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Ototoxicity is the property of being toxic to the ear (oto-), specifically the cochlea or auditory nerve and sometimes the vestibular system; it is commonly medication-induced. Ototoxic drugs include antibiotics such as gentamicin, loop diuretics such as furosemide and platinum-based chemotherapy agents such as cisplatin. A number of nonsteroidal anti-inflammatory drugs (NSAIDS) have also been shown to be ototoxic.^{[citation needed]} This can result in sensorineural hearing loss, dysequilibrium, or both. Either may be reversible and temporary, or irreversible and permanent.

Ototoxic agents

Antibiotics

Antibiotics in the aminoglycoside class, such as gentamicin and tobramycin, may produce cochleotoxicity through a poorly understood mechanism.^[1] It may result from antibiotic binding to NMDA receptors in the cochlea and damaging neurons through excitotoxicity.^[2] Aminoglycoside-induced production of reactive oxygen species may also injure cells of the cochlea.^[3] Once-daily dosing^[4] and co-administration of N-acetylcysteine^[5] may protect against aminoglycoside-induced ototoxicity. The ototoxicity of gentamicin can be exploited to treat some individuals with Ménière's disease by destroying the inner ear, which stops the vertigo attacks but causes permanent deafness.^[6]

Macrolide antibiotics, including erythromycin, are associated with reversible ototoxic effects.^[7] The underlying mechanism of ototoxicity may be impairment of ion transport in the stria vascularis.^[7] Predisposing factors include renal impairment, hepatic impairment, and recent organ transplantation.^[7]

Loop diuretics

The loop diuretic furosemide is associated with ototoxicity, particularly when doses exceed 240 mg per hour.^[8] The related compound ethacrynic acid has a higher association with ototoxicity, therefore it is preferred only for patients with sulfur allergies.^[9] Bumetanide confers a decreased risk of ototoxicity compared to furosemide.^[7]

Chemotherapeutic agents

Platinum-containing chemotherapeutic agents, including cisplatin and carboplatin, are associated with cochleotoxicity characterized by high-frequency hearing loss and tinnitus (ringing in the ears).^[10] Ototoxicity is less frequently seen with the related compound oxaliplatin.^[11] Cisplatin-induced ototoxicity is dose-dependent, typically occurring with doses greater than 60 mg/m², and tend to occur when chemotherapy is given every two weeks compared to every one week.^[10] Cisplatin and related agents are absorbed by the cochlear hair cells and result in ototoxicity through the production of reactive oxygen species.^[12] The decreased incidence of oxaliplatin ototoxicity has been attributed to decreased uptake of the drug by cells of the cochlea.^[11] Administration of amifostine has been used in attempts to prevent cisplatin-induced ototoxicity, but the American Society of Clinical Oncology recommends against its routine use.^[13]

The vinca alkaloids, including vincristine, are also associated with reversible ototoxicity.^[7]

Others

Ototoxic effects are also seen with quinine and heavy metals such as mercury and lead.^[7] At high doses, aspirin and other salicylates may also cause high-pitch tinnitus and hearing loss in both ears, typically reversible upon discontinuation of the drug.^[7] The erectile dysfunction medications Viagra, Levitra, and Cialis have also been reported to cause hearing loss.^[14]

Mixed exposures

Ototoxic chemicals interact with mechanical stresses on the hair cells of the cochlea in different ways. For organic solvents such as toluene, styrene or xylene, the combined exposure with noise increases the risk of hearing loss in a synergistic manner.^[15] Heavy metals, asphyxiants and endocrine disruptors have a variety of interactions as well. Specific toxicity limits for combined exposures are not well established. However, given the potential for enhanced risk of hearing loss, the noise exposures should be kept below 85 decibels, and the chemical exposures should be below the recommended exposure limits given by agencies such as OSHA, NIOSH, or ACGIH.

