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Aminoglycoside Ototoxicity: The Need to Consider More Than Auditory Status

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Title: Aminoglycoside Ototoxicity: The Need to Consider More Than Auditory Status


1
Aminoglycoside Ototoxicity The Need to Consider
More Than Auditory Status
  • Jaynee A. Handelsman, Ph.D.
  • ASHA Convention
  • November 20, 2008

2
Ototoxicity
  • Damage to the inner ear from toxic agents
  • Negative consequence of the availability and use
    of medications that prolong life through
    treatment of serious infections and cancer
  • Chemotherapy agents
  • Antibiotics
  • Result is damage to cochlear and/or the
    vestibular end organs
  • Evidence suggests that there are no safe levels

3
Session Objectives
  • Discuss clinical features of auditory and
    vestibular system damage
  • Discuss the challenges involved in monitoring for
    auditory and vestibular system changes
  • Discuss our experience in monitoring patients
    with CF during aminoglycoside exposure
  • Propose guidelines for monitoring auditory and
    vestibular function during and following exposure

4
Factors Determining Individual Ototoxicity
  • Individual tolerance including genetic
    predisposition
  • Impaired renal function
  • Hyperthermia
  • Prior or concomitant exposure to other ototoxic
    agents
  • Dosing strategy perhaps, although recent evidence
    suggests this might not be the case
  • Age

5
Aminoglycosides
  • Selective cochlear and/or vestibular toxic agents
  • Readily absorbed from intramuscular and
    subcutaneous sites poorly absorbed from
    intestinal tract
  • From blood, about 50 is excreted unchanged in
    24 hours
  • With renal insufficiency, blood levels may remain
    high for many days
  • Distributed to all extra-cellular fluids (e.g.
    endolymph and perilymph)

6
Mechanisms of Ototoxicity
  • It appears that ototoxicity is not caused by
    accumulation of the substance in the ear
  • Rather, it appears to be caused by the drugs
    penetration into compartments from which the
    half-life of distribution is extremely long
  • Likely results from rapid uptake, early
    saturation, and long exposure of the inner-ear
    tissues to the drug

7
Clinical Features of Ototoxicity on Audition
  • Tinnitus
  • Hearing loss
  • Difficulty understanding speech in noise
  • Sensorineural, usually bilateral, symmetric
  • Progresses from high to low frequencies
  • Symptoms can be delayed days, months
  • Usually permanent but some recovery may occur

8
Clinical Features of Ototoxicity on Vestibular
Function
  • Acute bilateral vestibular loss
  • Ataxia of stance
  • Ataxia of gait
  • Saccadic eye movements with rapid head turns
  • Changes in visual acuity with head shaking or
    nodding
  • Acute unilateral vestibular loss
  • Vertigo, nausea, unsteadiness
  • May have changes in visual acuity with head
    movement

9
Onset May be Acute or Insidious
  • dramatic onset of severe imbalance and loss of
    orientation in space
  • vertigo
  • illusion of tilting
  • slowly increasing unsteadiness of gait and
    imbalance
  • oscillopsia
  • frequent use of contact cues in darkness or when
    walking on uneven ground

10
Definition of Symptoms
  • Oscillopsia an illusory movement of viewed
    stationary objects or surrounds occurring with
    head movement
  • Gait ataxia uncoordinated wide-based gait that
    is commonly associated with a variety of
    disorders including cerebellar disease and
    bilateral peripheral vestibular loss

11
Vestibular System is Responsible for Sensing and
Controlling Motion
  • Receptors located within the labyrinth of each
    inner ear transduce information about angular and
    linear acceleration as well as gravity
  • Information combined with visual and
    somatosensory signals on neurons in vestibular
    nuclei
  • Integration of sensory signals produces
    information required to control vestibulo-ocular
    reflex (VOR) and the vestibulo-spinal reflex (VSR)

12
Responsibilities of VOR and VSR
  • VOR facilitates maintenance of binocular
    fixation, thereby stabilizing gaze during rapid,
    short-duration head movements
  • Reflexes move the eyes in the correct direction
    and by the precise angle required to offset the
    effects of head movements
  • VSR enables person to maintain desired head and
    body positions with respect to gravity, even
    following imposed movement of the head or trunk

