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, for very serious health conditions. Ototoxic drugs include aminoglycoside antibiotics (such as gentamicin, streptomycin, tobramycin), loop diuretics (such as furosemide), and platinum-based chemotherapy agents (such as cisplatin and carboplatin). 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 Ototoxicity results in cochlear and/or vestibular dysfunction which can manifest as sensorineural hearing loss, tinnitus, hyperacusis, dizziness, vertigo, or imbalance. Presentation of symptoms vary in singularity, onset, severity and reversibility.
Auditory symptoms
Hearing loss Ototoxicity-induced hearing loss typically impacts the high frequency range, affecting above 8000 Hz prior to impacting frequencies below. There is not a global consensus on measuring severity of ototoxicity-induced hearing loss as there are many criteria available to define and measure ototoxicity-induced hearing loss. Guidelines and criteria differ between children and adults.
Ototoxicity grades (Hearing Loss) There are at least 13 classifications for ototoxicity. Examples of ototoxicity grades for hearing loss are the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), Brock's Hearing Loss Grades, Tune grading system, and Chang grading system. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (as described in the American Academy of Audiology Ototoxicity Monitoring Guidelines from 2009):
Grade 1: Threshold shift or loss of 15–25 dB relative to baseline, averaged at two or more contiguous frequencies in at least one ear Grade 2: Threshold shift or loss of >25-90 dB, averaged at two contiguous test frequencies in at least one ear Grade 3: Hearing loss sufficient to indicate aural rehabilitation such as hearing aids and/or speech-language services Grade 4: Indications of cochlear implant candidacy Brock's Hearing Loss Grades (as described in the American Academy of Audiology Ototoxicity Monitoring Guidelines from 2009):
Grade 0: Hearing thresholds <40 dB at all frequencies Grade 1: Thresholds 40 dB or greater at 8000 Hz Grade 2: Thresholds 40 dB or greater at 4000-8000 Hz Grade 3: Thresholds 40 dB or greater at 2000-8000 Hz Grade 4: Thresholds 40 dB or greater at 1000-8000 Hz Chang grading system (as reported in Ganesan et al., 2018):
0: ≤ 20 dB at 1, 2, and 4 kHz 1a: ≥ 40 dB at any frequency 6 to 12 kHz 1b: > 20 and < 40 dB at 4 kHz 2a: ≥ 40 dB at 4 kHz and above 2b: > 20 and < 40 dB at any frequency below 4 kHz 3: ≥ 40 dB at 2 or 3 kHz and above 4: ≥ 40 dB at 1 kHz and above Tune grading system (as reported in Ganesan et al., 2018):
0: No hearing loss 1a: Threshold shift of ≥ 10 dB at 8, 10, and 12.5 kHz 1b: Threshold shift of ≥ 10 dB at 1, 2, and 4 kHz 2a: Threshold shift of ≥ 20 dB at 8, 10, and 12.5 kHz 2b: Threshold shift of ≥ 20 dB at 1, 2, and 4 kHz 3: ≥ 35 dB HL at 1, 2, and 4 kHz 4: ≥ 70 dB HL at 1, 2, and 4 kHz
Hyperacusis Hyperacusis is abnormally increased sensitivity to intensity (perceived as loudness) to what is typically deemed as normal/tolerable loudness.
Vestibular symptoms Vestibular symptoms from ototoxicity, which would specifically be vestibulotoxicity, can include general dizziness, vertigo, imbalance, and oscillopsia.
Ototoxic agents
Antibiotics 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.
Loop diuretics 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, and is therefore used only in 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.
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