Treatment

No specific treatment may be available, but withdrawal of the ototoxic drug may be warranted when the consequences of doing so are less severe than those of the ototoxicity.^[7]

It is difficult to distinguish between nerve damage and structural damage due to similarity of the symptoms. Diagnosis of ototoxicity typically results from ruling out all other possible sources of hearing loss and is often the catchall explanation for the symptoms. Treatment options vary depending on the patient and the diagnosis. Some patients experience only temporary symptoms that do not require drastic treatment while others can be treated with medication. Physical therapy may prove useful for regaining balance and walking abilities. Cochlear implants are sometimes an option to restore hearing. Such treatments are typically taken to comfort the patient, not to cure the disease or damage caused by ototoxicity. There is no cure or restoration capability if the damage becomes permanent,^[16]^[17] although cochlear nerve terminal regeneration has been observed in chickens,^[18] which suggests that there may be a way to accomplish this in humans.

Symptoms

Symptoms of ototoxicity include partial or profound hearing loss, vertigo, and tinnitus.^[7]

The cochlea is primarily a hearing structure situated in the inner ear. It is the snail-shaped shell containing several nerve endings that makes hearing possible.^[19] Ototoxicity typically results when the inner ear is poisoned by medication that damages the cochlea, vestibule, semi-circular canals, or the auditory/ vestibulocochlear nerve. The damaged structure then produces the symptoms the patient presents with. Ototoxicity in the cochlea may cause hearing loss of the high-frequency pitch ranges or complete deafness, or losses at points between.^[20] It may present with bilaterally symmetrical symptoms, or asymmetrically, with one ear developing the condition after the other or not at all.^[20] The time frames for progress of the disease vary greatly and symptoms of hearing loss may be temporary or permanent.^[19] Ototoxicity in the cochlea can also produce tinnitus.

The vestibule and semi-circular canal are inner-ear components that comprise the vestibular system.

Two types of otolith organs are housed in the vestibule: the saccule, which points vertically and detects vertical acceleration, and the utricle, which points horizontally and detects horizontal acceleration. The otolith organs together sense the head’s position with respect to gravity when the body is static; then the head’s movement when it tilts; and pitch changes during any linear motion of the head. The saccule and utricle detect different motions, which information the brain receives and integrates to determine where the head is and how and where it is moving.

The vestibule and the semi-circular canals together detect all directions of head movement.

The semi-circular canals are three bony structures filled with fluid. As with the vestibule, the primary purpose of the canals is to detect movement. Each canal is oriented at right angles to the others, enabling detection of movement in any plane. The posterior canal detects rolling motion, or motion about the X axis; the anterior canal detects pitch, or motion about the Y axis; the horizontal canal detects yaw motion, or motion about the Z axis. When a medication is toxic in the vestibule or the semi-circular canals, the patient senses loss of balance or orientation rather than losses in hearing. Symptoms in these organs present as vertigo, difficulties walking in low light and darkness, disequilibrium, oscillopsia among others.^[20] Each of these problems is related to balance and the mind is confused with the direction of motion or lack of motion. Both the vestibule and semi-circular canals transmit information to the brain about movement; when these are poisoned, they are unable to function properly which results in miscommunication with the brain.

When the vestibule and/or semi-circular canals are affected by ototoxicity, the eye can also be affected. Nystagmus and oscillopsia are two conditions that overlap the vestibular and ocular systems. These symptoms cause the patient to have difficulties with seeing and processing images. The body subconsciously tries to compensate for the imbalance signals being sent to the brain by trying to obtain visual cues to support the information it is receiving. This results in that dizziness and “woozy” feeling patients use to describe conditions such as oscillopsia and vertigo.^[20]

