|Classification and external resources|
Ototoxicity is the property of being toxic to the ear (oto-), specifically the cochlea or auditory nerve and sometimes the vestibular system, for example, as a side effect of a drug. The effects of ototoxicity can be reversible and temporary, or irreversible and permanent. It has been recognized since the 19th century. There are many well-known ototoxic drugs used in clinical situations, and they are prescribed, despite the risk of hearing disorders, to very serious health conditions. 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. This can result in sensorineural hearing loss, dysequilibrium, or both. Some environmental and occupational chemicals have also been shown to affect the auditory system and interact with noise.
Signs and symptoms
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. 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. It may present with bilaterally symmetrical symptoms, or asymmetrically, with one ear developing the condition after the other or not at all. The time frames for progress of the disease vary greatly and symptoms of hearing loss may be temporary or permanent.
The vestibule and semi-circular canal are inner-ear components that comprise the vestibular system. Together they detect all directions of head movement. 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 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. 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.
Cranial nerve VIII, is the least affected component of the ear when ototoxicity arises, but if the nerve is affected, the damage is most often permanent. Symptoms present similar to those resulting from vestibular and cochlear damage, including tinnitus, ringing of the ears, difficulty walking, deafness, and balance and orientation issues.
Antibiotics in the aminoglycoside class, such as gentamicin and tobramycin, may produce cochleotoxicity through a poorly understood mechanism. It may result from antibiotic binding to NMDA receptors in the cochlea and damaging neurons through excitotoxicity. Aminoglycoside-induced production of reactive oxygen species may also injure cells of the cochlea. Once-daily dosing and co-administration of N-acetylcysteine may protect against aminoglycoside-induced ototoxicity. The anti-bacterial activity of aminoglycoside compounds is due to inhibition of ribosome function and these compounds similarly inhibit protein synthesis by mitochondrial ribosomes because mitochondria evolved from a bacterial ancestor. Consequently, aminoglycoside effects on production of reactive oxygen species as well as dysregulation of cellular calcium ion homeostasis may result from disruption of mitochondrial function. 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. Due to the effects on mitochondria, certain inherited mitochondrial disorders result in increased sensitivity to the toxic effects of aminoglycosides.
Macrolide antibiotics, including erythromycin, are associated with reversible ototoxic effects. The underlying mechanism of ototoxicity may be impairment of ion transport in the stria vascularis. Predisposing factors include renal impairment, hepatic impairment, and recent organ transplantation.
Certain types of diuretics are associated with varying levels of risk for ototoxicity. Loop and thiazide diuretics carry this side effect. The loop diuretic furosemide is associated with ototoxicity, particularly when doses exceed 240 mg per hour. The related compound ethacrynic acid has a higher association with ototoxicity, therefore it is preferred only for patients with sulfa allergies. Diuretics are thought to alter the ionic gradient within the stria vascularis. Bumetanide confers a decreased risk of ototoxicity compared to furosemide.
Platinum-containing chemotherapeutic agents, including cisplatin and carboplatin, are associated with cochleotoxicity characterized by progressive, high-frequency hearing loss with or without tinnitus (ringing in the ears). Ototoxicity is less frequently seen with the related compound oxaliplatin. The severity of cisplatin-induced ototoxicity is dependent upon the cumulative dose administered and the age of the patient, with young children being most susceptible. The exact mechanism of cisplatin ototoxicity is not known. The drug is understood to damage multiple regions of the cochlea, causing the death of outer hair cells, as well as damage to the spiral ganglion neurons and cells of the stria vascularis. Long-term retention of cisplatin in the cochlea may contribute to the drug's cochleotoxic potential. Once inside the cochlea, cisplatin has been proposed to cause cellular toxicity through a number of different mechanisms, including through the production of reactive oxygen species. The decreased incidence of oxaliplatin ototoxicity has been attributed to decreased uptake of the drug by cells of the cochlea. 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.
Antiseptics and disinfectants
Topical skin preparations such as chlorhexidine and ethyl alcohol have the potential to be ototoxic should they enter the inner ear through the round window membrane. This potential was first noted after a small percentage of patients undergoing early myringoplasty operations experienced severe sensorineural hearing loss. It was found that in all operations involving this complication the preoperative sterilization was done with chlorhexidine. The ototoxicity of chlorhexidine was further confirmed by studies with animal models.
Several other skin preparations have been shown to be potentially ototoxic in the animal model. These preparations include acetic acid, propylene glycol, quaternary ammonium compounds, and any alcohol-based preparations. However, it is difficult to extrapolate these results to human ototoxicity because the human round window membrane is much thicker than in any animal model.
