Ototoxicity

Douglas J Lanska MD MS MSPH

Neuro-Ophthalmology & Neuro-Otology

Updated 05.20.2024
Released 05.09.2023
Expires For CME 05.20.2027

Ototoxicity

Author: Douglas J Lanska MD MS MSPH

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Ototoxicity

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Introduction

Overview

With the widespread use of streptomycin in the late 1940s, clinicians began to recognize the full clinical syndrome of acquired bilateral vestibulopathy. Some patients treated with streptomycin for tuberculosis developed severe ataxia and oscillopsia. The clinical features of patients with streptomycin ototoxicity resembled those described earlier in patients with Meniere disease following surgical section of both vestibular nerves to alleviate vertigo. It is now recognized that ototoxicity can present as cochleotoxicity, vestibulotoxicity, or both. Various drugs are ototoxic, including aminoglycosides, aspirin, furosemide, and platinum-based alkylating agents used in cancer chemotherapy. Aminoglycosides are by far the most commonly implicated agents in permanent drug-induced vestibulotoxicity. Aspirin and loop diuretics typically cause reversible cochleotoxicity, and alkylating agents uncommonly cause a mixed ototoxicity. Following vestibulotoxic insults (eg, from aminoglycosides), the hair cells do not regrow. In addition, vestibular damage may progress for months after the responsible drug is discontinued because the drugs are bound to inner ear membranes. Damage is usually complete by 6 months after aminoglycoside discontinuation. Compensation for bilateral vestibulopathy is often achieved by augmentation of visual and proprioceptive reflexes rather than by recovery of vestibular function. Aminoglycoside therapy should cease as soon as symptoms of either auditory or vestibular ototoxicity appear to avoid permanent impairment.

Key points

	• Ototoxicity can present as cochleotoxicity, vestibulotoxicity, or both.
	• Cochleotoxicity typically presents with subacute or chronic high-frequency hearing loss and subjective tinnitus.
	• Patients with vestibulotoxicity typically present with features of subacute bilateral vestibulopathy, with gait ataxia and oscillopsia.
	• Following vestibulotoxic insults (eg, from aminoglycosides), the hair cells do not regrow.
	• Vestibular damage may progress for months after the responsible drug is discontinued because the drugs are bound to inner ear membranes.
	• Damage is usually complete by 6 months after aminoglycoside discontinuation.
	• Compensation for bilateral vestibulopathy is often achieved by augmentation of visual and proprioceptive reflexes rather than by recovery of vestibular function.
	• Risk factors for aminoglycoside-induced ototoxicity include family history of ototoxicity, high serum levels, higher total dose, longer duration of therapy (beyond 7 to 10 days), intrathecal administration, previous exposure to ototoxins, concomitant use of other nephrotoxic or ototoxic drugs (eg, vancomycin, loop diuretics, cis-platinum, metronidazole), renal impairment, fever, and older age.
	• Prevention of aminoglycoside-induced vestibulotoxicity is essential because the hair cells do not regrow after vestibulotoxic insults; hence, vestibular function does not recover. Instead, the limited compensation that occurs after bilateral vestibulopathy is generally achieved by augmentation of visual and proprioceptive reflexes.
	• Corrective saccades after rapid head turns to either side (ie, the “head thrust test”) can be helpful in the diagnosis of bilateral vestibular dysfunction.

Historical note and terminology

The clinical features of patients with streptomycin ototoxicity resembled those described earlier in 1936 by neurologist Frank Rodolph Ford (1892–1970) and neuro-ophthalmologist Frank Burton Walsh (1895–1978) of Johns Hopkins in a patient of neurosurgeon Walter Dandy’s (1886–1946) (38; 27; 79). In their original report, Ford and Walsh stated: “During convalescence [following bilateral vestibular nerve section] it became evident that a new series of symptoms had developed. Objects seemed to move before his eyes unless his head was kept perfectly still. Walking caused objects to ‘jump’ before his eyes to some extent. . . He was also very unsteady in the dark.” Dandy had not reported these observations in his original report on this patient, although the postoperative period was brief at the time of Dandy’s report (28).

In 1941, 5 years after the report by Ford and Walsh, Dandy described oscillopsia and imbalance in the dark in patients with Meniere disease in whom he had sectioned both vestibular nerves to alleviate vertigo (27):

“Division of both vestibular nerves is attended by one rather surprising after effect, jumbling of objects (visual) when the patient is in motion. As soon as the patient is at rest, the objects are again perfectly clear. The other disturbance is uncertainty when the patient is walking in the dark. Both of these effects persist, though with gradual lessening in severity.”

Because of a historical misunderstanding of Dandy's role in recognizing the clinical features of bilateral vestibulopathy, the syndrome of bilateral vestibulopathy is sometimes mislabeled “Dandy syndrome” (79).

Ford later summarized the observations he made with Walsh in the 1930s (37):

“Destruction of the vestibular apparatus on both sides in man produces a constant unsteadiness of station and gait which is exaggerated in the dark and also by sudden movements of the head. There is also a striking inability to fix objects with the eyes when the head is in movement so that the patients complain of objects seeming to dance or oscillate before their eyes when they are walking or riding in a car. This oscillation ceases as soon as the head is held still.”

The classic description of aminoglycoside vestibulotoxicity by "JC" (John Crawford MD). In 1948, shortly after streptomycin became available, a 30-year-old physician was treated with intramuscular and intraarticular streptomycin for presumptive tuberculous arthritis of the knee (64; 82). After 2.5 months of treatment, the patient noted the dramatic onset and rapid progression of bilateral vestibular dysfunction over several days. Manifestations included postural instability in darkness (Romberg symptom), gait ataxia, motion-induced vertigo and nausea, and oscillopsia.

Oscillopsia was initially severe. Even the cardioballistic effects of the pulse produced disturbing perceptions of motion. He was able to read by bracing his head between two metal bars on the bed and keeping his place with a finger or a pencil. He had to stand still to read the lettering on signs or to recognize familiar faces.

To ambulate, he initially had to rely on tactile cues and hold on to objects for support. Later, he was able to walk by focusing on distant objects. After 4 years, he had learned to walk fairly well in the light and had resumed most of his former recreational activities, despite continued vestibular dysfunction. One partial benefit was a recognized resistance to seasickness. However, he was still severely impaired in the dark and sometimes had to move about on his hands and knees.

Forty years later he was still active with little disability. He noted continued resistance to motion sickness. He continued to have difficulty on uneven or unstable surfaces and in the dark.

Clinical manifestations

Presentation and course

	• Ototoxicity can present as cochleotoxicity, vestibulotoxicity, or both.
	• Cochleotoxicity typically presents with subacute or chronic high-frequency hearing loss and subjective tinnitus.
	• Patients with vestibulotoxicity typically present with features of subacute bilateral vestibulopathy, with gait ataxia and oscillopsia.
	• Following vestibulotoxic insults (eg, from aminoglycosides), the hair cells do not regrow.
	• Vestibular damage may progress for months after the responsible drug is discontinued because the drugs are bound to inner ear membranes.
	• Damage is usually complete by 6 months after aminoglycoside discontinuation.
	• Compensation for bilateral vestibulopathy is often achieved by augmentation of visual and proprioceptive reflexes rather than by recovery of vestibular function.

Ototoxicity can present as cochleotoxicity, vestibulotoxicity, or both.

Cochleotoxicity typically presents with subacute or chronic high-frequency hearing loss and subjective tinnitus. Cochleotoxicity classification systems can be divided into those that focus on hearing change from a baseline audiogram and those that focus on the functional impact of the hearing loss (26). Common weaknesses of these grading scales include a lack of sensitivity to small adverse changes in hearing thresholds, failure to incorporate high-frequency audiometry (> 8 kHz), and lack of indication of which changes are likely to be clinically significant for communication and quality of life.

