Meniere's disease (MD) is a severe inner ear condition known by debilitating symptoms, including spontaneous vertigo, fluctuating and progressive hearing loss, tinnitus, and aural fullness or pressure within the affected ear. Prosper Meniere first described the origins of MD in the 1860s, but its underlying mechanisms remain largely elusive today. Nevertheless, researchers have identified a key histopathological feature called Endolymphatic Hydrops (ELH), which refers to the excessive buildup of endolymph fluid in the membranous labyrinth of the inner ear. The exact root of ELH is not fully understood. Still, it is believed to involve several biological and bioenvironmental etiological factors such as genetics, autoimmunity, infection, trauma, allergy, and new theories, such as saccular otoconia blocking the endolymphatic duct and sac. Regarding treatment, there are no reliable and definitive cures for MD. Most therapies focus on managing symptoms and improving the overall quality of patients' life. To make significant advancements in addressing MD, it is crucial to gain a fundamental understanding of the disease process, laying the groundwork for more effective therapeutic approaches. This paper provides a comprehensive review of the pathophysiology of MD with a focus on old and recent theories. Current treatment strategies and future translational approaches (with low-level evidence but promising results) related to MD are also discussed, including patents, drug delivery, and nanotechnology, that may provide future benefits to patients suffering from MD.

Older studies of mammalian otolith physiology have focused mainly on sustained responses to low-frequency (<50 Hz) or maintained linear acceleration. So the otoliths have been regarded as accelerometers. Thus evidence of otolithic activation and high-precision phase locking to high-frequency sound and vibration appears to be very unusual. However, those results are exactly in accord with a substantial body of knowledge of otolith function in fish and frogs. It is likely that phase locking of otolith afferents to vibration is a general property of all vertebrates. This review examines the literature about the activation and phase locking of single otolithic neurons to air-conducted sound and bone-conducted vibration, in particular the high precision of phase locking shown by mammalian irregular afferents that synapse on striolar type I hair cells by calyx endings. Potassium in the synaptic cleft between the type I hair cell receptor and the calyx afferent ending may be responsible for the tight phase locking of these afferents even at very high discharge rates. Since frogs and fish do not possess full calyx endings, it is unlikely that they show phase locking with such high precision and to such high frequencies as has been found in mammals. The high-frequency responses have been modeled as the otoliths operating in a seismometer mode rather than an accelerometer mode. These high-frequency otolithic responses constitute the neural basis for clinical vestibular-evoked myogenic potential tests of otolith function.

Electrocochleography (EcochG), incorporating the Cochlear Microphonic (CM), the Summating Potential (SP), and the cochlear Compound Action Potential (CAP), has been used to study cochlear function in humans and experimental animals since the 1930s, providing a simple objective tool to assess both hair cell and nerve sensitivity. The vestibular equivalent of ECochG, termed here Electrovestibulography (EVestG), incorporates responses of the vestibular hair cells and nerve. Few research groups have utilized EVestG to study vestibular function. Arguably, this is because stimulating the cochlea in isolation with sound is a trivial matter, whereas stimulating the vestibular system in isolation requires significantly more technical effort. That is, the vestibular system is sensitive to both high-level sound and bone-conducted vibrations, but so is the cochlea, and gross electrical responses of the inner ear to such stimuli can be difficult to interpret. Fortunately, several simple techniques can be employed to isolate vestibular electrical responses. Here, we review the literature underpinning gross vestibular nerve and hair cell responses, and we discuss the nomenclature used in this field. We also discuss techniques for recording EVestG in experimental animals and humans, and highlight how EVestG is furthering our understanding of the vestibular system.

Amniotes evolved a unique postsynaptic terminal in the inner ear vestibular organs called the calyx that receives both quantal and nonquantal (NQ) synaptic inputs from Type I sensory hair cells. The nonquantal synaptic current includes an ultrafast component that has been hypothesized to underlie the exceptionally high synchronization index (vector strength) of vestibular afferent neurons in response to sound and vibration. Here, we present three lines of evidence supporting the hypothesis that nonquantal transmission is responsible for synchronized vestibular action potentials of short latency in the guinea pig utricle of either sex. First, synchronized vestibular nerve responses are unchanged after administration of the AMPA receptor antagonist CNQX, while auditory nerve responses are completely abolished. Second, stimulus evoked vestibular nerve compound action potentials (vCAP) are shown to occur without measurable synaptic delay and three times shorter than the latency of auditory nerve compound action potentials (cCAP), relative to the generation of extracellular receptor potentials. Third, paired-pulse stimuli designed to deplete the readily releasable pool (RRP) of synaptic vesicles in hair cells reveal forward masking in guinea pig auditory cCAPs, but a complete lack of forward masking in vestibular vCAPs. Results support the conclusion that the fast component of nonquantal transmission at calyceal synapses is indefatigable and responsible for ultrafast responses of vestibular organs evoked by transient stimuli.SIGNIFICANCE STATEMENTThe mammalian vestibular system drives some of the fastest reflex pathways in the nervous system, ensuring stable gaze and postural control for locomotion on land. To achieve this, terrestrial amniotes evolved a large, unique calyx afferent terminal which completely envelopes one or more presynaptic vestibular hair cells, which transmits mechanosensory signals mediated by quantal and nonquantal (NQ) synaptic transmission. We present several lines of evidence in the guinea pig which reveals the most sensitive vestibular afferents are remarkably fast, much faster than their auditory nerve counterparts. Here, we present neurophysiological and pharmacological evidence that demonstrates this vestibular speed advantage arises from ultrafast NQ electrical synaptic transmission from Type I hair cells to their calyx partners.

Despite considerable research, it remains controversial as to whether viral-infections are associated with Meniere’s Disease (MD), a clinically heterogeneous set of chronic inner-ear disorders strongly associated with endolymphatic hydrops. Here, we investigated whether viral-infections are associated with MD through a systematic review and meta-analysis of observational clinical studies using molecular-diagnostics. Eligible for inclusion were case-controlled studies which ascertained molecular-determinants of past or present viral-infection through either viral nucleic acids or host serological marker in MD cases and non-MD controls. Across online databases and grey literature, we identified 210 potentially relevant articles in the English language, from which a total of 14 articles fully satisfied our eligibility criteria such that meta-groups of 611 MD-cases and 373 controls resulted. The aggregate quality of the modest-sized (14 studies) body of evidence was limited and varied considerably with regards to participant selection, matching, and ascertainment(s) and determinant(s) of viral-infection. Most data identified concerned the human cytomegalovirus (CMV), and meta-analysis of eligible studies revealed that evidence of CMV-infection was associated approximately three-fold with MD compared to controls, however the timing of the infections was indeterminate as the pooled analyses combined antiviral serological markers with viral nucleic acid markers. No association was found for any of HSV-1, -2, VZV, or EBV. Associative analyses of any viral species not aforementioned were precluded by limited data, and thus potential associations between other viral species and MD, especially other than Herpesviridae, are yet to be characterised. Overall, we have found a small association between CMV-infection and MD, however it is to be determined for what sub-groups of MD this finding may be relevant, and ideally the reported association remains would be reproduced by a greater volume of higher quality evidence.