The auditory/vestibulocochlear nerve, or cranial nerve VIII, is the least afflicted component of the ear when ototoxicity arises, but if the nerve is affected, the damage is most often permanent. Cranial nerve VIII “has a vestibular part which functions in balance, equilibrium, and orientation in three-dimensional space, and a cochlear part which functions in hearing."^[21] Despite the vestibular or cochlear structures functioning normally, affliction of the nerve effectively arrests communication between these structures and the brain. Symptoms present similar to those resulting from vestibular and cochlear damage, including tinnitus, ringing of the ears, difficultly walking, deafness, and balance and orientation issues.^[21]

References

^ Dobie RA, Black FO, Pezsnecker SC, Stallings VL (March 2006). "Hearing loss in patients with vestibulotoxic reactions to gentamicin therapy". Archives of Otolaryngology--Head & Neck Surgery 132 (3): 253–7. doi:10.1001/archotol.132.3.253. PMID 16549744.
^ Basile AS, Huang JM, Xie C, Webster D, Berlin C, Skolnick P (December 1996). "N-methyl-D-aspartate antagonists limit aminoglycoside antibiotic-induced hearing loss". Nature Medicine 2 (12): 1338–43. doi:10.1038/nm1296-1338. PMID 8946832.
^ Wu WJ, Sha SH, Schacht J (2002). "Recent advances in understanding aminoglycoside ototoxicity and its prevention". Audiology & Neuro-otology 7 (3): 171–4. doi:10.1159/000058305. PMID 12053140.
^ Munckhof WJ, Grayson ML, Turnidge JD (April 1996). "A meta-analysis of studies on the safety and efficacy of aminoglycosides given either once daily or as divided doses". Journal of Antimicrobial Chemotherapy 37 (4): 645–63. doi:10.1093/jac/37.4.645. PMID 8722531.
^ Tepel M (August 2007). "N-Acetylcysteine in the prevention of ototoxicity". Kidney International 72 (3): 231–2. doi:10.1038/sj.ki.5002299. PMID 17653228.
^ Perez N, Martín E, García-Tapia R (March 2003). "Intratympanic gentamicin for intractable Ménière's disease". The Laryngoscope 113 (3): 456–64. doi:10.1097/00005537-200303000-00013. PMID 12616197.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ Roland, Peter S. (2004). Ototoxicity. Hamilton, Ont: B.C. Decker. ISBN 1-55009-263-4.
^ Voelker JR, Cartwright-Brown D, Anderson S et al. (October 1987). "Comparison of loop diuretics in patients with chronic renal insufficiency". Kidney International 32 (4): 572–8. doi:10.1038/ki.1987.246. PMID 3430953.
^ Schmitz, PG. Renal:An integrated approach to disease. McGraw Hill, New York NY 2012, pg 123
^ ^a ^b Rademaker-Lakhai JM, Crul M, Zuur L et al. (February 2006). "Relationship between cisplatin administration and the development of ototoxicity". Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 24 (6): 918–24. doi:10.1200/JCO.2006.10.077. PMID 16484702.
^ ^a ^b Hellberg V, Wallin I, Eriksson S et al. (January 2009). "Cisplatin and oxaliplatin toxicity: importance of cochlear kinetics as a determinant for ototoxicity". Journal of the National Cancer Institute 101 (1): 37–47. doi:10.1093/jnci/djn418. PMC 2639295. PMID 19116379.
^ Rybak LP, Whitworth CA, Mukherjea D, Ramkumar V (April 2007). "Mechanisms of cisplatin-induced ototoxicity and prevention". Hearing Research 226 (1-2): 157–67. doi:10.1016/j.heares.2006.09.015. PMID 17113254.
^ Hensley ML, Hagerty KL, Kewalramani T et al. (January 2009). "American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants". Journal of Clinical Oncology 27 (1): 127–45. doi:10.1200/JCO.2008.17.2627. PMID 19018081.
^ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109012.htm
^ Fechter L.D. "Promotion of noise-induced hearing loss by chemical contaminants," J. Tox. Env. Health Part A. 67:727-740 (2004)
^ My Deafness. "Ototoxicity: Ear Poisoning". Causes of Deafness and Types of Deafness (Hearing Loss). My Deafness. Retrieved 30 Nov 2011.
^ VEDA. "VEDA-VEstibular Disorders Association-Ototoxicity". VEDA-Vestibular Disorders Association. VEDA. Retrieved 30 Nov 2011.
^ "Regeneration of Cochlear Efferent Nerve Terminals after Gentamycin Damage". Retrieved 15 November 2014.
^ ^a ^b "ototoxicity". The Free Dictionary by Farlex.
^ ^a ^b ^c ^d Mudd, Pamela. "Ototoxicity". Medscape Reference. WebMD LLC. Retrieved 30 Nov 2011.
^ ^a ^b Farr, Gary. "The Cranial Nerves". Cranial Nerves. BecomeHealthyNow.com. Retrieved 30 Nov 2011.

