The Importance of Ototoxicity
World Small Animal Veterinary Association World Congress Proceedings, 2003
G. Ter Haar, DVM, DECVS
Department of Clinical Sciences of Companion Animals
Utrecht, The Netherlands

Introduction

Ototoxicity can be defined as the capacity of certain drugs or chemicals to damage inner ear structures, including the cochlea, the vestibule and the semicircular canals and/or inner ear function1. This can result in either hearing impairment and/or vestibular dysfunction (peripheral vestibular ataxia). The clinical signs of ototoxicity are dramatic in acute cases and rapidly brings the owner to the veterinarian. Even with acute treatment, the damage to the inner ear is usually permanent however, rendering a good reason to stress the importance of preventing or early recognizing the signs of ototoxicity. To be able to prevent ototoxicity, the agents with the propensity for ototoxicity have to be known, as well as their routes for reaching the inner ear, their toxic effects and clinical signs.

Ototoxic drugs

Over 180 compounds and classes of compounds have been identified as ototoxic2. Not all of them are equally toxic and some effects are reversible, but in most instances the deficit is permanent. In human medicine, the aminoglycoside antibiotics, the antineoplastic drugs cisplatin and carboplatin, loop diuretics, salicylates, quinine, deferoxamine, and various toxic substances are recognized for their propensity to cause ototoxicity1. The best recognized, and perhaps most frequent, agents of ototoxicity in veterinary medicine are the aminoglycoside antibiotics, especially gentamicin, but polypeptides, chloramphenicol, erythromycin, and (oxy)tetracycline are ototoxic as well3. The importance of disinfectant-based (clioquinol, chlorhexidine, cetrimide, iodine, povidone-iodine and 70% ethanol) ototoxicity, for instance used for ear surgery, should not be underestimated however. The ototoxicity of drugs and chemicals used in and around the ear has been tested in animals, especially guinea pigs, by introducing the agents into the middle ear after perforating the tympanic membrane or via the tympanic bulla. In addition to the drugs mentioned above, local anesthetics like lidocaine, benzocaine, procaine and cocaine, but also vehicles, detergents, and stabilizers, including propylene glycol, glycerol, and phenol, used in ear drops have been found to be ototoxic using this method3,4.

Routes of Ototoxicity

In order for a drug to exert ototoxicity, it must reach the inner ear. This may be the result of hematogenous spread following oral or parenteral dosage1-5. The severity of ototoxicity depends on the concentration of the drug in the blood, the period of time the drug has been used, individual susceptibility (probably determined primarily by heredity), whether other ototoxic drugs are also being used, whether renal function is unimpaired, and whether there is concurrent noise exposure1,4. Ototoxicity after systemic drug therapies usual follows high dosages, prolonged therapy, or concurrent renal failure (affecting drug excretion). In the cat, dihydrostreptomycin and neomycin have been reported to cause ototoxicity during prolonged systemic administration3,4. However, more commonly, ototoxicity follows topical application of ototoxic agents into the external ear canal and their subsequent passage into the middle ear via a ruptured tympanum3,4. Subsequent diffusion into the middle ear is enhanced by the presence of otitis media, which induces increased permeability through the round window membrane, which is an important portal for the passage of inflammatory mediators, toxins and drugs from the middle ear to the inner ear1. The agent passes through the membrane of the round window and enters the perilymph in the tunnel of Corti. It thereby comes in contact with the hair cells of the organ of Corti and causes degeneration of the perceptive cells3. This route of entry was demonstrated for gentamicin in the guinea pig6. Similar structures in the vestibule make it likely that perilymph also reaches the sensory cells of the vestibular labyrinth.

Pathophysiology of ototoxicity

The mechanism of toxicity is unclear, but the pathology includes hair cell loss with a progression from basal coil outer hair cells to more apical outer hair cells, followed by inner hair cells. The most current evidence points to binding of the drug to glycosaminoglycans of the stria vascularis, causing strial changes and secondary hair cell changes2. Degeneration of the spiral ganglion cells and cochlear neurons in patients with documented cisplatin ototoxicity in addition to outer hair cell degeneration in the basal turn of the cochlea was reported by Strauss et al.7. According to some authors, ototoxic antibiotics cause hearing loss by changing important biochemical processes that lead to metabolic exhaustion of hair cells and that can eventually lead to cell death5. It is generally assumed that oxygen free radicals are involved in causing injuries to the cochlea by ototoxic substances5.