Patients with vestibulotoxicity typically present with features of subacute bilateral vestibulopathy, with gait ataxia and oscillopsia (80). Other clinical features of bilateral vestibulopathy include the following:

	• Absence of spontaneous vertigo
	• A sense of continuous turning in bed
	• Absence of spontaneous nystagmus
	• Inability to walk in the dark or on uneven or soft surfaces, unless by holding on to the wall or objects in the room (ie, use of contact cues)
	• Romberg sign
	• No dysmetria or dysdiadochokinesis
	• Nausea and sometimes vomiting
	• Insensitivity to motion sickness
	• A bilateral, usually symmetric, decreased sensitivity to caloric and rotational stimulation (40; 64; 55; 58).
	• Decreased or absent ocular counter-rolling (104).

Occasionally, patients may have vertigo and illusions of tilt due to asymmetric involvement (58), but this rapidly decreases over hours or days and leaves the patient with oscillopsia. Some patients with asymmetric vestibular involvement do not develop vertigo or nystagmus because of either subacute development of vestibulopathy, which allows compensation to occur, or because of subacute but asymmetric recovery of vestibular function (140).

Oscillopsia in patients with bilateral vestibulopathy is manifest by bidirectional, to-and-fro, and up-and-down illusory movements of the visual world that occur in the same axis (but in the opposite direction) as head movements, including head movements associated with ambulation (16; 12; 13; 97; 111; 83; 80; 71; 50). There is no associated disorientation in space, illusion of self-motion, or autonomic system disturbance, such as nausea or diaphoresis (58). Because the visual pursuit system can compensate for slow head movements (up to about 1 Hz), oscillopsia typically occurs with more rapid head movements. Oscillopsia is not universal in patients with bilateral vestibulopathy. Many patients do not report this symptom (07; 116), perhaps because of compensatory mechanisms in some patients (21).

Corrective saccades after rapid head turns to either side can be helpful in the diagnosis of bilateral vestibular dysfunction (52; 71). In this test, the patient's head is turned rapidly to one side by the examiner while the patient attempts to maintain fixation on an object 6 or more feet away. The examiner then observes the patient for corrective saccades. Normally, a person makes smooth corrective eye movements and maintains fixation on the target. In contrast, the gaze of a patient with bilateral vestibulopathy shifts when the head is turned rapidly to either side. The gaze of a patient with unilateral labyrinthine dysfunction shifts only when the head moves quickly toward the dysfunctional side. In both cases, an oppositely directed compensatory saccade corrects the gaze error.

Patients with bilateral vestibulopathy also show a marked reduction in visual acuity with passive or active head oscillations in the horizontal or vertical planes, including during ambulation (71; 50). This can be evaluated clinically by assessing visual acuity before and during passive movements of the patient's head, at 0.5 to 2.0 Hz (91; 92; 145). Use of the higher-frequency oscillations prevents visual following reflexes from stabilizing the eyes and facilitating visualization of the target (145). In any case, patients should not be allowed to stop at the turnaround point, or they will override the dynamic nature of the test. Visual acuity for normal individuals will decline by one line at most on the eye chart with this test. A decline of more than two lines is definitely abnormal (92; 145; 116). Patients with severe bilateral vestibulopathy may show a decline of five or more lines (145). Unpredictable head movements cause a greater decrease in visual acuity than do predictable head movements (57).

Other techniques to assess dynamic visual acuity are more complicated and may require specialized equipment (136).

There is a strong correlation between the clinical absence of dynamic ocular counter-rolling and bilateral caloric paresis (104).

Patients with bilateral vestibulopathy have an unsteady wide-based gait and a tendency to fall to either side. They do much worse on uneven or soft surfaces, like foam cushions or mattresses. Patients with bilateral vestibulopathy are more susceptible to falls than are patients with unilateral vestibulopathy, particularly after several weeks following onset (118). Some of the increased falling risk in patients with bilateral vestibulopathy may be related to reduced activity and the use of assistive devices for ambulation.

Vestibulospinal and proprioceptive reflexes are gauged with the Romberg test. This test, however, is relatively insensitive for chronic bilateral vestibulopathy. The test's sensitivity can be increased by narrowing the patient's support base, which can be accomplished by performing the test in a tandem stance or on one foot (142; 84). The sensitivity can also be increased by having the patient stand on foam rubber in order to disrupt proprioceptive inputs (122; 84). Foam posturography demonstrates high levels of visual and somatosensory dependence in patients with bilateral vestibulopathy (43). Observing the patient walk or perform tandem gait, particularly with eyes closed, is also helpful.

Dynamic vestibulospinal function is assessed by observing gait, stability during rapid turns to either side, and the patient's ability to follow gentle perturbations imposed by the examiner (145).

Prognosis and complications

Following vestibulotoxic insults (eg, from aminoglycosides), the hair cells do not regrow. In addition, vestibular damage may progress for months after the responsible drug is discontinued because the drugs are bound to inner ear membranes. Damage is usually complete by 6 months after aminoglycoside discontinuation.

Compensation for bilateral vestibulopathy is often achieved by augmentation of visual and proprioceptive reflexes rather than by recovery of vestibular function (55; 21; 17; 129; 105; 05; 56; 149; 148; 15), although some limited recovery of vestibular function may occur in a few cases (105; 15).

Over more than 4 years of follow-up on average, about half of patients with bilateral vestibulopathy subjectively rate the course of their disease as stable, about a quarter as worsened, and another quarter as improved (148). In general, the mean peak slow phase velocity of nystagmus induced with bithermal caloric irrigation does not change.

Over a period of months, much of the initial disability can be compensated for (64; 55), but marked difficulty walking in the dark may persist (64). This is because patients need to rely strictly on proprioceptive reflexes rather than a combination of vestibular, visual, and proprioceptive reflexes for balance and ambulation. Recovery is inversely related to age, with children compensating more rapidly and more completely, whereas those over 50 years of age respond poorly or not at all (05). Gait instability and oscillopsia may improve more quickly and completely with vestibular rehabilitation therapy, but data supporting the use of such therapy are still limited and largely anecdotal (74; 103; 03).

Biological basis

Etiology and pathogenesis

	• Ototoxic bilateral vestibulopathy is typically due to dysfunction of the labyrinth on both sides.
	• The absence of vestibular function bilaterally produces impaired vestibulo-ocular and vestibulospinal reflexes, resulting in oscillopsia, gait ataxia, and worsened ambulation in darkness.
	• Various drugs are ototoxic, including aminoglycosides, aspirin, furosemide, and alkylating agents used in cancer chemotherapy.
	• Aminoglycosides are by far the most commonly implicated agents in permanent drug-induced vestibulotoxicity, whereas aspirin and loop diuretics typically cause reversible cochleotoxicity, and alkylating agents uncommonly cause a mixed ototoxicity.
	• Aminoglycoside antibiotics can cause both auditory and vestibular toxicity.
	• Aminoglycoside toxicity apparently results from an inhibition of mitochondrial protein synthesis because of a similarity between mitochondrial ribosomes and bacterial ribosomes (where aminoglycosides allow misreading of mRNA during translation).

In a comprehensive review of drug-induced ototoxicity, 194 systemically administered medications were associated with ototoxicity, most commonly antimicrobials (53), psychotropics (21), antihypertensive/antiarrhythmics (19), nonsteroidal antiinflammatory drugs (18), and antineoplastic drugs (16) (112). There was evidence of cochleotoxicity in 165 medications (evidence grading A [22], B [77], C [69]) and vestibulotoxicity in 100 medications (evidence grading A [23], B [47], and C [30]), where the evidence grades were as follows: grade A (randomized, controlled clinical trials), grade B (nonrandomized clinical trials, prospective observational studies, cohort studies, retrospective studies, case-controlled studies, or postmarketing surveillance studies), and grade C (case reports/case series).

