Abstract
Meniere’s disease (MD) still raises since its discovery in 1860 pathophysiological and etiopathogenical issues. The main pathophysiological feature that has emerged for decades is an anatomic one, the endolymphatic hydrops (EH), defined by the inflation of the endolymphatic part of the membranous labyrinth. However, the causal relationship between EH and MD has not been proven.
Several attempts have been achieved in animals to induce EH. The best known is the blockage of the vestibular duct, which causes a chronic volume inflation of the endolymphatic part. This model is characterized by the discrepancy between electrophysiological findings and scala media inflation. Pressure measurements vary among studies.
The endolymphatic infusion model, which attempts to model the acute clinical picture of MD consistently shows pressure equilibration between the endolymphatic and perilymphatic compartments, and rapid recovery of the electrophysiological finding once the injection is stopped.
Introduction
Meniere’s disease (MD) elicits a typical clinical picture that, over a time course of a few hours, associates vertigo, hearing loss, aural fullness and tinnitus[21]. Its causes are still the object of intense controversies.
A defining pathophysiological feature of MD is the endolymphatic hydrops (EH), first described in the temporal bones of MD patients[7]. The attempt to generate an EH in animal models in order to explore its functional consequences was successfully performed since 1967 b[11]y blocking the endolymphatic and vestibular duct, with a protracted volumetric inflation of the endolymphatic compartment as a result yet with variable pressure disturbances of the fluid compartments and variable physiological consequences.
Another class of EH model is generated by injection of artificial endolymph to produce an acute expansion of the endolymphatic compartment. In this model, pressure equalization occurs between the two inner ear compartments despite the flow rate of the infusion, and this model gives rise to mild electrophysiological signs.
The fact that models with EH often fail to reproduce acute attacks of MD although they had been developed with this goal suggests that volume inflation of the endolymphatic compartment is not the primary cause of MD symptoms. An alternative is to assume that, instead of hydrops, the pressure imbalance between perilymph and endolymph is the relevant feature. By pushing on the basilar membrane (BM) and deforming it, it would provoke the auditory signs. This hypothesis was thought pivotal by Tonndorf[29] for explaining hearing loss in the MD attack and attendant changes in electrocochleography (summating potential SP and its ratio to the compound action potential AP).
The aim of this manuscript is to discuss the animal models of hydrops.
Normal inner ear fluid pressures at baseline
The two inner-ear compartments are connected to the cerebrospinal fluid space by several canals through which the intralabyrinthine pressure and intracranial pressure (ICP)[5] equalize, so that any change in ICP is reflected in the inner ear without affecting its operation. Carlborg[5] has shown that both the cochlear and vestibular aqueducts contributed to balancing hydrostatic pressures, including after death thus in the absence of any active cellular mechanism. Inside the labyrinth, the hydrostatic pressures in the perilymph and endolymph are equal [1–3, 34], and any pressure change applied to one compartment is immediately transmitted to the other one [34]. The high compliance of Reissner’s membrane seems to be the regulating structure of this endolymphatic-perilymphatic pressure equalization, which persists despite the closure of the vestibular aqueduct[27] and in the presence of perilymphatic fistula [3, 23]
The inner ear sensorineural structures need to be under strict homeostatic conditions to work well. This homeostasis includes the resting BM position. Displacements of the BM toward scala vestibuli or scala tympani lead to deflections of outer-hair-cell stereocilia that, when sound-induced, modulate their membrane potential [15, 24] and in turn, affect inner-hair cell responses. As suggested by Tonndorf [28] and Klis [14], a static displacement of the BM towards scala tympani might be the main mechanism that increases auditory thresholds and probably induce tinnitus and diplacusis.
Chronic model of endolymphatic volume inflation by blockage of the vestibular duct
This model first developed by Kimura [12] emulates the post-mortem findings in MD patients. The impediment of the endolymphatic flow by blockage of the vestibular duct and endolymphatic sac cause endolymph accumulation and progressive stretching of looser spots of the membranous labyrinth starting with the saccule, the endolymphatic sinus, the scala media and finally to reach the utricle, in advanced cases the distended Reissner’s membrane can reach the bony wall of the labyrinth.
These morphological findings contrast with the electrophysiological aspects, the decrease of the endolymphatic potential [19], caused by degeneration the stria vascularis, reaches a limit and stabilizes. It is thought to play a significant role in the chronic hearing loss typical of treated animals in the long term. A progressive increase in action potential (AP) thresholds is reported [16–18, 31], sometimes with a typical low-frequency profile while high frequencies remain unaffected [8]. The SP/AP ratio, typically high in MD patients, is constant [13] or decreased in long term hydrops [9].
Histologically, atrophy of spiral ganglions and sensory cells predominates in the apex of the cochlea, without any correlation between the extent of cochlear sensory cell atrophy and the extent of hydrops. The vestibular sensory cells remained normal in light microscopy studies [11]. In contrast, electron microscopy in cochleas from patients with bilateral MD finds that only a small percentage of abnormal apical sensorineural elements. Thus, it is questionable whether these small ultrastructural changes in the organ of Corti are the cause of severe hearing loss [12], or even have a relation with a potential hydrops.