The nature of hearing loss caused by carboplatin in the guinea pig is different from that of other ototoxic substances because it affects neural transduction in the cochlea, rather than the mechanical properties of the basilar membrane. Its effect is humans is unknown5.

Clinical signs

Drugs that primarily affect the cochlea, resulting in hearing impairment, are cochleotoxic whereas drugs that affect the vestibular system, resulting in vestibular dysfunction, are vestibulotoxic. Some drugs are both cochleotoxic and vestibulotoxic.

The effects may reflect uni- or bilateral toxicity. Clinical signs of vestibular damage may be reflected very early (as soon as 10 minutes!) after the insult has been effected and these include horizontal nystagmus, with the fast component to the affected side, strabismus, ataxia, head tilt, circling, nausea and refusal of food1-5. Within three days central compensation results in diminishing and eventually disappearance of the nystagmus, gradual attempts to stand, and beginning efforts to eat and drink, but the head tilt is unchanged. Within three weeks the situation improves, but jumping and walking down stairs often still results in falling. The compensation is optimal after about three months. The head tilt however may still be obvious and permanent3,4. Clinical signs of cochlear damage usually go unnoticed until complete deafness is recognized. The early signs of cochlear damage in man include tinnitus and although this would be difficult to document in dogs and cats, it may be that an inappropriate, or unusually strong, response to an auditory stimulus is a reflection of early cochlear damage2. Bilateral ototoxicity causes bilateral loss of equilibrium and loss of hearing, expressed as a loss of orientation, loss of social contact, and sometimes changes in behavior and general malaise caused by insecurity3,4.

Clinical assessment

While the effect on the equilibrium of the animal is evident on clinical examination and can be assessed by simple observation, the effect on hearing, especially with unilateral loss, can only be objectively tested by cochlear microphony3. Frequency-specific hearing loss, for instance due to ototoxicity, can also be evaluated by the use of brainstem-evoked response audiometry8. Histologic evidence of loss of hair cells in the cochlea is obtained by the block-surface technique, which not only enables counting of cells to determine the proportion destroyed, but also definition of the specific area of the cochlea which has been affected9.

Preventing ototoxicity

In general, ototoxic effects are dose related, therefore avoiding ototoxic chemicals or reducing the dose and frequency of administration are the first principle. Careful observation and regular follow-up examinations of the patient may allow detection of vestibular signs early enough to allow the clinician to suspend therapy. It is, however, difficult to detect early cochlear damage without sophisticated investigatory tools, such as BAER.

References

1.  Rybak LP, Kanno H. Ototoxicity. In: JJ Balenger and JB Snow, Eds; Otorhinolaryngology: Head and Neck Surgery, 15th ed. Williams & Wilkins, Baltimore (1996), pp. 1102-1108.

2.  Harvey RG, Harari J and Delauche AJ. In: Ear Diseases of the Dog and Cat, London (2001), pp. 213-216.

3.  Gallé HG, Venker-van Haagen AJ. Ototoxicity of the antiseptic combination chlorhexidine/cetrimide (Savlon®): effects on equilibrium and hearing. Vet Quart 8: 56-60, 1986.

4.  Venker-van Haagen AJ. Diseases and Surgery of the Ear. In: RG Sherding Ed. The Cat, Diseases and Clinical Management, 2nd ed. Churchill Livingstone, New York. 1996, pp.1999-2009.

5.  Møller AR. Disorders of the Cochlea. In: Hearing; It's physiology and pathophysiology, California (2000), pp. 419422.

6.  De Groot JCMJ, Meeuwsen F, Ruizendaal WE, Veldman JE. Ultrastructural localization of gentamycin in the cochlea. Hearing Research 50:35-42, 1999.

7.  Strauss M, et al. Cisplatinum Ototoxicity: clinical experience and temporal bone histopathology. Laryngoscope 93:1554, 1983.

8.  Ter Haar G, Venker-van Haagen AJ, de Groot HNM and van den Brom WE. Click and Low-, Middle-, and High-Frequency Toneburst Stimulation of the Canine Cochlea. J Vet Intern Med 2002;16:274-280.

9.  Spoendlin h, Brun JP. The block-surface technique for evaluation of cochlear pathology. Oto-Rhino-Laryngol 208:137-45, 1974.

Speaker Information
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G. Ter Haar, DVM, DECVS
Department of Clinical Sciences of Companion Animals
Utrecht, The Netherlands


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