Assessment of middle ear structure and function with optical coherence tomography.

BACKGROUND: Current clinical tests for middle ear (ME) injuries and related conductive hearing loss (CHL) are lengthy and costly, lacking the ability to noninvasively evaluate both structure and function in real time. Optical coherence tomography (OCT) provides both, but its application to the audiological clinic is currently limited. OBJECTIVE: Adapt and use a commercial Spectral-Domain OCT (SD-OCT) to evaluate anatomy and sound-evoked vibrations of the tympanic membrane (TM) and ossicles in the human ME. MATERIALS AND METHODS: SD-OCT was used to capture high-resolution three-dimensional (3D) ME images and measure sound-induced vibrations of the TM and ossicles in fresh human temporal bones. RESULTS: The 3D images provided thickness maps of the TM. The system was, with some software adaptations, also capable of phase-sensitive vibrometry. Measurements revealed several modes of TM vibration that became more complex with frequency. Vibrations were also measured from the incus, through the TM. This quantified ME sound transmission, which is the essential measure to assess CHL. CONCLUSION AND SIGNIFICANCE: We adapted a commercial SD-OCT to visualize the anatomy and function of the human ME. OCT has the potential to revolutionize point-of-care assessment of ME disruptions that lead to CHL which are otherwise indistinguishable via otoscopy.

Intratympanic Lipopolysaccharide Elevates Systemic Fluorescent Gentamicin Uptake in the Cochlea.

OBJECTIVES/HYPOTHESIS: Lipopolysaccharide (LPS), a key component of bacterial endotoxins, activates macrophages and triggers the release of inflammatory cytokines in mammalian tissues. Recent studies have shown that intratympanic injection of LPS simulates acute otitis media (AOM) and results in morphological and functional changes in the inner ear. Here we established an AOM mouse model with LPS to investigate the uptake of ototoxic gentamicin in the inner ear, and elucidated the underlying mechanism by focusing on cochlear inflammation as a result of AOM. STUDY DESIGN: Preclinical rodent animal model. METHODS: Fluorescently tagged gentamicin (GTTR) was systemically administered to mice with AOM. Iba1-positive macrophage morphology and inner ear cytokine profile were evaluated by immunofluorescence technique and a mouse cytokine array kit, respectively. RESULTS: We observed characteristic symptoms of AOM in the LPS-treated ears with elevated hearing thresholds indicating a conductive hearing loss. More importantly, the LPS-induced AOM activated cochlear inflammatory responses, manifested by macrophage infiltration, particularly in the organ of Corti and the spiral ligament, in addition to the up-regulation of proinflammatory cytokines. Meanwhile, GTTR uptake in the stria vascularis and sensory hair cells from all the LPS-treated ears was significantly enhanced at 24, 48, and 72-hour post-treatment, as the most prominent enhancement was observed in the 48-hour group. CONCLUSION: In summary, this study suggests that the pathological cochlea is more susceptible to ototoxic drugs, including aminoglycosides, and justified the clinical concern of aminoglycoside ototoxicity in the AOM treatment. Laryngoscope, 131:E2573-E2582, 2021.

Forward and Reverse Middle Ear Transmission in Gerbil with a Normal or Spontaneously Healed Tympanic Membrane.

Tympanic membranes (TM) that have healed spontaneously after perforation present abnormalities in their structural and mechanical properties; i.e., they are thickened and abnormally dense. These changes result in a deterioration of middle ear (ME) sound transmission, which is clinically presented as a conductive hearing loss (CHL). To fully understand the ME sound transmission under TM pathological conditions, we created a gerbil model with a controlled 50% pars tensa perforation, which was left to heal spontaneously for up to 4 weeks (TM perforations had fully sealed after 2 weeks). After the recovery period, the ME sound transmission, both in the forward and reverse directions, was directly measured with two-tone stimulation. Measurements were performed at the input, the ossicular chain, and output of the ME system, i.e., at the TM, umbo, and scala vestibuli (SV) next to the stapes. We found that variations in ME transmission in forward and reverse directions were not symmetric. In the forward direction, the ME pressure gain decreased in a frequency-dependent manner, with smaller loss (within 10 dB) at low frequencies and more dramatic loss at high frequency regions. The loss pattern was mainly from the less efficient acoustical to mechanical coupling between the TM and umbo, with little changes along the ossicular chain. In the reverse direction, the variations in these ears are relatively smaller. Our results provide detailed functional observations that explain CHL seen in clinical patients with abnormal TM, e.g., caused by otitis media, that have healed spontaneously after perforation or post-tympanoplasty, especially at high frequencies. In addition, our data demonstrate that changes in distortion product otoacoustic emissions (DPOAEs) result from altered ME transmission in both the forward and reverse direction by a reduction of the effective stimulus levels and less efficient transfer of DPs from the ME into the ear canal. This confirms that DPOAEs can be used to assess both the health of the cochlea and the middle ear.

