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Dynamics of inner ear pressure release, measured with a double-barreled micropipette in the guinea pig.

The inner ear fluid pressure was measured in scala media of the guinea pig through one barrel of a double-barreled micropipette after a sudden volume increase or decrease, caused by injection or withdrawal of artificial endolymph through the other barrel. During injection or withdrawal, the inner ear pressure changed in the order of 1-10 cm water, but it returned to its initial value within a few seconds. The time constant for the pressure recovery depended on the flow direction. It was on average 1.1 s after a short overpressure and 2.8 s after underpressure. The obtained results could be fitted with a simple physical model, when it was assumed that inner ear pressure recovery is a non-linear process, governed by a pressure-dependent flow resistance and/or membrane compliance.

Animals↗

Human endolymphatic sac: possible mechanisms of pressure regulation.

The ultrastructure of the normal human endolymphatic sac (ES) has been observed by transmission electron microscopy (TEM). The role of the epithelium, the various regions of the subepithelial space and the general anatomy of the ES in pressure regulation were morphologically studied to generate testable hypotheses of human ES function. Light microscopic (LM) and TEM evidence of pressure regulatory mechanisms by endolymph resorption, mechanical factors, and secretory activity are presented. These mechanisms may be useful in designing experimental studies of the ES, and in interpretation of retrospective LM and TEM studies of patients with Menière's disease.

Adult↗

Effects of amiloride on the endolymphatic sac.

The effect of amiloride on the murine endolymphatic sac was investigated. The amiloride caused collapse of the lateral intercellular spaces in the endolymphatic sac epithelium and a subsequent mild endolymphatic hydrops. These changes indicated a decreased absorption of endolymph in the endolymphatic sac. Amiloride is known to inhibit the transcellular fluid transport without inducing any changes in the paracellular fluid transport. It is therefore suggested that amiloride specially inhibits the fluid and ion exchange in the apical portion of the epithelial cells resulting a decrease in transcellular fluid transport across the endolymphatic sac epithelium. The transcellular fluid transport seems to be one of the main mechanisms in the endolymphatic sac fluid exchange system.

Amiloride↗

A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome.

The Jervell and Lange-Nielsen (JLN) syndrome (MIM 220400) is an inherited autosomal recessive disease characterized by a congenital bilateral deafness associated with a QT prolongation on the electrocardiogram, syncopal attacks due to ventricular arrhythmias and a high risk of sudden death. JLN syndrome is a rare disease, which seems to affect less than one percent of all deaf children. Linkage to chromosome 11p15.5 markers was found by analysing four consanguinous families. Recombinants allowed us to map the JLN gene between D11S922 and D11S4146, to a 6-cM interval where KVLQT1, a potassium channel gene causing Romano-Ward (RW) syndrome, the dominant form of long QT syndrome, has been previously localized. An homozygous deletion-insertion event (1244, -7 +8) in the C-terminal domain of this gene was detected in three affected children of two families. We found that KVLQT1 is expressed in the stria vascularis of mouse inner ear by in situ hybridization. Taken together, our data indicate that KVLQT1 is responsible for both JLN and RW syndromes and has a key role not only in the ventricular repolarization but also in normal hearing, probably via the control of endolymph homeostasis.

Adult↗

[Mechanism of benign, peripheral, paroxysmal positional vertigo (BPPV)].

BACKGROUND: Positioning nystagmus of the peripheral benign type (BPPV) has long been considered to be due to cupulolithiasis-i.e. attachment of inorganic material to the cupula-of the posterior vertical semicircular canal. Meanwhile it has generally been recognized that not all characteristics of this type of nystagmus/vertigo can be explained by assuming a gravity-dependent reaction of the posterior canal. Canalolithiasis-i.e. floating material within the canal, heavier than endolymphe-of the posterior semicircular canal is now widely regarded as the cause of BPPV. Again, however, this is a concept far too simple to explain most of the properties of BPPV. METHODS: Clearly defined, carefully performed positioning and positional maneuvers were carried out on 79 patients suffering from typical BPPV in order to reveal those positioning movements and positions necessary to elicit BPPV. RESULTS: Detailed analysis of those positioning maneuvers necessary to elicit BPPV clearly reveals that canalolithiasis cannot be the cause of BBPV. CONCLUSIONS: BPPV is a combination of positioning, and positional-dependent reactions in which the otolithic organs, and particularly the sacculus, seem to be involved.