Ototoxic compounds include pharmaceuticals, such as aminoglycoside antibiotics, platinum chemotherapeutic agents, antimalarial drugs (eg, quinine), aspirin, loop diuretics (eg, furosemide), and industrial chemicals (eg, organic solvents and nitriles) (120). Aminoglycosides are by far the most commonly implicated agents in permanent drug-induced vestibulotoxicity, whereas aspirin and loop diuretics typically cause reversible cochleotoxicity, and platinum-based alkylating agents uncommonly cause a mixed ototoxicity (68; 69). Moreover, aminoglycosides have been the most commonly used antibiotics around the world (117).

Ototoxic bilateral vestibulopathy is typically due to dysfunction of the labyrinth on both sides. Ototoxicity primarily impacts the mechanosensory hair cells responsible for sensory transduction in both the auditory and vestibular systems (04); nevertheless, ototoxicity may also affect the auditory and vestibular ganglion neurons (120).

Exposure to ototoxic compounds causes hair cell apoptosis and necrosis, as well as damage to the afferent terminals (120). A major pathway involved in hair cell apoptosis is the c-jun N-terminal kinase (JNK) signaling pathway activated by reactive oxygen species.

In subjects with ototoxicity, subjective tinnitus and hyperacusis arise from aberrant neural signaling in a complex neural network that includes both auditory and nonauditory structures (113). Functional imaging studies found that salicylate increased spontaneous activity and enhanced functional connectivity between structures in the central auditory pathway and regions of the brain associated with arousal (reticular formation), emotion (amygdala), memory/spatial navigation (hippocampus), motor planning (cerebellum), and motor control (caudate/putamen).

The absence of vestibular function bilaterally produces impaired vestibulo-ocular and vestibulospinal reflexes. These result in oscillopsia, gait ataxia, and worsened ambulation in darkness, as well as the other manifestations. Normal balance requires continuous monitoring of body sway and other orientation information, which are provided by the somatosensory, vestibular, and visual systems (84; 81; 83). The functional ranges of these systems partially overlap, allowing partial compensation for deficits or distortions (101; 102). For example, a normal subject can maintain upright stance either with vision eliminated (with eye closure), proprioception disrupted (standing on a moving or tilting surface), or vestibular function distorted (as a result of rotationally induced vertigo) (84). However, loss or distortion of inputs from two or more systems is often associated with disequilibrium and falls. Thus, a patient with bilateral vestibular dysfunction may fall if vision is eliminated (with eyes closed) (84).

Aminoglycoside ototoxicity. The aminoglycosides include gentamicin, amikacin, tobramycin, neomycin, and streptomycin. Aminoglycosides are polar drugs, with poor gastrointestinal absorption, so intravenous or intramuscular administration is needed.

Aminoglycoside-induced nephrotoxicity can increase the potential for neurotoxicity. Fortunately, aminoglycoside-induced changes in renal function are typically reversible (87). Aminoglycoside ototoxicity occurs through the drug's ability to freely pass into hair cells and cause reactive oxygen species to damage the mitochondria, resulting in cell death. Exposure to aminoglycosides in utero can result in permanent ototoxicity.

Aminoglycoside antibiotics can cause both auditory and vestibular toxicity (69; 83; 66; 67), but gentamicin, streptomycin, and tobramycin are relatively specific toxins for the vestibular system (30; 66; 67). Gentamicin is more vestibulotoxic than tobramycin (34). Kanamycin, neomycin, netilmicin, and amikacin are more cochleotoxic (139; 58).

Of the vestibulotoxic aminoglycoside antibiotics, gentamicin is currently in widest clinical use. It can selectively destroy vestibular hair cells and thereby impair vestibular function, including the vestibule-ocular reflex (04), without markedly affecting auditory function (30). It can do this with appropriate dosing and pharmacologic monitoring (96). Patients with gentamicin vestibulotoxicity rarely complain of hearing loss because gentamicin rarely affects hearing in the range of human speech (1 to 3 kHz) (Black and Pesznecker 1993; 19; 30). Cochleotoxicity from gentamicin initially results in a high frequency hearing loss outside the human speech frequencies of 1 to 3 kHz and, hence, is often not monitored (53; 124).

Aminoglycoside-induced changes in the vestibular nerve and vestibular nuclei are secondary to damage to the vestibular hair cells (55; Huizing and de Groot 1987; 58) and variable direct damage to spiral ganglion cells (59). Damage to the vestibular system first develops in type I hair cells in the crista and develops later in type II hair cells (55). The otolith organs are relatively spared (58).

Unlike other common antibiotics, aminoglycosides are concentrated in endolymph and perilymph. This at least partly explains their predilection for ototoxicity (55). Gentamicin therapy does not have to be administered systemically to be vestibulotoxic. Topical aminoglycoside-containing eardrops can produce vestibulotoxicity if they reach the middle ear through a tympanic membrane defect (perforation or tympanostomy tube), especially if therapy is prolonged beyond 7 days (10), or in burn patients (06; 10).

Aminoglycoside toxicity apparently results from an inhibition of mitochondrial protein synthesis because of a similarity between mitochondrial ribosomes and bacterial ribosomes (where aminoglycosides allow misreading of mRNA during translation). A highly conserved region of ribosomal RNA binds aminoglycosides, and mutations in this region may result in increased susceptibility to aminoglycoside-induced ototoxicity in humans and in bacterial resistance in prokaryotic bacteria (109; 63; 124). Other (not necessarily mutually exclusive) theories of aminoglycoside-induced toxicity include free radical formation via binding of iron and subsequent formation of oxidative compounds, reversible blockade of sensory transduction by blocking calcium-sensitive potassium channels, and excessive N-methyl-D-aspartate (NMDA) receptor activation and excitotoxicity due to aminoglycoside agonist activity at the NMDA subtype of glutamate receptor (09; 33; 117; 124).

A variety of candidate otoprotective drugs with protective properties for vestibular hair cells and vestibular neurons have been identified in animal models of aminoglycoside ototoxicity (09; 33; 117; 124; 35). These include various neurotrophic factors (eg, nerve growth factor, brain-derived neurotrophic factors, and neurotrophin 3), an inducer of nerve growth factor synthesis (ie, 4-methylcatechol), iron chelators, free radical scavengers (eg, alpha-tocopherol), and NMDA antagonists.

Cortisol sensitizes cochlear hair cells to gentamicin ototoxicity via the endogenous apoptotic pathway (89). In a cell culture study of cochlear hair cells, cortisol significantly increased hair cell apoptosis and oxidative stress and altered apoptosis-related protein expressions induced by gentamicin. Blockade of either glucocorticoid or mineralocorticoid receptors attenuated cortisol-induced hair cell sensitization to gentamicin toxicity.

Aminoglycosides in cystic fibrosis. Persons with cystic fibrosis are at risk for aminoglycoside-induced ototoxicity due to repeated use of intravenous tobramycin for the treatment of pulmonary exacerbations. Cumulative intravenous aminoglycoside dosing is associated with a higher risk of ototoxic hearing loss, yet there is considerable interindividual heterogeneity, with some individuals losing substantial hearing after a single intravenous aminoglycoside treatment whereas others never seem to lose hearing (45).

Among patients with cystic fibrosis, one course of intravenous tobramycin was sufficient to cause hearing loss and other ototoxic symptoms 4 weeks after treatment ended (54). Audiometric measures were more sensitive to ototoxic change than the Tinnitus Functional Index and the Vertigo Symptoms Scale. Age and duration of tobramycin treatment were not obvious factors for predicting ototoxicity.