Preferences in stapes surgery among American otological society otologists.

OBJECTIVE: Stapes surgery is technically challenging, yet its methodology is not standardized. We aim to elucidate preferences in stapes surgery among American Otological Society (AOS) otologists and determine if any common practice patterns exist. STUDY DESIGN: Cross-sectional study via emailed questionnaire. SETTING: Surgery centers. SUBJECTS AND METHODS: Members of the AOS were an emailed a survey to quantify variables including surgical volume, anesthetic preference, laser use, type of procedure, footplate sealing technique, antibiotic use, and trainee participation. RESULTS: Most otologists (71%) performed 2 to 5 stapes surgeries per month under general anesthesia (69%) with stapedotomy (71%) as the preferred procedure. Most (56%) used the rosette method of laser stapedotomy with manual pick debris removal for footplate fenestration. Either the handheld potassium titanyl phosphate (KTP) laser (40%) or handheld carbon dioxide (CO2) laser (33%) was used. The heat-activated memory hook (51%) was the preferred prosthesis. Footplate sealing method was variable, as was antibiotic use among respondents. Trainee participation was limited, as 42% of otologists allowed residents to place the prosthesis, and fewer allowed residents to crimp the prosthesis, and laser or drill the footplate. Surgeons with higher surgical volume (≥ 6 surgeries per month) demonstrated the following statistically significant correlations: footplate fenestration with laser in a rosette pattern and pick for debris removal (r s  = -0.365, P = 0.014) and trainee participation with fellows only (r s  = 0.341, P = 0.022). CONCLUSIONS: Trends in various surgical decisions showed a lack of consensus in all aspects of stapes surgery.

Recovery from tympanic membrane perforation: Effects on membrane thickness, auditory thresholds, and middle ear transmission.

Sounds delivered to the ear move the tympanic membrane (TM), which drives the middle-ear (ME) ossicles and transfers the acoustic energy to the cochlea. Perforations of the TM result in hearing loss because of less efficient sound conduction through the ME. The patterns of TM motions, and thus ME sound transmission, vary with frequency and depend on many factors, including the TM thickness. In this study, we measured TM thickness, auditory brainstem responses (ABR), and ME transmission immediately following a controlled pars tensa perforation and after 4 weeks of spontaneous recovery in a gerbil model. It is found that after recovery, the hearing thresholds showed a sloping pattern across frequencies: almost back to normal levels at frequencies between 2 and 8 kHz, sloping loss in the low (<2 kHz) and mid-frequency (8-30 kHz) range, and little restoration at frequencies above 30 kHz. This pattern was confirmed by the measured ME pressure gains. The thickness of the healed TM did not return to normal but was 2-3 times thicker over a significant portion of the membrane. The increased thickness was not limited to the perforated area but expanded into intact regions adjacent to the perforation, which led to an increased thickness in general. Combined, these results suggest that TM thickness is an important factor in determining its vibration patterns and efficiency to transfer sounds to the ossicles and thus influencing ME sound transmission, especially for high-frequency sounds. The results provided both structural and functional observations to explain the conductive hearing loss seen in patients with abnormal TMs, e.g., caused by otitis media, spontaneously healed post-perforation, or repaired via tympanoplasty in the clinic.

