Influence of middle ear immune response on the immunological state and function of the inner ear.

According to clinical experience, a causative correlation between otitis media and sensorineural hearing loss is likely. During an otitis media, inflammatory mediators should be released and diffuse through the round window membrane to cause an immune response of the inner ear. Using 20 guinea pigs, an immunologically caused otitis media was induced. Auditory evoked potentials were registered by means of electrocochleography and electric response audiometry from day 0 to day 7. Each time, before and after starting the immune response serum, middle ear effusion and perilymph were sampled and the concentration of interleukin-2 (IL-2) analyzed. Decalcified temporal bones were examined immunohistochemically. In this study, IL-2 was found in the middle ear effusion and perilymph, and there was evidence of an immune response of the inner ear during an otitis media. Histological results were in close correlation with this event. Electrophysiological data showed conduction deafness and signs of sensorineural hearing loss with a maximum at day 3.     

Otitis media (silent): A potential cause of childhood meningitis

Sixteen temporal bones from 8 infants with otitis media, who died of meningitis, and 6 controls from infants with only otitis media, were studied histologically. All bones contained middle ear effusion and residual mesenchyme, but, unlike the controls, the meningitic cases showed considerable histopathological tissue changes of chronic and acute otitis media and chronic inflammatory cells in the round window membrane and within the perilymph, the modiolus, and the cochlear aqueduct, suggesting the latter as likely portals from the inner ear to the meninges. Since all tympanic membranes were intact and 3 were histologically normal, this silent route of infection warrants medical vigilance.     

Permeability of the normal round window membrane to Haemophilus influenzae type b endotoxin.

Sensorineural hearing loss associated with otitis media may be due to passage of ototoxic substances such as bacterial toxins and antibiotics, from the middle ear into the inner ear. The round window membrane is the most likely route for such transport. The aim of this study was to analyze the extent of endotoxin passage through the normal round window membrane. The round window membranes of 19 chinchillas were exposed in vivo to Gelfoam soaked in purified Haemophilus influenzae type b endotoxin at a concentration of 45,000 endotoxin units per ml (EU/ml) during 3 to 24 h. Endotoxin levels in the perilymph were measured with Limulus Amaebocyte Lysate or Quantitative Chromogenic Limulus Amaebocyte Lysate. Endotoxin was detected in half of the inner ears at concentrations close to the detection limit (approximately 4 EU/ml). The results suggest that the normal round window membrane efficiently protects the inner ear against the passage of bacterial endotoxins from the middle ear cavity. It is unlikely that endotoxin at concentrations found in the middle ear secretion during otitis media can traverse the round window membrane in sufficient amount to cause inner ear deterioration.     

Prostaglandins in middle ear effusions.

Although otitis media with effusion is usually a self-limiting disease, there are certain cases in which there appears to be chronic progression of the disease with serious sequelae. It has been demonstrated that there are biological mediators of inflammation in the middle ear that are capable of producing mucous membrane pathologic features. Some of these mediators of inflammation may be the prostaglandins. These cyclic fatty acids have been found in ten consecutive middle ear fluids in concentrations that are usually higher than the corresponding serum or plasma. It is suggested that prostaglandins may play an active role in maintaining the inflammatory response in the middle ear in otitis media with effusion.     

Round window membrane permeability. An in vitro model

The round window membrane is regarded to be the main route for passage of potentially ototoxic substances from the middle ear cavity into the inner ear. This may be of clinical importance in acute otitis media and chronic otitis media, where sensorineural hearing impairment sometimes develops. The accuracy and reliability of an in vitro round window membrane permeability model was studied. The round window membrane of the mongolian gerbil was resected, together with its bony niche. The preparation was mounted between two glass chambers representing the middle ear and the inner ear. Passage through the round window membrane did not occur within 3 h for low density lipoprotein with a molecular weight of 2,300 kD. Only minute amounts of highly density lipoprotein, of molecular weight 115-350 kD, passed the round window membrane. The passage rate of horseradish peroxidase, which has previously been shown to pass the round window membrane in vivo, was estimated. The design of the present model is considered to make feasible controlled permeability studies on the round window membrane. Passage rates for different substances through the round window membrane can be calculated under controlled conditions by using this type of in vitro model.     

Permeability of the round window membrane to middle-sized molecules in purulent otitis media

The effect of pneumococcal otitis media on the permeability of the round window membrane was evaluated using tetraethylammonium ions as a tracer. Round window membrane permeability is reduced significantly at resolved stages of purulent otitis media. In contrast, measurements of round window membrane permeability indicate that acute purulent otitis media has a tendency to facilitate such permeability. Moreover, histologic observations of the round window membrane following bacterial inoculation further support the evidence of functional changes in round window membrane permeability. These findings indicate that the round window membrane in resolved stages of purulent otitis media plays a protective role in preventing the penetration of harmful substances into the inner ear.     

