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.     

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.     

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.     

Clinical Aspects of Round Window Membrane Permeability Under Normal and Pathological Conditions

Current research and an overall review of 25 years of round window membrane studies are presented. The approach, rationale and concepts that have evolved from these studies are described. Ultrastructural studies of the round window membrane of humans, monkeys, felines and rodents have disclosed three basic layers: an outer epithelium, a middle core of connective tissue and an inner epithelium. Interspecies variations are mainly in terms of thickness, being thinnest in rodents and thickest in humans. Morphologic evidence suggests that the layers of the round window participate in resorption and secretion of substances to and from the inner ear, and that the membrane could play a role in the defense system of the ear. Different substances, including antibiotics and tracers, when placed in the middle ear side traverse the membrane. Tracers placed in perilymph become incorporated into the membrane by the inner epithelial cells. Permeability is selective and factors affecting permeability include size, concentration, electrical charge, thickness of the membrane and facilitating agents. Passage of substances through the membrane is by different pathways, the nature of which is seemingly decided at the outer epithelium of the membrane. Round window membrane studies have provided increased knowledge of the anatomy and function of this structure, as well as new insights into pathology and pathogenesis. The concepts that have evolved from these studies are potentially useful for understanding middle and inner ear interactions, and for eventual drug delivery (based on permeability) to the inner ear.     

Clinical aspects of round window membrane permeability under normal and pathological conditions

Current research and an overall review of 25 years of round window membrane studies are presented. The approach, rationale and concepts that have evolved from these studies are described. Ultrastructural studies of the round window membrane of humans, monkeys, felines and rodents have disclosed three basic layers: an outer epithelium, a middle core of connective tissue and an inner epithelium. Interspecies variations are mainly in terms of thickness, being thinnest in rodents and thickest in humans. Morphologic evidence suggests that the layers of the round window participate in resorption and secretion of substances to and from the inner ear, and that the membrane could play a role in the defense system of the ear. Different substances, including antibiotics and tracers, when placed in the middle ear side traverse the membrane. Tracers placed in perilymph become incorporated into the membrane by the inner epithelial cells. Permeability is selective and factors affecting permeability include size, concentration, electrical charge, thickness of the membrane and tacilitating agents. Passage of substances through the membrane is by different pathways, the nature of which is seemingly decided at the outer epithelium of the membrane. Round window membrane studies have provided increased knowledge of the anatomy and function of this structure, as well as new insights into pathology and pathogenesis. The concepts that have evolved from these studies are potentially useful for understanding middle and inner ear interactions, and for eventual drug delivery (based on permeability) to the inner ear.     

Cochlear Aqueduct Flow Resistance Depends on Round Window Membrane Position in Guinea Pigs

The resistance for fluid flow of the cochlear aqueduct was measured in guinea pigs for different positions of the round window membrane. These different positions were obtained by applying different constant pressures to the middle ear cavity. Fluid flow through the aqueduct was induced by small pressure steps superimposed on these constant pressures. It was found that the resistance for fluid flow through the aqueduct depended on the round window position but not on flow direction. The results can be explained by special fibrous structures that connect the round window with the entrance of the aqueduct. It was also found that the equilibrium inner ear pressure depends on middle ear pressure, indicating that the aqueduct does not connect the inner ear with a cavity with constant pressure.     

Immunodefense of the round window

A systematic analysis using serial sectioning of the round window membrane (RWM) in the cynomolgus monkey was performed. Light and transmission electron microscopy (LM and TEM) revealed that the RWM rim may be endowed with gland-like structures with glyco-protein material secernated into the window niche. This was detected in one third of the specimens. The secreted material displayed waste material and scavenger cells. There was also a rich network of capillaries, lymph channels, and sinusoidal veins containing leukocytes. Their abluminal surfaces displayed mature plasma cells and monocytes. These findings suggest that in certain primates the middle ear may have developed specific immunoprotective means for disposal of foreign and noxious substances before they reach the inner ear.     

Permeability of the round window membrane

Summary Cefmetazole sodium, a cephamycin antibiotic, was shown to pass through the round window membrane into the inner ear of the guinea pig. The concentration of the drug in the inner ear fluid indicated that a larger amount of the drug reached the inner ear through the round window membrane than when administered intraperitoneally.This study was supported by a Research Grant for Specific Diseases from the Ministry of Health and Welfare's Acute Profound Deafness Research Committee of Japan     

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.     

