Clinical Characteristics of Children With Cochlear Nerve Dysplasias

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1 The Laryngoscope VC 2012 The American Laryngological, Rhinological and Otological Society, Inc. Clinical Characteristics of Children With Cochlear Nerve Dysplasias Jessica Levi, MD; Julie Ames, MD; Katie Bacik, PA-C; Colin Drake, PA-C; Thierry Morlet, PhD; Robert C. O Reilly, MD Objectives/Hypothesis: To describe the clinical and audiometric characteristics of children with cochlear nerve dysplasia (CND). Study Design: Retrospective chart review of clinical database of children with inner ear anomalies treated at a tertiary care children s hospital. Methods: Institutional review board approved retrospective review from June 30, 2006, to July 1, 2011; 18 children were identified with magnetic resonance imaging (MRI) evidence of CND defined as a cochlear nerve 50% smaller than the adjacent facial nerve. Results: Of the 18 patients, nine were girls and nine were boys. Average age at time of MRI diagnosis of CND was 4.6 years. Twelve children had cochlear nerve aplasia, and six had hypoplasia. Three were affected bilaterally: two with aplasia and one with hypoplasia. Unilateral dysplasia was found in 15 children; of these, 60% occurred on the left side. Other inner ear anomalies were found in 50%, including all patients with bilateral CND. Severe-to-profound hearing loss was found in the involved ear(s) in 14 of 18 patients, including all bilateral patients. Of the 18 patients tested, 13 (72%) had an audiometric profile of auditory neuropathy/dys-synchrony syndrome (auditory neuropathy spectrum disorder [ANSD]). Comorbid conditions were present in 56% of patients. Two patients were syndromic. Family history of hearing loss was present in 11% of patients. Conclusions: Many patients with CND have ANSD, and more than half have comorbidities. Approximately half of affected patients have other inner ear anomalies in the involved ears. Unilateral CND may be more common on the left side. Key Words: Cochlear nerve aplasia, cochlear nerve dysplasia, auditory neuropathy, auditory dys-synchrony. Level of Evidence: 4 Laryngoscope, 123: , 2013 INTRODUCTION Hearing loss is the most common sensory abnormality, affecting 3% to 11% of children. The incidence of congenital bilateral sensorineural hearing loss (SNHL) is 1.4 to 3 per 1,000 live births. In SNHL, the cochlea is the most common abnormal site, and computed tomography (CT) can visualize this in almost 41% of these patients. 1 Auditory neuropathy spectrum disorder (ANSD) is a subset of this population in which outer hair cell (OHC) function is normal (present cochlear microphonic [CM] and/or otoacoustic emissions [OAE]) with disordered neural transduction (absent or abnormal auditory brainstem response [ABR]). The incidence of ANSD is From the Department of Otolaryngology (J.L., K.B., C.D., R.C.O.) and Department of Audiology (T.M.), Nemours/Alfred I. dupont Hospital for Children, Wilmington, Delaware; and Department of Otolaryngology (J.A.), Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, U.S.A. Editor s Note: This Manuscript was accepted for publication July 10, Work was performed at Nemours/Alfred I. dupont Hospital for Children. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Robert C. O Reilly, MD, Department of Otolaryngology, Nemours/Alfred I. dupont Hospital for Children, 1600 Rockland Road, Wilmington, DE roreilly@nemours.org DOI: /lary estimated at 10% to 15% of children with a SNHL diagnosis. 2 Interestingly, 6% to 28% of cases of ANSD are due to hypoplastic cochlear nerves. 3 5 Cochlear nerve hypoplasia (CNH), first described by Shelton et al. 6 in 1989, represents a literal or true form of ANSD. Nerve diameter varies in normal-hearing subjects; therefore, it is the relative size, in relation to either facial nerve, that determines hypoplasia. 7,8 Furthermore, normal-caliber nerves can be present in a narrow bony internal auditory canal (IAC); therefore, magnetic resonance imaging (MRI) is superior to CT in diagnosis. CNH is seen in 6% to 16.1% of children with SNHL, 9 but it is even more common in patients with ANSD. 3 5 According to Bamiou et al. 10 and Shelton et al., 6 CNH is often associated with a syndrome. Rates of associated inner ear abnormalities vary greatly in the literature. MATERIALS AND METHODS An institutional review board approved retrospective review of a clinical database of children with inner ear anomalies at a tertiary care children s hospital was performed. MRI was selected as the initial imaging modality because it is superior to CT for membranous labyrinth and nerve evaluation. 11 This included three-dimensional fast imaging employing steadystate acquisition sequence (FIESTA), T2 fat-saturation, T1 fatsaturation, and postcontrast images through the temporal bones on a 3.0-Tesla system. FIESTA visualizes nerves against the bright cerebral spinal fluid with a heavily T2-weighted

