Presenter: Dr.

Amal Das
1 January 2010

The tendency of certain therapeutic
agents and other chemical substances to
cause functional impairment and cellular
degeneration of the tissues of the inner ear
and especially of the end organs and
neurons of the cochlear and vestibular
divisions of the VIII
th
cranial nerve.

Tinnitus
Initial symptomatic manifestation.
Usually high-pitched & continuous.

Objective hearing loss
Bilateral high frequency Sensorineural threshold shift.
If speech frequencies are spared, the high frequency loss
may become quite marked without the patients being
aware of it.
Eventually, the loss progresses to the middle & lower
frequencies.

Dysequillibrium is the usual manifestation
Ataxic gait
Stumble easily
Loose their balance when turning quickly.

Transient positional vertigo

Oscillopsia
Sensation that visible objects jump or bob around
with head movement, walking or riding a car.
Loss of Vestibulo-ocular reflex (VOR) function and
inability of subjects to successfully stabilize objects on
the retina.


Cumulative drug dose
Duration of treatment
Renal or Liver failure
Genetic susceptibility (Nucleotide 1555 A to G
substitution on the mt. 12S rRNA)
Extremes of age
Simultaneous administration of other ototoxic
agents.
Prolonged therapy
Bacteremia, Dehydration & Fever
Poor nutritional status
Initial ototoxic destruction of hearing cells
occurs well outside the speech system and
outside the normal active and passive head
movement range.
No generally accepted criteria for the
occurrence of ototoxicity in animal models or
clinically for humans.
Inadequate or too few control groups.
Lack of widely available standard tests capable
of assessing the Vestibulo-ocular & Vestibulo-
spinal functions in a hospital or other clinical
setting where ototoxic drugs are administered.
Aminoglycosides
Streptomycin, Gentamycin, Tobramycin, Netilmycin,
Amikacin
Diuretics Furosemide, Ethacrinic acid
Cytotoxic Drugs
Cisplatin, Cyclophosphomide
Others Salicylates, Quinine
Recreational Drugs Alcohol, Heroin, Tobacco, Cocaine
VESTIBULOTOXIC COCHLEOTOXIC
Gentamycin
Tobramycin
Streptomycin
Kanamycin
Amikacin
Neomycin
Electrostatic attraction to negatively charged
apical portion of hair cell.
Active endocytosis & Uptake by lysosymes.
Eventual rupture of lysosome, allowing cytosolic
distribution of drug.
Irreversibly binds to PIP2 & also alter membrane
permeability.
AG binds to Iron and this complex promotes
formation of free radicles.
Caspase mediated apoptosis.
Aminoglycoside-induced hearing loss begins
at the high frequencies.
The OHCs at base is more sensitive to
aminoglycosides than the apex.

Streptomycin decrease no. of otoliths on the otolith
membrane of utricle & saccule, as well as affects the structure
of the remaining otoconia.

Gentamycin has been implicated in the otoconial membrane
damage.

In the cochlea they damage the Outer Hair Cells
(OHCs) of the basal turn preferentially. This
damage extends apically and when all the outer
hair cells in any particular section of cochlea
are gone, then the inner hair cells start to die.
This IHC loss may well be due to damage to the
supporting cells.
In the vestibular system, hair cell loss first
occurs on the crest of the cristae and in the
striolar regions of the maculae, spreading
outwards as the damage progresses.
Near total loss of both inner and outer hair cells in the cochlea
Degeneration of neuro-epithelium of the crista
Reversible flat SN hearing loss.
Oedema of stria vascularis
Loss of Endocochlear Potential.
Inhibition of K+ pumps in the stria
vascularis
Indirect inhibition of Adenylate Cyclase
through an effect on the G protein complex
of the stria vascularis.
Increase endolymph Na+ conc. & Decrease
endolymph K+ conc. Will lead to decrease in
the endocochlear potential.
Marked vacuolization of Stria Vascularis
Ototoxic Synergism
If an aminoglycoside antibiotic given first and then a
loop diuretic, the drugs act synergistically, and the Organ
of Corti is severely damaged.

The aminoglycoside facilitates the loop diuretic to
penetrate into the cells in higher concentration, causing
more severe damage.
High frequency hearing loss
Greater importance in children with
increasing use in management of pediatric
solid tumors.
Affects children with a standard dose, of
which 1/3
rd
requires hearing aids.
Ototoxicity is possibly enhanced by
concurrent or prior cranial irradiation.
Unilateral hearing loss is more common
with low dose regimens, whereas bilateral
involvement is a predominant finding in the
high dose, short term regimen.
Some consonants & phonemes become
inaudible ( ee, dt, ks, f, th ) with loss of
speech comprehension corresponding to
that frequency.
Oxidative stress, via increased intracellular
production of reactive oxygen species (ROS)
and free radicals.