External links

Ototoxic drugs at GPnotebook
Ototoxic Medications
Articles on Ototoxic Drugs by Neil Bauman, Ph.D.

UpToDate Contents

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1. アミノグリコシドの腎毒性および聴覚毒性の病因および予防 pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity
2. 成人における難聴の病因 etiology of hearing loss in adults
3. プラチナベースの化学療法の神経学的合併症の概要 overview of neurologic complications of platinum based chemotherapy
4. ループ利尿剤：最大有効量および主な副作用 loop diuretics maximum effective dose and major side effects
5. 成人における難治性浮腫の治療 treatment of refractory edema in adults

English Journal

Serum polychlorinated biphenyls concentrations and hearing impairment in adults.

Min JY1, Kim R2, Min KB3.Author information 1Institute of Health and Environment, Seoul National University, Seoul, Republic of Korea.2World Health Organization Regional Office for the Western Pacific, Suva, Fiji.3Department of Occupational and Environmental Medicine, Ajou University School of Medicine, Suwon, Republic of Korea. Electronic address: mink1999@ajou.ac.kr.AbstractExperimental studies have suggested the potential link between exposure to polychlorinated biphenyls (PCBs) and auditory impairment, but little evidence exists to support the ototoxicity of PCBs in human. Only a few studies have implicated PCB-induced hearing loss in children. This study investigated the association between serum PCB levels and hearing impairment in US adults. We analyzed data from 1946 adults aged 20years and older in the National Health and Nutrition Examination Survey 1999-2004: eleven PCB congeners detected in 60-90% of the samples at greater than the limit of detection (LOD) were selected, and hearing impairment was defined as a pure-tone average of the thresholds at 0.5, 1, 2 and 4kHz of >25dB hearing level in better ear. The adjusted odds ratio of hearing impairment was significantly increased comparing the highest quartile (Q4) of detectable PCB range with the reference (below LOD): 5.83 (95% CI: 1.20-28.24) for 2,2',3,3',4,4',5-heptachlorobiphenyl (PCB-170), 7.79(95% CI: 1.81-33.44) for 2,2',3,4,4',5,5'-heptachlorobiphenyl (PCB-180), 7.46 (95% CI: 1.62-34.47) for 2,2',3,4',5,5',6-heptachlorobiphenyl (PCB-187), 8.59 (95% CI: 1.26-58.73) for 2,2',3,3',4,4',5,5'-octachlorobiphenyl (PCB-194), 11.62 (95% CI: 2.20-61.55) for 2,2',3,3',4,4',5,6'-octachlorobiphenyl (PCB-196). Our findings suggest that specific classes of PCB levels may be associated with hearing impairment in a general sample of adults.
Chemosphere.Chemosphere.2014 May;102:6-11. doi: 10.1016/j.chemosphere.2013.11.046. Epub 2013 Dec 21.
Experimental studies have suggested the potential link between exposure to polychlorinated biphenyls (PCBs) and auditory impairment, but little evidence exists to support the ototoxicity of PCBs in human. Only a few studies have implicated PCB-induced hearing loss in children. This study investigate
PMID 24360845

Concordance between the chang and the International Society of Pediatric Oncology (SIOP) ototoxicity grading scales in patients treated with cisplatin for medulloblastoma.

