JSLHR

Review Article

Auditory Neuropathy Spectrum Disorder: A Review Linda W. Norrixa and David S. Velenovskya

Purpose: Auditory neuropathy spectrum disorder, or ANSD, can be a confusing diagnosis to physicians, clinicians, those diagnosed, and parents of children diagnosed with the condition. The purpose of this review is to provide the reader with an understanding of the disorder, the limitations in current tools to determine site(s) of lesion, and management techniques. Method: This article is a review of what is known about ANSD. It includes descriptions of assessment tools, causes of ANSD, and patient management techniques.

Conclusions: This review is a guide to audiologists, speech-language pathologists, and early interventionists who work with individuals diagnosed with ANSD and/or their families. It highlights the need for more precise tools to describe the disorder in order to facilitate decisions about interventions and lead to better predictions of outcome.

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outcomes, can be a confusing diagnosis. The purpose of this article was to provide the reader with background information about ANSD, the battery of tests used to diagnose ANSD, and resources for remediation and management strategies.

rody failed his newborn auditory brainstem response screening. His follow-up diagnostic evaluation, conducted at 1 month of age, revealed present evoked otoacoustic emissions (OAEs) for both ears. Although a cochlear microphonic (CM) was recorded during the auditory brainstem response (ABR) test, no ABR was detected for either ear. Mr. and Mrs. Johnson, Brody’s parents, are relaxed during the evaluation and are not suspecting hearing loss. They were told that babies often fail their newborn hearing screening due to debris in the ear canal or fluid remaining in the ears at the time of the screening. Mrs. Johnson had a normal pregnancy and Brody’s birth was uneventful. In addition, there is no family history of hearing loss. The audiologist who has just completed Brody’s evaluation knows that the pattern of results (i.e., OAEs and CM present with an absent ABR) is consistent with what has been called “auditory neuropathy spectrum disorder” (ANSD). But she wonders, “What do I tell Brody’s parents about ANSD? What do I tell them about possible functional outcomes? Will this child be a hearing aid or cochlear implant candidate? The parents will have questions and I am not sure I can give them definitive answers.” ANSD, because of a lack of tests to accurately diagnose the site of dysfunction and the vast array of functional

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University of Arizona, Tucson Correspondence to Linda W. Norrix: [email protected] Editor: Craig Champlin Associate Editor: Paul Abbas Received August 8, 2013 Revision received December 11, 2013 Accepted February 18, 2014 DOI: 10.1044/2014_JSLHR-H-13-0213

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Key Words: electrophysiology, diagnostics, otoacoustic emissions, aural rehabilitation

ANSD Profile Auditory neuropathy spectrum disorder is the term used to describe the condition in which an individual has present OAEs and/or a CM but an absent or abnormal ABR (cf. Berlin et al., 2010; Guidelines Development Conference, 2008; Rance & Barker, 2009; Starr, Picton, Sininger, Hood, & Berlin, 1996). Although the diagnosis is clear with an absent ABR and present OAEs, controversy exists regarding what defines an abnormal ABR. The Guidelines Development Conference (2008) defined an abnormal ABR as 1) a “flat” ABR with no evidence of any peaks or 2) presence of early peaks (waves up to III) with absence of later waves or 3) some poorly synchronized but evident later peaks (wave V) that appear only to stimuli at elevated stimulus levels. (p. 4) Guidelines developed in the United Kingdom for the Newborn Hearing Screening Program (NHS Newborn Hearing Screening Programme [NHS NHSP], 2011) described abnormal ABR waveforms as having unexpected latencies, amplitude, or morphology. In contrast, recent NHS NHSP (2013) guidelines adopt Sininger’s (2002) definition of a severely abnormal ABR, which may include,

Disclosure: The authors have declared that no competing interests existed at the time of publication.

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occasionally, a small amplitude wave V response at high stimulus levels. Although there is little consensus regarding the definition of an abnormal ABR, individuals diagnosed with ANSD clearly have evidence of outer hair cell (OHC) integrity but abnormal afferent auditory pathway function (beyond the OHC and up to and including the VIIIth nerve). Although OHC integrity can be assessed with OAE testing, audiologic tools used to examine the function of the afferent pathway, from the inner hair cell (IHC) to the VIIIth nerve, cannot identify the exact site of dysfunction. Physiologic Tools to Examine OHC Function Evoked OAEs. OAEs are by-products of an active amplification system within the cochlea (see Panel a of Figure 1) and can be recorded by placing a sensitive microphone in the ear canal. This amplification system consists of motile OHCs that increase basilar membrane/cochlear fluid displacement for soft sounds so that IHCs are able to release a sufficient amount of neurotransmitter into the synaptic cleft in order to excite VIIIth nerve fibers. Without functioning OHCs, a mild to moderate sensorineural hearing loss (SNHL) is predicted (cf. Stebbins, Hawkins, Johnson, & Moody, 1979)—that is, the amplifier is not providing gain for soft sounds. Typically, SNHL involves damage to OHCs along with various degrees of damage to IHCs. Therefore, OAEs are an excellent screening tool for hearing loss (Gorga et al., 1997; Kim, Paparello, Jung, Smurzynski, & Sun, 1996; Norton et al., 2000; Richardson, Williamson, Lenton, Tarlow, & Rudd, 1995). If OAEs are absent, as in Panel b of Figure 1, there is a high degree of certainty that the individual has a mild or greater hearing loss. Follow-up diagnostic testing will determine the degree and type of hearing impairment1 and will set the stage for appropriate intervention services. Although present OAEs, in most cases, are associated with normal hearing thresholds, the astute clinician must keep in mind that OAEs, although a good screening tool for hearing loss, provide no information about the function of the mechanisms beyond the OHCs (i.e., IHC, synapse, and auditory nerve). Selective damage to these mechanisms beyond the OHCs can result in a “pass” on otoacoustic emissions testing and a false-negative result. That is, hearing will be presumed to be normal when the individual has hearing loss due to IHC, synaptic, or neural dysfunction. CM. The CM is a preneural, cochlear response that originates primarily from OHCs. Although IHCs contribute to this response, their role is far less than that of the more numerous OHCs (Dallos, 1983). The CM mirrors the waveform of the acoustic stimulus and the fluctuating current flow through hair cells and cochlear fluids. Therefore, it will shift in phase with a shift in the phase of the stimulus. The CM can be measured from the scalp using 1