2 Patient No. Sex Age Type Side TABLE I. Results From 18 Patients Found to Have Cochlear Nerve Dysplasia. Inner Ear Anomalies HL ABR OAE or CM MEMR ANSD Profile Comorbid 1 F 2 wk H L N S Abnormal Y Y Y N 2 F 7 wk A L Y NA NA N N Y N 3 M 2 mo A R Y P Abnormal Y Y N N 4 F 5 mo H BL Y P Abnormal Y Y Y N 5 M 5 mo H R Y P Abnormal Y Y N N 6 F 2 yr A L N P Abnormal N N Y N 7 F 2 yr A BL Y P Abnormal Y Y N N 8 M 3 yr A L N SP Abnormal Y Y N N 9 M 4 yr A BL Y P Abnormal Y Not present Y N Y 10 M 4 yr A L Y P NA Y Not present Y Y N 11 M 5 yr H L N Mod NA Y Y Y N 12 F 5 yr A R N P Abnormal Y Y Y N 13 F 5 yr A R N P NA N N N N 14 F 6 yr H L Y MS Normal NA N Y N 15 M 7 yr A L Y P NA Y Not present Y N N 16 F 8 yr H L N Mod NA Y Not present Y Y Y 17 M 2 yr A R N P Abnormal Y Y Y N 18 M 7 yr A R N P NA Y Elevated N N N Family History All children had magnetic resonance imaging for diagnosis. HL ¼ hearing loss; ABR ¼ auditory brainstem response; OAE ¼ otoacoustic emissions; CM ¼ cochlear microphonic; MEMR ¼ middle ear muscle reflex; ANSD ¼ auditory neuropathy spectrum disorder; F ¼ female; H ¼ hypoplasia; L ¼ left; N ¼ no; S ¼ severe; Y ¼ yes; A ¼ aplasia; NA ¼ not available; M ¼ male; R ¼ right; P ¼ profound; BL ¼ bilateral; Mod ¼ moderate; MS ¼ Moderate to Severe. sequence. The ideal imaging technique as well as specific criteria for diagnosing cochlear nerve dysplasia (CND) have been debated, however. Because bony canal formation depends on an intact nerve, authors such as McClay et al. 1 (who observed that as canal diameters decrease, the percentage of ears with CND increases) suggest bony canal diameter can be used to diagnose CND (with a cutoff of 1.4 mm as diagnostic). However, Adunka et al. 8 found that the bony canal was unreliable for diagnosis; one third of their patients had normal canal dimensions. Alternatively, the diameter of the IAC may be used to diagnose CND 12 (generally when less than 3 mm), but Carner et al. 13 found 39.2% of patients with CNA had normal IAC size, and Adunka et al. 14 found 56% of the ears with CND had normal IAC diameter. Zanetti et al. 7 suggested that the relative, not absolute, size of the nerve within the IAC is the best criteria. More recently, Kutz et al. 11 argued that a cochlear nerve smaller than the adjacent facial nerve is deficient. Therefore, our CNH diagnostic criterion was a cochlear nerve 50% smaller than the adjacent facial nerve. RESULTS From from June 30, 2006, to July 1, 2011, MRI was used to identify 18 children with CND (Table I). The children ranged in age from 2 weeks to 8 years, with an average age at diagnosis of hearing loss of 3.3 years and an average age at diagnosis of CND of 4.6 years. Twelve of 18 children had an MRI within 6 months of hearing loss diagnosis. Six patients had a delayed MRI; the average delay was 22 months (range, months). CNH was found in six of the children, one of whom had bilateral hypoplasia. Cochlear nerve aplasia (CNA) was found in 12 children, two of whom had bilateral aplasia. Of the 18 children, nine were girls and nine were boys. Unilateral CND occurred on the left side 60% of the time (Fig. 1). Fifty percent of patients with CND had inner ear abnormalities including narrow IAC, hypoplastic facial nerve, absent inferior vestibular nerve, absent horizontal semicircular canal, absent posterior semicircular canal, dilated superior semicircular canal, dilated vestibule, enlarged vestibular aqueduct (EVA), cystic cochlea, and a common cavity. The three patients with bilateral CND all had additional inner ear anomalies. Hearing loss was identified in 17 of the 18 children and was severe, severe-to-profound, or profound in 14 children. The remaining three had moderate or moderate-to-severe hearing loss. One child was too young to determine the degree of hearing loss after failing ABR. The children with bilateral CND had profound hearing loss. Seventy-two percent (13 of 18) of the children had ANSD with presence of CM and/or OAE in the involved ear(s). A diagnosis of ANSD could not be ruled out (lack of ABR testing) in four of the remaining five patients. Comorbid conditions were present in 56%, including congenital cardiac anomalies, delayed myelination, G6PD deficiency, Klippel-Feil syndrome, polydactyly, VATER syndrome, and prematurity. Eleven percent had a family history of hearing loss. DISCUSSION CND is defined as absence or deficiency of one or both cochlear nerves or their divisions. Recently, several 753

