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.

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.

Reconstruction of mastoidectomy defect with titanium mesh.

OBJECTIVE: Intact-canal-wall mastoidectomy procedures leave an unsightly depression in the postauricular area. Until now, there have been few reports of successful reconstruction of mastoidectomy defects, and none using titanium mesh. When secondary mastoidectomy is not anticipated, as in endolymphatic sac shunt procedures, the postauricular defect resulting from mastoidectomy can be eliminated by reconstruction using titanium mesh. This is a retrospective study of 14 patients who underwent reconstruction of a mastoidectomy defect with titanium mesh. MATERIAL AND METHODS: All 14 patients underwent mastoidectomy as part of endolymphatic sac shunt procedures for Ménière's disease. All of the patients had mastoid bones free of chronic infection or cholesteatoma. At the time of mastoidectomy, a large piece of cortical bone was removed and saved instead of being drilled away. After the main procedure was completed, and before closing the postauricular skin, a piece of 1.3-mm titanium mesh was cut to cover the mastoidectomy defect. The mesh was then attached to the mastoid bone at the four corners using 4- or 6-mm screws. The piece of cortical bone removed at the beginning of the mastoidectomy was attached under the mesh and across the mastoid defect. Patients were followed for a period of 6 months to 3 years. The outcome was considered successful when there was no depression at the mastoidectomy site and no evidence of any infection. RESULTS: All patients who underwent reconstruction of a mastoidectomy defect with titanium mesh maintained a normal contour of the mastoid bone without depression or infection. There were no failures. CONCLUSIONS: Mastoidectomy defect reconstruction with titanium mesh is a reliable method for preventing an unsightly depression at the mastoidectomy site. This method is ideal when repeat mastoidectomy is not expected.

Effect of nitric oxide on mucin production in experimental otitis media.

OBJECTIVE: The purpose of this study was to determine the role of nitric oxide (NO) in the pathogenesis of mucoid otitis media (OM) in lipopolysaccharide (LPS)-induced OM. METHODS: OM was induced in chinchillas by injecting S-nitroso-N-acetylpenicillamine (SNAP), LPS, and LPS + SNAP into the superior bullae. Auditory brainstem response thresholds were measured every 24 hours. Samples of middle ear fluid were collected and analyzed for mucin by the periodic acid-Schiff method. At the end of each experiment, temporal bones were harvested for histopathologic study. RESULTS: Mucin concentration was greatest in the LPS + the SNAP group and least in the SNAP-alone group. Auditory brainstem response threshold was highest in the LPS group and lowest in the SNAP group, although not significantly. Histopathology showed the greatest mucosal thickening and inflammation in the LPS + SNAP group. CONCLUSION: The addition of NO in LPS-induced OM increased the mucin concentration in middle ear fluid and increased mucosal thickness and inflammation in middle ear mucosa. SIGNIFICANCE: In the OM disease process, NO may contribute to the pathogenesis of mucoid OM.

Early histopathologic changes after lateral semicircular canal transection and occlusion in guinea pigs.

Occlusion of the semicircular canals has been used in otoneurologic and skull base surgeries with preservation of hearing. In order to understand the role of occlusion in hearing preservation, we observed early histopathologic changes of the lateral semicircular canal following transection and occlusion in guinea pigs. After surgery, the membranous endolymphatic canal was collapsed, and its torn ends were sealed by intramural bone dust in the bony semicircular canal. On the first postoperative day, the endolymphatic canal was expanded to its normal shape, and the sealing at the torn ends was maintained by the bone dust. These findings suggest that occlusion after semicircular canal injuries, by making blind ducts in the membranous endolymphatic canal, is important for the preservation of postoperative hearing.