Auditory Neuropathy Spectrum Disorder

Disease Overview

Summary

Auditory neuropathy spectrum disorder (ANSD) is a newly described condition defined as a sensorineural hearing loss that affects a person’s ability to hear or understand speech. Sensorineural means that this disorder is due to a lesion or defect in the inner ear, auditory nerve or the connection between the nerve and brain. As a result, sound enters through the ear but doesn’t get adequately transmitted to the brain. The hearing loss varies from normal to severe while speech is generally perceived as distorted and hard to understand. ANSD is characterized by an abnormal speech perception that does not necessarily correlate with the patient’s hearing abilities. It is a disease that primarily affects children. Most people are affected from birth and are diagnosed early on in life. However, some adults may be affected but are undiagnosed. The general population incidence varies between study reports, but approximatively 1 to 3 children per 10,000 births are affected by ANSD. With a proper follow-up, medical devices and therapies, a child with ANSD can develop good language, communication and hearing skills.

Introduction

The term “auditory neuropathy” was first proposed by Arnold Starr, MD and colleagues in 1996 as hearing impairments due to a defect in the eighth cranial nerve (or auditory nerve that allows us to hear). This definition was later expanded to include loss of inner hair cells in the ear or damage between the nerve and brain. According to the affected site in that pathway, a patient can have a presentation ranging from mild hearing loss to functionally deaf. This is why this disorder has been subsequently renamed “auditory neuropathy spectrum disorder”. Hearing ability and speech perception may vary. When a child is suspected of having hearing problems, a proper diagnosis and early intervention are crucial for a better outcome.

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Synonyms

• auditory de-synchrony
• auditory neuropathy (AN)
• auditory dyssynchrony
• ANSD
• auditory mismatch

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Signs & Symptoms

If you are a parent and notice any or all of the following, it’s essential to consult a doctor.

• • In the presence of loud noises, your child doesn’t turn around.
  • By eight months, your baby is not laughing, babbling or cooing.
  • By twelve months, your baby does not try to reproduce surrounding sounds and actions.

If a hearing problem is suspected, you will be referred to an audiologist, a healthcare professional who can diagnose and treat hearing loss or an otolaryngologist (ENT = ear, nose and throat doctor).

If you are an adult and notice that you cannot hear well on the phone and have difficulty understanding speech, it’s important to talk about this with your general practitioner.

Symptoms of auditory neuropathy may present in various ways, depending on the affected site in the auditory pathway. They can also fluctuate day to day. For some patients, symptoms may improve with time, and for others, they might stay the same or get worse. A patient can present with one or more of the following:

• • Mild to severe hearing loss
  • Difficulty understanding spoken words
  • Normal hearing abilities with impaired speech perception (understanding speech)
  • Difficulty understanding speech especially in noisy environments
  • Difficulty determining where a sound is coming from

Newborn hearing screening protocols are not the same everywhere. Thus, sometimes ANSD is not detected in the early stages and symptoms can only be noticed over time. In children, speech may develop naturally or be delayed. Speech discrimination can range from no difficulty distinguishing sounds to difficulty discriminating sounds in a quiet environment. When a child is followed over time, spontaneous improvement is possible clinically by 12 months, and stabilization may happen around 18 months. However, improvement depends on the severity of the impairments, the underlying cause and the treatment’s efficacy.

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Causes

Sound waves usually enter thought the outer ear and travel via the ear canal. When they arrive at the eardrum, it vibrates. Those vibrations are then transmitted via a series of bones to the cochlea, a fluid-filled structure with a membrane that contains two types of cells: outer and inner hair cells. The inner ones are responsible for 95% of the information sent to the brain via the auditory nerve, while the outer cells amplify the sound stimulus. Damage to any of these sites may lead to hearing loss. A defect in the inner hair cells, the auditory nerve, the connection between them or the connection between the nerve and brain can lead to ANSD. If any or all are affected, the brain will receive a disorganized signal (hard to understand) or no signal at all (functionally deaf). Most of the time, ANSD affects both ears, but in some patients it can affect only one ear. A head injury can cause a lesion in the auditory nerve and lead to ANSD. However, this cause is rare and auditory neuropathy is most often due to health problems before or during birth, especially in children.

