The new england journal of medicine

Review Article

Allan H. Ropper, M.D., Editor Hearing Loss in Adults

Lisa L. Cunningham, Ph.D., and Debara L. Tucci, M.D., M.B.A.​​

earing loss in adults is encountered in all medical settings From the Section on Sensory Cell Biology, and frequently influences medical encounters. This disorder constitutes a National Institute on Deafness and Other Communication Disorders, Bethesda, MD substantial burden on the adult population in the United States, yet (L.L.C.); and the Division of Head and H 1 Neck Surgery and Communication Sci- screening for hearing loss is not routine, and treatments are often inaccessible because of the high cost or perceived ineffectiveness. ences, Duke University Medical Center, Durham, NC (D.L.T.). Address reprint re- quests to Dr. Tucci at the Division of Head and Neck Surgery and Communi- Burden of Hearing Loss cation Sciences, Box 3805, Duke Univer- 2 sity Medical Center, Durham, NC 27710, The Global Burden of Disease Study measured years lived with disability and or at [email protected]. found that hearing loss is the fourth leading cause of disability globally. In the N Engl J Med 2017;377:2465-73. United States, the prevalence of hearing loss doubles with every 10-year increase DOI: 10.1056/NEJMra1616601 in age. Approximately half of persons in their seventh decade (60 to 69 years of Copyright © 2017 Massachusetts Medical Society. age)3 and 80% who are 85 years of age or older4 have hearing loss that is severe enough to affect daily communication. Because of the aging population in this and other developed countries, hearing loss is likely to become an increasingly preva- lent disability. The primary effect of adult hearing loss is impaired communication, which can adversely affect relationships with family and friends and create difficulties in the workplace. Untreated hearing loss in adults also has indirect health, psychosocial, and economic effects and leads to social isolation and a reduced quality of life.5-7 As compared with age-matched adults with unimpaired hearing, older persons with hearing loss have higher rates of hospitalization,8 death,9,10 and falls and frailty,11,12 as well as higher rates of dementia13-15 and depression,16,17 even when known risks for these disorders are taken into account.13 On a societal level, be- cause of their hearing loss, persons with hearing loss achieve significantly lower levels of education than do those with normal hearing; they also have higher levels of unemployment or underemployment and lower levels of income than those with normal hearing.18,19 Annual health care costs for middle-age U.S. adults with hearing loss are significantly higher than the costs of care for those without hearing loss.19

Types of Hearing Loss Peripheral hearing loss is typically categorized as conductive (caused by impair- ment of the outer or middle ear) or sensorineural (caused by dysfunction in the cochlea or spiral ganglion). Hearing loss that has both conductive and sensorineu- ral components is categorized as mixed. Conductive hearing loss results from obstruction or disease of the outer or middle ear that prevents transmission of sound energy to the inner ear. The causes of conductive hearing loss range from cerumen impaction and otitis media to fixation of one or more of the middle-ear

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bones, mainly fixation of the stapes due to oto- Figure 1 (facing page). Diseases Affecting the Auditory sclerosis. Medical or surgical treatment of most System. types of conductive hearing loss often results in Shown are the auditory system and diseases affecting full restoration of hearing. each component of the system, including the ossicular chain of the middle ear, the cochlea, the organ of Corti and hair cells, and the auditory nerve. Assessment of Hearing Audiologic testing is performed to assess hear- ing thresholds across the range of frequencies mammalian cochlea are not regenerated after that are important for human communication. they are lost, the resulting hearing loss is per- Auditory thresholds are typically measured for manent. In many cases, the death of hair cells air- and bone-conducted pure-tone stimuli in results in degeneration of spiral ganglion neu- order to differentiate conductive from sensori- rons, which complicates the treatment of hear- neural hearing loss and to characterize the pat- ing loss with cochlear implants because these tern of hearing loss at various frequencies. The devices directly stimulate the spiral ganglion term “threshold shift” refers to a change in hear- neurons. ing thresholds between sequential audiologic Sensory hearing loss is the result of damage tests; it may reflect improvement or worsening to the organ of Corti (the sensory organ within of hearing. Testing the perception of speech the cochlea that houses the hair cells) or the signals of low redundancy (monosyllabic words) stria vascularis, a portion of the inner ear that presented at a comfortable listening level in the provides metabolic support for the organ of absence of background noise is another method Corti and generates the electrochemical (endo- of assessing hearing in adults. cochlear) potential that is the driving force for The broad term “sensorineural hearing loss” transduction of sound by sensory hair cells.20 In has been used by clinicians because, until re- contrast, neural hearing loss is the result of loss cently, diagnostic tests could not determine or dysfunction of spiral ganglion neurons or of whether a lesion was in the sensory or the neural more proximal auditory structures. Auditory portion of the peripheral auditory system. This neuropathy is characterized by normal (or near- distinction is now made by measuring otoacous- normal) sensory hair-cell function coupled with tic emissions, performed by simultaneously pre- abnormal neural responses and, usually, poorer senting tones of different frequencies and sound word recognition than is typical in sensory hear- pressures to the external canal and detecting ing loss18,21; this type of hearing loss is caused sound emissions from the cochlea itself; the re- by damage to the synapses that connect hair sults reflect the functioning of outer hair cells of cells to spiral ganglion neurons or to asynchro- the cochlea. Auditory brain-stem responses also nous neural firing within the auditory nerve. For test the neural component of audition by record- this reason, patients with auditory neuropathy ing synchronous neural activity of the auditory may benefit less from hearing aids than those nerve and auditory brain-stem nuclei. with sensory hearing loss.