Both an SNHL and a conductive hearing loss can result in absent OAEs. Absent OAEs in the presence of normal middle-ear function suggests an SNHL. Absent OAEs with middle-ear dysfunction provide no information about cochlear function.

stimulus and recording parameters similar to those used for detecting the ABR and therefore can be identified during typical ABR diagnostic evaluations, provided both high-level rarefaction and condensation click stimuli are used. Like OAEs, the CM provides no information about the function of mechanisms beyond the OHCs. Its presence simply confirms that OHCs, and possibly IHCs to a lesser extent, are being activated. Guidelines from the United Kingdom outline stimulus and acquisition parameters for recording the CM (NHS NHSP, 2011). These include a time window of 8–10 ms and both 80-dBnHL rarefaction and condensation clicks. A fast click rate (e.g., 87.1 clicks/s) is recommended as the CM is not a neural response and will not fatigue. Insert earphones should be used to separate electrical transducer artifacts from the CM. It is critical to demonstrate that the CM is not artifact by performing a control run by clamping the insert tube between the transducer and insert foam tip. In this control run, the CM should disappear as the sound stimulus is no longer stimulating the cochlea, but any electrical artifact will remain. Physiologic Tools to Examine Afferent Auditory Function Acoustic reflexes. The acoustic reflex pathway involves the IHCs, VIIIth nerve, cochlear nucleus, superior olivary complex, branch of the VIIth (facial) nerve, facial motor nucleus, and stapedius muscle. Therefore, because the IHCs and VIIIth nerve are critical links in this pathway, clients with ANSD could be expected to have abnormal acoustic reflex findings. In fact, Berlin et al. (2005) found absent or elevated middle ear muscle reflexes in the majority of their subjects diagnosed with ANSD. ABR. The ABR is a tool used to assess auditory nerve and low auditory brainstem function and is commonly used to estimate hearing thresholds in infants and individuals who cannot provide behavioral hearing responses (Stapells, Gravel, & Martin, 1995). Generation of the ABR requires that neurotransmitter be released into the synaptic cleft, resulting in synchronous firing of the VIIIth nerve fibers. The ABR is not an objective measure of hearing but an objective measure of neural activation and neural synchrony. For most individuals with hearing loss, there is a close correspondence between frequency-specific ABR thresholds and behavioral thresholds (Gorga et al., 2006; Stapells, 2000). However, in individuals with poor neural synchrony, ABR thresholds are unreliable estimates of behavioral hearing thresholds. In such individuals, an absent or abnormal ABR has been associated with a range of behavioral hearing thresholds from normal to a profound hearing loss (Berlin et al., 2010). Although the ABR depends on synchronous firing of auditory nerve and low brainstem auditory fibers, detecting sound behaviorally appears to be much less dependent on neural synchrony. Panel a of Figure 2 shows a response recorded from a 1-month-old diagnosed with ANSD using 70-dBnHL clicks presented at a rate of 37.7 clicks/s. The scalp electroencephalographic (EEG) was filtered from 30–1500 Hz and amplified 105 times. The averaged waveforms show CMs

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Figure 1. Evoked otoacoustic emissions. In Panel a, the evoked distortion product (DP) emissions are clearly above (> 6 dB) the noise floor (NF), resulting in a “pass” at each frequency. In Panel b, responses are less than 6 dB above the NF, resulting in a “refer” at each frequency. F1 and F2 levels were 65 and 55 dB SPL, respectively.

that change polarity with the polarity of the click stimulus, but no ABR. Using a fast click rate of 83.3 clicks/s demonstrates that the CM does not fatigue, as it has similar latency and amplitude characteristics to the CM recorded using 37.7 clicks/s. A control trial, with the insert earphone tube clamped, still placed in the infant’s ear and presenting the high-level clicks, confirms the CM is not stimulus or electrical artifact. In contrast, Panel b of Figure 2 shows a normal ABR recorded from a 2-month-old infant using the same stimulus and recording parameters as in Panel a of Figure 2. Note that the ABR waveforms in Panel b of Figure 2 have similar peak latencies regardless of whether the eliciting stimulus was a 37.7/s rarefaction or condensation click. In contrast to the absent ABR noted in Panel a of Figure 2, Panel a of Figure 3 shows an abnormal ABR with small amplitude peaks and a delayed IV interpeak interval of approximately 7.3 ms recorded from a 3-year-old child under general anesthesia. Rarefaction and condensation click stimuli presented at 80 dBnHL were used to generate the ABR. The scalp EEG was filtered from 100 Hz to 3000 Hz and amplified 105 times. Although the ABR shows some evidence of neural function (e.g., Waves I, III, and V are present in the averaged waveform), peak amplitudes are small. In addition, latencies of Waves III and V are prolonged.2 Although Wave I is present and has a normal latency of 1.45 ms, Wave II, which appears to be present in the average waveform, is not easy to identify in the separate rarefaction and condensation recordings. It is therefore possible that the longer than typical I–III interpeak latency of 3.75 ms is a result of a delayed Wave II, which is generated by the “intracranial portion of the auditory nerve” (Møller, Jannetta, Bennett, & Møller, 1981, p. 25). For comparison purposes, a typical ABR recorded from a 2

