty-eight (44%) of 64 patients who underwent VNG testing had abnormal test results. Of these, 4 patients had ocular motor abnormalities, and 21 patients had caloric abnormalities. Logistic regression was used to evaluate whether abnormal VNG test results were correlated with other genotypic and phenotypic features, adjusting for age and sex. We found that abnormal VNG test was associated with a history of head injury (coefficient, 1.66; P = .018; n = 60). Abnormal VNG was not associated with the size of EVA (coefficient, –0.021; P = .95; n = 59), the severity of hearing loss (coefficient, 0.011; P = .24; n = 63), the number of mutant alleles of SLC26A4 (coefficient, 0.13; P = .72; n = 59), or the number of vestibular signs and symptoms (coefficient, 0.058; P = .84; n = 63). An abnormal ocular motor test result was not associated with head trauma (coefficient, 0.023; P = .772; n = 59). Of the 64 patients who underwent VNG testing, 38 completed caloric testing. The caloric response in each ear was analyzed individually by calculating the relative caloric percentresponse (n = 76). Using multiple regression to adjust for age and sex, we found that the relative caloric percent-response was not associated with EVA size (coefficient, 0.0049; P = .82; n = 64) or the number of mutant alleles of SLC26A4 (coefficient, –1.55 3 10–9; P = 1; n = 72). The mean RVT VOR gain and phase in our patients were within the normal range (n = 24; Figure 1), but we observed abnormal RVT gain in 4 (17%) and phase in 6 patients (25%; Table 1). Only 1 patient had both abnormal RVT gain and phase. A Kruskal-Wallis 1-way analysis of variance comparing VOR gain at each rotational frequency between those patients with unilateral EVA (n = 9) and

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Table 1. Vestibular Test Summary (No. of Patients).

VNG RVT gain RVT phase cVEMP

Normal

Abnormal

Total

36 20 18 7

28 4 6 2

64 24 24 9

Abbreviations: cVEMP, cervical vestibular evoked myogenic potential; RVT, rotational vestibular testing; VNG, videonystagmography.

those patients with bilateral EVA (n = 14) revealed no significant differences between groups at any frequency. We found no association between RVT results and EVA size, severity of hearing loss, the number of SLC26A4 mutant alleles, or history of head injury. This may, in part, be due to the small number (n = 24) of patients who underwent RVT. A subset of 9 patients (mean age, 9.6 years; range, 4.617.3 years) received cVEMP testing. Five patients had bilateral EVA and 4 patients had unilateral EVA. None of these patients exhibited a present cVEMP in response to stimuli 75 dB nHL. Only 2 ears from 2 patients had abnormal cVEMP results: 1 ear from a patient with bilateral EVA had no measureable cVEMP response up to 107 dB nHL, and another ear from a patient with unilateral EVA had an abnormal amplitude symmetry ratio of 51%, with a larger cVEMP amplitude in the ear affected with EVA. We observed no significant difference in cVEMP amplitude between ears with and without EVA, although the amplitude was higher in ears with EVA (median, 163.6 mV; n = 13) than without EVA (median, 86.24 mV; n = 4; P = .0731).

Discussion Forty-five percent of our EVA cohort had vestibular signs and symptoms that included a combination of vertigo, clumsiness, head tilting with vomiting at a prelingual age, and/or motor developmental delay. Discrepancies among the reported prevalence of vestibular signs and symptoms in patients with EVA are likely due to small sample size in some studies, different follow-up time periods, ascertainment bias due to the method of subject recruitment, or a combination of these factors. We conclude that vestibular signs and symptoms affect a significant number of patients with EVA. Interestingly, not all patients with vestibular signs and symptoms had abnormal VNG results. This discordance of vestibular signs and symptoms with objective test results is consistent with published studies.11,14-17,19,25 A limitation of this study is that we did not employ a validated instrument to assess vestibular symptomatology. Also, we do not have equivalent data on the prevalence of these vestibular signs and symptoms in an age- and sex-matched healthy control population, so we cannot conclude whether these vestibular signs and symptoms are more common in patients with EVA.

