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 VIIIth 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

substitution on the mt. 12S rRNA) Extremes of age Simultaneous administration of other ototoxic agents. Prolonged therapy Bacteremia, Dehydration & Fever Poor nutritional status

1555 A to G

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 & Vestibulospinal functions in a hospital or other clinical setting where ototoxic drugs are administered.

Aminoglycosides

Streptomycin, Gentamycin, Tobramycin, Netilmycin, Amikacin Furosemide, Ethacrinic acid

DiureticsCytotoxic Drugs Others Recreational Drugs

Cisplatin, Cyclophosphomide Salicylates, Quinine Alcohol, Heroin, Tobacco, Cocaine

VESTIBULOTOXICGentamycin Tobramycin

COCHLEOTOXICKanamycin Amikacin

Streptomycin

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 SynergismIf 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 1/3rd 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. interact with cell membrane phospholipids to create aldehydic lipid peroxidation products that promote apoptosis.

These

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.

2. 3. 4. 5.

Diuretic inducing agents (Acetazolamide pretreatment, hypertonic 3 % or 4.5 % NaCl as vehicle for administration) Sulfur nucleophiles Metalloenzyme inhibitors and free O2 radical scavengers Base transport inhibitors 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 effectProposed 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.

2.

3.

4.

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. If used, potentially ototoxic antibiotic preparations should be used only in infected ears. Use should be discontinued shortly after the infection has resolved. 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. 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 up and down from side to side focusing on finger moving from 3 feet to 1 foot away from face

Eye movements -- at first slow, then quick

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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