Adult↗

[Pressure relations between endocranial and intracochlear fluid spaces in patients with inner ear diseases].

Intracranial pressure is transmitted to the perilymph of the cochlea via the cochlear aquaeduct and via Reissner's membrane to the endolymph. The "Tympanic Membrane Displacement Analyser (TDA)" is a new device that may be a useful non-invasive method to show intracranial and intracochlear pressure changes indirectly measured by tympanic membrane displacement during stapedial reflex contraction. The TDA was utilised in 20 normal persons and in 29 patients with unilateral diseases of the inner ear. No significant differences in the tympanic membrane displacement were found between patients with sensorineural hearing loss, patients with Ménière's disease, and normal persons.

Adolescent↗

Role of the new imaging modalities in the investigation of Meniere's disease.

The incidence of nonvisualization of the vestibular aqueduct and the endolymphatic duct-endolymphatic sac (ED-ES) complex as well as the type of periaqueductal pneumatization were evaluated in 23 patients with definite Meniere's disease (MD) by high-resolution CT and by MRI. Fifty subjects with no previous history of any ear disease were used as a control group. High-resolution CT results disclosed that in the control group the percentage of nonvisualized vestibular aqueduct (3.4%) was statistically significantly lower than in the MD group, when either the diseased ear (27.8%) or the nondiseased ear of the same group (22.2%) was examined. In addition, no differences were observed between the diseased and nondiseased ears of the patients with MD. The periaqueductal pneumatization was also found to be statistically significantly lower in the MD group. As regards the MRI examination, the results of the analysis showed that the ED-ES complex was visualized more frequently in the ears of the control subjects (64.1%) than in the diseased ears of the patients with Meniere's disease (39.1%). This difference had a marginal statistical significance (P approximately 0.05). We discussed the results in relation to possible underlying pathophysiologic mechanisms involving the flow of endolymph toward the ES during the different stages of the disease.

Adult↗

Developmental aspects of the rat endolymphatic sac and functional implications.

The purpose of this study was to determine specific characteristics of endolymphatic sac (ES) cells of the developing rat that are considered to be involved in endolymph homeostasis. Because intermediate filament proteins (IFPs) are regarded as markers of cell differentiation and basal lamina proteins (BLPs) are essential in cell<=>matrix interactions, we determined the presence of IFPs [cytokeratins (CKs) and vimentin] and BLPs [collagen IV, heparan sulphate proteoglycan (HSPG) and laminin] at different developmental stages before and after birth. In addition, we studied the expression of two enzymes of oxidative metabolism: cytochrome oxidase and succinate dehydrogenase. The presence of CKs 8, 18 and 19 in all epithelial cells of the ES during the embryonic stage is characteristic of simple (glandular) epithelial cells. Interestingly, a distinct population of these cells shows additional expression of CK 7, which is a feature of secretory cells. These CK 7-positive cells also contain a high concentration of oxidative enzymes and are rich in mitochondria, indicating that they are light cells. It is suggested that light cells possess specific energy-requiring transport capabilities. Loss of CK 19 expression in the distal part and in a large region of the intermediate part of the ES implies that these cells do not differentiate any further and acquire the capacity to proliferate. Furthermore, prominent co-expression of vimentin with the CKs in the distal part of the ES may confer viscoelastic properties on this epithelium. This may facilitate expansion and thus enable cushioning of pressure fluctuations. Finally, the early prominent occurrence of HSPG in the basal lamina of the ES enables transport of ions. In this light our recent observations of early functioning NaK-ATPases in certain ES cells are interesting.

Animals↗

Altered cupular mechanics: a cause of peripheral vestibular disorders?