Structures of the Ear Involved Causes of Hearing Loss in Hearing Loss Hearing loss can be caused by damage to any The peripheral auditory system consists of the portion of the peripheral and central auditory outer ear, the middle ear, and the inner ear systems. The main causes of sensorineural hear- (cochlea); the inner ear contains the mechano- ing loss are degenerative processes associated sensory hair cells that convert sound energy into with aging, genetic mutations, noise exposure, neural signals (Fig. 1). Cochlear hair cells are exposure to therapeutic drugs that have ototoxic innervated by neurons of the spiral ganglion, side effects, and chronic conditions. which project centrally to the auditory nuclei of the brain stem through the auditory nerve. Sen- Age-Related Degenerative Processes sory hair cells are susceptible to damage from a The leading cause of adult-onset hearing loss is variety of stresses, and since hair cells in the the effects of aging on the auditory system.

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Organs affected by disorders causing conductive hearing loss

BRAIN Organs affected by disorders causing sensorineural hearing loss Auditory Region Dysfunction or damage

Outer Ear

Outer Ear Damage or abnormality

BRAIN

Middle Ear Inner Ear

Semicircular canals Pinna Ossicles Damage or fixation

Tympanic Auditory Nerve membrane Asynchronous firing Damage or loss BONE

Cochlea Auditory Canal Middle Ear Damage from noise, aging, Cerumen impaction Otitis media genetic abnormalities, or ototoxic drugs

SCALA VESTIBULI Stria vascularis Damage from aging, vascular abnormalities, Synapses or ototoxic drugs Damage from noise or from possible loss SCALA MEDIA Tectorial due to hair-cell death membrane Inner hair cell Stereocilia Outer Spiral ganglion hair cell Degeneration from primary or Organ of Corti secondary causes Hair cell Damage from loud noises, ototoxic drugs, aging, or genetic abnormalities SCALA TYMPANI