These interact with cell membrane
phospholipids to create aldehydic lipid
peroxidation products that promote
apoptosis.
Initial swelling of the Hensens cells &
protrusion of the Deiters cells into the space
of Nuel enclosing the outer hair cells.
Gradual degeneration of the OHC starting at
the base.
Collapse of Reisners Membrane & entire
Organ of Corti with variable damage to the
inner hair cells.
Total loss of outer hair cells in the basal turn of cochlea
PTA before and after treatment with Cisplatin
1. Diuretic inducing agents (Acetazolamide
pretreatment, hypertonic 3 % or 4.5 % NaCl
as vehicle for administration)
2. Sulfur nucleophiles
3. Metalloenzyme inhibitors and free O2
radical scavengers
4. Base transport inhibitors
5. Phosphonic acid antibiotics (fosfomycin)
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
Inhibition of Cyclooxygenase
Increased LTs Decreased PGs
Vasoconstriction & increased conductance of OHC
Decreased CoBF Decreased Turgidity & Electromotility
Clinically
High-pitched tinnitus
Reversible, symmetric SNHL affecting high frequencies
first (4,6 & 8 kHz) with a characteristic 4 kHz notch.
Occasional vertigo

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

Noise exposure has been reported to
increase susceptibility to drug induced
cochleotoxicity.
Kanamycin & Noise are synergistic.
Aspirin & Noise Additive/ Potentiating
effect
Proposed Mechanisms
Cochlear vasoconstriction
Significant increase in blood flow


Ischemia- reperfusion injury
Excessive glutamate
Reactive oxygen species (ROS) in hair cells;
Increased nitric oxide synthase activity may lead to the production of
high levels of nitric oxide and related free radicals;
Depletion of glutathione (GSH) may occur predominantly within OHCs.
Increases in intracellular calcium may occur in hair cells through a
variety of mechanisms.
Interspecies differences in the anatomy and physiology of
the RWM.

Prime Reasons:
RWM is much thicker.
RW is not exposed.
Overall, the extrapolation of results from animal studies to
humans from topical ototoxicity should be done with
caution
Rolands review of the current world literature in 1994
estimated the incidence of ototoxicity (as measured by
reports of hearing loss) from ototopical aminoglycoside
drops to be approximately 1 in 10,000 or lower.

Otolaryngol Clin N Am 40 (2007) 669683
The permeability of the RWM was also found to
increase approximately 48 hours after middle ear
infection was experimentally induced.
Conversely, in patients with CSOM, the RWM may
become thickened secondary to an immune response
and the deposition of connective tissue (including
mucosal web formation), which renders the
membrane less permeable during this chronic
inflammatory state.
Chloramphenicol
Evidence of ototoxicity in animals
Animal studies (chinchillas) have shown that this preparation has no toxic
effect on inner ear function but is irritating to middle ear mucosa.


Antifungal agents
Fungal external otitis remains a commonly encountered and difficult to treat
Not approved by USFDA for use in Otomycosis
In animal studies (guinea pigs), miconazole, clotrimazole, tolnaftate, and
nystatin have demonstrated no evidence of ototoxicity when used as topical
antimycotic agents.


Gentian violet
Used for years as a topical antifungal agent.
Has shown significant evidence of ototoxicity in animal studies.

Cresylate and VoSol (hydrocortisone and acetic acid, nonaqueous 2%)
Commonly used as ototopical agents in the treatment of otomycosis,
Demonstrated evidence of ototoxicity in animal studies

Chlorhexidine
Antiseptic used for skin preparation for surgery
Causes ototoxicity if introduced to the middle ear.

Acetic acid and preparations that contain acetic acid
Found to be toxic to isolated chinchilla cochlear outer hair cells.
Similarly, in chinchillas an otic solution that contained acetic acid was ototoxic, as
demonstrated by changes in compound action potentials after the medications was
instilled into the inner ear through the RWM.

Corticosteroids
Corticosteroids (hydrocortisone, dexamethasone) have been used in combination
ear drops for years because of their anti-inflammatory effects.
These agents, considered to be safe and effective, have been found to have a protective
effect on the cochlea and are used transtympanically to reverse hearing loss.
Iron chelators
Glutathione
Corticosteroids
Salicylates
Alpha lipoic acid
Glial cell linederived neurotrophic factor
Leupeptin
N-methyl-D-aspartate receptor antagonist
1. When possible, topical antibiotic preparations free of potential
ototoxicity should be preferred over ototopical agents that have the
potential for ototoxic injury if the middle ear and mastoid are open.
2. If used, potentially ototoxic antibiotic preparations should be used only in
infected ears. Use should be discontinued shortly after the infection has
resolved.
3. If potentially ototoxic antibiotics are prescribed for use in the open
middle ear or mastoid, the patient should be warned of the risk of
ototoxicity.
4. If potentially ototoxic antibiotics are prescribed, the patient should be
specifically instructed to call the physician or return to his or her office if
the patient develops the following:

a. Dizziness or vertigo
b. Hearing loss
c. Tinnitus

5. If the TM is known to be intact and the middle ear and mastoid are closed,
then the use of potentially ototoxic preparations presents no risk of
ototoxic injury.

