Ototoxicity – Drug induced hearing loss

Ototoxicity is a chemical injury to the labyrinth occurring as a side effect of pharmacotherapy. An ototoxic insult may affect hearing, vestibular functions or both.

Types of ototoxicity

1. Reversible / Temporary – Mostly caused by salicylates, loop diuretics
2. Non-reversible / Permanent – Caused by Aminoglycosides and Cisplatin.

Common drugs associated with Ototoxicity

Temporary Ototoxicity

Loop diuretics

• Furosemide, Ethacrynic acid
• Usually reversible hearing loss, flat SNHL. But rarely permanent profound loss can happen.
• Mechanism of action
  • Edema of stria vascularis causing a loss of endocochlear potential by affecting Na/2Cl/K transporter.
  • Ethacrynic acid causes impaired blood flow in the lateral wall of the cochlea causing ischemia followed by reperfusion injury leading to generation of reactive oxygen species (ROS).
• Ototoxicity can be reduced by infusing drug at a rate less than 15mg/min.

Salicylates

• Used in treatment of rheumatoid arthritis.
• Clinical presentation
  • Reversible tinnitus, flat SNHL, nausea and transient vomiting.
  • Tinnitus is the most common and early side effect of salicylate.
• Mechanism of action
  • No significant hair cell damage, injury to the stria vascularis, spiral ganglion cells or myelin sheath of the eighth cranial nerve has been shown.
  • Effect on ionic conductance through outer hair cells at enzymatic level.
  • Causes tinnitus by activation of N-methyl-d-aspartate (NMDA) receptors in the cochlea.
  • Interestingly the regular dose of salicylate actually protects the cochlea against ototoxicity due to its radical scavenging / metal chelator action.

Quinine (Cinchonism)

• Used as an antimalarial, in SLE and Rheumatoid arthritis.
• Clinical presentation
  • Reversible SNHL, Tinnitus associated with nausea and vomiting.
  • Prolonged treatment causes permanent SNHL
  • Congenital deafness and hypoplasia of cochlea in infants whose mothers received this drug during first trimester.
• Mechanism of action
  • Selectively affects motility of outer hair cells
  • Causes vasoconstriction in small vessels of cochlea and stria vascularis.

Deferoxamine (Desferrioxamine)

• Used as an iron chelating substance in treatment of Thalassemia.
• Clinical features
  • Sudden or Delayed high frequency sensory neural hearing loss.
  • Usually permanent, but reversible in some cases when drug is discontinued.
• Mechanism of action
  • At level of outer hair cells

Erythromycin

• Causes Transient ototoxicity when used in high doses systemically.
• Clinical presentation
  • Reversible hearing loss (usually in elderly, renal / hepatic failure)
  • Decreases TEOAE
• Mechanism of action
  • At level of outer hair cells

Other drugs causing temporary ototoxicity

Following are some of the drugs that causes temporary / reversible ototoxicity – Vancomycin, Arsenic, Chlorhexidine, Chloramphenicol, Bromide, Mercury, Vincristine & Vinblastine. But only anecdotal evidences exist on ototoxicity of these.

Aminoglycoside induced ototoxicity

Aminoglycosides are group of antibiotics commonly used in neonatal sepsis and in MDR Tuberculosis. Aminoglycoside toxicity may occur following either systemic or topical administration. It can also occur following peritoneal dialysis.

Aminoglycoside associated ototoxicity develops once a threshold level is exceeded. But this threshold varies between individuals. Overall cochleotoxicity of aminoglycoside is 20% and vestibulotoxicity is 15%.