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Hearing loss in older persons is caused not only by among people who report that their hearing is the degenerative effects of aging on the cochlea “excellent” or “good,” nearly 20% have audio- but also by the accumulated effects of exposure metric evidence of noise-induced hearing loss.32 to noise and ototoxic drugs. Age-related hearing Workplaces such as factories and certain jobs in loss (presbycusis) is usually bilateral and sym- the military are associated with exposure to high metric and is most pronounced at higher fre- noise levels; however, even people who do not quencies (≥2000 Hz).19 A prominent feature of work in these environments have a risk of noise this type of hearing loss is reduction in the abil- exposure in daily life that they often underesti- ity to understand speech,22,23 even if the sounds mate. Loud sounds are pervasive in modern life, are loud enough. Sensory presbycusis refers to and noise exposure can occur in a variety of death or damage of the cochlear sensory hair seemingly innocuous settings, such as concerts, cells with aging, and metabolic presbycusis re- movie theaters, and fitness classes with loud fers to decreased functioning of the stria vascu- music, and through engagement in a range of laris through age-related mechanisms that have activities, such as listening to music at home, not been fully determined.24,25 participating in power sports (e.g., those involv- ing motorcycles, all-terrain vehicles, speed boats, Genetic Mutations or snowmobiles), shooting, and using power More than 100 genes have known mutations tools. that result in hearing loss that is not associated Noise damages the sensory hair cells of the with disorders of other organs or with dysmor- inner ear through the direct mechanical stress phic features (nonsyndromic hearing loss). Mu- of intense sound pressure and by activation of tations in approximately 30 of these genes are stress-induced molecular pathways, including associated with adult-onset or progressive hearing generation of reactive oxygen species and cal- loss that is inherited as an autosomal dominant cium overload.33 Noise-induced hearing loss can trait.26 In addition, more than 500 syndromes be temporary or permanent, depending on the that include hearing loss have been described. intensity and duration of exposure. The term Hereditary hearing loss is relatively common “temporary threshold shift” is used to describe among newborns, affecting approximately 1 in objective changes in hearing acuity that can be 1000 live births,27 but it is difficult to estimate measured on audiometry immediately after an epi- the heritability of adult-onset hearing loss, since sode of exposure to loud sounds (e.g., attendance genetic and environmental factors are not easily at a concert) and that revert to preexposure levels separable. Estimates of the heritability of adult- after a few days to 2 weeks. Temporary thresh- onset hearing loss range from 25 to 55%.28 The old shifts are characterized subjectively by de- majority of monogenetic causes of hearing loss creased hearing sensitivity, a feeling of fullness involve mutations in genes that are required for in the ears, tinnitus (ringing), and a perception normal functioning of the cochlea, and several that sounds are muffled. Prolonged or repeated of these genes specifically affect the functioning exposure to noise can cause the death of sen- of sensory hair cells.29 In addition, the genetics of sory hair cells and permanent hearing loss, re- susceptibility to age-related and noise-induced ferred to as a “permanent threshold shift.” Death hearing loss are beginning to be understood.30 of hair cells can be followed by a slower loss of The identification of genetic modifiers that en- spiral ganglion neurons over a period of months hance or reduce susceptibility to acquired hear- or years.34 ing loss will be important for the development In the past, temporary threshold shifts were of therapies to preserve hearing. not thought to be associated with permanent damage to the auditory system; however, recent Noise Exposure data indicate that noise exposures that result in Approximately 104 million people in the United temporary threshold shifts may cause permanent States are exposed to levels of noise that can damage to the cochlea. In animal models, noise cause hearing loss,31 and 1 in 4 adults in the exposures that result in temporary threshold United States has measurable hearing loss shifts lead to permanent loss of hair-cell ribbon caused by exposure to harmful noise.32 Even synapses,34,35 specialized synaptic structures that

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release neurotransmitters from hair cells in re- of data from the National Health and Nutrition sponse to sound. Although our understanding of Examination Survey for the years 1999 through this type of synaptic loss is incomplete, it has 2004, a study of patients with diabetes who were implications for hearing function and for recom- 20 to 69 years of age showed that low-density mendations regarding safe noise levels.36 It is not and high-density lipoprotein levels, as well as known whether synaptic loss is necessarily per- status with respect to coronary disease, periph- manent, since in some animal models, there is eral neuropathy, and general health, were cor- partial recovery of the functioning of these related with hearing impairment, whereas glyce- structures.37,38 A reliable, noninvasive clinical mic control, number of years since diagnosis, measure of cochlear synaptic damage has not and type of hypoglycemic medication were not.50 been developed, although this is an area of active These putative associations with chronic systemic research.39-41 diseases suggest that some contributors to hear- ing loss may be modifiable. Exposure to Therapeutic Drugs Autoimmune forms of ear disease are charac- Various chemicals and drugs adversely affect the terized by progressive, fluctuating hearing loss auditory system; the main ones in clinical use with a variable time course. Although typically are aminoglycoside antibiotics and cisplatin, both bilateral, symptoms may be more prominent in of which are toxic to sensory hair cells. Hearing one ear, and one possible cause of sudden, uni- loss develops in approximately 20% of patients lateral sensorineural hearing loss is an autoim- receiving aminoglycosides,42,43 and the prevalence mune disorder. Ear disease may be associated is as high as 56% among patients with cystic with rheumatoid arthritis, systemic lupus erythe- fibrosis,44,45 a population exposed to repeated matosus, Cogan’s syndrome, sarcoidosis, or other courses of aminoglycoside therapy. Among adults autoimmune disorders.51 Glucocorticoids are the who have received cisplatin, clinically significant main treatment and are often used for long pe- hearing loss develops in approximately 60% of riods. The complications of this prolonged treat- patients with testicular cancer46 and 65% of pa- ment led to a trial in which prednisone and tients with head and neck cancer.47 Susceptibility methotrexate were compared with prednisone to cisplatin-induced hearing loss depends on the and placebo; the trial failed to show a benefit cumulative dose of the drug, the age of the pa- from the addition of methotrexate.52 tient (children are more susceptible than adults), and status with respect to concurrent cranial Sudden Hearing Loss irradiation.48 Patients who have severe hearing The prevalence of sudden, idiopathic hearing loss loss caused by ototoxic drugs are likely to be is 5 to 20 cases per 100,000 population, with identified and referred for follow-up auditory approximately 4000 new cases per year in the testing, but many more patients with mild-to- United States. Sudden sensorineural hearing loss, moderate drug-induced hearing loss are not iden- defined as the onset of hearing loss over a period tified and hence do not receive treatment for of 72 hours or less in one or both ears, is con- their hearing loss.46 sidered an otologic emergency because of evi- dence, albeit uncertain, that there is a benefit of Smoking, Adiposity, and Chronic Diseases early treatment with glucocorticoids. The audio- Strong associations between hearing loss and metric criterion for diagnosis is a decrease in cigarette smoking, adiposity, diabetes mellitus, hearing of at least 30 dB, affecting at least three and other risk factors for cardiovascular disease sound frequencies. The cause of sudden hearing are supported by epidemiologic studies, but cau- loss is not known but is presumed to be viral, sality remains uncertain. For example, in the vascular, or autoimmune. The diagnostic work- Beaver Dam Eye Study, involving persons between up involves testing to exclude identifiable causes the ages of 43 and 84 years, smoking, central of sudden hearing loss, such as acoustic neuroma adiposity, and poorly controlled diabetes melli- and rare tumors of the internal auditory canal. tus were associated with hearing loss in later A clinical practice guideline from the Ameri- life, suggesting that vascular changes may con- can Academy of Otolaryngology–Head and Neck tribute to age-related hearing loss.49 On the basis Surgery53 recommends that physicians evaluate