3 Fig. 1. T2-weighted magnetic resonance image of a patient with unilateral cochlear nerve dysplasia. (A) Right internal auditory canal (IAC) with evidence of facial, cochlear, superior, and inferior vestibular nerves. (B) Left IAC with absent cochlear nerve. authors have suggested CND is more common than previously thought and accounts for a significant percentage of pediatric SNHL. Adunka et al. 14 estimated CND accounts for at least 1% of all cases of newly diagnosed SNHL. Laury et al. 15 examined 11 patients with unilateral SNHL and found 73% had CND. Rates of aplasia versus hypoplasia vary greatly. McClay et al. 1 found that more than 50% of their patients with CND had hypoplasia. The recent interest in CND may be due in part to the evolution of MRI and its ability to evaluate small neural structures. Associated Ear Abnormalities Rates of associated inner ear abnormalities vary greatly; in our study, the rate was 50%. Kutz et al. 11 looked at children with CND and noted all children had inner ear abnormalities, mostly malformed cochleas, and Laury et al. 15 noted all patients with CND had normal inner ears. More commonly, 40% to 85% of patients with CND have associated inner ear abnormalities. 13,14,16 This association makes embryological sense. The cochlear nerve develops concurrently with other vestibular and cochlear structures. Around the fourth week of gestation, the otic placode develops. It becomes the otic pit then becomes the otic vesicle. Around this time, ganglion cells form the acousticofacial ganglion, which later divides. The acoustic ganglion divides into superior and inferior branches. The spiral ganglion, where cochlear nerve neurons are found, develops from the inferior branch. At midterm, the cochlea achieves its final size 754 and is surrounded by the bony capsule. The sensory epithelium continues differentiating, functioning around the 26th week of gestation. The soft tissues of the inner ear form after the bony labyrinth; thus the bony labyrinth may be normal with abnormal membranous labyrinth or other soft tissues. Development of the IAC depends on normal caliber nerves within the canal to inhibit chondrogenesis, which is completed the 24th week. Not surprisingly, there is a higher rate of cochlear malformations in bilateral CND compared with unilateral. In this study, all patients with bilateral and 40% (6 of 15) with unilateral CND had associated inner ear malformations. Huang et al. 9 noted an association between bilateral CND and labyrinthine and hindbrain abnormalities. Cochlear abnormalities were more common in patients with bilateral versus unilateral CND: 73% versus 4.5%. Perhaps the discrepancy between unilateral and bilateral CND is due to timing of the insult causing CND, with bilateral possibly due to an earlier, larger, or less localized insult. Rarely are vestibular abnormalities reported with CND. This may be due to the separate development of the spiral and vestibular ganglions. However, Huang et al. 9 found 13 of 34 patients with either unilateral or bilateral CND had a vestibular abnormality, none with an EVA. Kutz et al. 11 reported five of nine children had CND and vestibular abnormalities. In our study, two patients had dilated vestibules; one of these had EVA. Audiology In this study, 14 patients had hearing loss ranging from severe to profound, including all patients with bilateral CND. Buchman et al. 3 found all patients with CND had profound hearing loss. Laury et al. 15 reported that bilateral CND is more likely than unilateral to have absent OAE/CM. Because bilateral CND is associated with inner ear anomalies more frequently than unilateral CND, perhaps disorders of the cochlear sensory epithelium (malfunctioning OHC) are more frequent as well. More commonly, CND has an ANSD-type profile. We defined ANSD as abnormal or absent ABR, and either present CM or OAE in at least one testing and one frequency, indicating functioning OHC at some point in time. Of the 18 patients, 13 had a profile of ANSD. All three patients with bilateral CND had ANSD profiles bilaterally. In four patients, data were insufficient to determine ANSD. In the patients with definitive ANSD, nine had partial OAE. It is unclear why some patients have only partial presence of OAE while others have more consistent OAE. Normal hair cell development can occur without innervation; thus they could function (present OAE) with absent innervation (CND). Nelson and Hinojosa 17 examined temporal bones of two patients (one aged 30 months, one aged 23 years) with CND but intact organ of Corti. Although function could not be tested, inner hair cells were preserved in both patients. Looking at eight individuals diagnosed with CND by a kindergarten screening test, Moxham et al. 12 noted all children had abnormal ABR with present OAE. Roche