Acquired ANSD can be due to many factors present either immediately before or after birth, such as:

• • Prematurity (<28 weeks) and low birth weight
  • Elevated bilirubin in the blood that causes jaundice
  • Absence of oxygen or inadequate supply of oxygen to tissues in the body
  • Congenital brain abnormalities
  • Intracranial hemorrhage (when blood vessels rupture in the brain or between the brain and the skull)
  • Family history of ANSD
  • A drug with a toxic effect on the ear

ANSD has also been associated with infections due to various viruses such as measles, mumps, cytomegalovirus (CMV) and HIV, seizure disorders and high fever. For some patients, the cause remains unknown.

Congenital ANSD may be due to genetic causes. More than 15 genetic mutations have been linked to ANSD. Some can present alone (non-syndromic) or with other symptoms (syndromic). Researchers continue to investigate the role of genetic mutations in ANSD and their variations in different populations. An OTOF gene mutation is the most common non-syndromic cause of ANSD. This gene is essential for the inner hair cell function and might also be necessary for the outer hair cells. It’s inherited in an autosomal recessive pattern, which means that an individual will develop the disorder only if they receive one non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. Various non-syndromic mutations can affect different parts of the auditory pathway and contribute to the variable presentation of ANSD.

Syndromic auditory neuropathies are abnormalities linked to other syndromes such as:

• • Charcot-Marie-Tooth (CMT) disease which is a group of disorders where the peripheral motor and sensory nerves are affected, resulting in muscle weakness, and atrophy and sensory loss. This disorder can lead to progressive motor and sensory neuropathy, including sensorineural hearing loss such as ANSD.
  • Autosomal dominant optic atrophy which is an inherited optic nerve disorder that can present in 20% with a sensorineural hearing loss such as ANSD.
  • Friedreich’s ataxia, which is a neurodegenerative movement disorder that affects many organs and can to hearing complications.

Auditory neuropathy can also be caused by a mitochondrial mutation associated with mitochondrial syndromes. Genes for mitochondria (mtDNA) are inherited from the mother. If a mother has a non-working mtDNA, she will pass these genes to all her children and only daughters will pass them on to future generations. Leber hereditary optic neuropathy (LHON) is a disorder inherited in this way that causes bilateral, painless loss of vision in teenagers or young adults. Rarely, it can cause ANSD.

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Affected populations

Auditory neuropathy occurs equally in males and females with a slightly higher frequency in males. Prevalence and incidence remain uncertain as many studies report different figures due to the variability of clinical presentations in ANSD patients. Overall, it is estimated that 1 to 3 children per 10,000 births are affected by this disorder. It can occur at any stage of life. Children, adults and seniors can be affected. However, in most cases, it’s detected in newborns, particularly those admitted to the neonatal intensive care units (NICU). In the NICU, 10 to 15% of the babies are diagnosed with a sensorineural hearing loss (SNHL).

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Disorders with Similar Symptoms

There are other disorders that result in hearing loss due to damage to outer hair cells that are different from ANSD. These include acquired hearing loss related to aging or noise exposure, hearing loss at birth from infections (rubella, herpes simplex) and genetic conditions such as Usher syndrome.

Usher syndrome is a rare genetic disorder characterized by deafness due to an abnormality of the inner ear hair cells leading to sensorineural hearing loss accompanied by retinitis pigmentosa, a disorder that affects the retina of the eyes and causes progressive loss of vision. The age of onset and the severity of symptoms are determined by the underlying genetic cause. Usher syndrome is inherited in an autosomal recessive pattern.

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Diagnosis

There are several tests that may be performed when someone is suspected of having hearing problems. In most screening programs, only the otoacoustic emission (OAE) is used, which is insufficient to detect ANSD. ANSD is classically characterized by normal OAE with an abnormal auditory brainstem response (ABR) test. Measuring the middle ear muscle reflex (MEMR) test or cochlear microphonic (CM) tests can be helpful in the diagnosis of ANSD. The following tests may be ordered:

Otoacoustic emission (OAE) test

• • Test that measures the function of outer hair cells in the cochlea. These cells are mainly responsible for sound stimulus amplification, as mentioned previously. This test is typically normal in ANSD and an abnormal result suggests an alternative cause for hearing loss.
  • While the patient is lying down or asleep (with sedation if necessary), a probe is placed in the ear canal to send sound. A machine records the echo produced by the hair cells.