Intratympanic ciprofloxacin and the human labyrinthine sampling model

OBJECTIVE: The aim of the study was to investigate the potential absorption of intratympanic ciprofloxacin through the human round window membrane. STUDY DESIGN: A prospective study. METHODS: Ciprofloxacin was instilled into the middle ear of 10 patients undergoing acoustic tumor removal. The lateral semicircular canal and vestibule were subsequently opened and, using a microsyringe, labyrinthine fluid was aspirated. A sample each of serum and cerebrospinal fluid was also drawn. RESULTS: Into each middle ear, 0.5 mL ciprofloxacin (0.3%) was instilled. The time interval between the ciprofloxacin application to the round window membrane and sampling of labyrinthine fluid and plasma ranged from 9 to 120 minutes. There was no measurable ciprofloxacin in the labyrinthine fluid, cerebrospinal fluid, or serum of 10 patients. CONCLUSION: The lack of measurable absorption of intratympanic ciprofloxacin into the inner ear indicates that the chance of ototoxicity when ciprofloxacin is used clinically, even in the presence of a tympanic membrane perforation, is low.     

Effect of lipooligosaccharide mutations of Haemophilus influenzae on the middle and inner ears

Objective

The purpose of this study was to determine the virulence of nontypeable Haemophilus influenzae 2019 (NTHi 2019) and its two lipooligosaccharide (LOS) mutant strains, B29 (gene htrB) and DK1 (gene rfaD), and compare their effect on the middle ear, round window membrane, and inner ear.

Results

Fifteen chinchillas were divided into three equal groups and their bullas inoculated bilaterally with 0.5 ml of 10² CFU/ml of parent NTHi 2019, B29 or DK1 mutant strains. Two days after inoculation all animals had otitis media and inflamed middle ear mucosa. There was a trend of greater thickness and infiltration of the round window membrane in animals inoculated with the wild-type NTHi strain compared to the mutant strains and a significant increase in both inflammatory cell infiltration and bacteria presence in the scala tympani area of the inner ear. Strial edema was only observed in the wild-type-inoculated group.

Conclusions

LOS mutants of NTHi appear to have a reduced ability to pass through the round window membrane resulting in less inner ear inflammation and pathological changes.     

Change of middle ear transfer function in otitis media with effusion model of guinea pigs

Otitis media with effusion (OME) is an inflammatory disease of the middle ear that causes most cases of conductive hearing loss observed in the pediatric population. With the long term goal of evaluating middle ear function with OME, the aim of the current study was to create an animal model of OME in which middle ear transfer functions could be measured. In guinea pigs, OME was created by injecting lipopolysaccharide (LPS) into the middle ear. Evidence of OME was assessed by otoscopy, tympanometry, histology, and by measuring the volume of fluid in the middle ear. Vibrations of the umbo and round window membrane were measured with a laser Doppler vibrometer at frequency range of 200-40kHz in three groups of 3, 7, and 14 days after injection of LPS. Changes in displacement of the umbo and round window membrane in response to 80dB SPL sound in the ear canal were measured across the frequency range. Displacement of both the umbo and round window membrane was reduced at all time points following LPS injections. Further, the change of the displacement transmission ratio (DTR) from the tympanic membrane to the round window occurred mainly in chronic (e.g. 14 days post-LPS injection) OME ears. This study provides useful data for analyzing the change of middle ear transfer function in OME ears.     

Blood flow of the round window

Summary Motion pictures of the blood flow of the round window in guinea pigs were taken. In this part the blood flow of the inner ear could be distinguished from that of the middle ear. Our motion pictures show that the blood flow of the inner ear can be observed through the round window membrane without an operation on the inner ear.     

Extraneous round window membranes and plugs: possible effect on intratympanic therapy

Recently there has been increasing interest in the possibility of treating inner ear disorders by application of medication into the middle ear on the premise that it will diffuse through the round window membrane into the inner ear. We examined 202 temporal bones from 117 patients to determine the frequency of round window niche obstruction. Patients ranged in age at the time of death from 31 to 97 years. Eleven percent of the ears were found to have fibrous tissue or a fat plug, and 21% had an extraneous (false) round window membrane. Of the 85 patients from whom both temporal bones were examined, 56% had no obstruction in either ear, while 22% had obstruction in both ears. We conclude that anatomic variations of the round window niche may explain the wide variations found in dosage of medication required to produce a clinical result.     

Surgical Management of Head and Neck Cancer: The Next Decade

Sensorineural hearing loss is known to be a significant sequela of otitis media (OM). The pathophysiology of such hearing loss in OM is thought to be due to transmission of toxins and other bacterial products through the round window membrane, damaging the hair cells of the basal turn of the cochlea. Other routes, such as those involving the oval window, blood vessels and lymphatics, may also be involved. The purpose of this study was to elucidate the routes from the middle ear cavity to the inner ear and also the distribution pattern of endotoxin in the inner ear after injection of fluorescence-labelled endotoxin into the tympanic cavity and detection of fluorescence in the cochleae, vestibular end organs and facial nerves. This fluorescence was far more intense in the lower turns of the cochlea. These findings suggest that endotoxin can reach the inner ear by various routes, e.g. the round window, blood vessels or lymphatics, and/or interscala exchange, resulting in a disturbance not only of the cochlea but also of the vestibular end organs.     