13
Explanation of Symptoms
  • Oscillopsia is a direct result of the loss of the
    VOR, which is responsible for maintaining foveal
    vision when the head is moving, especially at
    relatively high speeds
  • Quick movements of the head are associated with
    saccadic gaze readjustments rather than smooth
    compensatory eye movements
  • Ataxic gait is due to loss of vestibular input
    and the need to rely on visual and proprioceptive
    information for maintenance of postural control

14
Challenges - Audition
  • Complaints of ototoxic damage on hearing are
    uncommon until communication problem becomes
    significant
  • How much change at how many frequencies is
    significant
  • Difficult to predict ototoxic damage
  • Relationship to drug dosage, peak serum levels,
    and other toxicities is variable

15
Challenges - Vestibular
  • The symptoms of vestibular loss are not
    appreciated by physicians
  • Belief among many that monitoring blood levels
    and using safe levels will prevent loss
  • When ototoxicity follows a long illness, symptoms
    may be attributed to deconditioning
  • There are no accepted protocols for monitoring
    function

16
Factors Determining Oscillopsia in Bilateral
Vestibular Loss
  • Age at onset
  • Severity of semicircular canal dysfunction
  • Extent of otolithic dysfunction
  • Individual compensatory faculties

17
Evaluation Protocol for Ototoxicity Things to
Consider
  • Define the purpose of the monitoring protocol
  • Define the target population
  • Create a referral base by communicating with
    physicians
  • Select the monitoring tools
  • Test schedule
  • Definition of significant change
  • Communicate results
  • Education, Counseling, and Rehabilitation

18
Purpose of Monitoring
  • Early Identification and Prevention
  • Should we care about early changes enough to
    take the time to measure them?

19
Rationale for Monitoring Hearing
  • Hearing loss within 2 to 9 kHz range is
    clinically significant for children
  • Some impact of high frequency loss on speech
    understanding, even in adults
  • The use of amplification to remediate hearing
    loss above 5 kHz is problematic
  • Continued damage may affect more of the critical
    speech frequencies

20
Reasons to Monitor Cochlear and Vestibular
Function
  • Cochlear function is affected by almost all
    aminoglycosides
  • Even slight ototoxic cochlear dysfunction is
    noticeable, particularly via high frequency
    audiometry and otoacoustic emissions
  • Slowly progressive vestibular dysfunction may go
    undetected for some time
  • Vestibular ototoxicity is variable in terms of
    onset and progression

21
Benefits of Monitoring
  • Early detection may prevent hearing damage that
    requires amplification/rehabilitation
  • If change observed, treatment modification can
    prevent further hearing loss
  • If no change observed, continued treatment is
    warranted
  • Provides an opportunity for counseling and
    rehabilitation during and post treatment
  • It is the basis for informed medical decision
    making

22
Target Patient Population
  • Receiving highly ototoxic drugs
  • Very old and very young people
  • Poor medical condition
  • Poor renal function
  • Poor hydration status
  • Familial tendency for susceptibility
    (aminoglycoside antibiotics)
  • Receiving more than one ototoxic drug
  • Receiving large or multiple doses

23
At- Risk Populations
  • Diabetic patients may be more profoundly affected
    by bilateral vestibular loss due to concurrent
    loss of vision and proprioception
  • Renal patients are more susceptible to
    aminoglycoside ototoxicity because drugs are
    metabolized by the kidneys
  • Dialysis patients are frequently at increased
    risk of infection, and may be more likely to have
    repeated exposure to aminoglycosides
  • Patients with cystic fibrosis are frequently
    treated with aminoglycosides

24
Incidence is Difficult to Define
  • Patient population differences
  • Different risk factors
  • Methodological differences
  • Established baseline
  • No standard monitoring techniques
  • Criteria
  • Frequency range tested for hearing change

25
Ototoxic Medications
  • Antineoplastic Agents
  • Cisplatin
  • Carboplatin
  • Vinblastine
  • Vincristine
  • Vinorelbine
  • Difluoromethylornithine (DFMO)
  • Nitrogen mustard
  • Methotrexate
  • Dactinomycin
  • Bleomycin
  • Loop diuretics
  • Furosemide
  • Ethacrynic acid
  • Bumetanide
  • Torsemide
  • Limited evidence of ototoxicity