Temporal bone study of residual mastoid inflammation in ears with normally appearing tympanic membrane

We examined 395 temporal bones with an intact tympanic membrane to explore the relationship between residual inflammation in the middle ear cavity and development of mastoid pneumatization. Histopathological changes were studied in the middle ear cavity. Mastoid pneumatization was classified as good or poor based on the extent of mastoid tip development to the lateral semicircular canal. Specimens were 344 temporal bones with well-pneumatized mastoid and 51 with poorly-pneumatized mastoid. Otitis media was noted in 119 (34.6%) bones in the good group and 9 (17.6%) in the poor group. In well-pneumatized mastoid, chronic inflammatory changes were frequently observed at the lower portion of mastoid cells, the round window niche, and the tympanic sinus. In contrast, no such incidence of inflammatory change was noted in poorly-pneumatized mastoid. Our findings indicate that an intact tympanic membrane does not always mean freedom from mastoid inflammation, especially when the mastoid is well-pneumatized. This makes it important to check for possible remaining otitis media in patients with a well-pneumatized mastoid, even if the tympanic membrane appears normal.     

Pathophysiology of Streptococcus pneumoniae otitis media: kinetics of the middle ear biochemical and cytologic host responses.

Streptococcus pneumoniae is an important bacterial pathogen in the pathophysiology of otitis media. To elucidate the inflammatory responses that occur during pneumococcal otitis media, the kinetics of the biochemical and cytologic middle ear responses to heat-killed encapsulated and nonencapsulated pneumococci were studied in the chinchilla model. Inoculation of the middle ear cavity with at least 10(6) S pneumoniae cells induced an early, brief vascular response with leakage of small (albumin) followed by larger (alpha 2-macroglobulin) proteins, followed by sustained influx of acute inflammatory cells and lysozyme. The threshold for a sustained lysozyme response was 1,000 times lower for nonencapsulated than for encapsulated pneumococci. These results indicate that nonviable S pneumoniae organisms with an intact envelope initiate the middle ear inflammatory response. Therefore, interventions that enhance the clearance of pneumococcal cells from the middle ear may reduce the inflammatory response and prevent chronic middle ear inflammation.     

Labeling of the glucocorticoid receptor and Na,K-ATPase in a rat otitis media model

HYPOTHESIS: Glucocorticoid hormones exert an influence on the inflammatory response of the middle ear during acute otitis media. Rats with experimentally induced purulent otitis media were given either glucocorticoid hormones in excess or a glucocorticoid hormone blocker that deprived the animals of the hormone. BACKGROUND: Acute otitis media is a common inflammatory disease among children. Streptococcus pneumoniae is the most usual causative agent. The standard treatment today is phenoxymethylpenicillin. The role of glucocorticoid hormones in inflammatory reactions in the middle ear has been widely debated. METHODS: In an otitis media model, a suspension of pneumococci was inoculated into the bulla of the rat, after the animals were pretreated with either a dose of corticosteroid hormones or the glucocorticoid receptor blocking agent RU 486. Rats with induction of otitis media only, but no pretreatment, were used as control subjects, as were the left control-operated ears of all rats. The inflammatory response in the inner ear and in the middle ear was evaluated. The presence of glucocorticoid receptors and the enzyme Na,K-ATPase was investigated with immunohistochemistry. RESULTS: The inflammatory response in the animals with untreated otitis media and in the group with otitis media in rats pretreated with the receptor blocker was much more extensive than in the group of animals pretreated with corticosteroids. In the corticosteroid-treated group, the tympanic membrane and the mucous membrane of the middle ear were less edematous, but the middle ear cavity contained more pus. Only a few lymphocytes were found in the inner ears of these rats. When the inner ear was labeled with antibodies against glucocorticoid receptors, there seemed to be no difference between the labeling patterns in the three groups. This was also the case for antibody labeling against Na,K-ATPase. CONCLUSION: The present results indicate that the reaction in the middle ear mucous membrane is more pronounced in rats that had been pretreated with the hormone receptor blocking drug. An increase of corticosteroid hormone levels during the inflammatory process seem to diminish the reaction in the tympanic membrane and the middle ear mucosa. Neither the hormone receptor blocking drug nor the steroid hormones change the content of glucocorticoid receptors and Na,K-ATPase in the inner ear in the otitis media rat model.     

Cochlear implantation via middle fossa approach – a case report

Objective: Cochlear implantation is routinely performed all over the world via the post-auricular, facial recess approach. Our case study describes the middle fossa approach for the management of bilateral profound sensorineural hearing loss in a female child with multiple external, middle and inner ear malformations. The middle fossa approach has been reported sporadically and has been used inconsistently in patients with chronic otitis media and inner ear malformations.