See Norrix, Trepanier, Atlas, and Kim (2012a) for typical latencies obtained under general anesthesia in normal hearing children using the stimulus and recording parameters that were used to obtain the ABRs in Figure 3. The corresponding amplitude data, from the same cohort of children (unpublished data; Norrix, Trepanier, Atlas, and Kim, 2012b), revealed average ABR Wave I, III, and V amplitudes to be 0.82 m (SD = 0.29), 0.45 m (SD = 0.17), and 0.54 m (SD = 0.2), respectively.

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3-year-old, also under general anesthesia, is displayed in Panel b of Figure 3. The stimulus and recording parameters were the same as those used to obtain the responses displayed in Panel a of Figure 3. Interpreting the Physiologic Test Battery The presence of OAEs and/or the CM is evidence of OHC function. An absent ABR (see Panel a of Figure 2) or abnormal ABR (see Panel a of Figure 3) in the presence of OAEs and/or a CM are evidence of pathology beyond the OHCs. When OAEs are absent but an apparent CM is present (i.e., the averaged evoked waveform shifts in polarity when a rarefaction compared with condensation click is used), it is important to ensure that the phase-shifted response is not a result of good low-frequency hearing. To do this, the United Kingdom’s NHS NHSP (2011) guidelines recommend using a 1-kHz tonepip to determine whether the client has good low-frequency hearing with a steeply sloping high-frequency cochlear hearing loss. A 500-Hz toneburst stimulus would also be appropriate to assess low-frequency hearing sensitivity. In cases of ANSD, there are no audiologic tools to differentiate site of lesion beyond the OHCs; therefore, it is impossible, based on physiologic tests, to fully isolate a sensory (IHC loss) from synaptic dysfunction from a neural hearing loss (axonal loss or dys-synchrony due to demyelination). In addition, dysfunction can exist at more than one site and might include OHC, IHC, and the VIIIth nerve as well as a mosaic pattern of functioning IHC, OHC, and pre- and postganglionic nerve fibers (Berlin et al., 2010). This mosaic pattern is often evidenced when OAEs are absent upon retest in older children or adults diagnosed with ANSD (Starr, Zeng, Michalewski, & Moser, 2008). The mechanisms responsible for the deterioration of OHCs include circulatory issues and channel disruption (influx and efflux of ions). Unlike the progressive deterioration of OAEs, the CM is likely to remain for a longer period of time, possibly because its generation consists of both IHC and OHC mechanisms or differences in populations of OHCs that can be measured with OAEs (1000 Hz and above) versus with CM (250 Hz and above).

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Figure 2. Auditory brainstem response (ABR) traces showing the cochlear microphonic with no neural response recorded from a 1-month-old infant (Panel a): Note that the waveforms recorded using rarefaction (R) and condensation (C) clicks (37.7 clicks/s) appear to be mirror images (two upper traces). A fast click rate of 83.3 clicks/s results in no adaptation (third trace). The disappearance of the response in the clamped tube condition, bottom trace, confirms the response is not stimulus artifact. In contrast, the ABR traces in Panel b show an ABR recorded from a 2-month-old infant with normal hearing. Waves I, III, and V are present, and there is no significant latency shifts between the rarefaction and condensation waveforms.

Causes of ANSD Both genetic and acquired factors can result in a diagnosis of ANSD. With continued advances in genetic testing, the genetic mechanisms underlying ANSD will become more evident. Likewise, there is more to discover about the cellular, molecular, and neuronal mechanisms involved in acquired ANSD. Genetic Causes of ANSD An estimated 40% of the cases of ANSD have a genetic basis (Sininger, 2002). Genetic causes of ANSD can be

nonsyndromic (isolated) or syndromic (associated with a constellation of disorders). The most frequently described isolated genetic causes of ANSD are due to mutations in the DFNB9, DFNB59, and AUNA1 genes, each resulting in faulty protein coding (Del Castillo & Del Castillo, 2012). The OTOF gene is responsible for DFNB9 nonsyndromic congenital hearing loss inherited in an autosomal recessive manner. This gene codes a protein called otoferlin, which is crucial for calcium-dependent synaptic vesicle exocytosis at the hair cell afferent ribbon synapse (Beurg et al., 2010) and thus transmission of the sensory signal from the IHCs to the VIIIth nerve. According to Pangršič,

Figure 3. Waveforms recorded using R and C clicks in (Panel A) a child diagnosed with auditory neuropathy spectrum disorder and in (Panel B) a typical child, both obtained under general anesthesia. The wave traces in Panel A have a neural response, evident in the bottom average R and C traces. However, the ABR in Panel A would be classified as abnormal with a small amplitude and a delayed I–V interpeak interval of approximately 7.0 ms compared with the normal ABR in Panel B. Note that the display scales are different in Panels A and B.

