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Vestibular ototoxicity is defined as a chemical substance having a
destructive or damaging effect on the structure and function of the
labyrinthine hair cells and their connections through the eighth nerve to
the central nervous system. Vestibular toxicity can vary from minimal damage
to complete loss of auditory and vestibular function. Such losses may be
temporary or permanent. Vestibular toxicity, in particular, can be
devastating.8-10 The historical aspects of ototoxicity are
well-reviewed elsewhere.11 With vestibular toxicity, the initial
and most extensive hair cell damage occurs in the apex of the cristae and
the striolar regions of the maculae. Next there is further hair cell loss
extending toward the periphery of the vestibular receptor and additional
damage to the otoconial membrane and the otolith structures themselves. As
pointed out by Black and Pesznecker,11 we may not understand the
true incidence of ototoxicity as the initial ototoxic destruction of hair
cells occurs well outside the speech range for the auditory system and
outside the normal active and passive head movement frequency range for the
vestibular system.12,13 And even though the goal is always to use
the most effective drug, depending upon the pathogen, the use of specific
antibiotics may, in fact, be mandated by clinical factors beyond the
physician's control such as the patterns of bacterial resistance or
susceptibility. Costs may also be a factor11 as these authors
point out, because gentamicin is very vestibulotoxic but continues to be
widely used because it is relatively inexpensive.14
Prospective studies by Black and others13 strongly suggest that vestibular ototoxicity occurs precipitously and without warning. Vestibular toxicity may be associated with and follow signs and symptoms of cochleotoxicity. Tinnitus is often the initial symptomatic manifestation of cochleotoxicity and is usually high-pitched and continuous reflecting the cochlear hair cell damage in the basilar turn. If the tinnitus is subtle and a patient is very ill, the patient may not complain of tinnitus, only becoming aware of it later when they are well.11 A majority of patients who receive potentially ototoxic antibiotics because of life-threatening infection are those patients who spend long periods hospitalized or at bed rest. It is only when the patient becomes well enough to be up and about that vestibular symptoms are first noted. They are often attributed incorrectly to the patient's general debility. Unfortunately, an accurate diagnosis of toxicity may be delayed or even overlooked. If the patient is ambulatory, the disequilibration becomes readily apparent. They may show an ataxic gait, lose their balance when turning quickly, or need to ambulate while holding on to the wall. Patients may complain of transient positional vertigo, but mainly complain of disequilibration. As the vestibular toxicity progresses, they may begin to complain of movement of the external environment or oscillopsia. The patient is no longer able to sense head movements and make compensatory ocular movements within the orbit. The symptom of jiggling or bouncing of the external environment,oscillopsia, is caused by the loss of the vestibulo-ocular reflex. With progressive loss of vestibular function, patients may have to rely entirely upon visual and proprioceptive input to control ambulation and become Avestibular cripples@ being totally unable to ambulate without danger of falling. The patients then need to be confined to wheelchairs. Congenital ototoxicity can occur when a pregnant woman receives an ototoxic agent. If an ototoxic agent passes through the placenta to the developing embryo or fetus, damage to the auditory or vestibular system may occur, often with catastrophic results. Besides permanent deafness or balance impairment, cleft lip and palate, skeletal malformations, ocular defects, and abnormalities of the cardiovascular, genitourinary, and gastrointestinal systems have been identified. When these conditions are present in an infant, it may be prudent to query thoroughly the mother's medication history during pregnancy and to follow up with the appropriate auditory or vestibular screening tests. The first trimester, especially the 6th to 8th week, appears to be the most vulnerable period. Quinine, salicylates, streptomycin, and dihydorstreptomycin have been among the drugs implicated. In arriving at the proper diagnosis a careful history is most important. The symptoms may have remained unnoticed when the patient was bed-ridden. For patients who complain of balance problems after hospitalization for a severe illness, it is clear that medical records need to be reviewed carefully with a review of the drugs administered and cumulative doses. A recent prototypic case is presented: A sixty-eight year old woman was readmitted to the hospital with complaints of dizziness, nausea, and vomiting. Neurology was consulted for the possibility of new brainstem infarction. The patient had recently been discharged from the Urology Service who had treated the patient over four years for multiple urinary tract infections. The most recent admission was for another urethral infection. The initial evaluation included pelvic MRI and ultrasound studies which were negative. The patient was discharged on enteric coated aspirin and seen as an outpatient three weeks later. She then complained bitterly of Ablurry vision.