26
Ototoxic Medications
  • Aminoglycosides
  • Gentamicin
  • Sisomicin
  • Kanamycin
  • Neomycin
  • Paromomycin
  • Tobramycin
  • Streptomycin
  • Amikacin
  • Dibekacin
  • Netilimicin
  • Other Antibiotics
  • vancomycin

27
Most Vestibulotoxic Aminoglycosides in Humans
  • Gentamicin
  • Streptomycin
  • Tobramycin

28
Evaluation Tools
  • Pure-tone thresholds
  • near upper frequency hearing limit (for example
    ultra-high frequency audiometry)
  • Otoacoustic emissions
  • High frequency ABR
  • Tests of high frequency responses are likely to
    be the most sensitive indicators of early change

29
Criteria for Hearing Change
  • Always referenced to baseline measures
  • Criteria from ASHA 1994 guidelines
  • gt 20 dB change at any one test frequency
  • gt 10 dB change at any two consecutive test
    frequencies
  • Loss of response at three consecutive test
    frequencies where responses were previously
    obtained.
  • Hearing change by any of these criteria was
    confirmed by retest

30
ASHA Change Criteria
  • Normal variability in pure-tone thresholds occurs
    at random frequencies
  • Threshold shifts at adjacent test frequencies
    indicate more systematic change
  • Threshold shifts on repeated tests are also a
    stronger indication of a true threshold change

31
Extended High Frequency Audiometry - Sensitivity
  • High- to low- frequency progression
  • High-frequency testing is reliable
  • Studies have shown the efficacy of high-frequency
    monitoring
  • Studies have shown testing in 1/6-octave
    intervals provides earlier detection
  • Individualized protocols targeting the highest
    frequencies a person can hear

32
Extended High Frequency Audiometry - Problems
  • There are no normative high-frequency sensitivity
    (threshold) standards due to lack of
    standardization in
  • Calibration
  • Instrumentation
  • Methodological procedures
  • There is a high degree of inter-subject
    variability in sensitivity
  • Threshold variability increases with age and with
    higher frequencies

33
Does it Matter for Monitoring?
  • The key to serial monitoring is intra-subject
    (test-retest) reliability
  • High-frequency test-retest threshold variability
    is within a clinically acceptable range ( 10 dB)
  • As a result, monitoring near individuals
    high-frequency hearing limit is effective

34
ABR Sensitivity
  • Elongation of latency and/or disappearance of
    click-evoked wave V following administration of
    ototoxic drugs
  • Ultra-high frequency tone bursts (8-14 kHz) have
    been shown to be more sensitive than clicks

35
Problem Frequency Specificity
  • Two problems at high stimulus levels
  • Increased spectral splatter (stimulus energy
    spreads)
  • Response could be due to tails of off-frequency
    neurons
  • Pertains to all measures of auditory function
    with all kinds of stimuli
  • Evoked potentials, behavioral measures
  • Clicks, tone bursts, pure tones

36
Problem Change Criteria
  • There is no broadly accepted ABR latency change
    criteria
  • Adults
  • Children
  • Neonates

37
ABR Advantages
  • Good test-retest reliability
  • Can be performed at bedside
  • Can estimate thresholds (magnitude of
    ototoxicity-induced hearing loss)
  • Can obtain in patients with substantial
    pre-existing hearing loss (up to severe to
    profound)

38
ABR Disadvantages
  • Time consuming
  • Limited frequency specificity (depending on how
    performed)
  • Limited high-frequency output
  • Response interpretation at high frequencies
  • Subject noise, hearing loss may preclude
    measurement
  • Infants children may require sedation

39
DPOAE Advantages
  • Highly selective to outer hair cell function
  • Most ototoxic drugs attack outer hair cells
  • Might provide earliest detection of ototoxicity
  • It is frequency specific and can include a wide
    frequency range
  • Objective and can be performed at bedside
  • Good test-retest reliability
  • Rapid

40
Aminoglycoside Ototoxicity Outer hair cells and
otoacoustic emissions
  • Distortion product otoacoustic emissions test
    protocol
  • Intensity L1 65 dB SPL L2 55 dB SPL
  • f2/f1 ratio 1.20
  • Frequency range 500 or 1000 Hz to gt 8000 Hz
  • Newer equipment now available clinically for
    higher frequencies
  • Frequencies/octave 5 to 8