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Reisinger, and Moser (2012), more than 60 pathogenic mutations have been documented, which affect the coding for otoferlin. Most of these mutations result in severe to profound prelingual deafness, with some phenotypes characterized by extreme fluctuations in hearing, with changes in body temperature (Starr et al., 1998; Varga et al., 2006). Neural function is preserved in cases of DFNB9; thus, an ANSD diagnosis due to a mutation in otoferlin is not a neuropathy but a presynaptic disorder. In some cases of DFNB9, OHCs eventually become dysfunctional, likely due to environmental or genetic modifiers (Del Castillo & Del Castillo, 2012). The DFNB59 gene codes for a protein called pejvakin, which is found in the hair cells of the cochlea and vestibular system, pillar cells in the cochlea, as well as in spiral ganglion and cell bodies of neurons in the afferent auditory system cochlear nucleus to the midbrain (Del Castillo & Del Castillo, 2012). Several mutations in the DFMB59 gene have been identified, with one mutation associated with a disruption in the transmission of nerve impulses (Delmaghani et al., 2006). In contrast to nerve signal disruption, Delmaghani et al. (2006) found preserved cochlear IHCs and OHCs and speculated that this pejvakin mutation causes dys-synchronous auditory neural firing, which results in a severely abnormal ABR consisting of absent early ABR peaks and a delayed wave V response. This genetic form of ANSD is autosomal recessive (Mujtaba, Bukhari, Fatima, & Naz, 2012). The Diaph3 gene is responsible for an autosomal dominant form of auditory neuropathy (AUNA1). This gene codes for a protein that helps to maintain cell polarity and shape and is hypothesized to be important for actinrich postsynaptic dendritic spines (Schoen et al., 2010). As a result of overexpression of Diaph3, Schoen et al. (2010) hypothesized that the IHC synapse is affected initially with preserved function of the OHCs. However, the hearing loss progresses with eventual OHC involvement and profound SNHL by the fifth or sixth decade of life (Starr et al., 2004). In contrast to the isolated genetic causes, ANSD may be part of an inherited syndrome, such as Charcot– Marie–Tooth or Friedreich’s ataxia, in which individuals can exhibit a range of sensory and/or motor neuropathies. In cases in which the peripheral auditory system is affected, the sensory cells of the cochlea are spared; thus, OAEs are present, as are the synapses between the IHCs and auditory nerve fibers. Dysfunction occurs along the peripheral auditory nerve, and occasionally within the central nervous system, resulting in an abnormal ABR response (see the ANSD acquired or expressed later in life section, below, for a discussion of ANSD due to peripheral neuropathies). An ANSD diagnosis can also result from a sporadic or syndromic inheritance pattern that results in cochlear nerve deficiency (Clemmens, Germiller, & Cohn, 2012) and can be bilateral or unilateral. Liu, Bu, Wu, and Xing (2012) speculated that congenital dysplasia may be an underlying mechanism in cases of unilateral ANSD. Imaging can be a useful tool to examine the cochlear nerve in cases of both

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unilateral and bilateral ANSD, as Roche et al. (2010) found that a large percentage of ears with ANSD (28%) had evidence of cochlear nerve deficiency. Acquired ANSD The auditory manifestations of ANSD can arise early in life during the perinatal period. Alternatively, ANSD can be acquired or expressed later in life. Early acquired. The most significant perinatal risk factor for acquired ANSD is an extended neonatal intensive care unit (NICU) stay (cf. Teagle et al., 2010), where hypoxia, prematurity, and hyperbilirubinemia are potential causes of ANSD. Hypoxia. There is some evidence in the animal literature that hypoxia causes greater IHC damage compared with OHC damage (Mazurek, Winter, Fuchs, Haupt, & Gross, 2003; Sawada, Mori, Mount, & Harrison, 2001; Shirane & Harrison, 1987). Sawada et al. (2001) studied the effects of mild long-term hypoxia in adult chinchillas. They found that after a period of experimentally induced hypoxia, ABRs were lower in amplitude and OAEs essentially unchanged compared with baseline measures. Scanning electron microscopy revealed IHCs to have cytoplasmic protrusions with swelling and disarrayed stereocilia. OHCs were relatively normal in comparison. These authors concluded that long-term mild hypoxia affects the IHC/cochlear afferent system prior to the OHC system. Prematurity. Temporal bone studies in critically ill NICU infants who had expired revealed that a high percentage of premature infants had selective loss of IHCs (Amatuzzi et al., 2001; Amatuzzi, Liberman, & Northrop, 2011). There appears to be an early developmental period during which the comorbid factors associated with prematurity (cf. Beutner, Foerst, Lang-Roth, von Wedel, & Walger, 2007; Teagle et al., 2010) selectively damage IHCs. As evidence for prematurity being a risk factor for ANSD, Amatuzzi et al. (2011) found that the mean age of NICU infants with selective IHC damage was 32 weeks gestation compared with 36 weeks gestation for those with normal ears and those who showed both OHC and IHC loss. Hyperbilirubinema. Hyperbilirubinemia occurs when excess bilirubin, a breakdown product of hemoglobin or red blood cells, accumulates in the body. Clinically significant bilirubin levels are especially of concern for premature infants due to their immature hepatic system. It can also be seen in full-term infants as a consequence of poor breastfeeding, sepsis, central nervous system hemorrhage, fetal–maternal blood incompatibility, metabolic disorders, infections, and syndromes that are associated with decreased bilirubin conjugation or excretion (Porter & Dennis, 2002). In a normal functioning system, the unconjugated bilirubin, which is lipid soluble, is carried by albumin to the liver, where it is converted into a water-soluble form and can then be excreted in bile. Several factors put newborns at risk for high levels of unconjugated bilirubin. Infants have increased blood volume and higher hemoglobin concentrations, with a shortened blood cell life span, than adults.