4 et al. 18 noted that 28% of patients with ANSD had CND. Valero et al. 19 reported that within this population, the CND rate is between 6% and 28%. In our population of approximately 130 patients with ANSD, 13 had CND (10%). Interestingly, Huang et al. 9 noted that among patients with ANSD, those with CND had more inner ear abnormalities than those without CND (51% vs. 1.4%). Perhaps there is normal development of some portion of the cochlear nerve in CND. Comorbidities In our study, 56% of patients had comorbid conditions, but only two were syndromic (VATER and Klippel- Feil). Interestingly, 11% of patients had a family history of hearing loss. Bamiou et al. 10 noted patients with CND were more likely to have prelingual deafness, syndromes, congenital malformations, and delayed motor milestones. Of seven cochlear implant (CI) candidates with CND, Bamiou et al. 10 found six were syndromic. Shelton et al. 6 discovered four out of eight patients were syndromic. Adunka et al. 14 showed that of 14 patients with CND, five patients had syndromes. Moxham et al. 12 found eight cases of CND were in nonsyndromic, developmentally normal kindergartners. Imaging and Diagnosis The ideal imaging technique and criteria for diagnosing CND are debated. CT is superior for IAC size and bony cochlear nerve canal, but MRI is superior for nerve evaluation and was therefore our imaging modality of choice. As noted, there is no universal criterion for diagnosing CND; we defined CND as less than 50% of the size of the adjacent facial nerve. Thus, we may have missed some patients who fit other authors CND criteria, but the rate of false positives is decreased. Roche et al. 18 found that more than half (58%) of their patients with CND had two nerves at the cerebellopontine angle (CPA), but 68% of these had no nerves in the IAC. Thus, the presence of two nerves at the CPA does not exclude intracanalicular CND. Interestingly, Kutz et al. 11 argued nerve absence on imaging does not rule out presence of some fibers, perhaps traveling with other nerves. In our study, one patient had a normal ABR (indicating normal nerve function) and a large ipsilateral facial nerve canal on MRI, suggesting there are cochlear fibers traveling with the facial nerve (Fig. 1). Pagarkar et al. 16 concluded that no single finding on imaging can clearly diagnose CND and recommended that diagnosis be based on a combination of MRI, CT, and audiogram findings. The importance of early imaging cannot be underestimated in children with a new diagnosis of SNHL and, in particular, ANSD; MRI may reveal CND. In these patients, early imaging can greatly expedite treatment plans and interventions. Treatment The optimal treatment of patients with CND is controversial and depends on whether there is complete absence of nerve fibers or hypoplasia and on whether it is unilateral or bilateral, as well as presence of other abnormalities. There is some evidence that patients with CND may benefit from CI. Kutz et al. 11 suggest that the presence of wave V on ABR may have predictive value for CI. 20 It is possible that if some nerve fibers remain, wave V could be generated at high intensities; thus these patients may benefit from CI. On the other hand, Carner et al. 13 examined patients with CND receiving CI and found no response. Those patients with CND and ANSD may be more likely to benefit from preferential seating (when CND is unilateral) or amplification as opposed to CI. In the future, improved MRI or cortical potential measurements may aid in the distinction between hypoplasia and aplasia and, therefore, better guide-treatment options. Similarly, indications for auditory brainstem implant may expand to include patients with CND; Carner et al. 13 found patients with CND who underwent auditory brainstem implant had awareness of speech and environmental sounds. CONCLUSION Moxham et al. 12 suggest CND is an underrecognized entity. The significant prevalence of ANSD among pediatric patients presenting with SNHL and the high occurrence of ANSD in patients with CND highlight the need for MRI to search for CND. There are many proposed diagnostic criteria; we used a cochlear nerve 50% smaller than the adjacent facial nerve on MRI as diagnostic. In the literature, 40% to 