Distortion product otoacoustic emissions: Sensitive measures of tympanic -membrane perforation and healing processes in a gerbil model.

Distortion product otoacoustic emissions (DPOAEs) evoked by two pure tones carry information about the mechanisms that generate and shape them. Thus, DPOAEs hold promise for providing powerful noninvasive diagnostic details of cochlear operations, middle ear (ME) transmission, and impairments. DPOAEs are sensitive to ME function because they are influenced by ME transmission twice, i.e., by the inward-going primary tones in the forward direction and the outward traveling DPOAEs in the reverse direction. However, the effects of ME injuries on DPOAEs have not been systematically characterized. The current study focused on exploring the utility of DPOAEs for examining ME function by methodically characterizing DPOAEs and ME transmission under pathological ME conditions, specifically under conditions of tympanic-membrane (TM) perforation and spontaneous healing. Results indicated that DPOAEs were measurable with TM perforations up to ∼50%, and DPOAE reductions increased with increasing size of the TM perforation. DPOAE reductions were approximately flat across test frequencies when the TM was perforated about 10% (<1/8 of pars tensa) or less. However, with perforations greater than 10%, DPOAEs decreased further with a low-pass filter shape, with ∼30 dB loss at frequencies below 10 kHz and a quick downward sloping pattern at higher frequencies. The reduction pattern of DPOAEs across frequencies was similar to but much greater than, the directly measured ME pressure gain in the forward direction, which suggested that reduction in the DPOAE was a summation of losses of ME ear transmission in both the forward and reverse directions. Following 50% TM perforations, DPOAEs recovered over a 4-week spontaneously healing interval, and these recoveries were confirmed by improvements in auditory brainstem response (ABR) thresholds. However, up to 4-week post-perforation, DPOAEs never fully recovered to the levels obtained with normal intact TM, consistent with the incomplete recovery of ABR thresholds and ME transmission, especially at high-frequency regions, which could be explained by an irregularly dense and thickened healed TM. Since TM perforations in patients are commonly caused by either trauma or infection, the present results contribute towards providing insight into understanding ME transmission under pathological conditions as well as promoting the application of DPOAEs in the evaluation and diagnosis of deficits in the ME-transmission system.

Effects of tympanic membrane perforation on middle ear transmission in gerbil.

Perforations of the tympanic membrane (TM) alter its structural and mechanical properties, thus resulting in a deterioration of sound transmission through the middle ear (ME), which presents itself clinically as a conductive hearing loss (CHL). The resulting CHL is proposed to be due to the loss of the pressure difference across the TM between the outer ear canal space and the ME cavity, a hypothesis which has been tested with both theoretical and experimental approaches. In the past, direct experimental observations had been either from the ME input (umbo) or the output of the stapes, and were focused mainly on the low frequency region. However, there was little documentation providing a thorough picture of the influence of systematically increasing sizes of TM perforations on ME sound transmission from the input (i.e., pressure at the TM or motion of the umbo) to the output (pressure produced by the motion of the stapes). Our study explored ME transmission in gerbil under conditions of a normal, intact TM followed by the placement of mechanically-induced TM perforations ranging from miniscule to complete removal of the pars tensa, leaving the other parts of ME intact. Testing up to 50 kHz, variations of ME transmission were characterized in simultaneously measured tone induced pressure responses at the TM (PTM), pressure responses in the scala vestibuli next to the stapes (PSV), and velocity measurements of the umbo (Vumbo), as well as by detailed descriptions of sound transmission from the TM to the stapes, i.e., the umbo transfer function (TF), the transfer of the sound stimulus along the ossicular chain as found from the ratio of cochlear pressure to umbo motion, and ME pressure gain (MEPG). Our results suggested that increasing the size of TM perforations led to a reduction in MEPG, which appeared to be primarily due to the reduction in the effective/initial mechanical drive to the umbo, with a relatively smaller decrease of sound transfer along the ossicular chain. Expansion of the perforation more than 25% appeared to drastically reduce sound transmission through the ME, especially for the higher frequencies.

Dornase Alfa Ototoxic Effects in Animals and Efficacy in the Treatment of Clogged Tympanostomy Tubes in Children: A Preclinical Study and a Randomized Clinical Trial.