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This, coupled with deficiencies in both hepatic uptake and conjugation of bilirubin, results in high levels of unconjugated bilirubin and physiologic jaundice of the newborn (Gartner & Herschel, 2001). Unconjugated bilirubin can cross the infant’s immature blood–brain barrier if binding sites on albumin are saturated or if conditions such as acidosis or sepsis, which further open the blood–brain barrier, are present (Rosenthal, 1997). Excessive levels of unconjugated bilirubin are neurotoxic, entering brain cells and altering neuronal function in the peripheral and central nervous system, a condition called bilirubin encephalopathy or kernicterus (see Shapiro & Popelka, 2011, for a review). Primary sites of damage can include the basal ganglia, hippocampus, cranial nerve nuclei, and cerebellar vermis. Selective damage of the auditory brainstem nuclei and spiral ganglion of the auditory nerve can result in an abnormal ABR. There are a wide range of effects on central nervous system and auditory neural function as a result of high levels of unconjugated bilirubin. However, sensory cells in the auditory system are typically unaffected; thus, present OAEs would be expected. ANSD diagnosed during the perinatal period can be permanent or transient due to neuromaturational delay or factors such as hyperbilirubinemia, hydrocephalus, anoxia, metabolic toxins, and/or inflammation (Uus, 2011). Madden, Rutter, Hilbert, Greinwald, and Choo (2002) reported that infants with jaundice tended to show clinically significant improvements in hearing thresholds from time of ANSD diagnosis until about 12 months of age, with stable audiograms reached by 18 months of age. In contrast, infants with a hypothesized genetic cause of ANSD showed no evidence of improved hearing thresholds. The United Kingdom NHS NHSP (2013) guidelines suggest a repeat ABR at 8–10 weeks corrected age for infants diagnosed with ANSD and to “consider a repeat ABR at 12–18 months corrected age, depending on the circumstances of the individual case” (p. 4). The circumstances of each infant can be determined through measures such as genetic testing, a thorough case and birth history, and a neurological examination, as well as regular monitoring of behavioral and functional listening abilities. ANSD acquired or expressed later in life. ANSD, which occurs during childhood or adulthood, can be associated with peripheral neuropathies due to genetic or disease processes. In some cases, the neuropathy affects the VIIIth nerve (for a review, see Santarelli, Rossi, & Arsla, 2013). For example, Charcot–Marie–Tooth disease is an inherited condition associated with neuropathy that can affect both motor and sensory nerves. It is clinically and genetically heterogeneous with more than 50 possible gene mutations resulting in the disorder and can have a dominant, recessive or X-linked mode of inheritance. Some of the subtypes of Charcot–Marie–Tooth disease have been associated with demyelinating or axonal peripheral neuropathies affecting the auditory nerve (Rance et al., 2012). Age of onset can range from childhood to adulthood. Friedreich’s ataxia, which typically has an adult onset, is another example of an inherited polyneuropathy disease that can affect the VIIIth nerve. Other inherited syndromes

that can be associated with ANSD include, but are not limited to, Leber’s Hereditary Optic Neuropathy, Mohr– Tranebjaerg Syndrome, and Refsum disease (Manchaiah, Zhao, Danesh, & Duprey, 2011). The ANSDs associated with genetic peripheral neuropathies are typically progressive. Although onset of symptoms may occur during childhood, some individuals may not show symptoms until even later in life. The underlying disease process (e.g., demyelinating vs. axonal neuropathy) can result in various abnormalities in the latencies and amplitudes of the ABR. Rance et al. (2008) suggested that an axonal neuropathy will result in normal ABR latencies but reduced amplitudes due to a reduced number of neural elements contributing to the response. A demyelinating disease can result in delayed transmission times resulting in prolonged interpeak ABR latencies (Chiappa, Harrison, Brooks, & Young, 1980; Starr & Achor, 1975). As reviewed by Rance et al. (2012), this distinction between axonal and demyelinating effects on the ABR may be less clear cut as the disease state progresses. These authors explained that with a demyelinating disease, slow conduction times may initially be the sole presenting symptom; however, with progression of the disease and different degrees of demyelination across different nerve fibers, conduction times may become asynchronous, resulting in both delayed latencies and low amplitudes. With axonal disease, initial ABRs may show normal latencies with reduced amplitudes; however, as the disease state progresses, demyelination, secondary to axonal loss, is also possible, and ABRs may show both delayed latencies and low amplitudes. Late-acquired ANSD can also be caused by nongenetic factors such as immune responses, infections, systemic diseases, malignancies, toxic substances, nutritional deficiencies, and endocriopathies (for a review, see Amato & Dumitru, 2002). Examples of such neuropathies include chronic inflammatory demyelinating polyneuropathy, Guillain–Barr syndrome, and Epstein–Barr virus. In unilateral cases of late-acquired ANSD, Liu et al. (2012) speculated that degeneration of the nerve (e.g., from disease processes such as mumps) may be an underlying mechanism.

Functional Communication: Implications for Those Diagnosed With ANSD Because of the many possible sites of dysfunction resulting in a diagnosis of ANSD (e.g., IHC, synapse, number of or synchrony with which auditory nerve (AN) fibers can respond), functional outcomes are highly variable. Individuals diagnosed with ANSD can have normal hearing thresholds to a profound hearing loss (Berlin et al., 2010). Hearing thresholds can also fluctuate (Starr et al., 1998; Varga et al., 2006). Like pure-tone thresholds, speech perception ability can be variable in this population (Rance, McKay, & Grayden, 2004) and cannot always be predicted from the pure-tone audiogram (Starr, Sininger, & Pratt, 2000). There have been reported cases of individuals diagnosed with ANSD having normal to near-normal pure-tone thresholds but significant speech understanding difficulties (Rance et al., 2004, 2007).