James W. Hall III, Ph.D.
41
Problems Change Criteria
  • Greater than or equal to 6 dB change
  • Based on test-retest variability in normal
    subjects
  • 6 dB change was more than variability in about
    95 of subjects tested--so likely to be real
    change
  • Confirm by re-test to decrease false positive
    rates
  • Change at two adjacent frequencies would decrease
    false positive rates
  • Each clinic should establish its own change
    criteria

42
DPOAE Disadvantages
  • Limited high-frequency (gt 6 kHz) measurements
    typical for clinical systems
  • DPOAE amplitudes are linked to hearing
    sensitivity only for losses lt 50-60 dB
  • Hearing loss may preclude measurable responses at
    baseline
  • Depends on normal middle ear function

43
DPOAEs Essentials of Analysis and Interpretation
  • Verify that noise floor is low
  • below upper limit for a normal population
  • Verify the presence of reliable OAEs for each
    frequency
  • amplitude gt 6 dB above noise floor
  • Interpret amplitudes for each frequency relative
    to the normal region
  • OAEs within normal limits normal
  • OAEs present but below normal limits
    abnormal
  • OAEs lt 6 dB above noise floor (OAE NF lt 6
    dB) absent

James W. Hall III, Ph.D.
44
Relation Between OAE Amplitude and Hearing Loss
DPOAE 65/55 dB SPL TEOAE 80 dB SPL
WNL (Amplitude gt 95ile)
OAE Amplitude
Normal
Present but not normal
No OAE
No OAE (OAE NF lt 6 dB)
-10 0 10 20 30 40
50 60
Hearing Level in dB HL
James W. Hall III, Ph.D.
45
Laboratory Tests for Monitoring Vestibular
Ototoxicity
  • Dynamic visual acuity testing
  • Caloric testing
  • Rotational testing
  • Dynamic posturography

46
Rotational Testing Has Value
  • Caloric testing evaluates only very low frequency
    function (lt.003 Hz)
  • Rotational testing tests mid- to high frequency
    function (.01-.64 Hz)
  • Testing the VOR at lowest rotational frequencies
    may provide early signs of vestibular dysfunction

47
Dynamic Posturography
  • Useful for quantifying ataxia
  • Useful for evaluating patients ability to use
    visual and proprioceptive information to maintain
    postural stability following bilateral loss of
    vestibular function
  • In patients with CF, some have abnormal function
    even when they deny problems

48
Bedside Tests of Vestibular Function
  • Head thrust
  • Testing of dynamic visual acuity
  • Romberg, tandem walking, stepping test

49
Cystic Fibrosis Project
  • First aim of the project is to establish the
    prevalence of vestibular system involvement in
    patients treated with aminoglycosides for
    pulmonary exacerbations secondary to CF
  • Secondary aim is to determine whether incremental
    changes in function can be detected reliably over
    time
  • Hope is to develop guidelines for optimal
    monitoring protocol

50
Original Plan with CF Patients
  • Patients admitted into the hospital for
    initiation of aminoglycoside antibiotics
  • Test vestibular function while inpatient when
    possible, ideally within a couple of days of
    initiation of treatment
  • Completion of Dizziness Handicap Inventory (DHI)
  • Also complete audiological testing when possible
  • Test patients again at their three month
    follow-up appointment with pulmonologist

51
Categories of Vestibular Loss
  • Non-lateralized vestibular system involvement
  • Unilateral vestibular loss
  • Bilateral peripheral vestibular paresis

52
Non-lateralized Vestibular Involvement
  • Significant spontaneous, positional, or post head
    shaking nystagmus
  • Increased phase leads in sinusoidal rotational
    testing
  • Short time constants in rotational step testing
  • Patient may not be symptomatic

53
Unilateral Involvement
  • Significant unilateral weakness in caloric
    testing
  • During the acute phase, might have spontaneous
    nystagmus and asymmetries in rotational testing
  • Patient more likely to describe vertigo and
    unsteadiness, although oscillopsia is possible

54
Bilateral Vestibular Loss
  • Significant bilateral caloric reduction
  • Significant gain reductions in sinusoidal
    rotational tests
  • Significant gain reductions in rotational step
    testing
  • Gait instability and oscillopsia are common
    symptoms

55
Data Trends to Date
  • We have completed vestibular testing on 49
    patients to date
  • We do not have audiological test data on 11 of
    those individuals
  • Testing was attempted with minimal results
    obtained on additional patients
  • 18 have evidence of non-lateralized vestibular
    involvement
  • 5 have significant unilateral loss
  • 14 have bilateral peripheral vestibular paresis
  • 4 have documented normal hearing and vestibular
    function, with 5 others without hearing tests