Bass JK1, Huang J, Onar-Thomas A, Chang KW, Bhagat SP, Chintagumpala M, Bartels U, Gururangan S, Hassall T, Heath JA, McCowage G, Cohn RJ, Fisher MJ, Robinson G, Broniscer A, Gajjar A, Gurney JG.Author information 1Rehabilitation Services, St. Jude Children's Research Hospital, Memphis, Tennessee; School of Communication Sciences and Disorders, University of Memphis, Memphis, Tennessee.AbstractBACKGROUND: Reporting ototoxicity is frequently complicated by use of various ototoxicity criteria. The International Society of Pediatric Oncology (SIOP) ototoxicity grading scale was recently proposed for standardized use in reporting hearing loss outcomes across institutions. The aim of this study was to evaluate the concordance between the Chang and SIOP ototoxicity grading scales. Differences between the two scales were identified and the implications these differences may have in the clinical setting were discussed.
Pediatric blood & cancer.Pediatr Blood Cancer.2014 Apr;61(4):601-5. doi: 10.1002/pbc.24830. Epub 2013 Nov 1.
BACKGROUND: Reporting ototoxicity is frequently complicated by use of various ototoxicity criteria. The International Society of Pediatric Oncology (SIOP) ototoxicity grading scale was recently proposed for standardized use in reporting hearing loss outcomes across institutions. The aim of this stud
PMID 24504791

Chemoprotection by d-methionine against cisplatin-induced side-effects: insight from in vitro studies using human plasma.

Sooriyaarachchi M1, White WM, Narendran A, Gailer J.Author information 1Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, AB T2N 1N4, Canada. jgailer@ucalgary.ca.AbstractAnimal studies have shown that the nephrotoxicity and ototoxicity of the anti-cancer drug cisplatin (CP) can be ameliorated by the co-administration with d-methionine. The molecular mechanisms of this activity, however, are not well understood. Since CP is intravenously administered, the underlying chemistry may involve the interaction of CP-derived Pt-species with d-methionine in the bloodstream. Our previous studies have shown that the chemoprotective agents N-acetyl-l-cysteine and sodium thiosulfate modulate the metabolism of CP in human plasma in vitro, albeit in a different manner. Using a metallomics approach, we show that the incubation of human plasma with d-methionine and CP (molar ratio of 20 : 1) leads to the formation of a Pt-d-methionine complex independent of the order of addition. These results were corroborated by analogous experiments that were carried out using PBS-buffer instead of plasma. In addition, CP and d-methionine were added simultaneously to PBS-buffer and samples were analyzed at certain time intervals by the same metallomics method and LC-ESI-MS over a ∼21 h time period. Whereas the intermediate [Pt(NH3)Cl(d-methionine)](+) species was detected between 1-4 h, only the terminal [Pt(d-methionine)2](+) complex was present 21 h later. Combined, these studies demonstrate that in plasma and at the 20 : 1 d-methionine : CP molar ratio, an early CP hydrolysis product reacts with d-methionine to form a 1 : 1 complex that is followed by the formation of a 2 : 1 compound at a later time point. The formation of these Pt-d-methionine species may therefore play an important role in the processes by which d-methionine protects mammalian organisms against CP-induced toxicities.
Metallomics : integrated biometal science.Metallomics.2014 Mar 26;6(3):532-41. doi: 10.1039/c3mt00238a. Epub 2013 Dec 16.
Animal studies have shown that the nephrotoxicity and ototoxicity of the anti-cancer drug cisplatin (CP) can be ameliorated by the co-administration with d-methionine. The molecular mechanisms of this activity, however, are not well understood. Since CP is intravenously administered, the underlying
PMID 24337005