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Understanding speech in the presence of noise has been reported to be particularly difficult for individuals diagnosed with ANSD (Kraus et al., 2000; Rance et al., 2007, 2008). Speech perception ability appears to be correlated with the amount of temporal distortion of the signal (Rance et al., 2004; Zeng, Kong, Michaelewski, & Starr, 2005; Zeng, Oba, Garde, Sininger, & Starr, 1999). Temporal distortion can arise from asynchronous release of neurotransmitters (Glowatzki & Fuchs, 2002) and/or different degrees of demyelination of VIIIth nerve fibers, resulting in a “smeared” representation (Zeng et al., 2005). However, Rance et al. (2004) showed that not all clients with a diagnosis of ANSD show temporal abnormalities on psychophysical tasks and noted that the variability in temporal disruption may reflect different underlying pathological mechanisms or different degrees of the same pathology. In addition to the contributions of auditory bottomup processes (e.g., degree of audibility and amount of temporal distortion), speech perception will be influenced by top-down cognitive factors such as attention and working memory skills (Heinrich, Schneider, & Craik, 2008; ShinnCunningham & Best, 2008). Contextual knowledge and linguistic factors, such as knowing the topic, vocabulary, and language structure, impact a person’s ability to understand speech. Therefore, as is true for any individual with SNHL, communicative competency will be optimal if remedial efforts optimize audibility and speech clarity as well as emphasize the development and strengthening of cognitive and/or language skills. For these reasons, it is important that those who are diagnosed with the ANSD pattern of test results (e.g., OAEs and/or the CM present with an absent or abnormal ABR) have a comprehensive assessment of hearing thresholds, word recognition ability in quiet and in noise, and functional evaluations of listening, as well as language and communicative skills. The unique abilities of each client must be considered in designing the management plan (Padish Clarin, 2013).

Assessment Every child and adult diagnosed with ANSD should receive a comprehensive team evaluation following the diagnosis. For infants and children, the team should include, at a minimum, the family, a pediatric audiologist, a physician (otolaryngologist or pediatrician and/or neurologist), a speech-language therapist, and a teacher of the deaf (NHS NHSP, 2013). A parent guide (who has personal experiences with ANSD) and an early interventionist are also important team members. Genetic testing should be part of the team evaluation when ANSD appears isolated, as some genetic causes are successful in predicting functional outcome (see the “Genetic Causes of ANSD” section above). For adults diagnosed with ANSD, the team should include an audiologist, otolaryngologist, neurologist, speechlanguage pathologist (SLP), and primary care physician. The use of clinical markers and/or genetic testing may also facilitate a diagnosis when hereditary peripheral neuropathy is suspected (Wilmshurst & Ouvrie, 2011).

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Audiologic Assessment Reliable behavioral measures of hearing sensitivity, word recognition ability, and functional listening abilities will guide decisions about amplification or cochlear implantation, as well as optimal communication mode(s). In individuals with auditory nerve dys-synchrony, the ABR is not a good predictor of hearing thresholds; therefore, determining behavioral hearing thresholds and responses to auditory signals are critical. Hearing sensitivity. For the infant, birth to ~5 months of age, functional evaluations may be the primary assessments to obtain information about hearing, as behavioral hearing threshold responses are not adultlike due to developmental (Werner, 2007) and maturational factors. Assessment tools for this age include the use of behavioral observation audiometry (BOA) to determine the infant’s sound awareness and minimal responses to sounds. Functional listening evaluations, such as the Early Listening Function (Anderson, 2002) and the Infant Toddler Meaningful Auditory Integration Scale (Zimmerman-Phillips, Robbins, & Osberger, 2000), can also be used to document an infant’s responses to sound. Functional listening assessments can be completed by parents or caregivers with the assistance of the audiologist, SLP, or early interventionist. For those who have at least a developmental age of ~5–6 months, formal audiometric tests can be administered to begin to ascertain hearing thresholds for each ear. Visual reinforcement audiometry, conditioned play audiometry, and conventional hand-raising techniques can be used to obtain tonal thresholds with the method of choice, depending on the developmental age of the individual (American Academy of Audiology, 2012; Nielsen & Olsen, 1997; Thompson, Thompson, & Vethivelu, 1989; W. R. Wilson & Thompson, 1984). In addition to obtaining threshold measures of audibility, standardized audiologic assessments using speech materials can provide measures of the audibility and distortion effects of hearing loss on auditory function (cf. R. H. Wilson & McCardle, 2005). Within the framework of the World Health Organization International Classification of Functioning, Disability and Health (World Health Organization [WHO], 2001), it is important to assess not only function but also the impact of the hearing loss on the individual’s life. Assessments must address whether the individual can participate in everyday tasks, including social, academic, and vocational situations. Environmental and personal factors, which may facilitate or impede a person’s functioning and participation, should also be assessed within the WHO (2001) framework. Auditory function. Standardized word recognition testing can be performed once the client has the skills to recognize simple words and can reliably express recognition either by a verbal or by a pointing response. Assessments in quiet can provide information about optimal word recognition ability under standardized conditions, monitor a client’s performance over time, and guide amplification decisions (Hornsby & Mueller, 2013). Additionally, standardized testing of word recognition performance in background noise