Pharmacokinetic models can predict ototoxicity risk in patients with cystic fibrosis treated with tobramycin with moderate accuracy (31). There is a significant relationship between cumulative tobramycin exposure and changes in hearing acuity (94).

Genetic variations within one particular mitochondrial gene, MT-RNR1 (also referred to as MTRNR1), have been strongly linked with the development of hearing loss following administration of aminoglycoside antibiotics (08). Pretreatment screening in the cystic fibrosis population for aminoglycoside-induced hearing loss risk based on common pathogenic variants (MT-RNR1 m.1555 A > G and m.1494 C > T) is feasible using digital droplet polymerase chain reaction, a scalable and robust testing methodology at a fraction of the cost as compared to other sequencing-based methods (93).

In a study of 63 children with cystic fibrosis who received intravenous aminoglycosides, 15 (24%) had ototoxicity detected by extended high-frequency (EHF) audiometry and distortion-product otoacoustic emissions (DPOAE), whereas conventional pure tone audiometry detected ototoxicity in 13 children (02). A 25 to 85 dBHL hearing loss was identified across all EHF frequencies along with a significant drop in distortion-product otoacoustic emission (DPOAE) amplitudes at frequencies of 4 to 8 kHz. In contrast, conventional pure tone audiometry detected a significant hearing loss (> 20 dBHL) at only 8 kHz in five of these 15 children and none in two subjects who had significantly elevated EHF thresholds. The number of courses of intravenous aminoglycosides, age, and lower lung function were risk factors for ototoxicity. Extended high-frequency audiometry should be the test of choice for detecting ototoxicity in children with cystic fibrosis receiving intravenous aminoglycosides.

Amikacin in end-stage kidney disease on peritoneal dialysis. Amikacin is a frequently used aminoglycoside antibiotic in the treatment of peritoneal dialysis-related peritonitis, but ototoxicity is a well-known complication. In a randomized placebo-controlled trial, N-acetyl-cysteine (NAC) was safe and effective in preventing amikacin-related ototoxicity, especially in higher frequencies, in patients with peritoneal dialysis-related peritonitis (72). Unfortunately, although NAC may be otoprotective, the effect is not long-lasting, with no evident difference between treated and untreated groups at 12 months (137).

Aminoglycosides in multidrug-resistant tuberculosis. The use of aminoglycoside antibiotics to treat multidrug-resistant tuberculosis is associated with substantial morbidity due to long-term hearing loss. In a meta-analysis of 64 studies from 25 countries including 12,793 patients collectively, 28% (95% CI: 23%–33%) of patients treated with aminoglycosides reported hearing loss (144). Tinnitus and vertigo were experienced by 15% (95% CI: 10%–19%) and 8% (95% CI: 5%–12%), respectively. The incidence of hearing loss was highest among patients treated with amikacin (33%, 95% CI: 18%–49%) and lowest among those treated with capreomycin (2%, 95% CI: 0%–6%).

Among 70 drug-resistant tuberculosis patients, the incidence of aminoglycoside-induced ototoxicity was 23% (125). Clinical predictors of ototoxicity were age, body mass index (BMI) on admission, and coexisting retroviral infection.

Cumulative amikacin area under the concentration-time curve and duration of therapy are better predictors of aminoglycoside ototoxicity than peak and trough concentrations. Consequently, these indicators should be used as the primary decision-making parameters to minimize the likelihood of ototoxicity in multidrug-resistant tuberculosis (100).

A meta-analysis of three studies concluded that N-acetylcysteine (NAC) reduced ototoxicity in 146 patients with end-stage renal failure receiving aminoglycosides (73). The pooled relative risk for otoprotection at 4 to 6 weeks was 0.14 (95% CI: 0.05 to 0.45), and the risk difference was -33% (95% CI: 46% to 21%). Abdominal pain, nausea and vomiting, diarrhea, and arthralgia were increased 1.4- to 2.2-fold.

Ototoxicity in neonates requiring intensive care. Neonates admitted to the neonatal intensive care unit (NICU) are at greater risk of permanent hearing loss compared to infants in well mother and baby units (46). Several factors have been associated with this increased prevalence of hearing loss, including congenital infections (eg, cytomegalovirus or syphilis), ototoxic drugs (eg, aminoglycoside or glycopeptide antibiotics), low birth weight, hypoxia, and length of stay (46). Unfortunately, current audiological screening or monitoring protocols for neonates are not designed to adequately detect early onset of ototoxicity.

Exposure to vancomycin, a glycopeptide antibiotic, in very-low-birthweight infants is associated with an increased dose-dependent risk of pathological hearing test results at discharge and at 5 years of age (95).

A rapid MT-RNR1 point-of-care test can be integrated into clinical practice in neonatal intensive care units, with identified genotypes used to guide antibiotic prescription and avoid aminoglycoside-induced ototoxicity (98).

Ototoxicity in cancer patients. Ototoxicity is associated with various antineoplastic therapies, including platinum chemotherapy, and supportive care agents such as aminoglycoside antibiotics and loop diuretics. The reported prevalence of ototoxicity in cancer patients who have received potentially ototoxic therapy ranges from 4% to 90% depending on factors such as age of the patient population, agent(s) used, cumulative dose, and administration techniques (75). Considerable interindividual variability in the prevalence and severity of ototoxicity has been observed among patients receiving similar treatment, suggesting a significant role for genetic susceptibility.

Platinum-based chemotherapy. Platinum chemotherapy drugs (eg, cisplatin and carboplatin) are the cornerstone of many effective therapeutic protocols for childhood and adult cancers (78). However, the antitumor efficacy of platinum chemotherapeutic drugs comes at the cost of nephrotoxicity and ototoxicity—side effects that remain major clinical limitations (78; 76; 106; 24; 138; 143; 110; 22; 44; 114; 130; 25). More than half of adult and pediatric patients with cancer treated with cisplatin develop hearing impairment with a major impact on health-related quality of life (22).

Adult cancer patients. Cisplatin is one of the most used chemotherapeutic agents in the treatment of germ cell, lung, bladder, ovarian, and head and neck cancers (22). Germ cell tumors are the most common malignancy in adolescent and young adult men (44). Approximately 500,000 patients diagnosed annually with these cancer types in the United States could be candidates for treatment with cisplatin. There is a 5-fold increased risk of ototoxicity with cisplatin, which can manifest as tinnitus, high-frequency hearing loss, and, in the later stages, a decreased ability to hear normal conversation (22). Three-fourths of testicular cancer survivors report some type of ototoxicity following cisplatin-based chemotherapy (114).

High-dose carboplatin is an essential part of curative high-dose chemotherapy for patients with previously treated germ cell tumors (44). Of 106 patients with normal hearing to mild hearing loss in the speech frequencies (0.5–4 kHz) before high-dose chemotherapy, two thirds (66%) developed moderate to profound hearing in the speech frequencies after high-dose chemotherapy, and 22% were recommended for hearing aids after high-dose chemotherapy. Patients with moderate to profound hearing loss isolated to the higher frequencies (6–8 kHz) before high-dose chemotherapy were significantly more likely to develop moderate to profound hearing loss in the speech frequencies after high-dose chemotherapy (94% vs. 61%) and to be recommended for hearing aids (39% vs. 18%).

Pediatric cancer patients. Platinum-containing chemotherapy is often used to treat children with cancer. Although it is a very effective medication, it unfortunately causes permanent hearing loss in a large proportion of the children who receive it. In children, ototoxicity from platinum-based chemotherapy can profoundly handicap language development and social communication, with debilitating effects on quality of life (78). Very young children are particularly susceptible to ototoxicity from platinum agent chemotherapy, so the younger the child, the more frequently hearing should be tested during treatment.