Ultrastructure of the round window membrane

The round window membrane presents the only non-osseous wall of the labyrinth. Electron microscopic study of the round window membrane was undertaken in order to determine whether it could act as a route of transmission from the middle to the inner ear. In the cat round window membrane three layers can be identified. The tympanic surface is composed of a single layer of flat cells resting on the basal lamina. Multiple desmosomes and tight cell junctions are present. The intermediate layer contains supporting elements collagen and elastic tissues. The labyrinthine layer is composed of a single layer of long squamous cells which lie end to end on the basal lamina. The absence of intracellular organelles and microvilli, and the lack of basal lamina involutions into the epithelial cells preclude the presence of an active transport mechanism. The tight cell junctions also seem to present a barrier to free diffusion across the membrane. The chemical agents which have been observed to pass from the middle ear into the inner ear may have done so by diffusion through the round window membrane after altering the cell junctions; however, a readily accessible route of transmission through the round window membrane does not appear to be present.     

Localization of endotoxin in the inner ear following inoculation into the middle ear

Sensorineural hearing loss is known to be a significant sequela of otitis media (OM). The pathophysiology of such hearing loss in OM is thought to be due to transmission of toxins and other bacterial products through the round window membrane, damaging the hair cells of the basal turn of the cochlea. Other routes, such as those involving the oval window, blood vessels and lymphatics, may also be involved. The purpose of this study was to elucidate the routes from the middle ear cavity to the inner ear and also the distribution pattern of endotoxin in the inner ear after injection of fluorescence-labelled endotoxin into the tympanic cavity and detection of fluorescence in the cochleae, vestibular end organs and facial nerves. This fluorescence was far more intense in the lower turns of the cochlea. These findings suggest that endotoxin can reach the inner ear by various routes, e.g. the round window, blood vessels or lymphatics, and/or interscala exchange, resulting in a disturbance not only of the cochlea but also of the vestibular end organs.     

Experimental study of nystagmus induced by injecting various solutions into the middle ear cavity

Injecting of various solutions into the middle ear cavity of cats and rabbits provoked certain characteristic types of nystagmus which resembled caloric nystagmus or clinical cases of peripheral vestibular disorders. Solutions with different degrees of specific gravity, osmotic effect and ion composition were used in this study. Direction-changing positional nystagmus, irritative nystagmus, and paralytic nystagmus were elicited according to the physical or chemical properties of each solution. Histological findings showed mild changes in the perilymphatic space and/or in the endolymphatic space in the period with some characteristic types of nystagmus. Infiltration of the substances into the inner ear fluids from the middle ear cavity via a round window membrane were probably responsible for these types of nystagmus.     

Middle ear inflammatory mediators and cochlear function

Sensorineural hearing loss (SNHL) has been documented in patients with otitis media. Despite a number of clinical and pathologic works dealing with this common problem, animal studies searching for possible relationships between the middle ear inflammation and cochlear function remain insufficient. Bacterial inoculation and ototoxins and inflammatory products in the middle ear cavity cause SNHL in rodents. Human serum albumin placed in the middle ear cavity in chinchillas also produces SNHL, owing to the effects of nonspecific inflammation in the middle ear cavity. Most of the middle ear inflammatory mediators enter the inner ear through the round window route, and alteration of the permeability of the round window membrane plays an important role in causing cochlear dysfunction. Although an immunologic response in the middle ear plays an important role in otitis media, the immunologic response in the inner ear as it relates to middle ear inflammatory mediators requires further study.     

Round window membrane defect in divers]

BACKGROUND: The rupture of the round window membrane is a special form of traumatic inner ear deafness. Because of the changing pressure levels, divers are at risk of developing such a membrane rupture, especially if tube function is disturbed. As the popularity of diving as a sport increases, ENT specialists have to deal with diving related problems increasingly frequently. PATIENTS AND METHODS: Seven cases of divers are presented in whom a tympanotomy was performed following the diagnosis of a rupture of the round window membrane. The symptoms and intraoperative findings are discussed and the otologic and diving literature is reviewed. Following a case report, the pathophysiology, clinical symptoms and differential diagnosis of round window ruptures are discussed controversially. Possible therapeutical consequences are described. RESULTS: None of our patients exhibited the classical triad of deafness, tinnitus, and vertigo as described in the diving literature. The leading symptom in our patients was the loss of hearing; only two patients had vertigo. Tinnitus was found in half of the patients. Intraoperative a rupture of the round window membrane was presumed in five divers. CONCLUSIONS: If disturbance of inner ear function does occur concurrently with diving, a rupture of the round window membrane must be considered. An otologic examination must be performed in any diver with a loss of hearing and/or signs of a barotrauma of the middle ear. After differential diagnosis to exclude other possibilities, a tympanotomy to cover the round window membrane should be performed if symptoms persist more than 24 hours.