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should be measured, as speech-in-noise difficulties are common in individuals with SNHL (Carhart & Tillman, 1970). This may be particularly important for the client diagnosed with ANSD who has normal to near-normal hearing thresholds and/or good word recognition ability in quiet, thus leading his or her clinician to erroneously assume that functional difficulties would be minimal. Examples of speechin-noise tests include the Pediatric Speech Intelligibility Test (Jerger & Jerger, 1984), Words in Noise Test (R. H. Wilson, 2003; R. H. Wilson, Farmer, Gandhi, Shelburne, & Weaver, 2010), Bamford–Kowal–Bench Speech-in-Noise Test (Etymotic Research, 2005), and Quick-SIN (Killion, Niquette, Gudmundsen, Revit, & Banerjee, 2004). Impact of hearing loss. In order to obtain an estimate of real-world listening performance, functional listening questionnaires can be used. Parents, teachers, and clients can provide information about how the hearing disorder affects daily function. Such questionnaires include, but are not limited to, the Early Listening Function (Anderson, 2002), Listening Inventory for Education— Revised (Anderson, Smaldino, & Spangler, 2011), and the Self Assessment of Communication (Schow & Nerbonne, 1982). Nonaudiologic Assessments A full communication profile of the child or adult should be obtained by an SLP and/or early interventionist to assess how the client is able to use auditory and visual cues as well as higher level cognitive and language functions in his or her daily activities. Assessments should include a determination of the client’s potential as well as receptive and expressive language and communication skills in whatever modality or modalities the individual uses (Stredler-Brown, 2002). For those suspected of having concomitant central auditory dysfunction as a result of prenatal or postnatal causes (e.g., in utero insults, hyperbilirubinemia, oxygen deprivation), magnetic resonance imaging (MRI) has been useful in identifying abnormal intracranial findings, beyond the VIIIth nerve, which is common in children diagnosed with ANSD (Roche et al., 2010).

Re(Habilitation) and Management The treatment goal for young children identified with ANSD is the development of language (Stredler-Brown, 2002). For a child who does not have a language base, a communication method must be established for the child and family (NHS NHSP, 2013). For all individuals who choose to use oral communication, communication function will be optimized by maximizing speech audibility and clarity and providing auditory and communication experiences. Re(habilitation) and management approaches should be fluid, allowing for change as follow-up assessments reveal more about the auditory, speech/language, communication, and cognitive skills and progress of the client (Berlin, Morlet, & Hood, 2008; Stredler-Brown, 2002).

Maximizing Audibility and Clarity Hearing aids, cochlear implants, and frequency modulated (FM) systems are technologies available to improve audibility and clarity for those with ANSD. With mild to severe degrees of hearing loss, hearing aids and/or FM systems are typically the initial remediation of choice and usually the only remediation option for children under the age of 1 year regardless of degree of hearing loss. The Joint Committee on Infant Hearing (2007) recommends that children with hearing loss should receive hearing aids by 6 months of age. The Guidelines Development Conference (2008) recommends that as soon as reliable behavioral audiometry indicates elevated thresholds for pure tones and speech, hearing aids should be considered. They should be fit using standard pediatric fitting guidelines that use algorithms to prescribe the amount of gain across frequencies as a function of pure-tone thresholds (American Academy of Audiology, 2013; NHS NHSP, 2009). Because the ABR cannot be used to estimate pure-tone thresholds in children with ANSD, the fitting of amplification devices in a child with comorbid developmental delays may be delayed due to difficulties in obtaining behavioral thresholds. If reliable behavioral results cannot be obtained, BOA and informal observation can be useful in guiding management (NHS NHSP, 2013). The NHS NHSP (2013) guidelines recommend that in the absence of reliable behavioral thresholds, if there is significant concern from the family and early interventionist, hearing aid fitting(s) should begin on the basis of these concerns and BOA with the use of validation measures (e.g., compare the child’s responsiveness in the unaided and aided conditions). Although some individuals diagnosed with ANSD benefit from amplification, others do not (Berlin et al., 2008; Rance et al., 1999). Zeng et al. (2005) suggested that hearing aid technologies could compensate for impaired temporal processing that is common in individuals diagnosed with ANSD by eliminating low-frequency acoustic information or emphasizing high-frequency information. Further research regarding the effects of identifying individual psychoacoustic abilities will facilitate the selection, programming, and design of hearing aids for those diagnosed with ANSD. At 1 year of age, infants with a profound sensorineural hearing loss, based on pure-tone thresholds, become candidates for cochlear implants. MRI is important to assess the status of the cochlear nerve when considering cochlear implantation, as some cases of ANSD are due to abnormal or deficient VIIIth nerves (Roche et al., 2010). In contrast to hearing aids, cochlear implants have the potential to provide audibility across all speech frequencies for this population (Baudhuin, Cadieux, Firszt, Reeder, & Maxson, 2012; Firszt et al., 2004), with some children obtaining language skills commensurate with those of age-matched peers (Hammes et al., 2002; Leigh, Dettman, Dowell, & Briggs, 2013; Nicholas & Geers, 2007). For children with ANSD, some authors have recommended that they be cochlear implant candidates regardless of pure-tone thresholds (Guidelines Development Conference, 2008; Jeong, Kim, Kim, Bae, & Kim, 2007), with implant