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patients presenting with a sudden onset of hear- identify hearing loss, and they can play a role in ing loss in order to distinguish between sensori- referring patients for hearing evaluation and neural and conductive impairment, initially with management.56 a physical examination and tuning-fork tests, followed by audiometry when possible. Although Treatment of Sensorineural high doses of oral glucocorticoids (typical dose, Hearing Loss 1 mg per kilogram of body weight) and of intra- tympanic glucocorticoids have been used in the Despite increasing knowledge of the biology of treatment of sudden, idiopathic hearing loss, the inner ear, hearing restoration is not cur- spontaneous recovery in many patients and the rently available for most cases of hearing loss.57 lack of data from placebo-controlled trials make A review of novel therapies included 22 active these treatment recommendations tentative. Never- clinical drug trials registered on the National theless, most otolaryngologists recommend some Institutes of Health ClinicalTrials.gov website.58 form of glucocorticoid treatment for sudden Most of these proposed treatments address hearing loss.53 cell-death pathways and mitigate the effects of oxidative stressors on inner-ear hair cells. Com- Prevention of Hearing Loss mercially sponsored trials of antibiotic and chemotherapeutic medications for the treatment An epidemiologic study54 has shown that the or prevention of ototoxicity are planned or are age-adjusted prevalence of hearing loss is declin- under way (e.g., ClinicalTrials.gov number, ing in the United States. Possible explanations NCT02819856). One study uses a viral vector to for this decrease include a reduction in exposure deliver gene therapy to the inner ear.59,60 Pre- to occupational noise as a result of fewer manu- clinical studies in animal models suggest that facturing jobs and more widespread use of hear- viral-vector gene therapy may be valuable in ing protection, cessation of smoking, and better treating monogenetic hereditary hearing loss. management of cardiovascular risk factors. Al- Restoration or partial restoration of hearing and though the prevalence of hearing loss increases balance functions have been achieved with the with age, it is not inevitable. Adults should be use of gene therapy in mouse models of human made aware of the potentially damaging and deafness, including models of some forms of the slowly cumulative effects of exposure to loud Usher syndrome.61-66 sounds such as the common sources of exposure noted above. Hearing protection includes using Hearing Aids and Other Devices ear protectors (earmuffs or earplugs), avoiding A hearing aid is defined by the Food and Drug or limiting time spent in loud venues, and using Administration (FDA) as a “wearable sound- personal music systems at moderate volumes, amplifying device that is intended to compen- and wearing noise-canceling headphones or ear- sate for impaired hearing.” The goal of treat- phones. ment with well-fitted hearing aids is to improve Despite the high prevalence of hearing loss the audibility of even soft speech or music and among older adults, routine auditory screening other sounds while ensuring that sounds do not is not currently recommended for asymptomatic become uncomfortably loud. Hearing aids can be persons. A review of data on primary care screen- sophisticated instruments with a variety of cus- ing for hearing loss, performed for the U.S. tomizable features that contribute to their high Preventive Services Task Force,1 concluded that costs; whether performance improves with higher- additional research is needed to understand the cost devices is uncertain.67 A variety of noncus- potential effects of such screening on health out- tomized devices, termed “hearing assistive tech- comes but acknowledged that common screening nologies,” are also available; they include tests, such as validated hearing-loss question- amplified telephones, visual technologies such naires and the whisper, finger-rub, or watch-tick as captioning, video conferencing, and visual or test, or screening audiometry55 can identify vibrotactile alerts.68 Hearing aids are regulated patients at risk for hearing loss. Primary care by the FDA, and state laws may restrict access to physicians are often the first to suspect and them. The devices are sold through audiologists