We also examined whether the number of vestibular signs and symptoms was correlated with other aspects of EVA. Our patients with bilateral EVA were more likely to report vestibular signs and symptoms in comparison to patients with unilateral EVA. However, vestibular signs and symptoms were not associated with the severity of hearing loss, the number of mutant alleles of SLC26A4, or EVA size. We found that there was an association between the number of vestibular signs and symptoms and a history of head injury, as well as an association between an abnormal VNG test result and a history of head injury. Head injury has been reported in multiple studies as a precipitating factor of hearing loss in patients with EVA.6,16,17,23,25,26 Even though it is possible that head injury may trigger vestibular dysfunction in patients with EVA, similar to its effects on hearing status, it is also possible that patients with vestibular dysfunction are more prone to fall and sustain head injury. Therefore, we cannot infer a causal relationship from our results. Nevertheless, given the strong association between the number of vestibular signs and symptoms and a history of head injury, we continue to advise our patients with EVA to avoid contact sports in order to minimize the chances of head injury. In a previous study from our group, King et al8 reported a statistically significant correlation of 2 mutant alleles of SLC26A4 with increased severity of hearing loss, in comparison to patients with 0 or 1 mutant alleles. In contrast, we did not find a correlation between the number of SLC26A4 mutant alleles with either the number of vestibular signs and symptoms or abnormal VNG or RVT results. We also did not find a correlation between the severity of hearing loss and vestibular signs and symptoms or VNG or RVT abnormalities. These results suggest EVA may affect the auditory and vestibular systems differently. Zhou and Gopen31 reported abnormally low cVEMP thresholds in 34 (92%) of 37 EVA ears. Similarly, Sheykholeslami et al24 reported lower cVEMP thresholds in 3 patients with unilateral EVA, with higher cVEMP amplitudes in the EVA ears compared with the contralateral nonEVA ears. The proposed mechanism for this is that EVA can act as a ‘‘third window’’ in the inner ear, providing more direct access to the vestibule for a sound stimulus, thus leading to a lowered cVEMP threshold.32 Our data did not support abnormally low cVEMP thresholds (75 dB nHL) in EVA ears, and we did not observe a significant difference in cVEMP amplitude between ears with and without EVA, although the amplitude was higher in the EVA ears compared with non-EVA ears. The disparity in our results vs those of other studies may reflect small sample size, differences in testing protocols or response interpretation, differences in subject recruitment, or a combination of these factors.

Conclusions We examined 106 patients with EVA and found that 45% of patients had vestibular signs and symptoms, and 44%

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who underwent VNG testing had abnormal results. Bilateral EVA was associated with an increased number of vestibular signs and symptoms. We also found that a history of head injury is correlated with the number of vestibular signs and symptoms and VNG abnormalities. We did not find a correlation between vestibular dysfunction and the number of mutant alleles of SLC26A4, severity of hearing loss, or EVA size. We conclude that the pathogenic mechanism(s) leading to vestibular signs and symptoms and dysfunction may differ from that for hearing loss in patients with EVA. Clinicians should be aware of the prevalence and manifestations of vestibular dysfunction in patients with EVA and the possible risk of increased vestibular dysfunction from head injury. Author Contributions Chris K. Zalewski, data acquisition and analysis, manuscript revision; Wade W. Chien, data acquisition and analysis, manuscript drafting and revision; Kelly A. King, data acquisition and analysis, manuscript revision; Julie A. Muskett, data acquisition and analysis, manuscript revision; Rachel E. Baron, data acquisition and analysis, manuscript revision; John A. Butman, data acquisition and analysis, manuscript revision; Andrew J. Griffith, project conception and design, data acquisition and analysis, manuscript revision; Carmen C. Brewer, data acquisition and analysis, manuscript revision.

Disclosures Competing interests: None. Sponsorships: None. Funding source: This was study was funded by the National Institute on Deafness and Other Communication Disorders (NIDCD) under an intramural research program. The NIDCD provided funding for patient recruitment, examination, and testing.

References 1. Tomaski SM, Zalzal GH, Saal HM. Airway obstruction in the Pierre Robin sequence. Laryngoscope. 1995;105:111-114. 2. Mondini C. Anatomica surdi nati sectio. De Bononiensi Scientarium et Artium Instituto atque Academia Commenarii. Vol 7. 1791:417. 3. Gopen Q, Zhou G, Whittemore K, Kenna M. Enlarged vestibular aqueduct: review of controversial aspects. Laryngoscope. 2011;121:1971-1978. 4. Everett LA, Glaser B, Beck JC, et al. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet. 1997;17:411-422. 5. Choi BY, Kim HM, Ito T, et al. Mouse model of enlarged vestibular aqueducts defines temporal requirement of Slc26a4 expression for hearing acquisition. J Clin Invest. 2011;121: 4516-4525. 6. Antonelli PJ, Nall AV, Lemmerling MM, Mancuso AA, Kubilis PS. Hearing loss with cochlear modiolar defects and large vestibular aqueducts. Am J Otol. 1998;19:306-312. 7. Campbell AP, Adunka OF, Zhou B, Qaqish BF, Buchman CA. Large vestibular aqueduct syndrome: anatomic and functional parameters. Laryngoscope. 2011;121:352-357.