Mechanism of Action

• Aminoglycosides bind permanently to cell membrane and are actively transported into cell where they act primarily by binding to phosphatidyl-inositol bisphosphonate (a 2nd messenger involved in maintenance of membrane integrity).
• Binding of aminoglycosides with iron molecules generates free radicals causing oxidative stress of cells and eventually apoptosis.
• Aminoglycosides also blocks polyamine synthesis, which is essential for cellular growth, metabolism, repair and regeneration.
• The target of aminoglycoside associated ototoxicity is – Sensory neuroepithelium of inner ear.
  • Cochlea – Outer hair cells are more susceptible than inner hair cells. Loss of cochlear hair cells leads to secondary degeneration of auditory nerves.
    • Basal turns of cochlea are more extensively injured (at low doses) than apical turns (high doses) – Cochleotopic gradient presenting as high frequency hearing loss progressing to low frequency hearing loss.
    • Derangement of sensory hair cells resulting in hair fusion, creating deformed or so called ‘giant hairs’. The cell bodies change in shape and structure and are often filled with vacuoles and degenerating mitochondria. Eventually sensory hair cells dies and scar tissue formation happens.
    • Progressive destruction of spiral ganglion cells.
    • Thinning of stria vascularis.
  • Semi Circular Canals – Crista ampulli are more sensitive than utricle and saccule.
  • Utricle & Saccule – Type I hair cells are more susceptible than type II

Genetic susceptibility to aminoglycoside ototoxicity

There exists a genetic susceptibility to aminoglycoside ototoxicity.  This is seen in 0.5% of Caucasian population (Chinese, Japanese, Arab, Israeli and North American).

17% of patients with aminoglycoside toxicity have genetic mutation. The expression is maternally transmitted, non-syndromic (mitochondrial). The mutation is an A to G substitution in mitochondrial 12SrRNA at 1555 locus. In such patients, sudden sensory neural hearing loss can result even with a short duration of treatment / even a single dose aminoglycoside administered systemically / topically.

Those patients with protective antioxidant genes show protection against aminoglycoside ototoxicity.

Relative toxicity of Aminoglycosides

All aminoglycosides carry significant risk of toxicity. Randomized control trials have not revealed significant differences in ototoxicity when comparing individual aminoglycosides, though studies have shown that incidence of ototoxicity is highest with neomycin. Some studies shows that Netilmicin is less toxic than others. Gentamicin is more vestibulotoxic than cochleotoxic (10% cases cause SNHL).

Risk factors for Aminoglycosides induced ototoxicity

• • The cumulative drug dose,
  • Duration of treatment,
  • Associated bacteremia and renal / liver failure,
  • Poor metabolic reserve (in old / seriously ill patients),

• Nutritional status (less antioxidants cause more toxicity),
• Administration of drug in combination with potentiators
  • Use of Loop diuretics (ethacrynic acid, furosemide) increases permeability of strial blood vessels causing increased concentration of aminoglycosides with in scala media.
  • A permanent hearing loss can result even with a single dose of ethacrynic acid / mannitol administered together with Kanamycin.
• Genetic susceptibility.

Clinical presentation

Aminoglycoside associated autotoxicity will present as bilaterally symmetrical, gradually progressive and permanent hearing loss. Patients will have gait ataxia, oscillopsia, unsteadiness, dependence on visual fixation to maintain equilibrium (manifested as acute disorientation in dark).

Ototoxic injury and hearing loss may continue to progress for weeks even after stopping treatment, probably due to long half-life of aminoglycosides in cochlear tissues. Hence it may even present as delayed toxicity, 1 to 3 weeks after cessation on therapy.

Avoidance of aminoglycoside induced ototoxicity

Aminoglycoside induced ototoxicity can be avoided by

• Doing investigations like – Genetic testing, Renal and Liver function tests prior to drug administration
• Dose adjustment in renal / hepatic failure.
• Measurement of serum aminoglycoside concentration.
• From 18-20 weeks of gestation (after onset of cochlear function) fetus is susceptible to aminoglycoside toxicity, hence to be avoided in pregnant ladies.
• Premature babies treated in NICU are at higher risk than normal babies.
• Once daily dose is preferred over divided doses due to increased chemotherapeutic efficacy and reduced nephrotoxicity.
• Once ototoxicity develops, further dose should be withheld until serum level of aminoglycosides have fallen to low levels.
• Monitoring high frequency hearing can be used as a screening.
• N-Acetyl Cysteine administration is recommended to all end-stage kidney disease patients receiving an aminoglycoside.
• Less ototoxic forms of aminoglycosides may also be useful in preventing ototoxicity. An animal study of an aminoglycoside congener (N1MS) has demonstrated excellent activity against Escherichia coli, Klebsiella pneumoniae, and extended-spectrum B-lactamases while preserving hair cells and hearing relative to its parent compound. Similar results were found with gentamicin C1a, a congener of commercial gentamicin, and apramycin, an aminoglycoside used in veterinarian medicine.

