Ototoxicity

1. Ototoxicity Russell D. Briggs, M.D. Arun K. Gadre, M.D.

2. 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 Mercury used for treatment of syphilis– vertigo, deafness, tremors First clinical trial revealed irreversible deafness and disturbances of balance– bobbing oscillopsia Dihydrostreptomycin 1948– much more toxic to cochlear hair cellsMercury used for treatment of syphilis– vertigo, deafness, tremors First clinical trial revealed irreversible deafness and disturbances of balance– bobbing oscillopsia Dihydrostreptomycin 1948– much more toxic to cochlear hair cells

3. 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 Can be administered several ways– all of which can produce significant ototoxicity-- parentally, topically, intratympanically, intrathecally, orally Can be administered several ways– all of which can produce significant ototoxicity-- parentally, topically, intratympanically, intrathecally, orally

4. Aminoglycosides Cochlear toxicity Amikacin, kanamycin, neomycin, netilmicin Vestibular toxicity Streptomycin, gentamicin, sisomycin Can occur simultaneously

5. 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

6. Aminoglycosides Cochlear toxicity Outer hair cell loss first in basal turn then to apex Inner hair cell loss later

7. Aminoglycosides Pictures of histologyPictures of histology

8. Aminoglycosides Cochlear toxicity presentation High frequency SNHL first, then lower frequencies to profound loss Not reversible Damage usually heralded by tinnitus

9. 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

10. 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

11. Aminoglycosides

12. Aminoglycosides Prevention Pharmacological Clinical Consider less ototoxic drugs (netilmicin) Identify “high-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

13. 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

14. Macrolides Mechanism unknown Azithromycin and clarithromycin can cause similar findings in animals

15. 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

16. 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

17. Loop Diuretics Pathologically Edema of stria vascularis Ionic gradient changes Inhibition of adenylate cyclase and G-proteins

18. 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

19. Salicylates and NSAIDs

20. 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

21. 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

22. Antineoplastic Drugs

23. Antineoplastic Drugs Cisplatin Prevention Probenecid, WR 2721, DDTC, diuretics, calcium supplements– not effective L-N-acetyl-cysteine– protective in vitro

24. 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

25. Topical Antimicrobials Polymixin B (Brummett) Chloramphenicol (Patterson) Neomycin (Brummett) Gentamicin (Webster) Ticarcillin (Jakob) Vasocidin (Brown) Ciprofloxacin (Lenarz)

26. 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

27. Topical Antimicrobials Remains a possibility in humans Patient education important Prescribe for only necessary duration Avoid in healthy ear Caution with prexisting vestibular defects

28. Case Presentation 68 yowf presents to clinic with complaint of “ringing in my ears”

29. Case Presentation 68 yowf presents to clinic with complaint of “ringing in my ears” Described as high pitched in both ears, onset was 5 days prior and worsening, not able to sleep

30. Case Presentation 68 yowf presents to clinic with complaint of “ringing in my ears” Described as high pitched in both ears, onset was 5 days prior and worsening, not able to sleep Long history of mild hearing loss, now worsening also Denies vertigo or dysequilibrium

31. Case Presentation Has prior history of significant noise exposure (worked in factory) No recent or prior antibiotic use No prior otologic history except mild HL

32. Case Presentation PMH: HTN (controlled with medications), CRI (“no change”- creatinine 2.0) PSH: none

33. Case Presentation PMH: HTN (controlled with medications), CRI (“no change”- creatinine 2.0), arthritis, back pain PSH: none Medications: clonidine tid, lasix bid, vitamins qd, aspirin qid, ibuprofen prn

34. Case Presentation PMH: HTN (controlled with medications), CRI (“no change”- creatinine 2.0), arthritis, back pain PSH: none Medications: clonidine tid, lasix bid, vitamins qd, aspirin qid, ibuprofen prn SH/FH: noncontributory

35. Case Presentation PMH: HTN (controlled with medications), CRI (“no change”- creatinine 2.0), arthritis, back pain PSH: none Medications: clonidine tid, vitamins qd, aspirin qid, ibuprofen prn SH/FH: noncontributory ROS: leg swelling worsening, DOE, anterior neck pain, arthritis worsening

36. Case Presentation PE: H/N normal except ?left TVC paresis on IDL, tender nodules on pinna Neurologic exam normal Remainder exam normal except decreased ROM fingers, tender proximal joints

37. Case Presentation Labs: CBC normal, Cr=3.5, remainder nl

38. Case Presentation Labs: CBC normal, Cr=3.5, remainder nl Rheumatoid factor positive

39. Case Presentation Labs: CBC normal, Cr=3.5, remainder nl Rheumatoid factor positive

40. Case Presentation Labs: CBC normal, Cr=3.5, remainder nl Rheumatoid factor positive Salicylate level 20

41. Case Presentation Labs: CBC normal, Cr=3.5, remainder nl Rheumatoid factor positive Salicylate level 20