Ototoxicity following chemotherapy with cisplatin or carboplatin is common in children and frequently progresses after the completion of treatment (78; 76; 106; 110). Severe hearing loss is prevalent among children with high-risk neuroblastoma (76); exposure to cisplatin combined with myeloablative carboplatin significantly increases risk.

In a retrospective chart review of 306 pediatric patients treated with cisplatin or carboplatin between 2000 and 2012, post-chemotherapy ototoxicity was detected in 48%, and clinically significant ototoxicity was present in 30% (106). Among those with long-term follow-up, hearing deteriorated further in 48% after completion of treatment.

In a retrospective study of 51 children consecutively diagnosed with brain tumors and treated with platinum derivatives at a tertiary referral hospital between 2006 and 2015, the incidence of ototoxicity was 24% (110). Rates of hearing loss with carboplatinum were lower than with cisplatinum. Ototoxicity after treatment with platinum derivatives was significantly associated with the presence of hydrocephalus, radiotherapy exposure, and infratentorial tumor location (110).

Ototoxicity data on large cohorts of childhood cancer survivors who received platinum agents, but not cranial irradiation, are scarce. In a study of 451 childhood cancer survivors who received platinum agents but not cranial irradiation (median age at diagnosis: 4.9 years, range: 0.01–19 years), the overall frequency of ototoxicity was 42% (24). Ototoxicity was observed in 45% of childhood cancer survivors treated with cisplatin, 17% treated with carboplatin, and 75% of those who received both agents.

Risk factors for platinum agent ototoxicity. In a multivariate analysis of 451 childhood cancer survivors who received platinum agents but not cranial irradiation, ototoxicity was associated with younger age at diagnosis, higher total cumulative dose cisplatin, and co-treatment with furosemide (24).

Pediatric patients receiving cisplatin chemotherapy with a cumulative dose exceeding 400 mg/m², as well as patients younger than 5 years of age, are at greater risk of developing hearing loss (138). Accumulated cisplatin dose and single maximum cisplatin dose are independent and important predictors for moderate to severe hearing loss in children treated with cisplatin (143).

Ototoxicity risk factors among testicular cancer survivors following cisplatin-based chemotherapy include age, cisplatin dose, cardiovascular risk factors, and family history of hearing loss (114).

A meta-analysis identified polymorphisms that exert ototoxic or otoprotective effects in patients undergoing platinum-based chemotherapy (60). Because several of these alleles occur at high frequencies globally, a potential exists for polygenic screening and cumulative risk evaluation for personalized care. Unfortunately, the available evidence is of low quality because study cohorts were small, and replication studies are either missing or contradictory (85). Nevertheless, the SLC22A2 polymorphism rs316019 is a potential pharmacogenomic protective marker for cisplatin-induced ototoxicity and points to a critical role of SLC22A2 for cisplatin transport in humans and its contribution to the ototoxic side effects of this drug (86). In addition, a meta-analysis of studies of cancer patients treated with cisplatin found that ACYP2 rs1872328, which plays a role in calcium homeostasis, increased the risk of ototoxicity 4.6-fold (95% CI: 3.0–7.0), and LRP2 rs4668123 increased the risk of ototoxicity 3.5-fold (95% CI: 1.5–8.5) (133).

The LRP2 (LDL receptor–related protein 2) gene provides instructions for making a protein called megalin, which functions as a receptor. Megalin has many ligands and is involved in the absorption of vitamins A and D, immune functioning, the stress response, and the transport of fats in the bloodstream. Megalin is embedded in the membrane of cells that line the surfaces and cavities of the body (epithelial cells) and helps move its ligands from the cell surface into the cell (endocytosis). Megalin is also active in the development and function of the brain and spinal cord, eyes, ears, lungs, intestine, reproductive system, and renal tubules.

A systematic review of 40 reports involving 47 independent patient populations identified associations involving 24 genes: genetic variants in two genes (ACYP2 and TPMT) were strongly (ie, odds ratios ≥3) and consistently (ie, replication in at least three independent populations) predictive of cisplatin-induced ototoxicity (119). Specifically, an ACYP2 variant was associated with ototoxicity in both children and adults, and TPMT variants were associated with ototoxicity in children.

Conclusions. Genetic variation in ACYP2 and TPMT may be helpful in predicting patients at the highest risk of developing cisplatin-induced ototoxicity. Further research (including replication studies considering diverse pediatric and adult patient populations) is required to determine whether genetic variation in additional genes may further help identify patients most at risk.

Another study found that hereditary insufficiency of the antioxidant defense system predisposes to severe cisplatin-induced ototoxicity (42). In 26 patients with head and neck cancer undergoing chemoradiotherapy with three cycles of cisplatin (100 mg/m2), ototoxicity presence was genetically associated with the GSTT1 null genotype and G-allele of NFE2L2 rs6721961, whereas ototoxicity absence was associated with the GSTM1 null genotype. Dose-dependent progression of hearing loss was the greatest in the combined genotype pattern of GSTT1 null and the T/G or G/G variants of rs6721961. Glutathione S-transferase (GST) theta 1 (GSTT1) is a member of a superfamily of proteins that catalyze the conjugation of reduced glutathione to a variety of electrophilic and hydrophobic compounds. The NFE2L2 gene (NFE2-like bZIP transcription factor 2) encodes a transcription factor, which is a member of a small family of basic leucine zipper (bZIP) proteins; the encoded transcription factor regulates genes that contain antioxidant response elements in their promoters, many of which encode proteins involved in response to injury and inflammation (including the production of free radicals). The GSTM1 gene (glutathione S-transferase mu 1) encodes a glutathione S-transferase that belongs to the mu class. The mu class of enzymes functions in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress, by conjugation with glutathione. Genetic variations in GSTM1 can change an individual's susceptibility to carcinogens and toxins as well as affect the efficacy and toxicity of some drugs. Null mutations of this gene increase susceptibility to some cancers, likely mediated by an increased susceptibility to environmental toxins and carcinogens.

Pathophysiology. Cisplatin enters the endolymph in the scala media through capillaries in the stria vascularis and is subsequently absorbed by the sensory hair cells in the organ of Corti (130).

Overview of the cochlear structure and the site of cisplatin absorption

This illustration depicts the anatomical structure of the cochlea, highlighting the various cell types vulnerable to cisplatin-induced damage. The cochlea consists of three fluid-filled compartments: the scala vestibuli and sca...

Although cisplatin binding to DNA is the major cytotoxic mechanism in proliferating cancer cells, nephrotoxicity and ototoxicity appear to result from toxic levels of reactive oxygen species and protein dysregulation within various cellular compartments. Several mechanisms, including oxidative stress, DNA damage, and inflammatory responses, are closely associated with cisplatin-induced ototoxicity (70; 130). Following its entry into the cochlea and uptake by cells, cisplatin induces an inflammatory response through various signaling pathways (130)

Proposed mechanism of cisplatin-induced cochlear inflammation

Following its entry into the cochlea and uptake by cells via either simple or facilitated diffusion, cisplatin induces an inflammatory response through various signaling pathways, including TLR4-NF-kappaB activation, TLR4-NF-κB...

Upregulation of proinflammatory mediators in the cochlea leads to the infiltration and activation of macrophages (130). A major contributor to cisplatin ototoxicity is the formation of reactive oxygen species in cochlear tissue, with resulting apoptotic cell death (48). The nicotinamide adenine dinucleotide phosphate oxidase 3 isoform (NOX3) is apparently the main source of reactive oxygen species in the cochlea. These reactive oxygen species trigger processes, such as lipid peroxidation of the plasma membrane and increases in expression of the transient vanilloid receptor potential 1 ion channel. Disturbance in intracellular levels of the cofactor nicotinamide adenine dinucleotide [NAD(+)] is critically involved in cisplatin-induced cochlear damage associated with oxidative stress, DNA damage, and inflammatory responses (70).