56
Data Trends to Date
  • We have completed serial monitoring on a subset
    of patients
  • When comparing individual patient data for
    absolute caloric and rotational chair values, it
    appears that sub-clinical but consistent changes
    are occurring over time
  • From normal calorics to an eventual significant
    unilateral weakness
  • From evidence of non-lateralizing findings to
    bilateral involvement
  • From mild bilateral involvement to severe
    bilateral loss

57
Pragmatic Issues to Consider
  • Not all patients will tolerate vestibular testing
  • It is unrealistic to conduct serial testing as
    often as we had anticipated
  • When patients are admitted for initiation of
    aminoglycosides, there are time and scheduling
    constraints
  • Patients and parents are generally not well
    informed about the importance of monitoring
    function over time
  • Physicians, parents, and patients may not want to
    know when damage occurs

58
Acknowledgement
  • N008681-385013 Vestibular and Auditory Sensory
    Loss in CF Patients
  • W. Michael King, Ph.D., Jaynee Handelsman, Ph.D.
    and Samya Nasr, M.D.
  • Cystic Fibrosis Foundation Therapeutics, Inc.

59
Test Battery for Monitoring and Diagnosis
University of Florida
  • Diagnosis of auditory dysfunction
  • Distortion product otoacoustic emissions
  • Aural immittance measurement
  • Tympanometry
  • Acoustic reflexes
  • Pure tone audiometry
  • Conventional audiometric frequencies
  • High frequencies (10 K to 20 K Hz)
  • Speech audiometry
  • Word recognition (10 most difficult words first)
  • Speech-in-noise (as indicated by history)

James W. Hall III, Ph.D.
60
Hearing Findings in Patients with Cystic
Fibrosis University of Florida
OAEs
100
Audio lt 8K Hz
80
60
Audio gt 8K Hz
57 (N 33)
Abnormal Findings in
50 (N 2)
43
40
30
25
20
20
Children (N 15)
Adults (N 81)
James W. Hall III, Ph.D.
61
Vestibular Rehabilitation is Effective in Aiding
Patients with Unilateral and Bilateral Vestibular
Loss
  • Therapy aimed at fostering the substitution of
    visual and somatosensory cues for lost vestibular
    function
  • Gaze stabilization exercises
  • Balance retraining exercises

62
Adaptive and Compensatory Mechanisms Involved in
Stabilization of Eye Movements
  • Adaptation of saccadic eye and head movement
  • Use of neck and other somatosensory afferents
  • Enhanced eye tracking
  • Centrally preprogrammed eye movements
  • Central suppression of undesired image movement
    across the retina

63
Functional Adaptations Build within One Year
  • Gaze stabilization most improved through
    centrally preprogrammed slow eye movements during
    active (predictable) head movement
  • During unpredictable head movements,
    cervico-ocular reflexes and increased fixation
    may yield best stabilization
  • Strongest suppression of oscillopsia achieved by
    central adaptive rearrangements

64
Compensatory Mechanisms Effective in Suppressing
Oscillopsia
  • Only one third of adult patients with acquired
    bilateral vestibular loss of function suffer from
    permanent oscillopsia
  • This underlines the paramount biological
    importance of maintaining clear vision during
    locomotion

65
Roles of Vision and Propriception
  • Patients are able to use vision and somatosensory
    input to maintain postural control in the absence
    of vestibular function
  • When circumstance prevent their use (e.g. in
    darkness or when walking on uneven or
    compressible surfaces), gait ataxia persists for
    almost every patient

66
Bilateral Vestibular Loss - Practical Implications
  • Oscillopsia, which results in visual blurring or
    bobbling - may prevent patients from driving,
    or even walking unassisted
  • Because patients rely on vision and
    proprioception to maintain postural control while
    ambulating, darkness combined with compressible
    or uneven support surfaces result in increase
    risk of falling

67
Vestibular Rehabilitation The Good News
  • Research supports the fact that responses of a
    partially functioning vestibular system can be
    modified
  • For patients with some residual function, VR is
    focused on optimizing the use of the remaining
    VOR, as well as increasing the effectiveness of
    the COR
  • For all patients with bilateral vestibular loss,
    increasing the use of vision and proprioception
    is a goal