Cochlear microphonic (CM) test

• • A measure of the outer hair cells (OHC) function in the cochlea. Sometimes used in conjunction with ABR.
  • The patient is put to sleep. Earphones are placed in the ear to send sounds while electrodes on his forehead record OHC activity.

Auditory brainstem response (ABR) test

• • Test that measures the function of the ear to brain pathway and can help detect where along that pathway a problem exists. It can show if the brain doesn’t receive any signal or if it requires a loud stimulus to receive a signal.
    The patient is put to sleep. Then, electrodes are placed on the forehead to measure brain activity while earphones in the ear are sending sound.

Middle ear muscle reflex (MEMR) test

• • Test that measures the contraction of the muscles in the middle ear in response to loud sounds. It will contract in a healthy ear while in ANSD, the reflex is absent or louder sound is needed to trigger it.
  • While the patient is put to sleep, loud noises are sent and a machine records if any reflex muscle contraction is generated.

For ANSD screening, most universal newborn hearing screening (UNHS) programs recommend screening newborns by one month, not only with OAE but also with an ABR test since OAE alone cannot diagnose ANSD. If the baby fails the first test, a second ABR test should be performed to confirm ANSD diagnosis. Ideally, the diagnosis should be verified by three months of age, and interventions should begin by six months.

To diagnose ANSD, all of the following criteria must be present:

• • Absent or severely abnormal ABR test results when the maximal stimulus is used
  • Normal CM or OAE test results that indicate normal outer hair cells function

Additional tests can be performed when suspecting ANSD in older children and adults:

Pure tone audiogram testing

• • Behavioural test that measures patients’ ability to hear sounds. It determines the pure-tone threshold at various pitches, representing the softest sound heard by a person 50% of the time.
  • This detects the degree of hearing loss at various pitches

Speech audiometry

• • Test that measures the understanding of speech by exposing the patient to different words and speeches.
  • This detects the degree hearing loss and helps identify central hearing deficits.

Once diagnostic tests show that a person has ANSD, other tests are needed to determine severity. Some of these tests, such as imaging tests, cannot be performed in the newborn period. Children may need to be at least one-year-old to receive these tests.

• • Magnetic resonance imaging (MRI) can detect structural inner ear abnormalities and auditory nerve lesions.
  • Genetic testing can rule in or out some genetic causes
  • Ongoing speech and language testing and assessment are essential to optimize treatment.
  • Ophthalmology testing is important since ANSD can be associated with eye abnormalities, so vision screening is needed.

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Standard Therapies

Treatment

Since the clinical presentation of ANSD varies, treatments are chosen according to the site in the auditory pathway affected, the severity of the ANSD and clinical deficits. A multidisciplinary approach is necessary to ensure adequate follow-up and to optimize treatment choice. Genetic evaluation can help the clinician understand the cause of ANSD in some cases. Ongoing therapy with a speech-language (SLP) is recommended to optimize language skills development. Even if improvements are observed in most cases, many children continue to have some or many abnormal hearing tests results that require a lifelong follow-up with several health care professionals (e.g. audiologist, otolaryngologist, neurologist, SLP, genetic counselor, etc.). No cure has been found for ANSD. However, many assistive listening devices (ALDs), like the ones listed below, can help with hearing deficits and acquiring language skills.

Frequency modulation (FM) system

• • Allows the user to hear sound with reduced background noise via a receiver in the ear or elsewhere in the body. The FM system has a microphone for the speaker, which is transmitted to the receiver wirelessly. By minimizing noise, the speaker’s voice is louder, and the user can better understand what they hear.
  • Can be used alone or with other devices like hearing aids and cochlear implant. FM can be useful in classroom settings.

Hearing aids (HA)

• • Indicated for patients with mild to moderate hearing loss, starting from the age of 3 months.
  • Amplifies the sound coming to the ear (makes it louder). HAs do not address the major problem of ANSD, which is transmission of sounds through the auditory nerve to the brain. HAs have limited utility and are typically used with hearing loss caused by dysfunction of the outer hair cells, which are normal in ANSD. Thus, depending on the cause of ANSD, HA may or may not be indicated.
  • May be used in conjunction with FM.
  • Requires monitoring of auditory skill, speech, and language development to evaluate therapy choice.