Importance: Many treatments for clogged tympanostomy tubes (TTs) have been proposed, but none have met scientific rigor for safety and efficacy, including the popular empirical use of ototopical antibiotic drops. Dornase alfa, a recombinant molecule with the unique property of cleaving DNA, may be ideal in treating clogged TTs because both middle-ear effusion and the plug are abundant with DNA. Objective: To investigate the ototoxic effects of dornase alfa in a chinchilla model and its efficacy in a clinical trial in children with clogged TTs. Design, Setting, and Participants: The safety profiles of dornase alfa (full-strength and 1:10 strength) were evaluated in chinchilla middle ears using serial auditory brainstem response. The efficacy of ototopical dornase alfa (full-strength) was evaluated in children with clogged TTs in a prospective, single-blind randomized clinical trial. The animal study included 21 chinchillas and was conducted at Loma Linda University, Loma Linda, California, and the clinical trial was conducted at Children's Hospital Colorado, Aurora. A total of 40 children (50 ears with tubes) were enrolled. Interventions: In the animal study, chinchillas were assigned to 3 groups: controls (saline), full-strength dornase alfa, or 1:10 dornase alfa dilution. Children were randomly assigned to receive either topical dornase alfa or ofloxacin for clogged TT, 5 drops each ear twice a day for 7 days. Main Outcomes and Measures: Animal study: Auditory brainstem responses. Randomized trial of children participants: The primary outcome was patency of TT at day 14 assessed by otoscopy and tympanometry. Results: The chinchilla study showed similar auditory brainstem response degradation during a 6-hour period between the control (n = 5) and treatment groups (n = 21). In the clinical trial, a total of 40 clogged TTs (in 33 children, including 25 boys [76%]; mean age, 4.3 years; median [range] age, 3.4 [1.0-14.3] years) were analyzed. The number of unclogged TTs was higher in the dornase alfa group (13 [59%]) compared with the ofloxacin group (8 [44%]), with a difference of 15% (odds ratio, 1.8; 95% CI, 0.54-6.72). Conclusions and Relevance: The chinchilla model suggests that dornase alfa is likely nonototoxic. The pilot clinical trial failed to show efficacy of dornase alfa to unclog TTs. With the difference seen between the treatment groups, a sample size estimate could be calculated for a future large-scale trial. Trial Registration: ClinicalTrials.gov identifier: NCT00419380.

Middle-Ear Sound Transmission Under Normal, Damaged, Repaired, and Reconstructed Conditions.

HYPOTHESIS: We hypothesize that current clinical treatment strategies for the disarticulated or eroded incus have the effect of combining the incus and stapes of the human middle ear (ME) into one rigid structure, which, while capable of adequately transmitting lower-frequency sounds, fails for higher frequencies. BACKGROUND: ME damage causes conductive hearing loss (CHL) and while great progress has been made in repairing or reconstructing damaged MEs, the outcomes are often far from ideal. METHODS: Temporal bones (TBs) from human cadavers, a laser Doppler vibrometer (LDV), and a fiber-optic based micro-pressure sensor were used to characterize ME transmission under various ME conditions: normal; with a disarticulated incus; repaired using medical glue; or reconstructed using a partial ossicular replacement prosthesis (PORP). RESULTS: Repairing the disarticulated incus using medical glue, or replacing the incus using a commercial PORP, provided similar restoration of ME function including almost perfect function at frequencies below 4 kHz, but with more than a 20-dB loss at higher frequencies. Associated phase responses under these conditions sometimes varied and seemed dependent on the degree of coupling of the PORP to the remaining ME structure. A new ME-prosthesis design may be required to allow the stapes to move in three-dimensional (3-D) space to correct this deficiency at higher frequencies. CONCLUSIONS: Fixation of the incus to the stapes or ossicular reconstruction using a PORP limited the efficiency of sound transmission at high frequencies.

Panel 8: Complications and sequelae.

