Pharmacologic and Molecular Therapies of the Cochlear and Vestibular Labyrinth

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CHAPTER 155 Pharmacologic and Molecular Therapies of the Cochlear and Vestibular Labyrinth

Key Points

Protected by one of the hardest bones in body, the cochlea is nearly an impenetrable structure, frustrating bacteria and humans trying to gain access to it. Were it not for its windows, delivery of therapeutic agents to the inner ear would always necessitate traumatic disruption of the bony walls and fearful consequences to hearing. In the past 20 years, there has been a resurgence of interest in directed therapy to address inner ear disorders because indirect, systemic therapy has shown limited success and significant morbidity. Experimentally, as reviewed later, investigators have shown that intratympanic and intracochlear therapy is feasible and efficacious. The direct intracochlear application of therapeutic agents, previously feared, may become the standard therapy of the future. Inner ear “surgery” is expected to be developed to the fullest to prevent hearing loss and to restore hearing. This chapter reviews the knowledge regarding delivery of material into the inner ear and its therapeutic consequences. The dawning of a new era in ototherapy is here.

Round Window Membrane

Anatomy

The round and oval windows sit on the medial wall of the middle ear. The conduction apparatus of the middle ear converges on the oval window, an arrangement designed to transfer the mechanical energy of sound waves into fluid waves that pass through the cochlea. Although situated at the tail end of this apparatus, the round window membrane (RWM) plays an essential role in acoustic dynamics because the compliance of the membrane allows for this mechanical energy to be released from the cochlea; without this outlet, no waves could travel through the perilymph. The actual RWM sits in the round window niche (fossula fenestrae cochleae) just posteroinferior to the promontory. When viewed from the intact tympanic membrane, the round window niche can be found an average of 3.44 mm (±0.68 mm) from the umbo, at an average angle of 113.2 degrees (±9.8 degrees) from the long process of the malleus.1

The RWM is a three-layered structure designed to protect the inner ear from middle ear pathology and to facilitate active transport. There is an outer epithelial layer that faces the middle ear, a central connective tissue layer, and an inner epithelial layer interfacing with the scala tympani. The outer epithelial layer is continuous with the promontory. Mucoperiosteal folds from the neighboring epithelium sometimes can obstruct the round window niche, forming a “false” RWM. The most prominent feature of the outer epithelial layer is the extensive interdigitations and tight junctions of its cells; in addition, there is a continuous basement membrane layer. This architecture, with tight junctions and a continuous basement membrane, functions as a defensive shield designed to protect the inner ear from middle ear infections. The cells also feature a well-developed rough endoplasmic reticulum and Golgi complex with occasional microvilli, suggesting that active transport of elements across the middle and inner ear compartments may occur.

The connective tissue core contains fibroblasts, collagen, and elastic fibers, and houses blood and lymph vessels. The connective tissue layer is divided roughly into thirds, differing by fiber type and cellular material. Closest to the middle ear epithelium are coarse, loosely arranged collagen fibers, devoid of elastic fibers. In the middle of this layer, these fibers are joined by fibroblasts and ground substance, with occasional blood vessels and elastic fibers. Bordering the inner ear epithelium, there is a gradual increase in fibroblasts, collagen, and elastic fibers. As a whole, the connective tissue layer is responsible for providing compliance to the RWM. A discontinuous inner epithelial layer bathes in the perilymph of the scala tympani. Cells in this layer house pinocytotic vesicles and amorphous intracellular components, and feature long lateral extensions that bathe in the perilymph, suggesting that the RWM participates in some form of active transport.2 Figure 155-1 depicts the histologic complexity of the RWM.

Physiology

The RWM is a dynamic biologic membrane. All three layers of the RWM participate in a defensive response to pathogen insult. In the context of otitis media, the outer epithelial cells become hyperplastic, whereas blood vessels within the connective tissue layer become edematous and dilated, permitting extravasation of neutrophils and macrophages. Fibroblasts also become hyperplastic, displaying an increased volume of basophilic cytoplasm.2 Yoon and Hellstrom3 found that although all layers of the RWM are involved in the defense response, the most dramatic changes are seen in the subepithelial space close to the basement membrane (Fig. 155-2). Certain toxins can also initiate these metaplastic changes, resulting in a thicker RWM. The thickness of the RWM doubles after exposure to Pseudomonas exotoxin.4 Streptolysin O has been shown to cause breakdown of the RWM, increasing its permeability to substances in the middle ear space.5

Another dynamic aspect of the RWM is its ability to transport macromolecules. This process seems to be receptor mediated.6 Transport starts at the outer layer, where molecules are taken up by pinocytosis and are brought into the connective tissue layer. From there, substances either are absorbed by blood or lymphatic vessels or are mobilized further to the inner epithelial layer, where they are released by pinocytosis into the perilymph. The RWM may also participate in the absorption of perilymph because experimental evidence has shown the passage of tracer substances from the perilymph compartment into the RWM.2

The RWM displays dynamic changes as it ages. Although there is no change in the thickness of the RWM with aging, changes in cellular density and elastic fiber patterns can be seen. These changes may decrease the compliance of the membrane and compromise the overall function of the auditory system.7

Permeability

A large range of materials are able to cross the RWM, including various antimicrobials, steroids, anesthetics, tracers, albumin, horseradish peroxidase, latex spheres, germicidal solutions, water, ions, and macromolecules (including bacterial toxins).8 Several factors contribute to the permeability of the RWM, including size, charge, the morphology of the compound, and the thickness of the RWM. Size has proved to be a factor in permeability because 1-µm microspheres cross the RWM, but 3-µm microspheres do not.9 Substances with a molecular weight of less than 1000 kD diffuse across the RWM rapidly, whereas substances greater than 1000 kD are transported by pinocytosis.10 Charge of the molecule can also affect its ability to traverse the RWM: cationic ferritin crosses the RWM, but anionic ferritin does not.9 The implication is that liposolubility is a factor in RWM permeability, a feature that is important in the design of liposome vectors for gene therapy.8 The morphologic features of the compound can stimulate pinocytosis, presumably by a receptor-mediated mechanism.8,10 Increased thickness of the RWM decreases permeability of substances.8 Although the average thickness of the human RWM is 10 to 30 µm, this thickness can double in inflammatory conditions.11,12

RWM permeability can be altered with the use of exogenous adjuvants. Chandrasekhar and colleagues6 compared the ability of three exogenous adjuvants to increase the perfusion of dexamethasone applied to the round window niche. These compounds included histamine (for its vasodilatory effects), hyaluronic acid (for its proposed osmotic effect), and dimethyl sulfoxide (for its ability to increase medication solubility in perilymph). Histamine adjuvant with dexamethasone resulted in significantly higher perilymph steroid levels than all other combinations, whereas hyaluronic acid and dimethyl sulfoxide had no significant effect. Although this study failed to show an increase in steroid perfusion with the use of hyaluronic acid, several practitioners advocate use of hyaluronic acid in their intratympanic steroid protocols.1,13

Kinetics

Delivery of therapeutic agents across the RWM displays a nonuniform distribution in the perilymph. Concentrations of the delivered agent are usually high in the basal turns in close proximity to the RWM, and are low at the apical turns. The permeability characteristics of the substance across the RWM and the rate of its clearance from the perilymph are the two major factors that determine the dispersal characteristics of substances in perilymph; this can include a combination of clearance to blood, clearance to any other scala, uptake or binding by cells, or metabolism by any of the cochlear tissues.14 Knowing the RWM permeability and clearance rates of a given agent permits the simulation of its perilymphatic distribution with reasonable accuracy.

With these observations, Salt and Ma14 described the development of a computer-simulated model of drug distribution in the perilymphatic space (Fig. 155-3). Their model, the Washington University Cochlear Fluids Simulator, is a public-domain program that is available on the Internet at otowustl.edu/cochlea/. An example of the power of this program is provided in the study by Plontke and coworkers,15 in which a model of gentamicin kinetics in the perilymph was closely approximated to published in vivo kinetics data by adjusting input parameters defining RWM permeability, clearance, and interscala drug exchange. These investigators were able to establish that intratympanically administered gentamicin spreads from the RWM to the vestibule by communication through the scala, rather than by diffusion through the helicotrema. The study also suggested that drug concentrations and distribution in the perilymph were substantially influenced by the delivery method and the duration of exposure of the drug to the RWM. These computer-generated simulations are useful because they permit the optimization of different treatment protocols in humans, without resorting to simple trial and error or costly animal trials.

image

Figure 155-3. Schematic of the physical processes incorporated into the simulation program (the Washington University Cochlear Fluids Simulator, version 1.6, a public-domain computer program available at oto.wustl.edu/cochlea/). The compartments shown include the middle ear (ME), scala tympani (ST), cochlear endolymphatic space (ELS), scala vestibuli (SV), and vestibule (V). Drug enters through the round window (RW) in an amount depending on the permeability, and spreads longitudinally by diffusion. Local interscala exchange allows drug to spread to the endolymphatic space and the scala vestibuli, and from there to the vestibule. Drug clearance (losses to other compartments such as to blood) occurs from each compartment. Diffusion, clearance, and interscala exchange are calculated for each 0.1-mm segment of the fluid space.

(From Plontke SKR, Wood AW, Salt AN. Analysis of gentamicin kinetics in fluids of the inner ear with round window administration. Otol Neurotol. 2002;23:967.)

Another important finding from this simulated research is that the distribution of substances in perilymph is dramatically altered after perforation of the otic capsule. This finding is important because many previous pharmacokinetic studies have perforated the otic capsule to access perilymph for drug concentration sampling; their findings may be distorted by this phenomenon.14

Adhesions

As noted previously, the epithelium that neighbors the round window niche sometimes can create a veil that separates the RWM from the middle ear. Other reactive changes, such as scarring from repeated middle ear infections or from prior middle ear surgery, may also lead to adhesions that obstruct the RWM.16 In a cadaveric study of 202 ears to determine the rate and nature of RWM obstruction, Alzamil and Linthicum17 identified RWM obstruction in one third of ears. In their series, 21% had false RWMs, 10% had fibrous plugs, and 1.5% had fatty plugs. In cases in which temporal bones came from the same cadaver, 57% had no obstruction, 22% had bilateral obstruction, and 21% had unilateral obstruction. These investigators noted that the plugs filling the round window niche are 1 mm (in contrast to the RWM, which is approximately 20 µm thick).

Silverstein and coworkers16 provided further evidence of RWM obstruction. In a series of 41 patients, they found that 17% of ears had partial obstruction and 12% had total obstruction of the round window niche. Because these adhesions may cause significant variability in the pharmacokinetics of intratympanically applied medications, these authors recommended that endoscopic removal of these adhesions should be performed before any intratympanic drug treatments. In their practice, they use a 1.7-mm endoscope with 0-degree and 30-degree viewing angles. Adhesions, if identified, are removed with a small right-angle pick. The clinical and therapeutic advantages of lysing adhesions before intratympanic drug therapy have yet to be shown in controlled clinical trials.

Delivery Method

Following is a description of how typical intratympanic injections are performed. The patient lies flat with the affected ear facing the ceiling. The external ear canal is cleaned of debris, and the tympanic membrane is visualized with an operating microscope. The round window niche can be found an average of 3.44 mm (±0.68 mm) from the umbo, at an average angle of 113.2 degrees (±9.8 degrees) from the long process of the malleus (Fig. 155-4).18 Local anesthetic is applied to the tympanic membrane. Anesthetic preparations include topical tetracaine with alcohol, topical 15% phenol preparation, or ear canal injection of 1% lidocaine with 1 : 100,000 epinephrine.19 If endoscopy is to be performed, a generous myringotomy incision is made from the umbo posteriorly to the anulus, large enough to pass the endoscope (with scope diameters of approximately 1.7 to 2.4 mm). If simple injection is performed, myringotomy may still be necessary because there needs to be a vent for air to escape the middle ear space as it is filled with fluid.

image

Figure 155-4. Illustration shows how the angle between the handle of the malleus and the round window (shown in the supine operative position) was calculated.

(From Silverstein H, Durand B, Jackson LE, et al. Use of the malleus handle as a landmark for localizing the round window membrane. Ear Nose Throat J. 2001;80:444.)

If endoscopic examination is performed, the round window niche is identified, and any mucosal adhesions are removed by use of an angled pick. The injection follows with a 1-mL tuberculin syringe and a spinal needle. Cutting 2 inches off of the tip shortens the needle and dulls the tip, decreasing the risk of a traumatic puncture of surrounding tissue. The injection should be administered slowly and directed so that the solution pools around the round window niche. Because the solution often drains into deeper air cells after the first injection, a second injection can be applied. The patient should remain with the injected ear toward the ceiling for approximately 15 to 30 minutes. It is important to instruct the patient to refrain from swallowing, talking, or yawning during this time.

Some protocols call for multiple injections over a short time. In these cases, it is useful to place a tympanostomy tube after the initial myringotomy. Montandon and colleagues20 found that placement of tympanostomy tubes resulted in resolution of vertigo in 71% of patients with Meniere’s disease in their study; if tubes are going to be used in a study, they should be acknowledged as a confounding variable.

Advances in microendoscopes may significantly increase the ease and accuracy of intratympanic drug delivery. Plontke and associates21 described the development of a 1.2-mm endoscope that incorporates a thin fiberoptic, a working/laser channel (0.3 mm), and a suction/irrigation channel (0.27 mm). This new device would allow for several manipulations to occur at once, including direct observation of the RWM, lysis of adhesions (if present), and application of medications directly to the RWM.

Intratympanic injection is inherently inaccurate because the injected medication can leak down the eustachian tube, escape out of the external canal, or be sequestered in the middle ear. The amount of medication delivered potentially changes with each patient and each dose.22 In an attempt to address this problem, several static sustained-release vehicles have been developed. A dry 2 mm × 3 mm Gelfoam (Upjohn, Kalamazoo, MI) pledget can be placed directly in the round window niche against the RWM. The treatment compound can be injected directly onto the Gelfoam pad. Because of the slow dissipation of Gelfoam, this injection can be repeated several times (as in titration protocols for gentamicin treatment of Meniere’s disease).19 Gelfoam slurry can also be used to suspend the medicine. This slurry can be directly injected into the middle ear space. This method has the advantage of the Gelfoam being easily removed from the middle ear in the case of an adverse reaction to the applied medicine.23

A two-component fibrin glue system also can be used (developed by Red Cross–Holland Lab, College Park, MD). The first component of the glue is deposited in the round window niche. The other component is mixed with the medicine and is added to the first (which is already in the round window niche). The two are mixed in situ and subsequently solidified, allowing the medicine to be slowly released from the glue onto the RWM.23

The ultimate degree of pharmacokinetic control is achieved with the use of mechanical sustained-release devices. These devices allow researchers to manipulate inner ear kinetic curves reliably by changing the rate and amount of dose delivered to the RWM.22 Two devices are currently approved for use in humans and have been studied in clinical trials: the Silverstein MicroWick (Micromedics, Eaton, MN) and the IntraEar Microcatheter (Durect, Cupertino, CA). The Silverstein MicroWick (Fig. 155-5) is made from polyvinyl acetate and measures 1 mm × 9 mm long, small enough to fit through a tympanostomy tube. The wick absorbs medication (which can be administered by the patient at home) that has been applied to the external ear canal and delivers it to the RWM. The advantage of this system is that fitting the device is a simple, minimally invasive procedure (only nominally more invasive than tympanostomy tube placement), and the device can be removed without anesthesia. Long-term use is not advised because the wick material may become adherent to the mucosa of the round window niche. This device has been used to deliver steroids and gentamicin treatments in human clinical trials.19

image

Figure 155-5. Silverstein MicroWick.

(Reprinted with permission of Micromedics, Inc.)

The IntraEar Microcatheter (Fig. 155-6) consists of an electronic pump (Disetronics, Minneapolis, MN) connected to a catheter tip that is placed directly on the RWM. Implantation of the microcatheter is more invasive and requires the elevation of a tympanomeatal flap. Several sizes are available to secure a good fit of the catheter tip into the round window niche. The rate and dose of drug delivery are set by the practitioner at the time of implantation, but can be adjusted in the middle of the treatment period. This device has also been extensively tested in human subjects for steroid and gentamicin therapy to the inner ear.24

image

Figure 155-6. IntraEar Microcatheter.

(Reprinted with permission of the DURECT corporation.)

Several new therapeutic agents (e.g., neurotrophins) require long-term or continuous application, which presents a serious challenge from a delivery point of view. In an attempt to address the need for a long-term delivery device, Praetorius and colleagues25 developed a fully implantable micropump system. The device is made from pure titanium, polyethylene, and silicone, and is designed for lifelong implantation in humans. To place the device, a cavity is drilled out of the mastoid bone to house the pump and reservoir system, a procedure that is similar to the one used to place cochlear implants or implantable hearing devices. The catheter tip is placed into the round window niche. The design allows for variation in kinetics, enabling bolus and continuous infusions. The device is designed so that it can be refilled by a simple procedure without the need for reimplantation.

Steroids

The two principal indications for intratympanic steroids are sudden sensorineural hearing loss (SNHL) and Meniere’s disease. The pathogenesis, pathophysiology, and diagnostic criteria for these indications are subject to controversy, making a comprehensive evaluation of the use of intratympanic steroids as a treatment for these conditions exceedingly difficult. The mechanism of action of steroids in the inner ear is incompletely understood. We review what is known about how steroids affect the inner ear, their systemic use for treatment of inner ear diseases, and the reported clinical outcomes of intratympanic steroid therapy.

Mechanism of Action

Steroids mitigate the destructive processes caused by the immune response by decreasing the number of circulating blood leukocytes and inhibiting the formation and liberation of inflammatory mediators.26 They also inhibit the release of chemoattractive and vasoactive factors, decrease the secretion of lipolytic and proteolytic enzymes, and inhibit the release of proinflammatory cytokines, such as interferon-γ, granulocyte/monocyte colony-stimulating factor, interleukins, and tumor necrosis factor-α.27 These actions decrease the damage from an inflammatory response, whether the insult is secondary to mechanic, hypoxic, ischemic, infectious, or autoimmunologic causes.28

Several studies have established how steroids attenuate pathogen-induced immune responses in the ear. On exposure to lipopolysaccharide, cultured endothelial modiolar cells and tissue exhibit a generic response and release proinflammatory cytokines.29 These proinflammatory cytokines cause vasculitis, vascular leakage syndrome, entry of immunocompetent cells, and perivasculitis, ultimately leading to cochlear ischemia, intracochlear tissue damage, and hearing loss. Administration of dexamethasone can inhibit this cytokine immune response, and can potentially interrupt the beginnings of the inflammatory cascade at the level of cytokine expression.

Several other studies support the role of steroids in ion homeostasis in the inner ear. Serum glucocorticoid levels are directly correlated with activity and concentration of Na+,K+-ATPase in the inner ear.30 Lee and Marcus31 found that potassium secretion by marginal cells is immediately increased after the administration of steroids. Because the kinetics are too rapid for transcriptional activation to cause this change (it takes at least 30 minutes for RNA polymerase to be activated), a nongenomic mechanism is implicated. Modern theories of steroid pharmacology include not only nongenomic and genomic pathways of steroid hormone action, but also a nongenomic modulation of the genomic effects.32 These relationships in the inner ear are just beginning to be understood.

Pharmacokinetics

Intratympanic administration yields much higher concentrations of steroids in the inner ear than either intravenous or oral administration.6,33 Parnes and colleagues33 compared intravenous and intratympanic administration of hydrocortisone, methylprednisolone, and dexamethasone (short-acting, intermediate-acting, and long-acting steroids). Although all three steroids successfully penetrated the blood-labyrinthine barrier, there was a much higher concentration of steroids in inner ear tissues with intratympanic administration. Other investigators have shown that the metabolism of steroids, including uptake and elimination, is different in cochlear tissues compared with other organs.34 Methylprednisolone had the highest concentration and longest duration in perilymph and endolymph of the three compounds.33 Similar concentrations of steroids were found in the scala tympani and scala vestibuli. The authors argue that the concentration of steroids in the endolymph implies some form of active transport through the membranous labyrinth.

The findings regarding the superior concentrations of methylprednisolone are controversial. First, other forms of steroids have been tolerated much better by middle ear tissues. Dexamethasone seems to be better tolerated and less irritative to middle ear tissues. Second, higher concentrations have not led to superior clinical results. It may be that higher perilymph and endolymph concentrations do not translate into greater efficacy. In addition, although high methylprednisolone concentrations and high anti-inflammatory activity associated with attainable levels are observed with methylprednisolone, therapeutic efficacy may rely on other mechanisms of action. One possibility relates to Na+-K+ channel activity. The mineralocorticoid and glucocorticoid classes of steroids induce markedly different responses in Na+-K+ channel activity.31 At this point, it is reasonable to use the less morbid middle ear therapeutic agents (i.e., dexamethasone) until more definitive studies can determine whether the higher concentrations in the study by Parnes and colleagues33 translate into better clinical results, despite decreased tolerability.

Systemic Steroids

Currently, systemic steroids are the treatment of choice for sudden SNHL35,36 and acute vestibular vertigo.37 The most frequently used protocol of oral steroids for inner ear disease is 60 mg of prednisone (or 1 mg/kg/day for adults) taken for 10 to 14 days in idiopathic sudden SNHL or for 1 month in suspected autoimmune inner ear disease.38 Both indications call for a gradual taper after the initial treatment period is finished. If hearing loss returns during the taper, a higher dose of prednisone is restarted. Relapse of hearing loss is often preceded by tinnitus.39 Shea40 recommended that in addition to oral steroids, 16 mg of intravenous dexamethasone should be perfused over 3 hours. The value of adjunctive intravenous delivery of steroids in addition to oral therapy remains to be established.

Meniere’s Disease

Meniere’s disease may be due in some cases to immune dysfunction. Steroids are often used in Meniere’s disease treatment protocols.1 Itoh and Sakata41 reported the first intratympanic steroid protocol in 1987, in which four to five weekly injections of 2 mg of dexamethasone were administered to 61 patients with unilateral Meniere’s disease. This protocol resulted in relief of vertigo in 80% of patients and reduction in tinnitus in 74% of patients. Subsequently, additional studies have used intratympanic steroids to treat Meniere’s disease, some with more promising results than others.

Sennaroglu and colleagues42 placed tympanostomy tubes in 24 patients with Meniere’s disease with intractable vertigo and applied 5 drops of 1 mg/mL dexamethasone solution into the middle ear space every other day for 3 months (administered at home by the patient). This protocol resulted in a vertigo control rate of 72%, improved hearing in 17%, decreased tinnitus in 75%, and reduced aural fullness in 75%. This protocol is attractive because the drug is self-administered, the entire procedure can be accomplished under local anesthesia, and the delivery method provides flexibility to titrate the dose. The authors acknowledge that their results may be confounded by a placebo effect secondary to the tympanostomy tubes. They cite a study by Montandon and associates20 that reported that tympanostomy tube placement prevented vertigo attacks in 71% of patients.

Barrs and coworkers43 also used tympanostomy tubes to administer intratympanic dexamethasone. They used a dose of 0.3 to 0.5 mL of 4 mg/mL dexamethasone. Injections were given daily for the first 2 days and weekly thereafter for a total of 1 month and five treatments. The vertigo control responses were reported in time intervals, with an 86% response at less than 3 months, a 52% response at 3 months, and a 43% response at 6 months. There was an average of 2.7-dB hearing loss, but one patient had a 35-dB hearing loss. The authors propose that intratympanic steroid treatment is effective for short-term management of vertigo, but is less successful for long-term vertigo control.

Shea40 reported on a protocol that uses a combination of intravenous, intratympanic, and oral dexamethasone to treat patients with Meniere’s disease. A mixture of 0.5 mL hyaluronan containing 16 mg/mL of dexamethasone is injected into the middle ear after argon laser myringotomy and removal of RWM adhesions. The patient sits with the injected ear up for 3 hours while receiving 16 mg of intravenous dexamethasone. This treatment is performed for 3 consecutive days. Then 0.25 mg of oral dexamethasone is taken for 30 to 90 days, depending on the response to treatment. This protocol resulted in a vertigo control rate of 77%, hearing improvement in 35.4%, and hearing loss in 6.3%. With the 6-point functional level score recommended by the American Academy of Otolaryngology–Head and Neck Surgeons (AAO-HNS) guidelines,44 61.3% of patients were improved, 32.3% were unchanged, and 6.4% were worse after treatment.

In a rare controlled trial, Silverstein and colleagues1 conducted a prospective, randomized, double-blind, crossover trial of intratympanic dexamethasone and placebo in 17 patients with Meniere’s disease. All patients had stage IV Meniere’s disease by the Shea classification (they no longer had vertigo, had poor hearing, and had significant fullness and tinnitus). Patients received intratympanic injection of either placebo (0.2 to 0.3 mL of 1 : 1 normal saline and sodium hyaluronate) or 0.2 to 0.3 mL of a 1 : 1 mixture of 16 mg/mL dexamethasone and sodium hyaluronate. This treatment was performed for 3 consecutive days. Three weeks after the initial treatment, the groups received the crossover treatment (the placebo group received intratympanic steroids and vice versa). The parameters recorded were audiometric data, electronystagmography recordings, and tinnitus evaluations; several questionnaires and telephone interviews were included. Intratympanic steroids provided no significant benefit over placebo in any of the parameters recorded, and patients could not guess which arm of the study they were in. This study would seem to confirm the lack of benefit of intratympanic steroid use for Meniere’s disease. The severely diseased patient population (all stage IV) may be a selection bias not present in other studies, however, leaving open the possibility that intratympanic steroids may be useful in less severe cases. Also, most successful intratympanic steroid protocols involve steroid treatments that last longer than 3 days.

In another well-designed study, Garduño-Anaya and associates45 conducted a prospective, placebo-controlled, double-blind, randomized study with 2-year follow-up, and found dramatically different results than Silverstein and colleagues.1 A regimen of 5 consecutive days of intratympanic dexamethasone (4 mg/mL) versus saline for placebo control was administered to 11 study patients and 11 controls, all having unilateral disease as outlined by the 1995 AAO-HNS Committee on Hearing and Equilibrium. In the dexamethasone group at 2-year follow-up, complete control of vertigo (class A) was achieved in 9 of 11 patients (82%), and substantial control of vertigo (class B) was achieved in the remaining 2 patients. In the control group, only 7 of 11 patients finished the trial, and of these, 4 patients (57%) achieved class A vertigo control, 2 patients (29%) achieved class C, and 1 patient (14%) achieved class F. These results were statistically significant. There were several other outcome measures with variable results, with significant improvement in AAO-HNS 6-point functional level; Dizziness Handicap Inventory; and subjective vertigo, tinnitus, and aural fullness scores in the treatment group, but no significant changes in the Tinnitus Handicap Score, pure-tone average, speech discrimination score, electronystagmography, or electrocochleography tests between the two groups. The final verdict on intratympanic steroid use for Meniere’s disease is still pending, and more data on optimal dosing and protocols are needed.

Sudden Sensorineural Hearing Loss

Systemic and intratympanic steroid therapy has also been used for treatment of sudden SNHL. The major prognostic factors predicting response to treatment for sudden SNHL are initial severity of hearing loss and time between onset and treatment.6,46 There is a high spontaneous recovery rate of 30% to 60%; treatment efficacy of any intervention has to be greater than the spontaneous recovery rate. Oral steroid therapy within the first 2 weeks has shown recovery rates approaching 80% and decreasing thereafter.46,47 Because of the high initial response to oral steroids, few practitioners have attempted to use intratympanic steroids, and most intratympanic steroid trials enroll patients who had oral treatment fail. That being said, numerous studies, mostly retrospective, have shown that intratympanic steroids do provide an excellent method for salvage of hearing in the case of systemic steroid treatment failure.

Gianoli and Li35 reported results of a trial of intratympanic steroids for patients with sudden SNHL who had failed to improve after high-dose systemic steroids (1 mg/kg/day of prednisone for a minimum of 1 week). The protocol consisted of tympanostomy tube placement followed by instillation of 0.5 mL of steroid solution consisting of either 25 mg/mL of dexamethasone or 62.5 mg/mL of methylprednisolone. Four treatments were administered over 10 to 14 days, and audiometric data were recorded 1 to 2 weeks after treatment. The results showed a pure-tone average improvement of 10 dB or greater in 44% of patients. The authors argued that although this improvement seems modest, this is in a cohort of patients who would otherwise be considered refractory to steroid treatment. Although there was a trend toward better outcomes for methylprednisolone, there was no significant difference between the two steroid solutions.

Kopke and colleagues46 reported results of the use of methylprednisolone perfusion by means of an RWM microcatheter in patients with sudden SNHL who failed oral prednisone therapy. The catheter delivered 62.5 mg/mL of methylprednisolone at a continuous rate of 10 µL/hour for 14 days with an electronic pump. Audiometric changes were the main outcome measures recorded. Of the six patients who had catheter placement 6 weeks or less after the onset of hearing loss, five had improvements of 10 dB or more in pure-tone averages, and four of these had a return to baseline pure-tone averages. Results were less promising for patients receiving treatment more than 6 weeks after onset of symptoms; in one patient, there was additional hearing loss associated with vertigo.

Several other, smaller reports have been published. Chandrasekhar47 reported results from a series of 10 patients treated with intratympanic dexamethasone. The dexamethasone concentration and number of intratympanic injections varied among patients, and several patients were taking oral medications in addition to intratympanically administered steroids, making outcomes difficult to assess. Of the 10 patients treated, 6 experienced hearing improvements greater than 10 dB, however. Parnes and colleagues33 reported results from a similar series of 13 patients with sudden SNHL treated with intratympanic steroids. Because there was considerable variation in the number of treatments applied and the drug administered (dexamethasone vs. methylprednisolone), the results are difficult to assess. Of the 13 patients treated, 6 showed hearing improvements of 10 dB or more.

One point of consensus about these studies is that they show that the longer between the insult and the administration of intratympanic steroid treatment after oral steroid failure, the lower are the chances of salvaging hearing. If intratympanic steroids are to be used, they should be used as soon as possible after it becomes clear that oral steroids are not improving hearing, preferably within the first 2 weeks of the original insult.48

Dosing

The most widely used steroid for intratympanic protocols is dexamethasone, followed by methylprednisolone. Intratympanic dexamethasone preparations vary from 1 to 25 mg/mL.49,50 Some studies use a hyaluronic acid preparation consisting of a 1 : 1 mixture of 16 mg/mL of dexamethasone and 0.5 mg/mL of hyaluronate sodium.1,40 Most intratympanic methylprednisolone studies use a solution of 62.5 mg/mL.22,46 The amount of solution injected in each protocol is designed to fill the middle ear space (which is 0.3 to 0.5 mL). The interval of dosing depends mostly on the instillation method. Protocols that include self-administration through tympanostomy tubes have every-other-day dosing.49 Intratympanic injection protocols are much less frequent, and often include “shotgun” dosing with multiple injections over the first 2 weeks of treatment.1,51

Side Effects

The side effects of long-term systemic steroid use are well known and include compromise of the immune system leading to infections, osteoporosis, peptic ulcers, hypertension, myopathy, ocular effects, impaired healing, psychologic effects, and avascular necrosis.52 In contrast, intratympanic steroids are characterized by minor local morbidities. Several preclinical studies have documented that intratympanic steroids cause no morphologic or functional compromise in animal models.27,53 Human clinical trials have reported benign side-effect profiles, even after multiple and long-term treatments.33 There are several reports of decreased hearing in human clinical trials of patients with Meniere’s disease,40,43 but it is unclear whether this is a side effect of treatment or part of the natural course of the disease.51,54 There are some reports of tympanic membrane perforations and otitis media secondary to the perfusion process.35 Some patients experience a mild burning sensation in the ear after injection of methylprednisolone. This side effect has been avoided by combining 0.1 mL of 1% lidocaine with 0.9 mL of standard intravenous methylprednisolone solution (40 mg/mL).33

Gentamicin

Fowler55 first described the use of aminoglycosides for chemical ablation of the labyrinth in 1948, using systemic streptomycin to treat patients with Meniere’s disease with intractable vertigo. Bilateral cochlear damage led to the abandonment of this effort, but in 1957, Schuknecht56 revived interest in chemical ablation with the introduction of intratympanic administration of aminoglycosides. Although loss of hearing was almost as common as the resolution of vertigo, his work set the stage for the development of modern intratympanic chemical ablation protocols. In the mid-1970s, Beck and Schmidt57 described a low-dose strategy that departed from the goal of total vestibular ablation. They compared a high-dose ablative protocol with a low-dose, low-injection-frequency protocol, and found that although vertigo control was essentially the same, the hearing loss rate decreased from 58% to 15%. This improvement rekindled interest in intratympanic gentamicin therapy, and led to the development of strategies that maximize vertigo control, while minimizing hearing loss.

Mechanism of Action

Despite the widespread belief that gentamicin is selectively toxic to vestibular hair cells, this assertion is not fully supported by the literature. Several researchers have shown that gentamicin and streptomycin cause parallel and dose-dependent damage to vestibular and cochlear hair cells.58,59 Wanamaker and colleagues59 stated, “When the vestibular system was severely damaged, the cochlea was severely damaged; when loss in the vestibular system was mild, loss in the cochlea was mild. We did not observe any dose-related selectivity for the vestibular system over the cochlea.” The clinical finding of significant correlation between loss of caloric response and hearing loss after gentamicin exposure further betrays the notion of selective vestibular toxicity.60,61

If there is no selective vestibular toxicity, how is it that clinicians have achieved good vertigo control with minimal hearing loss? In part, the answer may lie in pharmacokinetics.22,62,63 Hoffer and colleagues22 compared the kinetic profiles of intratympanic injection versus microcatheter delivery of gentamicin, and correlated these data with the functional and morphologic changes observed in the inner ear. Despite the fact that the total dose in both methods was roughly equal, the resulting morphologic changes were quite different. Intratympanic injection led to erratic changes, sometimes causing obliteration of auditory functioning within 4 hours, and in other cases showing significantly delayed ototoxic effects. In contrast, controlled perfusion by microcatheter caused predictable and uniform damage.

Hoffer and colleagues22 explained that these different morphologic changes may be due to two different patterns of hair cell loss, patterns that correlate with the timing and concentration of aminoglycoside delivery. These patterns include a necrotic pattern that is associated with rapid and high-dose perfusion, and an apoptotic pattern that is associated with slower or chronic perfusion.53,64 This complicated relationship may be secondary to saturation of anionic binding sites on the cell membrane or to modifiable active uptake patterns that depend on gentamicin kinetics.65

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