8. King KA, Choi BY, Zalewski C, et al. SLC26A4 genotype, but not cochlear radiologic structure, is correlated with hearing loss in ears with an enlarged vestibular aqueduct. Laryngoscope. 2010;120:384-389. 9. Albert S, Blons H, Jonard L, et al. SLC26A4 gene is frequently involved in nonsyndromic hearing impairment with enlarged vestibular aqueduct in Caucasian populations. Eur J Hum Genet. 2006;14:773-779. 10. Madden C, Halsted M, Meinzen-Derr J, et al. The influence of mutations in the SLC26A4 gene on the temporal bone in a population with enlarged vestibular aqueduct. Arch Otolaryngol Head Neck Surg. 2007;133:162-168. 11. Schessel DA, Nedzelski JM. Presentation of large vestibular aqueduct syndrome to a dizziness unit. J Otolaryngol. 1992; 21:265-269. 12. Sugiura M, Sato E, Nakashima T, et al. Long-term follow-up in patients with Pendred syndrome: vestibular, auditory and other phenotypes. Eur Arch Otorhinolaryngol. 2005;262:737-743. 13. Valvassori GE, Clemis JD. The large vestibular aqueduct syndrome. Laryngoscope. 1978;88:723-728. 14. Valvassori GE. The large vestibular aqueduct and associated anomalies of the inner ear. Otolaryngol Clin North Am. 1983; 16:95-101. 15. Emmett JR. The large vestibular aqueduct syndrome. Am J Otol. 1985;6:387-415. 16. Jackler RK, De La Cruz A. The large vestibular aqueduct syndrome. Laryngoscope. 1989;99:1238-1243. 17. Okumura T, Takahashi H, Honjo I, et al. Vestibular function in patients with a large vestibular aqueduct. Acta Otolaryngol Suppl. 1995;520(pt 2):323-326. 18. Okumura T, Takahashi H, Honjo I, Takagi A, Azato R. Magnetic resonance imaging of patients with large vestibular aqueducts. Eur Arch Otorhinolaryngol. 1996;253:425-428. 19. Yetiser S, Kertmen M, Ozkaptan Y. Vestibular disturbance in patients with large vestibular aqueduct syndrome (LVAS). Acta Otolaryngol. 1999;119:641-646. 20. Nakashima T, Ueda H, Furuhashi A, et al. Air-bone gap and resonant frequency in large vestibular aqueduct syndrome. Am J Otol. 2000;21:671-674. 21. Oh AK, Ishiyama A, Baloh RW. Vertigo and the enlarged vestibular aqueduct syndrome. J Neurol. 2001;248:971-974. 22. Naganawa S, Koshikawa T, Fukatsu H, Ishigaki T, Nakashima T. Serial MR imaging studies in enlarged endolymphatic duct and sac syndrome. Eur Radiol. 2002;12(suppl 3):S114-S117. 23. Madden C, Halsted M, Benton C, Greinwald J, Choo D. Enlarged vestibular aqueduct syndrome in the pediatric population. Otol Neurotol. 2003;24:625-632. 24. Sheykholeslami K, Schmerber S, Habiby Kermany M, Kaga K. Vestibular-evoked myogenic potentials in three patients with large vestibular aqueduct. Hear Res. 2004;190:161-168. 25. Berrettini S, Forli F, Bogazzi F, et al. Large vestibular aqueduct syndrome: audiological, radiological, clinical, and genetic features. Am J Otolaryngol. 2005;26:363-371. 26. Grimmer JF, Hedlund G. Vestibular symptoms in children with enlarged vestibular aqueduct anomaly. Int J Pediatr Otorhinolaryngol. 2007;71:275-282.

Downloaded from oto.sagepub.com at GEORGETOWN UNIV MED CTR on September 7, 2015

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27. Merchant SN, Nakajima HH, Halpin C, et al. Clinical investigation and mechanism of air-bone gaps in large vestibular aqueduct syndrome. Ann Otol Rhinol Laryngol. 2007;116:532-541. 28. Guo YF, Wang YL, Xu BC, et al. Identification of two novel mutations, c.232T.C and c.2006A.T, in SLC26A4 in a Chinese family associated with enlarged vestibular aqueduct. Int J Pediatr Otorhinolaryngol. 2010;74:831-835. 29. Chattaraj P, Reimold FR, Muskett JA, et al. Use of SLC26A4 mutation testing for unilateral enlargement of the vestibular aqueduct. JAMA Otolaryngol Head Neck Surg. 2013;139:907913.

30. Pryor SP, Madeo AC, Reynolds JC, et al. SLC26A4/PDS genotype-phenotype correlation in hearing loss with enlargement of the vestibular aqueduct (EVA): evidence that Pendred syndrome and non-syndromic EVA are distinct clinical and genetic entities. J Med Genet. 2005;42:159-165. 31. Zhou G, Gopen Q. Characteristics of vestibular evoked myogenic potentials in children with enlarged vestibular aqueduct. Laryngoscope. 2011;121:220-225. 32. Merchant SN, Rosowski JJ. Conductive hearing loss caused by third-window lesions of the inner ear. Otol Neurotol. 2008;29: 282-289.

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Vestibular Dysfunction in Patients with Enlarged Vestibular Aqueduct.

Enlarged vestibular aqueduct (EVA) is the most common inner ear malformation. While a strong correlative relationship between EVA and hearing loss is ...
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