BACKGROUND AND OBJECTIVES: Although serious complications of otitis media (OM) such as brain abscess are rare, sequelae of OM such as tympanic membrane perforation and atelectatic tympanic membrane are quite common. Inner ear sequelae can cause hearing loss and speech and language problems. The objectives of this article are to provide a state-of-the-art review on recent articles on complications and sequelae of OM in different anatomic locations, from the tympanic membrane to intracranial sites, as well as hearing loss and speech and language development. DATA SOURCES: Primarily PubMed supplemented by Ovid MEDLINE and the Cochrane Database. REVIEW METHODS: All types of articles related to OM complications and sequelae published in English between January 2007 and June 2011 were identified. A total of 127 relevant quality articles are summarized and included in this report. RESULTS: Key findings are summarized based on the following major anatomic locations and categories: tympanic membrane; cholesteatoma; ossicular problems; mucosal sequelae; inner ear sequelae; speech and language development; extracranial areas, including mastoiditis and facial nerve paralysis; intracranial complications; and future research goals. New information and insights were gained to prevent complications and sequelae. CONCLUSION AND IMPLICATIONS FOR PRACTICE: Over the past 4 years, progress has been made in advancing the knowledge on the complications and sequelae of OM, which can be used to prevent and treat them effectively. Areas of potential future research have been identified and outlined.

Panel 4: Recent advances in otitis media in molecular biology, biochemistry, genetics, and animal models.

BACKGROUND: Otitis media (OM) is the most common childhood bacterial infection and also the leading cause of conductive hearing loss in children. Currently, there is an urgent need for developing novel therapeutic agents for treating OM based on full understanding of molecular pathogenesis in the areas of molecular biology, biochemistry, genetics, and animal model studies in OM. OBJECTIVE: To provide a state-of-the-art review concerning recent advances in OM in the areas of molecular biology, biochemistry, genetics, and animal model studies and to discuss the future directions of OM studies in these areas. DATA SOURCES AND REVIEW METHODS: A structured search of the current literature (since June 2007). The authors searched PubMed for published literature in the areas of molecular biology, biochemistry, genetics, and animal model studies in OM. RESULTS: Over the past 4 years, significant progress has been made in the areas of molecular biology, biochemistry, genetics, and animal model studies in OM. These studies brought new insights into our understanding of the molecular and biochemical mechanisms underlying the molecular pathogenesis of OM and helped identify novel therapeutic targets for OM. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Our understanding of the molecular pathogenesis of OM has been significantly advanced, particularly in the areas of inflammation, innate immunity, mucus overproduction, mucosal hyperplasia, middle ear and inner ear interaction, genetics, genome sequencing, and animal model studies. Although these studies are still in their experimental stages, they help identify new potential therapeutic targets. Future preclinical and clinical studies will help to translate these exciting experimental research findings into clinical applications.

The role of inflammatory mediators in the pathogenesis of otitis media and sequelae.

This review deals with the characteristics of various inflammatory mediators identified in the middle ear during otitis media and in cholesteatoma. The role of each inflammatory mediator in the pathogenesis of otitis media and cholesteatoma has been discussed. Further, the relation of each inflammatory mediator to the pathophysiology of the middle and inner ear along with its mechanisms of pathological change has been described. The mechanisms of hearing loss including sensorineural hearing loss (SNHL) as a sequela of otitis media are also discussed. The passage of inflammatory mediators through the round window membrane into the scala tympani is indicated. In an experimental animal model, an application of cytokines and lipopolysaccharide (LPS), a bacterial toxin, on the round window membrane induced sensorineural hearing loss as identified through auditory brainstem response threshold shifts. An increase in permeability of the blood-labyrinth barrier (BLB) was observed following application of these inflammatory mediators and LPS. The leakage of the blood components into the lateral wall of the cochlea through an increase in BLB permeability appears to be related to the sensorineural hearing loss by hindering K(+) recycling through the lateral wall disrupting the ion homeostasis of the endolymph. Further studies on the roles of various inflammatory mediators and bacterial toxins in inducing the sensorineumral hearing loss in otitis media should be pursued.

Mediolateral graft tympanoplasty for anterior or subtotal tympanic membrane perforation.