It has taken many decades to arrive at today's concept of cupula mechanics in the stimulation of endolymphatic flows on the hair cells in the ampullae of the semicircular canal. While Steinhausen assumed free swing-door movement of the cupula in the 1930s, Hillman was the first to demonstrate firm cupula attachment to the ampulla wall as a physiological necessity in the 1970s. In contrast to the present clinical concepts of acute peripheral vestibular functional disorders (circulatory disturbances, viral or bacterial infection, altered electrolytes in the endolymph), this study examines the extent to which an impaired attachment mechanism can trigger peripheral vestibular disorders. For this purpose, we used a pigeon model (n = 8), in which mechanical detachment of the cupula from the ampulla wall was achieved by means of a targeted pressure increase in the ampulla of the lateral semicircular canal. In two additional animals the labyrinth was completely destroyed on one side in order to directly compare partial and complete vestibular disorders. In this way partial damage to the lateral semicircular canal ampulla presents a clinical picture whose symptoms are very similar to those of an idiopathic vestibular disorder in humans. Their intensity and course of compensation differ markedly from the symptoms of complete vestibular destruction. Subsequent histological examination revealed that the hair cells remained intact during the experimental detachment of the cupula. Our results thus show that only altered cupula mechanics seem to trigger the clinical picture of a peripheral vestibular disorder. This may result in completely new approaches to differential diagnosis and the therapy of vestibular neuronitis.

Animals↗

Persistent geotropic nystagmus--a different kind of cupular pathology and its localizing signs.

CONCLUSION: A persistent geotropic positional nystagmus indicates a dysfunction in the lateral semicircular canal with a cupula of less specific weight than the surrounding endolymph. It is possible to determine the side of the affected cupula by recording the nystagmus pattern in yaw and pitch plane. OBJECTIVES: To identify the clinical features in patients with a persistent geotropic positional nystagmus, establish lateralizing signs and relate the findings to a pathophysiologic mechanism. PATIENTS AND METHODS: Six patients with acute onset vertigo of a peripheral origin and persistent geotropic nystagmus were examined with videonystagmoscopy and the nystagmus characteristics in different positions of the head in yaw and pitch plane were studied. RESULTS: Besides the persistent geotropic nystagmus, a zero zone was found with no nystagmus, beyond which the nystagmus changed direction when the head of the patient in supine position was gradually rotated from side to side. The zero zone was present when the head was turned slightly towards one side and is thought to represent a position where the affected cupula is aligned with the gravitational vertical. With the head bent forwards the nystagmus direction was to the non-affected side and when the head was bent backwards to the affected side.

Adult↗

Canalolithiasis of the superior semicircular canal: an anomaly in benign paroxysmal vertigo.

According to the canalolithiasis theory, benign paroxysmal vertigo (BPPV) is caused by gravity-dependent movements of otoconial debris that collects in the endolymph of the posterior semicircular canal. Other parts of the vestibular organ are rarely affected, and it is mainly the horizontal canal that is affected by this atypical form of BPPV. Canalolithiasis of the superior semicircular canal must be considered an anomaly because the superior semicircular canal is the highest point of the vestibular organ and debris normally cannot collect in this special location. Until now, BPPV of the superior canal has mainly been dealt with theoretically in the literature. The authors present three patients with canalolithiasis of the superior semicircular canal and offer direct proof of the condition using high-resolution 3D MRI.

Adult↗

In vivo study of the electrochemical composition of luminal fluid in the guinea pig endolymphatic sac.

The aim of this study was to investigate the ionic composition (sodium, potassium) of the luminal fluid in the endolymphatic sac and to correlate it with the transepithelial potential. Experiments were performed in guinea pigs using either an intradural posterior fossa approach or a translabyrinthine approach. The endolymphatic sac transepithelial potential (ESP) was measured and the luminal fluid was sampled. The sodium, potassium and protein concentrations were determined. The results were: i) the luminal fluid in the endolymphatic sac differs in composition from perilymph, on the one hand, and from both cochlear and vestibular endolymph, on the other hand, indicating that the endolymphatic sac maintains chemical (sodium, potassium) and electrical (ESP) gradients; ii) the calculated osmolarity (Na + K) x 2 was about 230 mosm/l; iii) no correlation was observed between sodium and potassium concentrations; iv) large interindividual variations exist from one animal to another, suggesting physiological variations in the functional status of the endolymphatic sac. In conclusion, the variation in composition of the endolymphatic sac luminal fluid reflected variations in ion transport by the epithelium and thus a possible adaptation of the ion transport to different physiopathological conditions.

Animals↗

Pharmacokinetics and ototoxicity of gentamicin, tobramycin, and amikacin.