Cochlear implant (CI)

• • Indicated as the first-choice treatment for patients with moderate to profound hearing loss and severe speech perception deficiency. It can also be used when there is no progress in speech understanding ability and language development.
  • Useful when the cause of ANSD affects the inner hair cell by replacing the ear’s non-working part. May not be sufficient for patients with auditory nerve lesions.
  • In many cases, CI was shown to be effective at improving children’s language skills with ANSD.
  • CI may be delayed for optimal outcome until the hearing threshold stabilizes at 18 months and is usually done before the age of 24 months.
  • Radiological testing such as MRI is generally needed to better understand the anatomy prior to this surgery.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
 
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
 
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

Textbook
Parikh SR, ed. Pediatric Otolaryngology – Head & Neck Surgery: Clinical Reference Guide. San Diego, CA: Plural Published 2014. https://ebookcentral.proquest.com Accessed August 01, 2020.

Journal articles
Colucci DA. Updates on auditory neuropathy spectrum disorder. The Hearing Journal. 2020;73(6):32-32. doi:10.1097/01.HJ.0000669900.75620.75

Lalayants MR, Mironovich OL, Bliznets EA, Markova TG, Polyakov AV, Tavartkiladze GA. OTOF-related auditory neuropathy spectrum disorder. Vestn Otorinolaringol. 2020;85(2):21-25. DOI: 10.17116/otorino20208502121

Romolo Daniele De Siati, Flora Rosenzweig, Guillaume Gersdorff, Anaïs Gregoire, Philippe Rombaux, Naïma Deggouj. Auditory neuropathy spectrum disorders: from diagnosis to treatment: literature review and case reports. Journal of Clinical Medicine. 2020;9(1074). doi:10.3390/jcm9041074

Roman AN, Runge CL. Update on auditory neuropathy/dyssynchrony in children. Current Otorhinolaryngology Reports. 2020;8(3):276-284. doi:10.1007/s40136-020-00297-4

Gabr T. Amplification options in children with auditory neuropathy spectrum disorder. Commun Disord Deaf Stud Hearing Aids. 2016; 04(01): 1-3. doi:10.4172/2375-4427.1000151

Gary Rance, Martin Delatycki, Louise Corben. Auditory processing deficits in children with friedreich ataxia. Journal of Child Neurology. 2012;27(9):1197-1203. doi:10.1177/0883073812448963

Manchaiah VK, Zhao F, Danesh AA, Duprey R. The genetic basis of auditory neuropathy spectrum disorder (ANSD). International Journal of Pediatric Otorhinolaryngology. 2011;75(2):151-158. doi:10.1016/j.ijporl.2010.11.023

INTERNET
Hain TC. Auditory Neuropathy. https://www.dizziness-and-balance.com.Updated March 2, 2021. https://dizziness-and-balance.com/disorders/hearing/aud_neuropathy.html. Accessed July 1, 2021.

How you hear-Part of the ear. Mayo Clinic. Updated March 2020. https://www.mayoclinic.org/diseases-conditions/hearing-loss/multimedia/ear-infections/sls-20077144?s=2. Accessed July 1, 2021.

Wayne TS, Bojrab D and May JG. Auditory Neuropathy. Medscape. Updated May 2018. https://emedicine.medscape.com/article/836769-overview#showall Accessed July 1, 2021.

Auditory Neuropathy. National Institute on Deafness and Other Communication Disorders (NIDCD). Updated January 26, 2018. https://www.nidcd.nih.gov/health/auditory-neuropathy. Accessed July 1, 2021.

Auditory neuropathy spectrum disorder. Genetic and Rare Diseases Information Center. Updated December 2015. https://rarediseases.info.nih.gov/diseases/9274/auditory-neuropathy-spectrum-disorder. Accessed July 1, 2021.

Morlet T. Auditory Neuropathy Spectrum Disorder (ANSD). Nemours Kidshealth. Updated September 2014. https://kidshealth.org/en/parents/ansd.html Accessed July 1, 2021.

Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates. Two Kinds of Hair Cells in the Cochlea. Published 2001. https://www.ncbi.nlm.nih.gov/books/NBK11122/ Accessed July 1, 2021.

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Programs & Resources

• Assistance Programs
• Patient Organizations

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