Case study: A 3-year-old female child presented with bilateral profound sensorineural hearing loss, bilateral anotia, right cochlear nerve agenesis, right facial paralysis, bilateral mild inner ear dysplasia and an aberrant left facial nerve covering the left round window. Further tests indicated that she was a suitable candidate for cochlear implantation and was medically cleared for surgery. In view of the multiple malformations and high risk of injury to her only functioning left facial nerve on the side with a cochlear nerve, cochlear implantation via a middle fossa approach was performed.

Conclusion: Middle fossa approach to cochlear implantation is challenging but can be safely performed even in children and offers an option in patients when a routine mastoidectomy, facial recess and round window approach cannot be undertaken.     

Temporal bone histopathology in a patient suspected of inner ear extension of otitis media

We report the histopathological findings in the temporal bone of a 30-year-old female who died of cervical esophageal carcinoma. The temporal bone sections revealed severe bilateral suppurative labyrinthitis and otitis media that presumably occurred immediately before her death. Many inflammatory cells were present in the middle ear, particularly around the stapes and the round window niche. They had also infiltrated the inner ear via the annular ligament of the stapes and the round window membrane. Inflammatory cell accumulation was also observed in the peri- and endolymphatic spaces, and it was most severe in the basal turn. Most of the inner and outer hair cells were preserved, but some had degenerated or were missing. Numerous round cells were observed in the modiolus, and some of the spiral ganglion cells had degenerated. On the basis of these findings, we concluded that bacterial otitis media had extended in to the inner ear via the oval window and round window membrane and had resulted in suppurative labyrinthitis. These findings are consistent with those of stage II suppurative labyrinthitis according to the classification of Schuknecht.     

Role of cytokines in pathomechanism of otitis media

Otitis media is one of the most common diseases in children. A variety if cytokines, potent inflammatory mediators, play a crucial role in the initiation and maintenance of the immunological response in otitis media. We discussed a profile of cytokines in various forms of otitis media (otitis media acute, chronic otitis media with effusion) and we underlined the differences between these types. We also described the influence of the most common pathogens of otitis media (S. pneumoniae and H. influenzae) on the cytokine panel in middle ear effusion. We discussed the current data supporting the hypothesis that in some cases the middle ear may act as a target organ for allergic inflammation. Since numerous authors demonstrated that the cytokine profiles are relevant for the evolution of otitis media it has been proposed that measurement of some proinflammatory cytokines in the middle ear effusion may be used in order to monitor the inflammatory process. It has been also proposed using cytokines as a target for pharmacological manipulation in the treatment of otitis media.     

Cochlear cytokine gene expression in murine acute otitis media

OBJECTIVE: Recurrent acute otitis media (AOM) causes sensorineural hearing loss by unknown mechanisms. It is widely accepted that inflammatory cytokines diffuse across the round window membrane to exert cytotoxic effects. This study addresses whether inner ear cells are capable of expressing genes for inflammatory cytokines. STUDY DESIGN: The authors conducted a prospective animal study. METHODS: BALB/C mice underwent transtympanic injection of heat-killed Haemophilus influenzae to create an acute inflammatory response. These mice were compared with a control group in addition to a group of uninjected mice found to have otomicroscopic changes consistent with persistent or chronic otitis media. The cochleas of these mice were obtained, their RNA harvested, and cytokine gene expression analyzed using prefabricated cDNA arrays. RESULTS: Four groups of mice (control, 3-day postinjection, 7-day postinjection, and mice with chronic otitis media) with five mice in each group were analyzed. Numerous classes of genes were found to be upregulated or downregulated by more than twofold. Some genes differed from control mice by more than 10-fold. These genes included numerous fibroblast growth factors, interleukins, tumor necrosis factors, and colony-stimulating factors. CONCLUSION: The genes of numerous inflammatory cytokines are either up- or downregulated by murine inner ear cells in response to either acute or chronic inflammation of the middle ear. This study provides a novel site of production of cytokines that may be responsible for the damage seen in sensorineural hearing loss.     

Bacterial tympanogenic labyrinthitis, meningitis, and sensorineural damage.

Pathologic changes (sensorineural hearing loss, labyrinthitis, meningitis) can follow otitis media. Various macromolecular substances demonstrably enter the inner ear via the round window membrane, but its permeability to bacteria is less known. We inoculated Streptococcus pneumoniae type 7F bilaterally into the middle ears of two groups of chinchillas, with and without grafted round window membranes. Inner ears of inoculated animals were observed by light and electron microscopy. None with continuous grafts had labyrinthitis. Bacteria penetrated all three layers of nongrafted round window membranes and into all cochlear turns, entering Schuknecht's channels and following neuronal pathways; nerves were often degenerated, hair cells were damaged or missing, and the stria vascularis was edematous and hemorrhagic. The neural damage suggests a mechanism for the hearing loss that can follow otitis media. Absence of labyrinthitis and meningitis in grafted animals suggests a tympanogenic pathway for the bacteria.     