Long-term outcomes of platinum agent ototoxicity. Cisplatin causes high-frequency hearing loss, but speech perception tests (both in quiet and in background noise) in 101 individuals who received cisplatin-based chemotherapy for testicular cancer between 1980 and 1994 showed that the clinical relevance is limited for most patients—even 30 years after cisplatin-based chemotherapy (123). Few of these patients developed severe hearing loss requiring rehabilitation.

Otoprotective therapies with platinum agents. In an updated systematic review of randomized trials for the prevention of cisplatin-induced ototoxicity, an international, multidisciplinary panel of experts and patient advocates established several clinical practice guidelines (41):

(1) The panel made a strong recommendation for administration of systemic sodium thiosulfate in nonmetastatic hepatoblastoma, a weak recommendation for administration in other nonmetastatic cancers, and a weak recommendation against its routine use in metastatic cancers.
(2) Amifostine, sodium diethyldithiocarbamate, and intratympanic therapy should not be routinely used.
(3) Cisplatin infusion duration should not be altered to reduce ototoxicity.

Despite the clinical practice guideline advising against the routine use of intratympanic therapy, the role of transtympanic injection of N-acetylcysteine (NAC) is unclear and continues to be explored. Transtympanic injection of N-acetylcysteine (NAC) is a safe and effective otoprotective strategy for the prevention of cisplatin-induced ototoxicity and for increasing quality of life, especially in children. In a randomized, double-blind clinical trial study of 60 cisplatin-treated patients treated with either transtympanic injection of N-acetylcysteine (10%) or dexamethasone, no significant changes in auditory thresholds were recorded in the ears treated with N-acetylcysteine, whereas cisplatin induced a significant decrease of auditory thresholds at the 8000 Hz frequency band in the ears treated with dexamethasone (115).

In a systematic review, 19 randomized controlled trials and five quasi-experimental studies with collectively 1673 patients were analyzed (25). Six interventions (sodium thiosulphate, corticoids, sertraline, statins, multivitamins, and D-methionine) showed mild benefits in preventing cisplatin-induced ototoxicity. Sodium thiosulphate was deemed the most promising preventive strategy. Only one trial assessed corticoids as a potential treatment. Overall, only six trials were deemed to have a low risk of bias. Most of these studies inadequately documented intervention-related adverse effects, thereby limiting safety conclusions.

Neuroradiologic markers of platinum agent ototoxicity. In a cohort of 96 consecutive patients with lung cancer, labyrinthine enhancement was an imaging feature related to cisplatin ototoxicity: in particular, cisplatin cochleotoxicity was associated with cochlear enhancement, and vestibular impairment was associated with vestibular/semicircular enhancement on 3D black blood (3D-BB) images, which remained invisible on 3D-T1W images (135). Labyrinthine enhancement on 3D-BB images with normal signal intensity of the intralabyrinthine fluid is an imaging biomarker for cisplatin toxicity and should not be mistaken for intralabyrinthine metastases (135).

Chelator ototoxicity. Among transfusion-dependent patients with hemoglobinopathies, the ototoxicity incidence with deferoxamine (DFO) at doses below 50 mg/kg/day was 27%, whereas deferiprone and deferasirox were not associated with recognized ototoxicity.

Organic solvent ototoxicity. Ototoxicity is common in those exposed to organic solvents, with a significantly declining trend of inner ear deficits evident from the utricle to the saccule, cochlea, and semicircular canals among exposed individuals but not in nonexposed individuals (61).

Salicylate ototoxicity. Salicylates induce a transient subjective tinnitus and hearing loss characterized by a reduction in otoacoustic emissions, a moderate cochlear threshold shift, and a large reduction in the neural output of the cochlea (51; 113).

Quinine ototoxicity. The cinchona bark–derived antimalarial alkaloid quinine is ototoxic. Isolated and named in 1820 by the French scientists Pierre-Joseph Pelletier and Joseph-Bienaime Caventou, the first identified reference of quinine ototoxicity was in 1824 (121). Quinine was acknowledged as an ototoxic drug in the 19th century, and analogously to gentamicin, quinine was used in Meniere disease specifically for its ototoxic effects.

Glycopeptide antibiotic ototoxicity (eg, vancomycin). Glycopeptide antibiotics are composed of glycosylated cyclic or polycyclic nonribosomal peptides. Glycopeptide antibiotics include anti-infective medications (ie, vancomycin, teicoplanin, telavancin, ramoplanin, decaplanin, corbomycin, complestatin, and dalbavancin) and the antitumor antibiotic bleomycin. They inhibit the cell wall structure of susceptible organisms (principally Gram-positive cocci) by inhibiting peptidoglycan synthesis. Vancomycin is used if infection with methicillin-resistant Staphylococcus aureus (MRSA) is suspected.

A retrospective study of 89 patients who had baseline audiograms and follow-up audiograms after approximately 27 days of vancomycin therapy demonstrated a 12% risk of ototoxicity, which manifested as high-frequency hearing loss, particularly in older patients (39).

In a prospective cohort study of 742 consecutive cancer patients who received vancomycin at a comprehensive cancer center during a 3-month period, clinical evidence of ototoxicity developed in 6% of patients (95% CI, 4%–9%) who were receiving vancomycin plus other ototoxic agents and in only 3% of patients (95% CI, 2%–5%) not receiving other ototoxic agents (32).

Exposure to vancomycin in very-low-birthweight infants is associated with an increased, dose-dependent risk of pathological hearing test results at discharge and at 5 years of age (95).

Dalbavancin is a second-generation semisynthetic lipoglycopeptide antibiotic medication in the same class as vancomycin. Dalbavancin is also ototoxic (77). Patients on dalbavancin should be monitored for ototoxicity, especially when administering dalbavancin beyond approved dosing guidelines.

Audiograms after dalbavancin use in man with hearing loss

Audiograms of a 55-year-old man with a prosthetic shoulder infection who reported hearing loss (a) after four doses of dalbavancin and (b) at the 1-year follow-up visit. Circles represent the right ear, and crosses represent th...

Chloroquine, hydroxychloroquine, and ivermectin ototoxicity. Largely driven by political factors, chloroquine, hydroxychloroquine, and ivermectin were proposed as therapies for COVID-19, but subsequent controlled studies found no evidence of efficacy. Nevertheless, these agents have multiple potential adverse effects, including ototoxicity (cochleotoxicity) (108; 29; 90). Sensorineural hearing loss or tinnitus after chloroquine or hydroxychloroquine treatment can be temporary, but auditory and vestibular dysfunction may persist (108). In addition, abnormal cochleovestibular development in the newborn was reported after chloroquine treatment in pregnant women.

Macrolide antibiotic ototoxicity. Macrolide use is significantly associated with both prevalent and incident tinnitus (134); macrolide-associated tinnitus is likely cumulative dose-dependent.

Alpha-difluoromethylornithine (DFMO) ototoxicity. Alpha-difluoromethylornithine (DFMO) may help prevent and treat certain types of cancers, but it can result in some hearing loss even when administered at low doses, highlighting the importance of closely monitoring hearing thresholds in subjects taking DFMO (23).