68
Variables Affecting Therapy Outcome
  • Extent of the vestibular loss
  • The presence of coexisting disease that may
    impact sensory system function
  • Overall patient heath and fitness
  • Patient motivation and compliance with program

69
Pharmacologic Protection from Aminoglycoside
Induced Ototoxicity
  • Our Hope for the Future

70
Proposed Otoprotective Agentsfor Aminoglycoside
Ototoxicity
  • Lipoic Acid
  • N-acetylcysteine (NAC)
  • Aspirin
  • Iron chelators
  • Caspase inhibitors
  • Gene therapies
  • D-methionine (D-met)

Kathleen C.M. Campbell, Ph.D
71
D-methionine (D-met)
  • Provides excellent but not complete protection
    against aminoglycoside-induced hearing loss in
    animal studies to date.
  • Excellent protection from noise-induced hearing
    loss for pre/peri- and even post exposure
    administration.
  • Also effective in preventing NIHL,
    cisplatin-induced ototoxicity, and radiation
    induced oral mucositis in studies to date.
  • Some patients are exposed to a combination of
    these factors.

Kathleen C.M. Campbell, Ph.D
72
Current Status of D-met Research
  • FDA approved ISUs Investigational New Drug
    Application January 2005 for D-met protection
    from radiation induced oral mucositis.
  • FDA approved Clinical Trials in progress
  • Phase II clinical trials for cisplatin in
    progress in India.
  • Looking for US patient populations.
  • In discussions with military for NIHL protection.
  • More bench work also needed. Currently performing
    additional basic research to go to clinical
    trials for aminoglycoside otoprotection.

Kathleen C.M. Campbell, Ph.D
73
Protection from Amikacin Induced Ototoxicity by
D-methionine Klemens and Campbell
  • Three Groups 5 albino guinea pigs each
  • Amikacin 200 mg/kg/day subcutaneously for 28
    days
  • D-methionine 300mg/kg/day ip 30 minutes prior to
    the amikacin
  • Control animals given equal volume saline

Kathleen C.M. Campbell, Ph.D
74
D-met Protection from Aminoglycoside Induced
Hearing Loss
  • D-met provides partial but significant protection
    against amikacin-induced hearing loss.
  • Planning further studies on dosing protocols and
    additional aminoglycosides

Kathleen C.M. Campbell, Ph.D
75
Sha and Schacht Two Studies Published in 2000
  • Both Studies used pigmented male guinea pigs and
    19 day administration of amikacin
  • Study 1
  • 100 mg/kg histidine combined w/gent
  • 3) 200 mg/kg D-met combined w/gent
  • 4) saline only
  • 5) D-met only
  • 6) histidine only
  • Study 2200 mg/kg d-met twice daily
  • First dose combined with 120mg gentamicin
  • Second dose of D-met injected 7 hours later

Kathleen C.M. Campbell, Ph.D
76
Conclusions
  • D-methionine can protect against aminoglycoside
    induced ototoxicity.
  • More work needs to be done on dosing protocols.
  • More work needs to be done on nephroprotection
  • More work needs to be done to be done to ensure
    lack of interference with the aminoglycosides
    antimicrobial activity

Kathleen C.M. Campbell, Ph.D
77
Current Work D-met and Aminoglycosides
  • Thanks to NIH/NIDCD
  • The group at ISU is performing the translational
    research laboratory studies to prepare for FDA
    approved clinical trials.
  • Studies include developing D-met protection for
    gentamicin, amikacin, and tobramycin.
  • Performing dosing studies (i.e. fractionated
    versus daily dosing, dose response curves)
  • Performing antimicrobial interference studies.
  • Collecting control data on patients currently on
    aminoglycosides to establish data base for
    clinical trials.

Kathleen C.M. Campbell, Ph.D
78
Summary
  • Ototoxicity not only relates to hearing, but to
    vestibular system function
  • Bilateral vestibular loss can be devastating,
    causing ataxia and oscillopsia
  • Unilateral loss is possible as well
  • There is a need to monitor closely patients at
    risk for vestibular loss
  • Vestibular rehabilitation should be considered in
    all cases of uncompensated vestibular system
    involvement
  • Future Outlook Protective Drugs May Limit
    Aminoglycoside Ototoxicity
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