Other medicinal ototoxic drugs
At high doses, quinine, aspirin and other salicylates may also cause high-pitch tinnitus and hearing loss in both ears, typically reversible upon discontinuation of the drug. Erectile dysfunction medications may have the potential to cause hearing loss. However the link between erectile dysfunction medications and hearing loss remains uncertain.
Previous noise exposure has not been found to potentiate ototoxic hearing loss. The American Academy of Audiology includes in their position statement that exposure to noise at the same time as aminoglycosides may exacerbate ototoxicity. The American Academy of Audiology recommends people being treated with ototoxic chemotherapeutics avoid excessive noise levels during treatment and for several months following cessation of treatment. Opiates in combination with excessive noise levels may also have an additive affect on ototoxic hearing loss.
Ototoxicants in the environment and workplace
Ototoxic effects are also seen with quinine, pesticides, solvents, asphyxiants, and heavy metals such as mercury and lead. When combining multiple ototoxicants, the risk of hearing loss becomes greater. As these exposures are common, this hearing impairment can affects many occupations and industries.
Ototoxic chemicals in the environment (from contaminated air or water) or in the workplace 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 occupational hearing loss in a synergistic manner. The risk is greatest when the co-exposure is with impulse noise. Carbon monoxide has been shown to increase the severity of the hearing loss from noise. Given the potential for enhanced risk of hearing loss, exposures and contact with products such as paint thinners, degreasers, white spirits, exhaust, should be kept to a minimum. Noise exposures should be kept below 85 decibels, and the chemical exposures should be below the recommended exposure limits given by regulatory agencies.
Drug exposures mixed with noise potentially lead to increased risk of ototoxic hearing loss. Noise exposure combined with the chemotherapeutic cisplatin puts individuals at increased risk of ototoxic hearing loss. Noise at 85 dB SPL or above added to the amount of hair cell death in the high frequency region of the cochlea In chinchillas.
The hearing loss caused by chemicals can be very similar to a hearing loss caused by excessive noise. A 2018 informational bulletin by the US Occupational Safety and Health Administration (OSHA) and the National Institute for Occupational Safety and Health (NIOSH) introduces the issue, provides examples of ototoxic chemicals, lists the industries and occupations at risk and provides prevention information.
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. Co-administration of anti-oxidants may limit the ototoxic effects.
Ototoxic monitoring during exposure is recommended by the American Academy of Audiology to allow for proper detection and possible prevention or rehabilitation of the hearing loss through a cochlear implant or hearing aid. Monitoring can be completed through performing otoacoustic emissions testing or high frequency audiometry. Successful monitoring includes a baseline test before, or soon after, exposure to the ototoxicant. Follow-up testing is completed in increments after the first exposure, throughout the cessation of treatment. Shifts in hearing status are monitored and relayed to the prescribing physician to make treatment decisions.
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, although cochlear nerve terminal regeneration has been observed in chickens, which suggests that there may be a way to accomplish this in humans.
- Schacht J, Hawkins JE (2006-01-01). "Sketches of otohistory. Part 11: Ototoxicity: drug-induced hearing loss". Audiology and Neuro-Otology. 11 (1): 1–6. doi:10.1159/000088850. PMID 16219991.
- Position Statement and Practice Guidelines on Ototoxicity Monitoring (PDF). American Academy of Audiology. 2009.
- Cazals Y (December 2000). "Auditory sensori-neural alterations induced by salicylate". Progress in Neurobiology. 62 (6): 583–631. doi:10.1016/s0301-0082(00)00027-7. PMID 10880852.
- Jung, T. T.; Rhee, C. K.; Lee, C. S.; Park, Y. S.; Choi, D. C. (1993-10). "Ototoxicity of salicylate, nonsteroidal antiinflammatory drugs, and quinine". Otolaryngologic Clinics of North America. 26 (5): 791–810. ISSN 0030-6665. PMID 8233489. Check date values in:
- Johnson AC, Morata TC (2010). "Occupational exposure to chemicals and hearing impairment. The Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals" (PDF). Arbete och Hälsa. 44 (4): 177. Retrieved May 4, 2016.
- Roland PS (2004). Ototoxicity. Hamilton, Ont: B.C. Decker. ISBN 978-1-55009-263-9.
- "ototoxicity". The Free Dictionary by Farlex.
- Mudd P. "Ototoxicity". Medscape Reference. WebMD LLC. Retrieved 30 Nov 2011.
