Potential complications associated with steroid use in the middle and inner ear

Ear, Nose & Throat Journal, Nov, 2007 by Ann L. Edmunds

Glucocorticoids have been used to treat disorders such as sudden sensorineural hearing loss, autoimmune hearing loss, Meniere's disease, and hearing loss secondary to trauma, viral insult, and idiopathic causes. When used to treat disorders of the inner ear, steroids have traditionally been administered systemically. However, it has been postulated that the steroid levels achieved in the inner ear with systemic administration are not consistent because of the presence of the blood-labyrinth barrier. (1) This can lead to potentially suboptimal therapeutic concentrations and subsequent treatment failure.

Another concern with the systemic administration of steroids is the side effects associated with this route. Possible complications include fluid and electrolyte imbalance, muscle weakness and a loss of muscle mass, tendon rupture, osteoporosis, vertebral fractures, aseptic necrosis of the humeral and femoral heads, peptic ulcer, impaired wound healing, a cushingoid state, adrenocortical insufficiency, cataracts, and decreased carbohydrate tolerance.

In view of these concerns with systemic administration, other delivery routes have been investigated. Among the alternatives are intratympanic injection and topical administration into the middle ear cavity via a tympanostomy tube. But these routes have their own possible complications, including delayed healing of the tympanic membrane, vertigo, heating loss, and morphologic changes in the round window membrane. (2-5) In this article, the author reviews the advantages and disadvantages of topical steroid use in the middle and inner ear.

Literature search

The author searched the MEDLINE database for evidence-based articles that would help answer the clinical question, Are there potential risks associated with the use of steroids administered directly to the middle and inner ear spaces? The search terms used were "glucocorticoids and inner ear toxicity," "glucocorticoids and middle ear toxicity," "ototoxicity and ototopical steroids," "intratympanic steroids-middle ear toxicity," and "intratympanic steroids-inner ear toxicity."

The articles that were retrieved were reviewed in detail to ascertain whether they answered the question. Most of those that did were reports of animal studies, although a few small series in humans were applicable, as well.

Extrapolating animal data to humans

Can data obtained from animal studies be extrapolated to humans? For practical reasons, the bulk of information available on the potential toxicity of steroid administration to the middle and inner ears via transtympanic administration has been derived from animal studies; sampling of inner ear fluids in humans poses a risk of permanent hearing loss.

There are several anatomic differences between animal models and human models. For example, guinea pigs have a patent cochlear aqueduct, and this can lead to CSF contamination during perilymph sampling. Also, the human round window membrane is thicker than that of lower-order animals (70 [micro]m for humans vs. 10 to 14 [micro]m for rodents), and this difference may affect drug transport into the middle ear. Finally, because the human inner ear is considerably larger than that of animals used in most studies, it is difficult to make generalizations about drug concentrations within inner ear fluids. (6)

Roland et al identified several anatomic as well as nonanatomic differences between animals and humans and described some of the ramifications of these differences. (7) For example, the human round window membrane is recessed in a triangular fossa and therefore is less accessible than the round window membrane in animals. As a result, substances placed in the middle ear of humans may remain in contact with the round window for a shorter period of time, thus potentially lessening their effect at this site. In an investigation of inner ear perfusion, Silverstein et al reported that nearly 30% of the human ears in their study had obstructing mucosal folds that obscured the round window membrane. (8)

Differences between humans and animals in eustachian tube function may exist as well, although much investigation in this area remains to be done. Again, if the anatomy of the human eustachian tube promotes the rapid movement of substances from the middle ear, potential contact time with the round window membrane would be reduced.

With regard to the nonanatomic differences, histologic changes in the round window have been seen in animals with otitis media. Specifically, these changes include increased vascularity, infiltration of immunoreactive cells and, eventually, thickening of the membrane, which may result in decreased permeability of the membrane over time.

Pending the accumulation of more data, we can only conclude for now that the extent to which animal data can be extrapolated to represent a human model is unknown.

Physiology: How steroids exert their effect

Corticosteroids exert their effect by strongly suppressing the immune system-mediated inflammatory response. This suppression occurs as a result of the interaction between the drug and the intracellular glucocorticoid receptors, which have been shown to exist in both cochlear and vestibular tissues of humans and rats. With respect to the location of steroid receptors, Rarey and Curtis found that the highest concentrations of receptors were in the cochlear labyrinth, specifically the spiral ligament, followed by the organ of Corti; the lowest concentration was in the stria vascularis. (9) In the vestibular labyrinth, the highest concentrations of receptors were in the crista ampullaris and utricular macula, and the lowest levels were in the macula of the saccule.