@ Upon further questioning, she reported that things Ajump around@ as she looked at them. Upon examination, the patient had a greatly impaired vestibulo-ocular reflex, being unable to fixate on a target as her head was gently moved from side to side. Review of her recent admission revealed that she had been treated with gentamicin for four days. She was asymptomatic until four days following discharge. A single trough level was 4.2 was noted during her hospitalization. My impression was that the patient, whose renal function was not impaired, had an idiosyncratic sensitivity to gentamicin and a delayed vestibular toxicity. Unfortunately, she was totally unable to ambulate and had a major reduction in vestibular function, demonstrated by no response to caloric testing during standard ENG. Vestibular testing has been discussed in detail by Black.11 Figure 14-1 shows serial responses for the vestibular ocular reflex at baseline, when the patient was ototoxic, and during recovery.13 Electrocochleography (EcoG) has been shown to demonstrate an immediate reduction in action potential and cochlear microphonic within minutes after an intravenous dose of aminoglycoside.15 Such testing is not routinely done, but may have a role as a screening tool in patients that are particularly susceptible to ototoxic drugs. In general, such drugs should be avoided in patient with risk factors or those predisposed to ototoxicity such as with end-stage renal or hepatic impairment, or a previous history of hearing or balance disorders. Whether there will be recovery is unknown. If ototoxic damage is in complete, and this may be difficult to tell clinically, the chances of some reversibility has been quoted as 10-15% depending upon the agent involved and the risk factors.11 If damage is severe, it is said that in all likelihood that the damage would be permanent and a subject must be prepared for this eventuality.11,16 In my experience, however, significant recovery can occur in even the most severely vestibulotoxic patients. One patient with impaired renal function received gentamicin because of a shunt infection. She was inadvertently given the full dose rather than the renal dose. Severe oscillopsia and total imbalance persisted for a year, but over the next twenty-four months gradual improvement ensued. She was able to move from a wheelchair, to a walker, to two canes, and eventually to ambulation with the use of a single cane at which time she no longer complaining of oscillopsia. The recovery in this patient was unique in my experience. Following the induced loss of vestibular function from aminoglycosides the patient becomes Avisually dependent@ relying exclusively on vision and proprioception to compensate for the loss of control.11 Such patients should be advised not to attempt to navigate in situations of reduced illumination and, because they are dependent upon proprioceptive cues, must be extremely careful when upon uneven surfaces. Black and colleagues11 indicate that they have never seen an ototoxic patient completely adapt or compensate. Because of Avisual dependence@ and oscillopsia, ototoxic patients should not climb on chairs or step stools, ladders, roofs, or other high places from which they could fall and be injured. They should also not operate dangerous machinery (e.g., power lawn mowers, construction equipment) and should not drive until balance and coordination has stabilized and until they can pass the driver=s license test. Patients should avoid swimming underwater, as the perceived Aloss of gravity@ induced by the water=s buoyance could cause a loss of orientation, so they are unable to locate the surface; in preparation for this eventuality, patients should be trained to blow out a bubble and follow it upward.@11 It is difficult to monitor for potential vestibular ototoxicity because of the expense and time-consuming nature of vestibular testing. Most patients receiving potentially ototoxic drugs are confined to bed and are unable to cooperate fully and maintain alertness for the testing. If any vestibular toxicity is suspected the decision should be made to discontinue the aminoglycoside drug unless there is no other way to treat the infection. Serum trough levels are not uniformly useful in determining whether there will be vestibular toxicity. According to Black and Pesznecker,11 on the basis of their studies, there was no correlation between serum levels and vestibular ototoxicity (unpublished data). They remarked that Aserum levels can be useful in guiding clinicians to use a systemic dose that achieves a minimum effective blood level while avoiding and reducing additional risk of ototoxicity related to excessive dosage.@ The following high risk groups should be periodically monitored:16 (1) patients with impaired renal function, evident either before or during therapy, (2) patients with elevated peak and trough serum levels, (3) patients with pre-existing sensorineural hearing loss, (4) patients receiving more than one ototoxic drug (particularly an aminoglycoside and a loop diuretic), (5) patients with a history of receiving ototoxic drugs, (6) patients who are expected to receive ototoxic agents for more than 14 days, (7) patients with symptoms of cochlear or vestibular toxicity that become obvious during treatment, and (8) patients over the age of 65. If dose and monitoring guidelines for individual drugs published in the Physician's Desk Reference17 should be followed.
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