85% of patients with CND have associated inner ear abnormalities; 13,14,16 similarly, 50% of our patients had inner ear abnormalities. There is a higher rate of malformations in bilateral CND compared with unilateral cases: all patients with bilateral and 40% (6 of 15) with unilateral CND had associated inner ear malformations. Perhaps unilateral CND is a result of a genetically programmed event or a perinatal insult while bilateral CND represents a more global insult or one occurring earlier in development. All patients with bilateral CND had profound hearing loss, and 72.2% of our patients had ANSD profiles. Only two of our patients were syndromic, which is less than most studies, but 56% had other comorbidities. Interestingly, our study found a predominance of left-sided CND. It is unclear whether this represents an anomaly or a trend, as there are many leftpredominant congenital lesions in the head and neck. Overall, our study was limited by its retrospective nature and small sample size but brought up a number of interesting findings. Improved imaging techniques or cortical potentials may help differentiate aplasia from hypoplasia and guide treatment, but further clarification of diagnostic criteria (including age- and sex-matched control values for IAC and bony canal diameters) is also needed. This, as well as additional characterization of patients with CND, represents an important avenue for investigation. BIBLIOGRAPHY 1. McClay JE, Booth TN, Parry DA, Johnson R, Roland P. Evaluation of pediatric sensorineural hearing loss with magnetic resonance imaging. Arch Otolaryngol Head Neck Surg 2008;134:

5 2. Berlin CI, Hood LJ, Morlet T, et al. Multi-site diagnosis and management of 260 patients with auditory neuropathy/dys-synchrony (auditory neuropathy spectrum disorder). Int J Audiol 2010;49: Buchman CA, Roush PA, Teagle HF, Brown CJ, Zdanski CJ, Grose JH. Auditory neuropathy characteristics in children with cochlear nerve deficiency. Ear Hear 2006;27: Walton J, Gibson WP, Sanli H, Prelog K. Predicting cochlear implant outcomes in children with auditory neuropathy. Otol Neurotol 2008;29: Teagle HF, Roush PA, Woodard JS, et al. Cochlear implantation in children with auditory neuropathy spectrum disorder. Ear Hear 2010;31: Shelton C, Luxford WM, Tonokawa LL, Lo WW, House WF. The narrow internal auditory canal in children: a contraindication to cochlear implants. Otolaryngol Head Neck Surg 1989;100: Zanetti D, Guida M, Barezzani MG, et al. Favorable outcomes of cochlear implant in VIIIth nerve deficiency. Otol Neurotol 2006;27: Adunka OF, Jewells V, Buchman CA. Value of computed tomography in the evaluation of children with cochlear nerve deficiency. Otol Neurotol 2007;28: Huang BY, Roche JP, Buchman CA, Castillo M. Brain stem and inner ear abnormalities in children with auditory neuropathy spectrum disorder and cochlear nerve deficiency. AJNR Am J Neuroradiol 2010;31: Bamiou DE, Worth S, Phelps P, Sirimanna T, Rajput K. Eighth nerve aplasia and hypoplasia in cochlear implant candidates: the clinical perspective. Otol Neurotol 2001;22: Kutz JW Jr, Lee KH, Isaacson B, Booth TN, Sweeney MH, Roland PS. Cochlear implantation in children with cochlear nerve absence or deficiency. Otol Neurotol 2011;32: Moxham JP, Dickson JM, Sargent MA, Ludemann JP. Cochlear nerve aplasia detected through kindergarten hearing screening. J Otolaryngol Head Neck Surg 2009;38: Carner M, Colletti L, Shannon R, et al. Imaging in 28 children with cochlear nerve aplasia. Acta Otolaryngol 2009;129: Adunka OF, Roush PA, Teagle HF, et al. Internal auditory canal morphology in children with cochlear nerve deficiency. Otol Neurotol 2006;27: Laury AM, Casey S, McKay S, Germiller JA. Etiology of unilateral neural hearing loss in children. Int J Pediatr Otorhinolaryngol 2009;73: Pagarkar W, Gunny R, Saunders DE, Yung W, Rajput K. The bony cochlear nerve canal in children with absent or hypoplastic cochlear nerves. Int J Pediatr Otorhinolaryngol 2011;75: Nelson EG, Hinojosa R. Aplasia of the cochlear nerve: a temporal bone study. Otol Neurotol 2001;22: Roche JP, Huang BY, Castillo M, Bassim MK, Adunka OF, Buchman CA. Imaging characteristics of children with auditory neuropathy spectrum disorder. Otol Neurotol 2010;31: Valero J, Blaser S, Papsin BC, James AL, Gordon KA.Electrophysiologic and beahavioral outcomes of cochlear implantation in children with auditory nerve hypoplasia. Ear Hear 2012;33: Nikolopoulos TP, Mason SM, Gibbin KP, O Donoghue GM. The prognostic value of promontory electric auditory brain stem response in pediatric patients with cochlear implantation. Ear Hear 2000;21: