Intratympanic Pharmacotherapy

Conceptual Basis of Intratympanic Therapy

There are several important advantages of an IT pharmacologic approach. First, focused delivery of medications directly into the middle ear with subsequent diffusion into the inner ear can avoid the adverse effects of systemic medications or effects on the contralateral ear. Tracer studies have shown that the primary route of drug entry into the vestibule of the inner ear is predominantly through the round window membrane ; however, entry via the annular ligament of the stapes has also been demonstrated. In a guinea pig model, relative diffusion of gentamicin into the inner ear was 57% through the round window and 35% through the oval window. It is important to appreciate that in the clinical situation, the round window membrane may have variable permeability or even be blocked, which could affect drug diffusion in the inner ear. Second, clinic-based IT therapy allows the practitioner to deliver the needed medication quickly and efficiently as point-of-care treatment. Third, in certain cases these therapies may obviate the need for surgery which reduces risks, morbidity, and inconveniences, in addition to being cost-effective.

Transtympanic Injection Procedure

The transtympanic injection procedure is identical for all the clinical applications described in this chapter. The patient is positioned lying back in a chair and made as comfortable as possible in order to avoid movement during the procedure. The patient’s head is turned, the TM visualized via otomicroscopy, and the injection site planned. The posterosuperior TM should be avoided due to the close proximity of the incudostapedial joint; a posterior or posterior-inferior location is safer and easier to access. The eardrum is typically anesthetized with a small dot of topical phenol or EMLA cream. The medication is warmed roughly to body temperature by rubbing the vial between the hands. A tuberculin syringe with a 25-gauge 1½-inch (3.81-cm) needle is long enough to permit access through a speculum, though some practitioners prefer a spinal needle. The needle is first used to make a micropuncture hole immediately adjacent to the planned injection site. This additional ventilation outlet is useful to avoid uncomfortable buildup of pressure as liquid is instilled into the fixed space. Gentle pressure should be applied to the syringe plunger to produce a slow, steady infusion to minimize discomfort. Typically, approximately 0.2 to 0.5 mL is injected into the middle ear space until a fluid meniscus is seen rising to the level of the injection site ( Figs. 36.1 and 36.2 ). Additional liquid injection beyond this amount will likely start to fill the ear canal, or escape via the ET. The patient is asked to remain in the supine position for 30 minutes and to refrain from excessive swallowing, which may contribute to early evacuation of the drug through the eustachian tube.

Intratympanic Corticosteroid Therapy for Sudden Snhl

Idiopathic SSNHL is a devastating event with an incidence that may be as high as 60 per 100,000. It is defined as a sensorineural hearing loss of at least 30 dB over three consecutive frequencies which occurs within a 72-hour time frame. Although the etiology remains unproven, viral infection and vascular occlusion are two leading theories, although most concur that SSNHL is likely a common endpoint for a variety of different pathophysiologic processes. Failure to recover lost hearing has a negative impact on quality of life, causing both mental and emotional distress.

The risk factors for SSNHL include coronary artery disease, thrombophilic mutations, chronic kidney disease and dialysis, ^, and preexisting SNHL. Other disease processes which increase the risk for vascular events and viral sequelae—obstructive sleep apnea and herpes zoster ^, —have not been shown to result in an increased incidence of SSNHL. Data conflict on whether the risk is increased in the presence of other cardiovascular risk factors such as obesity, ^, diabetes, ^{, ,} increased serum lipids, and smoking and alcohol use. ^,

The natural history of this clinical entity was examined by Mattox and Simmons in 1977. They showed that, similar to Bell’s Palsy, patients presenting for medical care earlier tend to have higher chances for recovery. Since they found no relationship between treatment and recovery, they attributed this differential recovery not to early treatment but to selection bias: many patients who experience sudden hearing loss do not seek treatment immediately, and thus a cohort of patients who present early represent a true cohort of this syndrome and the majority are likely to recover well. Conversely, those who present later are precisely those who have failed the initial conservative (observation) treatment and who are less likely to improve. The clinical implications of the recovery time course and inherent selection bias should inform the analysis of any research manuscript on this topic.

The prognosis for hearing recovery varies greatly from individual to individual, but some risk factors have been ascertained. Older age, higher thresholds (i.e., poorer hearing at onset), and significant vertigo at presentation are correlated with a poorer prognosis for good recovery. ^, Metabolic syndrome was also found to be associated with decreased recovery rates. Recurrence of SSNHL is low. However, patients who have suffered from SSNHL have been found to have a slightly increased risk of stroke, although not of myocardial infarction. ^{, ,}

Multiple drugs, both systemic and local, have been used in the attempted treatment of this devastating symptom; difficulty in assessing outcomes is understandably difficult, since no drug is likely to produce a beneficial effect toward recovery from all postulated causes. Corticosteroid is one of the few drugs that is still used. Although many practitioners consider the potential benefits to be worth the risks, no consensus exists regarding the true efficacy of corticosteroid treatment for hearing recovery; the AAOHNS Clinical Practice Guideline lists this therapy as optional, in the same category as hyperbaric oxygen. However, even when used, the optimal route, timing, frequency, and dosing of corticosteroid administration are likewise unclear.

Glucocorticoids induce a variety of effects of the inflammatory and immune responses. Inhibition of phospholipase A2 in the arachidonic acid pathway leads to global reduction in prostaglandin and leukotriene output by macrophages, monocytes, and endothelial cells. Steroids inhibit the production of other pro-inflammatory molecules such as cytokines and tumor necrosis factor α, and down-regulate the gene expression of pro-inflammatory transcription factors such as NF-κB and AP-1 ; the downstream effect is inhibition of fibroblast proliferation and T cell activation. Glucocorticoid and mineralocorticoid receptors have been identified in inner ear tissue. Endogenous steroids may stabilize junctions in the stria vascularis and upregulate the synthesis of glutathione, an endogenous antioxidant, in the spiral ganglion. Steroids have been shown to prevent ABR threshold elevation and protect against outer hair cell loss after noise exposure in guinea pigs. Additionally, although robust clinical evidence is lacking, results suggest that systemic steroids may protect against inner ear trauma during middle ear surgery and cochlear implantation. ^, Overall, steroids serve to attenuate inflammatory or autoimmune processes in the middle and inner ear when administered systemically or intratympanically.

The efficacy of oral corticosteroids versus placebo for SSNHL was endorsed by Wilson et al., who in 1980 published a placebo-controlled, double-blind study performed at two clinical sites. They examined 67 patients with idiopathic SSNHL within the previous 10 days, without contraindications to steroid treatment (pregnant, diabetic, etc.), and randomized them to receive either oral steroids or placebo. Each clinical site used a different drug and had a different dosing schedule. They found that 61% of those in the steroid group achieved complete or partial recovery [defined as ≥50% recovery in the pure-tone average (PTA) or speech discrimination threshold compared to the contralateral ear] at either 4 weeks or 3 months, compared to only 32% in the placebo group.

The concept of IT steroid administration was introduced by Silverstein et al. in 1996. A variety of studies have examined the pharmacokinetics of IT steroids. Parnes et al. found significantly increased accumulation of steroids within the perilymph and endolymph in guinea pigs when administered IT (dexamethasone 4 mg/mL, methylprednisolone 40 mg/mL, or hydrocortisone 50 mg/mL) compared to oral and IV. Chandrasekhar et al. likewise showed higher drug levels in the perilymph after IT injection of dexamethasone (10 mg/mL) than after IV dexamethasone (0.45 mg/mL) in guinea pigs. A similar study by Bird et al. and subsequent further analysis was performed in humans undergoing cochlear implantation who received methylprednisolone intraoperatively via IT (40 mg/mL), one dose IV (1 mg/kg once), or slow infusion IV (10 mg/kg over 30 minutes). These authors found that IT dosing resulted in significantly (at least 33-fold) higher concentrations of the drug in the perilymph. A multi-institutional noninferiority study was published by Rauch et al. in 2011 evaluating oral versus IT corticosteroids for recovery of hearing after unilateral SSNHL of greater than 50 dB PTA. The authors compared 120 patients receiving oral prednisone (60 mg daily for 14 days followed by a 5-day taper) to 129 patients receiving IT methylprednisolone (40 mg/mL, four doses within 14 days). They found that, overall, IT therapy was not inferior to oral therapy, improving the PTA by 28.7 dB and 30.7 dB, respectively.

Multiple studies have evaluated the use of IT steroids as salvage therapy after failure of oral steroids to significantly improve hearing. Haynes et al. reported a 27.5% rate of improvement (defined as 20 dB improvement in PTA or 20% improvement in speech discrimination) with a single dose of IT dexamethasone (24 mg/mL); a control group consisting of 11 patients who did not undergo any injection had only one patient (9.1%) achieve such improvement. Patients who received injections earlier had a higher chance of experiencing improvement, especially compared to those who were >6 weeks out from the initial loss, which parallels the natural history of the condition. Wu et al. also examined salvage therapy in those who failed oral therapy, and demonstrated a modest improvement in PTA (9.8 dB vs. 4.5 dB) with four injections of IT dexamethasone (4 mg/mL) over 2 weeks compared to the same number of placebo injections with normal saline.

Combination therapy using both oral and IT corticosteroids is another possibility in the treatment of SSNHL. One retrospective study found no significant differences in the hearing outcomes of over 700 patients treated with either oral steroids (prednisone 60 mg for 6 days with a 4-day taper), four IT steroid injections over 2 weeks (dexamethasone 5 mg/mL), or both. Yoo et al. performed a prospective randomized trial on 50 subjects presenting <3 days after hearing loss, examining combination oral (methylprednisolone 48 mg for 9 days with a 6-day taper) and IT therapy (dexamethasone 5 mg/mL four times over 2 weeks) compared to sequential treatment using just oral therapy for 2 weeks with salvage IT therapy if the PTA remained >30 dB. Their findings of rates of 26% and 30% of complete or partial recovery in the simultaneous and sequential groups, respectively, were not significantly different. However, a randomized, double-blind, placebo-controlled study was performed by Battaglia et al. on patients within 6 weeks of their hearing loss, comparing combination oral (prednisone 60 mg for 7 days with a 7-day taper) and IT (dexamethasone 12 mg/mL weekly for 3 weeks) steroids, versus oral steroid and IT placebo (normal saline), versus oral placebo and IT steroid. Subjects on combination therapy experienced greater average improvement in PTA (40 dB) and speech discrimination (44%) than did those given administered IT steroid alone (31 dB PTA and 36% speech discrimination) or oral steroid alone (21 dB PTA and 20% speech discrimination).

A meta-analysis of the use of IT dexamethasone for SSNHL found insufficient evidence to support a difference between its use and that of alternative treatments such as oral steroids. A recent meta-analysis of outcomes in the use of drugs to treat this condition support some form of corticosteroids as demonstrating benefit over placebo; notwithstanding the limitations of the existing data, the authors concluded that IT plus systemic steroid treatment exhibited the most significant improvement.

Ménière Disease Diagnostic Criteria and Reporting Guidelines

Clinical studies of treatment results in MD are subject to well-known challenges. When carefully defined, MD is not common. The symptoms are subjective, difficult to measure, variable, and unpredictable. Inevitably, there are variations in practice patterns, patient selection, treatment protocols, and interpretation of reporting methods. There are issues with regression to the mean and the placebo effect. In the 1990s and subsequently, it was recognized that studies of MD treatment should follow a more rigorous and consistent approach with standardized reporting methods. In 1995, the Committee on Hearing and Equilibrium of the AAOHNS issued diagnostic criteria and a set of clinical research reporting guidelines, which have been followed by most clinical investigators. The diagnostic criteria were updated in 2015 with the elimination of the “certain” and “possible” MD categories, the requirement for audiometrically documented low- to mid-tone fluctuating loss in the affected ear only in the “definite” category, and a defined range of vertigo duration (20 minutes to 12 hours). Treatment outcome reporting guidelines have not been updated and, while still in use and important for understanding the 2-year outcomes, they do not address how to handle treatment approaches where repeated interventions such as IT injection of steroids or gentamicin are used, nor do they provide information on short-term effectiveness which arguably is most important to many patients.

The current guidelines establish the categories of control of vertigo as class A (complete), class B (substantial), etc., based on a numerical value. The numerical value = X/Y ×100, rounded to the nearest whole number, where X is the average number of definitive spells of vertigo per month for the 6 months occurring from 18 to 24 months after therapy and Y , the average number of definitive spells per month for the 6 months before therapy. Class A (complete) control refers to a numerical value of 0; that is, no spells. Class B (substantial) control applies to a numerical score of 1 to 40. Class C control applies to a numerical score of 41 to 80. Class D control applies to a numerical score of 81 to 120. Class E control refers to a numerical score of more than 120. Class F refers to treatment failure, defined as the initiation of a secondary treatment, usually surgical, due to disability from vertigo. It should be noted that some patients with substantial (class B) control may still be having enough severe spells to be disabled from work at certain occupations, and may require further treatment. Others in class B may have greatly reduced severity of vertigo but prefer to receive additional treatment to eliminate episodes of vertigo completely. In this chapter, “effective” control refers to the sum of class A and class B control.