Prevention

	• The ototoxic effects of some drugs may be improved or mitigated by stopping the offending agent.
	• Recognition of drug-induced hearing loss, tinnitus, or imbalance/vertigo is crucial to facilitate early intervention and prevent long-term damage, especially in high-risk patient groups, such as the elderly and hearing impaired.
	• Prospective monitoring for ototoxicity allows for early detection, potential alterations in therapy, and auditory intervention and rehabilitation to ameliorate the adverse consequences of hearing loss.
	• Although several potential otoprotective agents have been investigated in clinical trials, none have been approved by the U.S. Food and Drug Administration.
	• Whenever possible, the following precautions should be followed to prevent aminoglycoside ototoxicity: (1) Document preexisting hearing loss or vestibular dysfunction before prescribing vestibulotoxic or cochleotoxic medications; (2) Ensure correct dosing to avoid toxic concentrations; (3) Administer aminoglycosides for no longer than 1 week; (4) Avoid aminoglycosides in patients whose calculated creatinine clearance is less than 1.2 L/hr; (5) Avoid prescribing aminoglycosides with other nephrotoxic or ototoxic drugs; (6) Use extended dosing intervals; (7) Discontinue aminoglycosides when clinical vestibulotoxicity or ototoxicity is detected; and (8) Monitor peak and trough aminoglycoside levels and area under the concentration-time curve, and adjust dosing accordingly.

Available evidence suggests that the ototoxic effects of some drugs may be improved or mitigated by stopping the offending agent. Recognition of drug-induced hearing loss, tinnitus, or imbalance/vertigo is, therefore, crucial to facilitate early intervention and prevent long-term damage, especially in high-risk patient groups, such as the elderly and hearing impaired. Prospective monitoring for ototoxicity allows for early detection, potential alterations in therapy, and auditory intervention and rehabilitation to ameliorate the adverse consequences of hearing loss (75).

Although several potential otoprotective agents have been investigated in clinical trials, none have been approved by the U.S. Food and Drug Administration.

Prevention of aminoglycoside ototoxicity is often feasible with proper management of patients considered for, or receiving, aminoglycoside antibiotics. Whenever possible, the following precautions should be followed (19; 96; 132):

	• Document preexisting hearing loss or vestibular dysfunction before prescribing vestibulotoxic or cochleotoxic medications.
	• Ensure correct dosing to avoid toxic concentrations, particularly as some commonly used nomograms result in dosing errors (88).
	• Administer aminoglycosides for no longer than 1 week.
	• Avoid aminoglycosides in patients whose calculated creatinine clearance is less than 1.2 L/hr.
	• Avoid prescribing aminoglycosides with other nephrotoxic (eg, vancomycin, nonsteroidal anti-inflammatory drugs) or ototoxic drugs (eg, loop diuretics), and avoid other insults to the cochlea and vestibular labyrinth (eg, sustained exposure to higher levels of ambient sound) (66).
	• Use extended dosing intervals (ie, once daily, rather than multiple daily administration).
	• Discontinue aminoglycosides when clinical vestibulotoxicity or ototoxicity is detected.
	• Monitor peak and trough aminoglycoside levels and area under the concentration-time curve, and adjust dosing accordingly (11).

Mutations in the mitochondrial 12S ribosomal RNA (abbreviated as 12S or 12S rRNA) have been identified in a significant proportion (17%) of patients with aminoglycoside-induced ototoxicity. 12S rRNA is the small subunit ribosomal ribonucleic acid (SSU rRNA) of the mitochondrial ribosome. In humans, 12S is encoded by the MT-RNR1 gene; this can now be detected by DNA screening (36).

Many cases of aminoglycoside ototoxicity have a family history of aminoglycoside-induced ototoxicity, and bilateral vestibulopathy could have been prevented with an adequate clinical interview (36). Therefore, it is essential to obtain a family history of drug-induced ototoxicity in all patients before administering aminoglycosides. To prevent further cases within the family, sporadic patients with aminoglycoside-induced ototoxicity should be screened with molecular tests for the presence of known mutations (20).

The m.1555A > G and m.1494C > T mutations in the 12S ribosomal RNA gene contribute to aminoglycoside-induced hearing loss (146; 62). Various other genetic variants have been linked to an increased or decreased risk for ototoxicity with various agents, but available evidence is generally of low quality because study cohorts were small, and replication studies were either missing or contradictory (85).

As shown in a large cohort of preterm infants, mitochondrial mutation m.1555A>G is a risk factor for failed newborn hearing screening (49). Noninvasive prenatal testing of cell-free DNA obtained from maternal plasma can successfully detect mitochondrial DNA (mtDNA) mutations (ie, m.1555A > G and m.1494C > T mutations) in the 12 S ribosomal RNA gene that contribute to aminoglycoside-induced hearing loss (62).

Most familial cases received aminoglycoside antibiotics for a much shorter period and at a lower total dose than sporadic cases. In identified families, the inheritance pattern of aminoglycoside-antibiotic susceptibility to ototoxicity has matched that of a mitochondrially inherited trait (ie, with maternal transmission) (109). Therefore, maternal relatives in families with known familial aminoglycoside-induced deafness or vestibular dysfunction should also certainly avoid aminoglycosides (109). Mutations in a highly conserved region of the mitochondrial 12S rRNA gene have been identified in families with aminoglycoside-induced deafness. The mutation occurs in the region known to bind aminoglycosides. Aminoglycoside-resistance mutations in this region have also been identified in other species (109).

Aminoglycoside therapy should cease as soon as symptoms of either auditory or vestibular ototoxicity appear to avoid permanent impairment (53). If identified early, much of the symptomatic toxicity is reversible (139; 34; 14). Unfortunately, vestibulotoxicity is often not recognized before discharge from the hospital (53). This lack of identification occurs because many clinicians mistakenly believe that vestibulotoxicity does not occur in the absence of cochleotoxicity. Furthermore, many patients who receive aminoglycoside antibiotics are severely ill and bedridden; vestibulotoxic symptoms are often not clinically evident in such patients.

Differential diagnosis

Confusing conditions

Identified causes of bilateral vestibulopathy include vestibulotoxic drugs (particularly aminoglycoside antibiotics), Meniere syndrome, meningitis (bacterial or carcinomatous), aseptic meningoencephalitis, infectious labyrinthitis (bacterial including syphilitic, viral including measles, and fungal), bilateral vascular occlusion, autoimmune disease (Cogan syndrome), some neuropathies, neurofibromatosis, otosclerosis, head injury, bilateral cerebellopontine angle tumors, multisystem degeneration, cerebellar degenerations, and rare congenital or hereditary conditions. There have also been several reports of familial bilateral vestibulopathy, suggesting genetic predisposition (65).

Associated hearing loss occurs, particularly with otologic diseases (including Meniere syndrome), meningitis, and autoimmune disease (including Cogan syndrome) (147), but hearing can be normal in these conditions, even in the presence of significant bilateral vestibulopathy (01). With most causes, the dysfunction occurs insidiously or in a subacute fashion, though Meniere syndrome, viral labyrinthitis, and vascular occlusion may produce acute bilateral sequential labyrinthine dysfunction.

Chronic bilateral vestibulopathy resembles chronic cerebellar syndromes, such as alcoholic cerebellar degeneration affecting the anterior cerebellar vermis and late-onset sporadic cerebellar atrophy (Marie-Foix-Alajouanine syndrome). When cerebellar dysfunction occurs in isolation, there is no oscillopsia, and stance and gait do not commonly worsen in the dark as assessed with bedside evaluation. Some cerebellar degenerations, such as Friedreich ataxia, are associated with severe degeneration of dorsal columns and spinocerebellar tracts, further compounding the gait ataxia and, thus, producing a marked Romberg sign. In addition, some cerebellar syndromes, such as paraneoplastic cerebellar degeneration, may be associated with vestibular involvement. Multisystem degeneration may have features of cerebellar ataxia in combination with bilateral vestibulopathy, possibly with impairment of the visually enhanced vestibule-ocular reflex (doll's head reflex), downbeat nystagmus, and sensory peripheral neuropathy (147; 148; 128; 127). This condition has been labelled "cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome" or CANVAS (128).

The gait ataxia of bilateral posterior column dysfunction (as classically manifested by tabes dorsalis) can also be confused with that of bilateral vestibulopathy. The vestibulo-ocular reflexes are typically preserved with posterior column dysfunction, and oscillopsia is, therefore, absent.