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and hearing-aid dispensers. The costs of services these assessments have shown that cochlear im- related to hearing-aid fitting are often bundled plants compare favorably with other treatments. with the cost of the device, so the specific costs of the services and the technology are not trans- Increasing Access to Hearing parent.68 Aids The frequency of use of hearing aids by adults with hearing loss is low.68 In a survey published Hearing loss is increasingly being viewed as a in 2012, only 14.2% of adults with hearing loss public health problem.68 In October 2015, the reported wearing hearing aids.69 Although the President’s Council of Advisors on Science and cost of the devices, typically $1,400 to $2,200, is Technology recommended that the FDA create a probably a factor, other deterrents to the adop- new regulatory class for hearing aids that can be tion of hearing aids include stigma, perceived sold over the counter for persons with mild or ineffectiveness, ongoing costs (for batteries and moderate hearing loss.78 This recommendation maintenance), lack of comfort, and cosmetic ap- was endorsed by the National Academies of Sci- pearance.68 The United States is one of the few ences, Engineering, and Medicine in their report developed countries that does not offer govern- titled “Hearing Health Care for Adults: Priorities ment assistance for the purchase of hearing de- for Improving Access and Affordability,” released vices.68 However, even in countries where assis- in June 2016.68 They recommended that the FDA tance is provided, hearing-aid use is not universal create a category of over-the-counter, wearable among candidates; for example, the rate of use hearing devices that would be regulated to meet is less than 15% in Finland and is 50% in Den- specific safety and quality standards and label- mark.68 Efforts to increase use will therefore ing specifications; the new FDA classification have to address multiple impediments. would preempt current state laws and regula- tions in order not to limit access to affordable Cochlear Implants hearing aids. Legislation has recently been signed Persons with severe or total sensorineural hear- into law that requires the FDA to create and ing loss do not typically benefit from hearing regulate a category of over-the-counter hearing aids, since inner-ear hair cells are not able to aids for adults who have mild to moderate hear- stimulate the auditory nerve in response to sound. ing loss.79,80 Opening the market to these devices In such cases, cochlear implants, which are sur- should increase the options available to patients, gically implanted devices that bypass the cochlear decrease costs, and increase access.81 Bulk pur- hair cells to electrically stimulate the auditory chasing by government agencies provides another nerve, permit partial restoration of hearing and opportunity to decrease costs. The Department have been shown to improve speech perception of Veterans Affairs, for example, purchased ap- and vocational, social, and psychological func- proximately 20% of hearing aids on the U.S. tioning,70-72 as well as the quality of life for market in 2013,82 at an average cost of $369 per adults, including older adults.73 Details of the hearing aid as compared with $1,400 to $2,200 function and use of cochlear implants can be on the open market.68 found at https:/​­/​­www​.­nidcd​.­nih​.­gov/​­health/​­cochlear -implants. Conclusions The cost-effectiveness of cochlear implants has been established in developed countries71 Hearing loss is a major source of disability in and in some developing countries.71,74-77 These adults, associated with serious communication analyses have evaluated the lifetime costs of and psychosocial problems and high health care cochlear implants, including the costs of the costs, with economic implications at the societal device and of surgery and rehabilitation, versus and individual levels. Technologies exist to ame- the benefits, as determined on the basis of liorate hearing loss, but cost, health policies, and health-preference measures. Measures of cost- regulations limit access to these therapies. Efforts effectiveness have also been used to compare are under way to improve access to auditory cochlear implants with other treatments, such health care for adults. Recent advances in our as educational programs for deaf persons, and understanding of the underlying causes of hear-

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ing loss have led to efforts to develop drugs and and consulting fees from Otonomy and serving as chair of a data therapies that can prevent or reverse hearing loss. and safety monitoring board for Otonomy. No other potential conflict of interest relevant to this article was reported. Dr. Tucci reports receiving consulting fees and travel support Disclosure forms provided by the authors are available with from Roche Pharmaceuticals, consulting fees from Otic Pharma, the full text of this article at NEJM.org.

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