Discrepancies exist also when the pressure was monitored during hydrops experiments, with some authors reporting no difference [15, 32] between the two compartments whereas others measure a larger endolymphatic than perilymphatic pressure [1, 10]. Andrews et al [1] suggested that at the late stages of hydrops, if Reissner’s membrane compliance decreases, sustained pressure difference may exceed 0.5 mmHg and come with hearing loss. Long and Morizono [20] found a pressure difference only in the first seven days of hydrops, smaller than 1 mmHg, and proposed that Reissner’s membrane elasticity allows fluid inflation, which leads to pressure imbalance, with pressure balance occurring after a while once elasticity decreased.
Of note, if a membrane bulges, Laplace’s law dictates that there is a pressure difference across the membrane, in proportion to the inverse of the radius of curvature, which may lead to sizeable pressure gradients when the radius is that allowed by the dimensions of scala media.
The pivotal place of endolymphatic hydrops is even more obviously questioned by thorough temporal-bone studies showing that if hydrops was confirmed postmortem in all MD patients, it could also be found in temporal bones from asymptomatic subjects [25]. The existence of patients with sensorineural hearing loss but no clinical picture of MD and yet, idiopathic hydrops is a challenge to the tenet that the symptoms of MD are caused by endolymphatic hydrops, itself the result of several possible etiological factors [22]. Overall, a striking feature of objective functional tests in animal models with a given degree of hydrops is their variability, which tends to confirm the lack of direct part played by hydrops in triggering symptoms and particularly those of MD.
chronic hydrops models have been sensitized with the addition of vasopressin [6], induced severe endolymphatic hydrops in the cochlea and the saccule, and showed episodes of balance disorder similar to the vertiginous attacks in patients with MD.
Acute injection model
Completely different from the previous technique in so far as it provokes an acute hydrops, it consists of injecting artificial endolymph in the endolymphatic compartment. It induces, during the injection, a similar increase of both the endolymphatic and perilymphatic pressures [27, 33]. Once the injection is stopped, both pressures simultaneously return to initial levels, presumably by perilymphatic flow through the cochlear aqueduct towards the cerebrospinal spaces, even if a significant amount, similar to the total volume of endolymph in scala media, is injected [33]. The leading mechanism of pressure equalization is probably the Reissner’s membrane compliance, so that the authors of this model usually conclude that rather than by some pressure imbalance between the two fluid compartments, symptoms of a Meniere’s attack are triggered by volume inflation, in contrast with the conclusions of the chronic model.
Kitahara et al [13] attempted to inject in both compartments. When injecting animals in the endolymphatic compartment, with minor volume infusion inducing a mild distension of the Reissner’s membrane, they observed a decrease in AP superior to 15%. With a larger volume inflation, a large expansion of the Reissner’s membrane occurred and the AP became undetectable. When artificial perilymph was injected in scala tympani with higher than normal K + concentration, they reported an increase of SP/AP and a nystagmus suggesting that symptoms of MD can be generated by the endolymph contamination of the perilymph.
In another injection experiment, Sirjani [26] discussed their results as a function of the rate of endolymph injection. With a low rate, they found an effect on the AP at low frequencies and changes in the f2-f1 distortion-product otoacoustic emission suggestive of a change in operating point of the outer hair cells during injection. At a high rate of injection, f2-f1 and 2f1-f2 distortion products were more strongly affected, as were the AP at medium and low frequencies with an increase of SP.
The functional consequences of the acute injection model thus differ from those in the chronic model. A possible explanation is that the acute injection provokes a modification of the geometry of the BM, and a resulting change in the operation of sensory cells. In the chronic model, as long as it remains compliant, the Reissner membrane adjusts the pressure in scala media so that the BM and organ of Corti suffer no change in operation. The same observation likely holds for the vestibular part. This advantage of the acute-injection model is offset by the rapid recovery of the functional responses once the injection stops, at variance with a real Meniere’s attack during which the symptoms persist for a few hours.
Conclusion
Several models have been proposed and tested in attempts to produce anatomical and functional changes as close as possible to the pathophysiologic features of MD.
The chronic hydrops model correctly simulates several post mortem findings in MD patients. While it cannot account for the attacks, it leads to a long-term evolution of the abnormal features, similar to those experienced by patients at the later stages when their hearing loss has become severe and stable. The acute-injection model, on the other hand, presents with features indicative of displaced operating point of sensory cells, affecting otoacoustic emissions, summating and action potentials, and suggesting changes at the BM level. However, their time course does not account for the typical MD attack as functional changes vanish when injection stops instead of being protracted.
A challenge that remains to be taken up for clearly answering the questions raised in the title of this article is to ensure that a long-lasting pressure difference could be maintained between endolymph and perilymph, in order to examine whether the functional consequences are closer to those of a MD attack than in the existing models.