OBJECTIVE: To describe and evaluate the mediolateral graft tympanoplasty for the reconstruction of anterior or subtotal tympanic membrane (TM) perforation. STUDY DESIGN AND SETTING: Retrospective study of 100 patients who underwent the mediolateral graft tympanoplasty at community and tertiary care centers from 1995 to 2001. All patients underwent preoperative and postoperative audiograms. Posterior tympanomeatal flap is elevated same as in the medial (underlay) graft tympanoplasty. Anterior-medial canal skin is elevated down to the annulus. At the annulus, only squamous epithelial layer of TM is elevated up to anterior half of the TM perforation. Temporalis fascia is grafted medial (underlay) to the posterior half of the perforation and lateral (overlay) to the anterior half of the de-epithelialized TM perforation, up to the annulus. Anterior canal skin is rotated to cover the fascia graft and TM perforation as a second-layer closure. Patients were followed for at least 6 months. Outcome was considered successful if the TM is intact. RESULTS: There were 3 failures (97% success rate), attributable to a postoperative infection, anterior blunting, and recurrent cholesteatoma, respectively. There was no significant postoperative hearing loss compared with preoperative hearing. More than 70% of the operated ears had hearing improvement of 0-40 dB (0-10 dB in 19% of ears, 11-20 dB in 44%, 21-30 dB in 7%, and 31-40 dB in 4%) even without ossiculoplasty. With ossiculoplasty using either partial ossicular replacement prosthesis (PORP, 15%) or total ossicular replacement prosthesis (TORP, 11%), there were various degree of hearing improvement from 11 to 30 dB. CONCLUSION AND SIGNIFICANCE: The mediolateral graft method is superior to the traditional medial or lateral graft technique for the reconstruction of large anterior or subtotal TM perforation. This new method should help otologic surgeons to improve outcome of tympanoplasty for anterior or total TM perforation. EBM RATING: C-1.

Effect of aminoglycoside otic drops on isolated cochlear outer hair cells with and without liver extract activation.

OBJECTIVE: To assess the ototoxicity of commercially available Gentacidin and TobraDex ear drops with and without liver extract activation using isolated cochlear outer hair cells (OHCs). MATERIAL AND METHODS: OHCs from adult chinchilla cochleae were exposed to standard bathing solution (SBS), liver extract alone and Gentacidin and TobraDex ear drops with and without liver extract. All experiments were performed at an osmolality of 305 +/-5 mOsm, at room temperature and for up to 60 min. OHC images were recorded using an inverted microscope and analyzed electronically. Time to cell death and changes in cell length were measured. RESULTS: The time to cell death and the percent change in cell length were significantly shorter in the Gentacidin+liver extract group than in the Gentacidin alone group (p < 0.05). The TobraDex+liver extract group showed a significantly decreased time to cell death compared to the SBS control group (p < 0.05). There were no significant differences in cell length or time to cell death between the TobraDex+liver extract group and the TobraDex alone group (p > 0.05). CONCLUSION: This study suggests that the cytotoxicity of aminoglycoside ear drops to isolated OHCs in vitro requires

Effect of corticosteroid on salicylate-induced morphological changes of isolated cochlear outer hair cells.

Our previous studies showed that pretreatment with corticosteroids, which inhibits release of arachidonic acid (precursor of prostaglandins and leukotrienes), partially prevented salicylate-induced hearing loss in vivo. The purpose of this study was to determine the effect of pretreatment with corticosteroid (dexamethasone sodium phosphate) on isolated cochlear outer hair cells (OHCs) exposed to salicylate in vitro. Isolated OHCs from the chinchilla cochlea were exposed to salicylate with or without pretreatment with dexamethasone. Images were stored and analyzed on the Image program. The OHCs exposed to salicylate demonstrated a significant shortening in cell length. The OHCs exposed to salicylate after pretreatment with dexamethasone exhibited no significant change in cell length. We conclude that corticosteroid treatment of isolated OHCs is effective in blocking the morphological changes induced by salicylate. This study gives additional evidence that salicylate ototoxicity is mediated by alteration in the levels of arachidonic acid metabolites.