- 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 and 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". The 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.
- Wirmer J, Westhof E (2006). Molecular contacts between antibiotics and the 30S ribosomal particle. Methods in Enzymology. 415. pp. 180–202. doi:10.1016/S0076-6879(06)15012-0. ISBN 9780121828202. PMID 17116475.
- Esterberg R, Hailey DW, Coffin AB, Raible DW, Rubel EW (April 2013). "Disruption of intracellular calcium regulation is integral to aminoglycoside-induced hair cell death". The Journal of Neuroscience. 33 (17): 7513–25. doi:10.1523/JNEUROSCI.4559-12.2013. PMC 3703319. PMID 23616556.
- Perez N, Martín E, García-Tapia R (March 2003). "Intratympanic gentamicin for intractable Meniere's disease". The Laryngoscope. 113 (3): 456–64. doi:10.1097/00005537-200303000-00013. PMID 12616197.
- Voelker JR, Cartwright-Brown D, Anderson S, Leinfelder J, Sica DA, Kokko JP, Brater DC (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 (2012). Renal: An Integrated Approach to Disease. New York: McGraw-Hill. p. 123. ISBN 978-0-07-162155-7.
- Rademaker-Lakhai JM, Crul M, Zuur L, Baas P, Beijnen JH, Simis YJ, van Zandwijk N, Schellens JH (February 2006). "Relationship between cisplatin administration and the development of ototoxicity". Journal of Clinical Oncology. 24 (6): 918–24. doi:10.1200/JCO.2006.10.077. PMID 16484702.
- Hellberg V, Wallin I, Eriksson S, Hernlund E, Jerremalm E, Berndtsson M, Eksborg S, Arnér ES, Shoshan M, Ehrsson H, Laurell G (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.
- Bokemeyer C, Berger CC, Hartmann JT, Kollmannsberger C, Schmoll HJ, Kuczyk MA, Kanz L (April 1998). "Analysis of risk factors for cisplatin-induced ototoxicity in patients with testicular cancer". British Journal of Cancer. 77 (8): 1355–62. PMC 2150148. PMID 9579846.
- Li Y, Womer RB, Silber JH (November 2004). "Predicting cisplatin ototoxicity in children: the influence of age and the cumulative dose". European Journal of Cancer. 40 (16): 2445–51. doi:10.1016/j.ejca.2003.08.009. PMID 15519518.
- Callejo A, Sedó-Cabezón L, Juan ID, Llorens J (July 2015). "Cisplatin-Induced Ototoxicity: Effects, Mechanisms and Protection Strategies". Toxics. 3 (3): 268–293. doi:10.3390/toxics3030268. PMC 5606684. PMID 29051464.
- Breglio AM, Rusheen AE, Shide ED, Fernandez KA, Spielbauer KK, McLachlin KM, Hall MD, Amable L, Cunningham LL (November 2017). "Cisplatin is retained in the cochlea indefinitely following chemotherapy". Nature Communications. 8 (1): 1654. doi:10.1038/s41467-017-01837-1. PMC 5698400. PMID 29162831.
- 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, Green DM, Meropol NJ, Wasserman TH, Cohen GI, Emami B, Gradishar WJ, Mitchell RB, Thigpen JT, Trotti A, von Hoff D, Schuchter LM (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.
- van Der Heijden R, Jacobs DI, Snoeijer W, Hallard D, Verpoorte R (March 2004). "The Catharanthus alkaloids: pharmacognosy and biotechnology". Current Medicinal Chemistry. 11 (5): 607–28. doi:10.2174/0929867043455846. PMID 15032608.
- Raviña E (2011). "Vinca alkaloids". The evolution of drug discovery: From traditional medicines to modern drugs. John Wiley & Sons. pp. 157–159. ISBN 978-3-527-32669-3.
- Cooper R, Deakin JJ (2016). "Africa's gift to the world". Botanical Miracles: Chemistry of Plants That Changed the World. CRC Press. pp. 46–51. ISBN 978-1-4987-0430-4.
- Keglevich P, Hazai L, Kalaus G, Szántay C (May 2012). "Modifications on the basic skeletons of vinblastine and vincristine". Molecules. 17 (5): 5893–914. doi:10.3390/molecules17055893. PMID 22609781.
- Bicknell, P. G. (1971). "Sensorineural deafness following myringoplasty operations". The Journal of Laryngology & Otology. 85 (9): 957–962. doi:10.1017/S0022215100074272.