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candidacy determined by an evaluation of whether the progression of auditory and spoken language skills are commensurate with the maturational development typically seen in normal hearing peers (Breneman, Gifford, & DeJong, 2012). These recommendations are based on beliefs that electrical stimulation, in contrast to acoustic stimulation, can provide greater neural synchrony and better speech perception outcomes for children with neural dyssynchrony (cf. Rance, 2005). In support of these claims, several studies have revealed that cochlear implantation, in those with a neural site of dysfunction, can lead to improved speech and language skills (Breneman et al., 2012; Peterson et al., 2003). The overall speech and language outcomes for children diagnosed with ANSD and fitted with a cochlear implant are mixed. Although there are children who benefit, some do not. Etiology is likely a factor in determining speech and language benefit using cochlear implants. Comorbid medical conditions, common in those diagnosed with ANSD (Uus, Young, & Day, 2012), may contribute to delays in the child’s speech and language development (Padish Clarin, 2013). In contrast, for children with ANSD who have a profound loss due to an isolated presynaptic disorder such as the OTOF mutation, the expectations for success of individuals with a cochlear implant are similar to those of individuals with SNHL (Rouillon et al., 2006). Once the client is implanted, the audiologist has the challenge of programming the cochlear implant. An individualized approach is needed because those with ANSD due to IHC dysfunction will likely succeed with programming similar to any child with SNHL. However, for those with neural dys-synchrony, alternate programming strategies may be needed to optimize speech perception (Pelosi et al., 2012; Teagle, 2013). Future studies will be required to determine whether etiology as well as psychoacoustic measures can be used to optimize cochlear implant mapping for those with ANSD. Hearing aids and cochlear implants can provide improved signal audibility in quiet environments; however, those with ANSD can experience severe difficulties understanding speech in noise (cf. Kraus et al., 2000; Rance et al., 2007, 2008; Shallop, 2002). Personal FM devices can be used alone or coupled with hearing aids or cochlear implants to improve the signal-to-noise ratio, speech perception, and language-learning ability (Cone-Wesson, Rance, & Sininger, 2001; Guidelines Development Conference, 2008). Optimizing Communication Competency The audiologist, SLP, and/or early interventionist have knowledge and skills to facilitate communicative competence. After discussing the client’s strengths and limitations as well as the needs and desires of the client and/or client’s family, a therapy plan should be initiated. For the adult, an aural rehabilitation program, administered in group and/or individual sessions, can be used to teach strategies such as control of the environment, self-advocacy, and cognitive approaches to enhance communication (cf. Marrone & Harris, 2012). For the infant

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or young child with ANSD, early intervention services that promote language and preverbal communicative interactions can help lay the foundation for future language and communicative competencies regardless of the communication mode used (Magnuson, 2000; Tait, Lutman, & Robinson, 2000; Yoshinaga-Itano, 2006). The choice of communication mode may not be straightforward for children or infants who exhibit comorbid issues. The amount of concomitant neural dysfunction throughout the central auditory system, from the VIIIth nerve to the cortex, will impact the individual’s ability to use higher order cognitive and language strategies for interpreting sound patterns. In these children, the ability to use a hearing aid or cochlear implant successfully is more limited (cf. Bagatto et al., 2011; Pelosi et al., 2012). The infant should be assessed regularly to determine whether adequate progress with the chosen mode(s) of communication is being made. When adequate progress is not being made, alternative modes of communication and/ or supplementing the current method with other communication methods should be explored. The NHS NHSP (2013) guidelines state that communication systems such as auditory/aural with lipreading and natural gesture, total communication, and sign language are appropriate for children with ANSD. Stredler-Brown (2002) proposed that visual approaches such as speechreading, cued speech, and English-based sign language, such as Manually Coded English, should be considered if a child has difficulty understanding auditory information. Future research, to better predict outcomes, will assist in determining which children with ANSD will succeed with aural/oral communication using the technologies and remediation approaches that benefit so many children with SNHL versus which children require alternate technologies and supplements to aural/ oral communication.

Counseling the Family The audiologist in the hypothetical case described at the outset of the article may wish to explain Brody’s situation to his parents in the following way: Mr. and Mrs. Johnson, Brody has a hearing disorder. His hearing nerve is not sending the signal to the brain in a normal way. Some children with this disorder function with very little difficulty, while others require hearing aids or other technologies to function. We will need to assess how Brody responds to sounds to determine if hearing aids are needed and to determine the most beneficial communication options for him and for your family. Your child’s progress with hearing and speech and language development will be monitored regularly to determine if he is making good progress or if alternative treatments are indicated.

Summary This review is a guide to the clinicians who work with individuals diagnosed with ANSD and/or their families. From this review, it is evident that in some cases of ANSD,

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the auditory nerve is intact and the breakdown is preneural, either due to damaged IHCs that are unable to release neurotransmitters into the synaptic cleft or due to a problem with receptor sites on the auditory nerve fiber. In other cases, neural dysfunction (e.g., demyelination of the VIIIth nerve or an absent or hypoplastic VIIIth nerve) can result in the pattern of test results that leads to a diagnosis of ANSD. Although current audiologic tools to determine the exact site of lesion for those with ANSD do not exist, genetic testing and a thorough case history can provide insights into the underlying mechanisms involved. With continued advances in technology, tools will become available that can provide more definitive answers regarding etiology and predicted outcomes as well as methods to improve audibility and speech clarity for clients with ANSD. Regardless of etiology, and even when etiology can be determined, intervention should be approached within the context of the client’s functional deficits and unique needs and should include frequent monitoring of hearing thresholds, speech perception abilities, and communication function so that the remediation and management plan can be modified as needed.

Acknowledgment We thank the Tucson Listening, Spoken Language Professional Interest Group, for inspiring us to write a summary for professionals and for allowing us to share this information with this professional group.

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Journal of Speech, Language, and Hearing Research • Vol. 57 • 1564–1576 • August 2014

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