Antigenic as well as nonantigenic stimuli induce similar middle ear responses in the rat

OBJECTIVES/HYPOTHESIS: The observation that during otitis media many different types of micro-organisms have been cultured from effusions indicate that, once present in the middle ear cavity, most types of micro-organisms are able to trigger an inflammatory reaction leading to otitis media. The present study was designed to determine the middle ear response after injection of different substances into the middle ear cavity. STUDY DESIGN: To determine whether and to what extent an inflammatory response of the middle ear depends on the entering agent, the response in the tympanic cavity was studied by otomicroscopy and histological examination after inoculation of various substances. METHODS: Lewis rats were inoculated in transtympanic fashion either with live or heat-killed bacteria (pathogenic and nonpathogenic), Keyhole limpet hemocyanin, active charcoal, or saline. The mucosal response of the challenged middle ears was studied histologically. RESULTS: Irrespective of the inoculated substance, no essential differences in the mucosal response were found. The intensity of the inflammatory response was greater when live bacteria were inoculated. CONCLUSIONS: The present study demonstrates that any substance reaching the middle ear cavity is likely to induce otitis media. These observations emphasize the role of the eustachian tube as "porte d'entrée" in the pathogenesis of this disorder. Determination of specific aspects of the eustachian tube involved in protection or in facilitating bacterial translocation will be important for the understanding of the pathogenesis of otitis media and the subsequent development of new therapeutic strategies. In addition, elucidation of bacterial factors involved in the process of colonization and translocation will be of equal importance.     

Comparison of immune-mediated models of acute and chronic otitis media

Summary The distribution of immunoglobulin-bearing cells and the pattern of histopathological changes in the middle ear (ME) mucosa, round window membrane (RWM), and inner ear were compared during acute and chronic immune-mediated otitis media with effusion (OME) in the guinea pig as an animal model. In both acute and chronic immune responses (IRs), mucosal hyperplasia, edema, neovascularization, and cellular infiltration were observed. IgG+ cells were predominant in both the acute and chronic IRs. The number of IgA+ cells, however, increased in the mucosa and RWM during chronic IRs. Only the chronic IR resulted in gland formation within the ME and inflammation within the cochlea. These results indicate that the chronic IR was more similar to reports of clinical OME than the acute IR, The cochlear inflammation associated with chronic OME can lead to sensorineural hearing loss, as reported in clinical studies.     

Round window membrane and labyrinthine pathological changes: an overview

The round window membrane is considered the most likely pathway from the middle to the inner ear. Various substances placed in the middle ear have been seen to pass through the round window membrane. Once toxic substances or inflammatory mediators such as cytokines and nitric oxide enter the inner ear, various inner ear sequelae such as labyrinthitis, endolymphatic hydrops, sensorineural hearing loss or more insidious diseases can occur.     

Round window membrane and labyrinthine pathological changes: an overview

The round window membrane is considered the most likely pathway from the middle to the inner ear. Various substances placed in the middle ear have been seen to pass through the round window membrane. Once toxic substances or inflammatory mediators such as cytokines and nitric oxide enter the inner ear, various inner ear sequelae such as labyrinthitis, endolymphatic hydrops, sensorineural hearing loss or more insidious diseases can occur.     

泊洛沙姆407局部灌注对豚鼠中耳及内耳的影响

目的观察泊洛沙姆407在豚鼠体内的生物降解与排出过程，以及对听泡结构及功能的影响。方法10只健康豚鼠右侧圆窗龛灌注100μl 20％泊洛沙姆407原位凝胶作为实验组，左侧灌注生理盐水作为对照组，另取2只豚鼠不予处理作为阴性对照。灌注前及灌注后第3、7、14、28及49天行听性脑干反应（auditory brainstem response，ABR）检测，每次检测后处死2只动物，取出听泡，固定，石蜡包埋连续切片，观察凝胶在中耳腔内的生物降解情况以及对中耳腔黏膜、圆窗膜、耳蜗和前庭终器结构的影响。结果圆窗龛灌注泊洛沙姆407凝胶后ABR阈值较灌注前有所提高，但在第49天恢复至灌注前水平。第49天时凝胶基本完全降解或排出，光镜下残留少量絮状物，内含少量炎性细胞。凝胶灌注对中耳腔黏膜、圆窗膜、耳蜗及前庭终器结构均无明显影响。结论泊洛沙姆407凝胶在听泡内通过生物降解和经咽鼓管排出两种形式清除，对听泡组织无明显致炎作用，对ABR阈值有暂时性影响，但未见耳蜗及前庭终器功能和结构有不可逆性损伤。