The pharmacokinetics of gentamicin, tobramycin, and amikacin in inner ear fluids, serum, cerebrospinal fluid, and the compartments of the eye were studied and compared in guinea pigs. The concentrations of antibiotic were determined by microbiologic methods and were confirmed by the use of 14C-labeled gentamicin. Retention was clearly demonstrated in perilymph, in which the half-lives of gentamicin, tobramycin, and amikacin were 12, 11, and 10 hr, respectively. The concentrations of drug in perilymph were symmetrical and were many times higher than the concentrations of antibiotic in the brain. There was no difference between the concentration of drug in endolymph and that in perilymph. A linear relation between concentrations in the perilymph and the dosage of gentamicin was ascertained. Long-term treatment did not influence the pharmacokinetics of the three antibiotics in the inner ear. However, increased levels of drug in the inner ear in animals with uremia and in some animals with otitis media explained the increased ototoxicity that occurs in treatment of these two conditions. Suboccipital puncture and diuresis did not change the concentrations of aminoglycoside antibiotics in the inner ear. Antibiotics applied locally in the middle ear had high degrees of ototoxicity.

Amikacin↗

Aquaporin-2 regulation by vasopressin in the rat inner ear.

Our previous studies have suggested a close relationship between vasopressin and endolymphatic hydrops, or the increased volume of endolymph in the inner ear. Endolymphatic hydrops is also thought to occur in Ménière's disease patients. In the kidney collecting duct, vasopressin induces the expression of aquaporin-2 (AQP2), resulting in increased water reabsorption. We explored the possibility, using a quantitative PCR method, that vasopressin regulates the expression of AQP2 mRNA in the rat inner ear, as it does in the kidney. The levels of AQP2 mRNA in the cochlea and endolymphatic sac were significantly higher in rats treated with vasopressin than the levels in control animals. We speculate that over-expression of AQP2 may be involved in the formation of endolymphatic hydrops.

Animals↗

Effect of locally applied drugs on the endolymphatic sac potential.

In Ménière's disease, an inner ear disorder related to an endolymphatic hydrops, an alteration of the functioning of the endolymphatic sac has been proposed. The endolymphatic sac is assumed to be involved in the secretion/resorption of endolymph. The epithelial transport systems have been indirectly studied by the recording of the endolymphatic sac transepithelial potential (ESP) in control conditions and after the local injection of drugs such as diuretics that have been proposed in the treatment of Ménière's disease. The ESP was recorded, in vivo, in guinea pigs up to 150 minutes after the perisaccular injection of 5 microL of a 150 mmol/L (mM) NaCl solution containing various drugs known to inhibit ionic transport systems. The initial ESP was +8.4+/-0.3 mV (mean +/- SEM, n = 78). The basolateral injection of 5 microL of 150 mM NaCl induced an ESP decrease of 64%+/-6.0% (n = 12), 5 minutes after the end of the injection. Then ESP increased, returning to its initial value at 60 minutes and surpassing it at 120 minutes. Diuretics such as acetazolamide (10[-3] mol/L [M]), an inhibitor of carbonic anhydrase, and amiloride (10[-4] M), an inhibitor of Na channel or Na/H exchanger, decreased the ESP recovery. At variance, bumetanide (10[-6] M, 10[-4] M), the Na-K-Cl cotransport inhibitor, and chlorothiazide (10[-4] M), a Na-Cl cotransporter inhibitor, failed to alter the ESP as compared with the control group. Ouabain (10[-3] M), the Na+,K+-adenosine triphosphatase (ATPase) inhibitor, prevented the ESP recovery otherwise observed 60 minutes after the NaCl injection. Bafilomycin A1, the inhibitor of the vacuolar-type H+-ATPase, prevented the recovery of the ESP with a log-dose/effect (10[-5] M, 10[-6] M, 10[-8] M). Disulfonic acid stilbene (DIDS) (10[-4] M), an inhibitor of transporters involving HCO3-, also prevented the ESP recovery. These results suggest that the genesis of the ESP was highly dependent on acid-base transport systems including carbonic anhydrase, a vacuolar-type H+-ATPase, and an anionic transport system blocked by DIDS. Further studies are needed to confirm the alteration of the acid-base balance in this epithelium and its possible involvement in the pathogenesis of Ménière's disease.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

Repositioning maneuver for the treatment of the apogeotropic variant of horizontal canal benign paroxysmal positional vertigo.