Prognosis

• Mammalian vestibular cells can regenerate – some patients shows recovery over periods up to 12 months.

Cisplatin (Cis-Diammine Cichloroplatinum II) induced ototoxicity.

Cisplatin is a chemotherapeutic agent used for treating solid head and neck malignancies. Its therapeutic efficacy is limited by its ototoxicity.

Mechanism of action

• Cisplatin causes oxidative stress via an increased intracellular production of reactive oxygen species (ROS) and free radicals causing apoptosis.
• Semicircular Crista Ampulla are more susceptible to damage than utricle.
• Cisplatin selectively affects inner hair cell function, effectively removing transduction process, including release of neurotransmitters.

Risk factors

The risk factors include cumulative dose of the drug administered, history of previous noise exposure, associated renal / liver dysfunction etc. Incidence and severity of ototoxicity is increased in those patients who receive cranial irradiation also.

Presentation

Clinical presentation is bilateral symmetric, gradually progressive high frequency SNHL. Mammalian vestibule appears to be less sensitive to cisplatin than aminoglycoside toxicity.

Avoidance

Extend of cisplatin ototoxicity depends on cumulative dose. Transient tinnitus & hearing loss are observed when cumulative dose is greater than 200mg/m2. Temporary vestibulotoxicity on doses greater than 400mg/m2. Concurrent administration of antioxidants – N-acetylcysteine, a-tocopherol, lipoic acid, sodium thiosulfate, salicylate, ebselen, D-methionine, and amifostine etc can reduce ototoxicity.

Ultra-high frequency audiometry / OAE helps in screening.

Though cisplatin causes permanent hearing loss, there are case reports of spontaneous recovery also reported in Cisplatin induced SSNHL.

Management of Ototoxicity

Recognition of at-risk groups

• Patient symptoms – Tinnitus and / or reduced hearing, imbalance, gait ataxia, oscillopsia etc. should warn the treating physician about development of ototoxicity.
• Genetic screening before aminoglycoside administration can be considered. Genetic counselling of family members (Family members should be screened for SNHL).
• Reduce drug dosage especially in patients with renal / hepatic failure
• Close monitoring
  • Auditory monitoring
    • It is advisable to consider most of auditory symptoms to be consistent with, but not pathognomic of ototoxicity.
    • Objective audiometry is mandatory in all patients (especially symptomatic and in children)
    • Because of cochleotopic gradient of sensitivity for drugs (aminoglycosides & cisplatin), early cochleotoxicity can be recognized by ultrahigh frequency (12Khz) SNHL progressing to lower frequency SNHL.
    • OAE is more sensitive at detecting auditory dysfunction than high frequency PTA during treatment with aminoglycosides / cisplatin.
      • DPOAE are more sensitive than TEOAE for detecting early signs of ototoxicity.
    • If high frequency SNHL is detected, patient’s chemotherapeutic regime should be modified / stopped.
  • Vestibular monitoring
    • No consensus on best way of vestibular function screening.
    • ENG & rotational chair test have been used to detect early toxicity, but limited data only available.
• Prior administration of protective agents before use of ototoxic agents can lower the risk.
• Co-administration of antioxidants or iron chelators
• Those patients in whom permanent hearing loss occurs
  • Hearing aids / Cochlear implants should be considered.
  • Reassess hearing after several months because of chance of improvement.
• Vestibular toxicity
  • Vestibular rehabilitation exercises should be advised for patients with symptoms suggestive of vestibular toxicity.
• Perinatal exposure
  • Parental counselling
  • Age appropriate hearing screening of infant – Behavior audiometry, OAE, BERA
  • Long term follow up should be done in such kids.

Summary of Ototoxic drugs