Symptoms of vertigo, not hearing loss, may predominate in these
cases.
Safer and equally effective alternative ototopical agent
(fluoroquinolone drops) without risk.
Treatment with drops for prolonged periods of time (O7 days) or
multiple refills of potentially ototoxic drops, especially when the
otorrhea has ceased is not recommended.
Ophthalmologic drops that contain potentially ototoxic antibiotics
have no written or approved indication for use in the ear, and are
not approved by the USFDA.
Costs and availability are important issues.
Failure to provide the appropriate informed consent on the
potential for the aminoglycoside containing drops to result in
ototoxicity is emphasized.
Not always possible monitor inner ear
function in all patients receiving ototoxic
drugs.
Baseline Audiometric & Vestibular function
tests should be performed.
Measure peak & trough levels of drug
Refer to the drug company data sheets, so
that the dose can be titrated to remain
within therapeutic range.

Hearing aids in case of permanent hearing
loss.
Tinnitus masker in case of severe tinnitus
Cooksey Cawthorne vestibular
rehabilitation exercises in individuals having
disequilibrium & bobbing oscillopsia.
Rescue or blocking agents against adverse
effects of cisplatin.
In bed or sitting
Eye movements -- at first slow, then quick
up and down
from side to side
focusing on finger moving from 3 feet to 1 foot away from face
Head movements at first slow, then quick, later with eyes closed
bending forward and backward
turning from side to side.
Sitting
Eye movements and head movements as above
Shoulder shrugging and circling
Bending forward and picking up objects from the ground .
Standing
Eye, head and shoulder movements as before
Changing from sitting to standing position with eyes open and shut
Throwing a small ball from hand to hand (above eye level)
Throwing a ball from hand to hand under knee
Changing from sitting to standing and turning around in between
Moving about (in class)
Circle around centre person who will throw a large ball and to whom it will
be returned
Walk across room with eyes open and then closed
Walk up and down slope with eyes open and then closed
Walk up and down steps with eyes open and then closed
Any game involving stooping and stretching and aiming such as bowling and
basketball
Conventional audiometry
High frequency audiometry
Otoacoustic emissions
Hearing survey or checklists
Pediatric monitoring

Ear & Hearing 1994;15:232-239
OAEs are signals generated by the ear
spontaneously or in response to acoustic
stimulation.
On the basis of current available data, they
are generated in the cochlea, presumably
OHC.
Spontaneous OAE
Transient OAE
Distortion Product OAE
Both TOAE & DPOAE are used to identify SN
hearing loss.
TOAE are present normally, but are absent
when SNHL exceeds 30dB.
DPOAEs occur when 2 simultaneous signals
of different frequencies are presented to the
ear. The ear generates a third signal at
frequency of 2F1 - F2.

Advantage
Can be measured quickly, non-invasively and no
voluntary response from patient.

Precaution
Middle ear dysfunction has to be ruled out as it
disrupts the pathway of emission to the recording
microphone.
Insufficient human data exist to evaluate its clinical
efficacy in monitoring for ototoxicity.
Earliest ototoxic detection is possible.
Good test retest reliability
Can be done using currently available
equipment.
Can be recorded in the presence of more
severe SNHL.
Auditory Brainstem Response (ABR)
Visual Reinforcement Audiometry (VRA)
Play Audiometry
OAEs
Permanent increases in threshold at
particular frequencies correlate with the
loss of hair cells at appropriate locations of
cochlea.
Disadvantages
Require sedation
Difficult to pin-point the location of lesion.
Computer systems for signal analysis.
Costly and time consuming, especially if repeated.
Normal baseline could be monitored
reasonably well by monitoring at 3000 or
4000 Hz only
Should be done in conjunction with
Tympanometry, to check for OM.
High freq. audiometry with single frequency
follow up may prove useful.

Scott Browns Otorhinolaryngology - Sixth edition, Seventh edition
Ototoxicity - Otolaryngologic Clinics of North America October
1993
Ototoxicity of Ototopical Drops - An Update. Otolaryngologic
Clinics of North America 2007,40: 669683
Mechanisms of cisplatin ototoxicity and progress in otoprotection
- Leonard P. Rybak. Current Opinion in Otolaryngology & Head and
Neck Surgery 2007, 15:364369
Ototoxicity: mechanisms, protective agents, and monitoring
Current Opinion in Otolaryngology & Head and Neck Surgery
2000,8:436440
High Frequency Audiometric Monitoring Strategies for Early
Detection of Ototoxicity. Ear & Hearing 1994; 15: 232 -239

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