OBJECTIVE: The purpose of this study was to determine the effectiveness of a new physical maneuver in the treatment of the apogeotropic variant of horizontal canal benign paroxysmal positional vertigo. STUDY DESIGN: Case review. SETTING: Outpatient clinic. PATIENTS: The diagnosis of apogeotropic horizontal canal benign paroxysmal positional vertigo was based on the history of recurrent sudden crisis of vertigo associated with bursts of horizontal apogeotropic paroxysmal nystagmus provoked by turning the head from the supine to either lateral position. The patients were three men and five women ranging in age from 31 to 73 years (average, 49.2 yr). INTERVENTIONS: All patients were treated with a repositioning maneuver based on the hypothesis that the syndrome is caused by the presence of free-floating dense particles inside the endolymph of the anterior arm of the horizontal canal. The maneuver favors their shifting into the posterior arm of the canal. Patients were reexamined immediately after the treatment and underwent Gufoni's liberatory maneuver for the geotropic variant of horizontal canal benign paroxysmal positional vertigo. MAIN OUTCOME MEASURE: The treatment outcome was considered as responsive when, after one repositioning maneuver, nystagmus shifted from apogeotropic to geotropic. RESULTS: The repositioning maneuver resulted in a transformation from the apogeotropic variant into a geotropic variant of horizontal canal benign paroxysmal positional vertigo in all patients. CONCLUSION: This maneuver represents a simple and effective approach to the treatment of the apogeotropic variant of horizontal canal benign paroxysmal positional vertigo. It favors the shifting of the canaliths from the anterior into the posterior arm of the horizontal canal from where they can migrate into the utricle with Gufoni's maneuver.

Adult↗

Analysis of cortisol and other stress-related hormones in patients with Ménière's disease.

OBJECTIVE: To evaluate cortisol and catecholamine levels in patients with Ménière's disease. STUDY DESIGN: Prospective, controlled study. SETTING: Tertiary referral center. PATIENTS: Thirty patients with Ménière's disease and 18 healthy controls. MAIN OUTCOME MEASURES: Serum and saliva cortisol, serum cortisol after the dexamethasone suppression test, urine free cortisol, and urine catecholamines. RESULTS: The serum and saliva cortisol levels were higher in Ménière's patients compared with their control group: 440 +/- 127 (n = 28) versus 366 +/- 90 (nmol/L) (n = 18) and 17.2 +/- 6.1 (n = 18) versus 11.6 +/- 4.6 (nmol/L) (n = 9), respectively. Both differences were significant (p < 0.05). There were no dissimilarities in urine cortisol or urine catecholamines for either group. Twenty-eight Ménière's patients were divided into two subgroups, namely, high- and low-cortisol groups, using a serum cortisol level cutoff point of 465 nmol/L (median). The total Ménière's disease time and the duration of tinnitus tended to be longer in the high-cortisol group (p = 0.07, two-tailed). The total Ménière's disease time was 13.5 +/- 9.9 years in the high-cortisol group and 7.1 +/- 7.4 years in the low-cortisol group (n = 14 for both). The subgroups were matched for age, gender, and unilaterally or bilaterally affected ears. CONCLUSION: Patients with Ménière's disease have higher serum cortisol levels. It is suggested that these higher cortisol levels are rather the result than the cause of this chronic disease, because patients affected longer seem to have higher cortisol levels. The exact impact of these higher cortisol levels on the inner ear and endolymph homeostasis is yet unknown.

Adult↗

A potential portal flow in the inner ear.

OBJECTIVES/HYPOTHESIS: The aim of the present study was to visualize the flow direction of blood in the extraosseous part of the vein of the vestibular aqueduct (VVA) and to explore the effect of an induced obstruction in the distal part of the VVA before it merges with the sigmoid sinus. The endolymphatic sac has been implicated as a potential endocrine gland, which venules drain to the VVA. A reversal of the direction of flow in the VVA toward the inner ear could, through vestibular arteriovenous anastomosis, cause portal circulation in the inner ear. STUDY DESIGN: The authors conducted an experimental animal study using in vivo fluorescence microscopy. RESULTS: Obstructing the distal part of the VVA just before it empties into the sigmoid sinus immediately reverses the flow of blood in the VVA toward the inner ear. CONCLUSIONS: After an obstruction of the VVA, the drained venous blood from the endolymphatic sac may enter a portal circulation in the inner ear, which could cause disturbances in the endolymph homeostasis and potentially symptoms as seen in Meniere disease.

Animals↗