Diagnostic workup

	• Laboratory testing should be directed at supporting and quantifying the clinical diagnosis; evaluating associated dysfunction, such as hearing; and identifying suspected etiologies.
	• Testing can include electronystagmography with bithermal caloric testing, rotational testing of the horizontal semicircular ducts, and posturography.

Laboratory testing should be directed at supporting and quantifying the clinical diagnosis; evaluating associated dysfunction, such as hearing; and identifying suspected etiologies.

Assessment of cochleotoxicity. Extended high-frequency (EHF) audiometry (9–16 kHz) is more sensitive than conventional pure tone audiometry (0.25–8 kHz) for the early detection of cochleotoxicity and should be included in monitoring programs (126).

Distortion product otoacoustic emissions (DPOAE) testing is a sensitive tool that can, for example, detect early cochleotoxicity from streptomycin much better than conventional pure tone audiometry (99). In a study of newly diagnosed patients treated with streptomycin, 63% had vertigo and 38% complained of tinnitus during the treatment period. DPOAE detected ototoxicity in 48% on day 7, 66% on day 14, 70% on day 28, and 77% at day 56 of streptomycin treatment, whereas hearing loss was detected by pure tone audiometry in only 2% on day 7, 11% on day 14, 22% on day 48, and 29% on day 56. The higher frequencies were more affected by ototoxicity.

Assessment of vestibulotoxicity. Head impulse testing is useful for early bedside detection of gentamicin vestibulotoxicity (141). Most patients with aminoglycoside vestibulotoxicity, even those with partial bilateral vestibular loss, have large overt saccades. Indeed, in one study, the cumulative amplitude of overt saccades after head impulses was 5.6 times larger in patients with gentamicin vestibulotoxicity than in normal subjects (141). Covert saccades, which can conceal the extent of bilateral vestibular loss, are only approximately half as frequent as in unilateral patients (141).

Testing of vestibulotoxicity can include electronystagmography with bithermal caloric testing, rotational testing of the horizontal semicircular ducts, and posturography (06; 71). In addition, tests of vertical semicircular ducts and otolith function are available in some vestibular laboratories (06). Caloric testing evaluates vestibulo-ocular reflexes corresponding to a low-frequency angular acceleration stimulus; therefore, results of caloric testing correlate most closely with low-frequency sinusoidal rotatory stimuli (07). Diminished or absent caloric responses alone do not establish a diagnosis of bilateral vestibulopathy; such responses can be impaired for physical reasons (impacted cerumen, narrow external auditory canals, and highly pneumatized temporal bones).

Rotary chair testing at several frequencies is helpful in confirming and quantifying bilateral vestibular dysfunction and should include stimuli corresponding to the higher frequency rotational head perturbations experienced during locomotion (0.5 Hz and higher) (131). Even when caloric responses are absent, responses to rotary stimuli may be normal or near normal with higher frequency rotatory testing (above 0.4 Hz) (07; 131). Both gain and time constant are reduced or absent in patients with bilateral vestibulopathy with impulsive rotatory testing. This can be better quantified with sinusoidal rotatory testing, which allows measurement of gain and phase of per rotatory eye movements at different frequencies. Partial bilateral vestibulopathy produces symmetrically decreased vestibulo-ocular reflex gain and increased phase lead at low frequencies (below 0.2 Hz) but normal gain and phase lead at higher frequencies (07). Patients with more severe bilateral vestibular impairment have dysfunction at all measured frequencies. With recovery of function, vestibulo-ocular high-frequency gains may recover to within normal limits, but time constants show only limited recovery and remain below the normal range (14). The early ocular response to random, high-acceleration yaw rotation of the whole body (ie, peak acceleration of 2800°/sec) may demonstrate profound deficits of semicircular canal and otolith function in patients with relatively mild abnormalities on standard sinusoidal rotation testing.

Posturography is abnormal in the vast majority of patients with bilateral vestibulopathy and typically shows vestibular or severe dysfunction patterns (131).

Many patients with bilateral vestibulopathy have some degree of sensorineural hearing loss that can be demonstrated with pure-tone audiometry and extended high-frequency audiometry.

Management

	• Patients with ototoxic bilateral vestibulopathy should avoid situations that exacerbate their dysfunction, such as walking in the dark or attempting to read while walking.
	• Patients should attempt to fixate on distant stable points when walking in the light and use contact cues in the dark.
	• Oscillopsia can be reduced if high-frequency oscillations are minimized or dampened during ambulation.
	• Limited anecdotal data suggest that vestibular rehabilitation therapy may improve oscillopsia, postural stability, strategies for maintaining posture, and dynamic stability during locomotion.
	• Poor results with vestibular rehabilitation (and in general with bilateral vestibulopathy) may result from more severe vestibular dysfunction, progressive vestibular dysfunction, and multiple medical problems.

Patients with ototoxic bilateral vestibulopathy should avoid situations that exacerbate their dysfunction, such as walking in the dark or attempting to read while walking (64; 58). Patients should attempt to fixate on distant stable points when walking in the light and use contact cues in the dark. Furthermore, oscillopsia can be reduced if high-frequency oscillations are minimized or dampened during ambulation (58).

There are few data on the efficacy of vestibular rehabilitation therapy in such patients (74; 103; 03; 47; 18). Limited anecdotal data suggest that vestibular rehabilitation therapy may improve oscillopsia, postural stability, strategies for maintaining posture, and dynamic stability during locomotion (74; 103; 03). Some patients benefit from an individualized vestibular exercise program with improved physical function and less self-perceived handicap, but no change has been demonstrated in the number of falls or the use of assistive devices (18). Poor results with vestibular rehabilitation (and in general with bilateral vestibulopathy) may result from more severe vestibular dysfunction, progressive vestibular dysfunction, and multiple medical problems (47). Further controlled studies of such therapy are needed in this group of patients.

Media

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Patient Profile

Age range of presentation: All ages
Sex preponderance: female>male, >1:1
Heredity: heredity may be a factor
Population groups selectively affected: None selectively affected
Occupation groups selectively affected: None selectively affected

ICD & OMIM codes

ICD-10: Ototoxicity, other and unspecified hearing loss: H91

Ototoxicity, other disorders of ear, not elsewhere classified: H93
ICD-11: Ototoxic hearing loss: AB53

Chronic bilateral vestibulopathy: AB32.5

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Ototoxicity

Also Relevant

Bilateral vestibulopathy
Disequilibrium
Vertigo

Clinical Categories

Neuro-Ophthalmology & Neuro-Otology

	• Family history of ototoxicity
	• High serum levels
	• Higher total dose
	• Longer duration of therapy (beyond 7 to 10 days)
	• Intrathecal administration
	• Previous exposure to ototoxins
	• Concomitant use of other nephrotoxic or ototoxic drugs, which may potentiate the ototoxicity of aminoglycosides (eg, vancomycin, loop diuretics, cis-platinum, metronidazole)
	• Renal impairment (calculated creatinine clearance greater than or equal to 1.2 L/h)
	• Fever
	• Older age

Ototoxicity

Ototoxicity

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Media

References

Contributors

Author

Patient Profile

ICD & OMIM codes

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Also in This Category

Giant cell arteritis

Ischemic optic neuropathy

Transient visual loss

Ophthalmic electrophysiology

Hyperventilation syndrome

Cortical blindness

Ophthalmic imaging

Orbital disease in neuro-ophthalmology

Ototoxicity

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Media

References

Contributors

Author

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Giant cell arteritis

Ischemic optic neuropathy

Transient visual loss

Ophthalmic electrophysiology

Hyperventilation syndrome

Cortical blindness

Ophthalmic imaging

Orbital disease in neuro-ophthalmology

This is an article preview.
Start a Free Account
to access the full version.