- "FDA Announces Revisions to Labels for Cialis, Levitra and Viagra. Potential risk of sudden hearing loss with ED drugs to be displayed more prominently". United States Food and Drug Administration. Archived from the original on 9 July 2009.
- Yafi FA, Sharlip ID, Becher EF (2017). "Update on the Safety of Phosphodiesterase Type 5 Inhibitors for the Treatment of Erectile Dysfunction". Sexual Medicine Reviews. 6 (2): 242–252. doi:10.1016/j.sxmr.2017.08.001. PMID 28923561.
- Campbell K (2007). Pharmacology and Ototoxicity for Audiologists. Clifton Park, NY: Delmar Centrage Learning. p. 145. ISBN 978-1-4180-1130-7.
- Laurell G, Borg E (1986-01-01). "Cis-platin ototoxicity in previously noise-exposed guinea pigs". Acta Oto-Laryngologica. 101 (1–2): 66–74. doi:10.3109/00016488609108609. PMID 3962651.
- Rawool VW (2012). Hearing Conservation in Occupational, Recreational, Educational, and Home Settings. New York: Thieme. p. 13. ISBN 978-1-60406-256-4.
- Campo P, Morata TC, Hong O (April 2013). "Chemical exposure and hearing loss". Disease-A-Month. 59 (4): 119–38. doi:10.1016/j.disamonth.2013.01.003. PMC 4693596. PMID 23507352.
- Rawool V (2012). Hearing Conservation: In Occupational, Recreational, Educational, and Home settings. New York, NY: Thieme. p. 10. ISBN 978-1-60406-256-4.
- 1955-, Johnson, Ann-Christin, (2009). The Nordic Expert Group for criteria documentation of health risks from chemicals. 142, Occupational exposure to chemicals and hearing impairment. Morata, Thais C. Göteborg: University of Gothenburg. ISBN 9789185971213. OCLC 939229378.
- Fechter LD (2004). "Promotion of noise-induced hearing loss by chemical contaminants". Journal of Toxicology and Environmental Health. Part A. 67 (8–10): 727–40. doi:10.1080/15287390490428206. PMID 15192865.
- Venet, Thomas; Campo, Pierre; Thomas, Aurélie; Cour, Chantal; Rieger, Benoît; Cosnier, Frédéric (2015). "The tonotopicity of styrene-induced hearing loss depends on the associated noise spectrum". Neurotoxicology and Teratology. 48: 56–63. doi:10.1016/j.ntt.2015.02.003. PMID 25689156.
- Fuente, Adrian; Qiu, Wei; Zhang, Meibian; Xie, Hongwei; Kardous, Chucri A.; Campo, Pierre; Morata, Thais C. (March 2018). "Use of the kurtosis statistic in an evaluation of the effects of noise and solvent exposures on the hearing thresholds of workers: An exploratory study". The Journal of the Acoustical Society of America. 143 (3): 1704. doi:10.1121/1.5028368. ISSN 1520-8524. PMID 29604694.
- Gratton MA, Salvi RJ, Kamen BA, Saunders SS (1990). "Interaction of cisplatin and noise on the peripheral auditory system". Hearing Research. 50 (1–2): 211–23. doi:10.1016/0378-5955(90)90046-R. PMID 2076973.
- Occupational Safety and Health Administration, National Institute for Occupational Safety and Heath (April 3, 2018). "Preventing Hearing Loss Caused by Chemical (Ototoxicity) and Noise Exposure" (PDF). OSHA, NIOSH. Archived from the original (PDF) on March 2018. Retrieved April 3, 2018.
- Durrant J (October 2009). "American Academy of Audiology Position Statement and Clinical Practice Guidelines: Ototoxic Monitoring" (PDF). American Academy of Audiology. American Academy of Audiology. Retrieved 4 December 2016.
- 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.
- Hennig AK, Cotanche DA (1998). "Regeneration of cochlear efferent nerve terminals after gentamycin damage". The Journal of Neuroscience. 18 (9): 3282–96. PMID 9547237.
- Ototoxic Medications
- Articles on Ototoxic Drugs by Neil Bauman, Ph.D.
- OSHA-NIOSH 2018. Preventing Hearing Loss Caused by Chemical (Ototoxicity) and Noise Exposure Safety and Health Information Bulletin (SHIB), Occupational Safety and Health Administration and the National Institute for Occupational Safety and Health. SHIB 03-08-2018. DHHS (NIOSH) Publication No. 2018-124. https://doi.org/10.26616/NIOSHPUB2018124
- The Ear Poisons, The Synergist, American Industrial Hygiene Association, 2018.