Ototoxicity Wobblers Reference

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Ototoxicity

by:Russell D. Briggs, M.D.
Arun K. Gadre, M.D.

Introduction

Definition

Damage to the cochlea or vestibular apparatus from exposure to a chemical source

Many sources

• Mercury
• Herbs
• Streptomycin (1944)
• Dihydrostreptomycin (1948)
• Gentamicin (1965)
• Others

Aminoglycosides

• Streptomycin, kanamycin, neomycin, amikacin, gentamicin, tobramycin, sisomycin, netilmicin
• Enter into inner ear by unknown mechanism
• Secreted into the perilymph by spiral ligament or endolymph by stria vascularis
• Diffuse through round window membrane
• Eliminated by kidney

Aminoglycosides

Cochlear toxicity

• Amikacin, kanamycin, neomycin, netilmicin

Vestibular toxicity

• Streptomycin, gentamicin, sisomycin

Can occur simultaneously

Aminoglycosides

Cochlear toxicity

• Increase of 10-20 dB in thresholds of one or more frequencies
• Incidence (6-13%), netilmicin lowest
• Risk factors
• Diuretics, renal failure, prolonged treatment, old age, preexisting SNHL
• Infants less affected, once daily dosing

Aminoglycosides

Cochlear toxicity

• Outer hair cell loss first in basal turn then to apex
• Inner hair cell loss later

Aminoglycosides

Cochlear toxicity presentation

• High frequency SNHL first, then lower frequencies to profound loss
• Not reversible
• Damage usually heralded by tinnitus

Aminoglycosides

Cochlear toxicity

• Can be familial form of nonsyndromic HL"€" maternal inheritance
• Associated with mtDNA 1555A to G point mutation in 12S ribosomal RNA gene"€" causes increased binding to ribosome

Aminoglycosides

Vestibular toxicity

• Assessment is difficult
• Dynamic posturography can detect
• Pathologically
• Type I hair cells more sensitive
• Cristae ampullaris then utricle and saccule
• Clinically (ambulatory vs. bedridden)
• Ataxic gait, lose balance when turning
• Bobbing oscillopsia

Aminoglycosides

Prevention

• Pharmacological
• Clinical
• Consider less ototoxic drugs (netilmicin)
• Identify "€œhigh-risk"€� patients
• Audiogram before and weekly after starting
• ENG prior if possible
• History and physical exam daily (Romberg, VA)
• Adjust doses or switch drugs if toxic

Macrolides

Discovered erythromycin 1952 (McGuire)

Mintz (1972) first report of ototoxicity

• Reversible 50-55 dB losses in two cases

Clinically

• Hearing loss with/without tinnitus"€" 2 days
• All frequencies, recovery after stopping
• Rarely permanent (hepatic)
• Incidence unknown

Macrolides

• Mechanism unknown
• Azithromycin and clarithromycin can cause similar findings in animals

Other antibiotics

Vancomycin

• Believed to be ototoxic (no data)

Penicillin, sulfonamides, cephalosporins

• May have topical toxicity in middle ear

Nucleoside analog reverse transcriptase inhibitors

• Poor study

Loop Diuretics

Ethacrinic acid, furosemide, bumetaside

Clinically (6-7%)

• Usually tinnitus, temporary and reversible SNHL, rare vertigo within minutes
• High doses can cause permanent SNHL
• Highest risk"€" coadministration of aminoglycosides

Loop Diuretics

Pathologically

• Edema of stria vascularis
• Ionic gradient changes
• Inhibition of adenylate cyclase and G-proteins

Salicylates and NSAIDS

Most common OTC drugs in US

Mechanism

• Normal histology (no hair cell loss)
• Decreased blood flow, decreased enzymes

Clinically

• Tonal, high frequency tinnitus (7-9 kHz)
• Reversible mild to moderate SNHL (usually high frequency)"€" rarely permanent

Salicylates and NSAIDs

Quinine

• Similar clinical findings with aspirin
• Usage up for leg cramps
• Clinically
• High-pitched tinnitus
• Reversible, symmetric SNHL
• Occasional vertigo

Mechanism

• Decreased perfusion, direct damage to outer hair cells, biochemical alterations

Antineoplastic Agents

Cisplatin

• Incidence is high (62%-81%)
• Pathologically
• Outer hair cell degeneration
• Clinically
• Bilateral symmetric SNHL, usually high frequency"€" not reversible, cumulative
• Risks factors"€" age extremes, cranial irradiation, high dose therapy, high cumulative dose

Antineoplastic Drugs

Cisplatin

• Prevention
• Probenecid, WR 2721, DDTC, diuretics, calcium supplements"€" not effective
• L-N-acetyl-cysteine"€" protective in vitro

Topical Antimicrobials

Commonly prescribed for otorrhea after tubes and CSOM

Controversial subject

• Agents may enter middle ear and gain access to membranous labyrinth
• Animal testing reveals irrefutable evidence of severe ototoxicity

Topical Antimicrobials

Polymixin B (Brummett)

Chloramphenicol (Patterson)

Neomycin (Brummett)

Gentamicin (Webster)

Ticarcillin (Jakob)

Vasocidin (Brown)

Ciprofloxacin (Lenarz)

Topical Antimicrobials

Differences in humans

• Round window is not exposed
• Round window thicker
• Mucosal membrane protective
• Mucosal edema with or without exudates typically present
• Widespread usage with few side effects
• One in ten thousand

Topical Antimicrobials

Remains a possibility in humans

Patient education important

Prescribe for only necessary duration

Avoid in healthy ear

Caution with prexisting vestibular defects

This page created and maintained by Dave Palmer

Dave