Saccular Otoconia Research Articles

A review of Meniere’s disease – reflection of published MRI, ECochG and newer otoconial theory from Aotearoa New Zealand

ABSTRACT Vertigo, or the symptom of an hallucination of motion, is usually caused by disorders of the inner ear. Buried in the bone of the otic capsule, the inner ear is the most difficult human sensory organ to image and investigate. As an inner ear disorder, Meniere’s disease (MD) is characterised as recurrent vertiginous attacks, fluctuating hearing loss which can be progressive, tinnitus and aural fullness. Post-mortem studies, and now MRI inner ear imaging, show an excess of endolymph or endolymphatic hydrops (ELH) which has been assumed to usually commence in the cochlea. However, the cause of the initial hydrops is still debated. This paper reflects on the research published in Ōtautahi Christchurch, Aotearoa New Zealand. There is evidence from post-mortem studies, electrophysiological test, and some inner ear imaging that endolymphatic obstruction from clumps of detached saccular otoconia may be a cause of MD.

Three-dimensionally visualized ossification and mineralization process of the otic capsule in a postnatal developmental mouse.

We aimed to elucidate the ossification process of the otic capsule in postnatal C57BL/6 mice and depict the three-dimensional (3D) process of otoconial mineralization in vivo. The otic capsules of C57BL/6 mice were stained with alizarin red and imaged/compared using micro-computed tomography on postnatal day (P) between P0 and P8, P10, P15, and P30 and 3-4 months old (P3-4Mo). We reconstructed 3D images of the otic capsule and otoconia and measured the bone mineral density using x-ray absorptiometry on each age. The 3D reconstructed otic capsule images revealed two ossification centers of the otic capsule at P0. One was observed around the ampulla of the superior semicircular canal and utricle, and the other was observed around the ampulla of the posterior semicircular canal. The cross-sectional views demonstrated that modiolar ossification developed from the base to the apex from P4 to P8. The inter-scalar septum ossified bidirectionally from the modiolus and bony otic capsule from P8 to P15. The mineralized otoconia were first detected in the utricle at P3 and saccular otoconia at P6. The density of the utricle and saccular otoconia showed different growth trends. To the best of our knowledge, this is the first study to demonstrate the 3D appearance of the otic capsule and otoconia in different developmental stages of mice. We also revealed that modiolar and inter-scalar septal calcification is the final event in the cochlea and that it can be susceptible to pathological conditions (cochlear congenital malformations and hereditary vestibular diseases). The unique features of the ossification process and duration may explain these pathological conditions observed in humans. 3.

Anatomy of the neurocranium, encephalon, and main sensory organs of the roundel skate, Rostroraja texana (Rajiformes: Rajidae)

The organization of the neurocranium, the encephalon, and the main sensory organs of Rostroraja texana (Family Rajidae) corresponds to the general morphological pattern of the elasmobranchs and, in particular, of the batoids. The neurocranium presents the rostrum, which corresponds to about 50% of the cranial length; additionally, it shows two dorsal fontanelles of similar shape and size. The anatomical relations of the neurocranium of R. texana are with the encephalon, the main sensory organs, the antorbital, synarcual, and spiracular cartilages, and with the mandibular, hyoid, and extra-ocular musculature. The encephalon is relatively narrow. The cerebellum is symmetrical and shows a partial division in the anterior and posterior portions. In the olfactory system, the following characteristics stand out: the external pigmentation of the olfactory organs, the high number of olfactory lamellae, and the asymmetry of the olfactory bulbs. In the optical system, the presence of the pupillary operculum and the division into two sections of the superior oblique muscle is notable. And, in the statoacoustic system, the large size of the saccular otoconia stands out.

Ductus Reuniens and Its Possible Role in Menière's Disease.

After 160 years the true underlying cause of Meniere's disease remains enigmatic. The aim of our study is to discuss the possible implication of an obstruction of the ductus reuniens as a cause in Menière's disease. We first conducted an historical study of the description of the ductus reuniens. We then reviewed the literature regarding ductus reuniens obstruction in animal experiments, human post-mortem studies and living ear imaging. We completed its description by modern microCT imaging. Limited knowledge on the fate of dislodged saccular otoconia is summarized. The possible implications for Meniere's attacks are discussed. Victor Hensen was the first to describe the ductus reuniens in 1863. He described its length and width and predicted that saccular otoconia might enter the ductus and the cochlea. On microCT the narrowest width of the human ductus reuniens was 0.14 mm. The literature reports cochlear endolymphatic hydrops occurring after animal experimental obstruction of the duct. Human postmortem studies have confirmed saccular otoconial clumps entering the ductus and the cochlea. A postmortem study has shown sites of endolymphatic obstruction, and imaging speculates on blockages in ears with Meniere's disease. Dislodged utricular otoconia can be in clumps of otolithic membranes. Blockages of the ductus reuniens and at other endolymphatic system sites appear to be a feature in Meniere's disease ears. The blockages have been postulated to be saccular otoconia either causing or aggravating hydrops. This could be consistent with observed nystagmus reversals during attacks as the endolymphatic sac attempts to clear the hydrops and the otoconia.

Lermoyez syndrome revisited: 100-year mystery

Objective: This study revisited seven patients with Lermoyez syndrome over the past 25 years using an inner ear test battery to elucidate its mechanism. Methods: From 1992 to 2017, we have experienced 4096 patients with Meniere’s disease (MD) and seven patients (5 males and 2 females, 8 ears) with Lermoyez syndrome. Two of the Lermoyez patients were elderly, aged 71 and 85 years. An inner ear test battery comprising audiometry, ocular and cervical vestibular-evoked myogenic potential (oVEMP and cVEMP) tests, and caloric test were performed. Results: Significant improvement of mean hearing levels (MHLs) was identified at low and middle frequencies after vertiginous attack, but not at high frequencies. Inner ear deficits in Lermoyez patients ran from abnormal hearing (100%) to abnormal cVEMP (43%), caloric (38%) and oVEMP (0) tests, exhibiting a significantly declining sequence. This declining sequence differed from that in MD. Conclusions: Lermoyez syndrome is extremely rare, with prevalence relative to MD of 0.2%. The mechanism is considered as blockage in the ductus reuniens caused by dislodged saccular otoconia. Aging and trauma are two precipitating factors for the dislodged saccular otoconia, which may explain why Lermoyez syndrome occurs most frequently in males and some elderly.

Saccular otoconia as a cause of Ménière's disease: hypothesis based on two theories

The cause of Ménière's disease remains enigmatic after 156 years. Schuknecht's rupture and potassium intoxication theory of attacks was based on histological studies. This paper aimed to: present the most contemporary evidence indicating that ruptures do not usually occur, and discuss the possibility that detached saccular otoconia are the main cause of Ménière's disease; and to establish an unequivocal definition of the age of Ménière's disease onset. The paper reviews the electrophysiological basis of the Gibson-Arenberg drainage theory used to explain vertigo attacks. The current, limited knowledge of the likely fate of detached saccular otoconia is discussed. Electrophysiological studies during attacks do not support endolymph ruptures, but rather endolymph flowing in one direction and then in the opposite direction. Age of onset for Ménière's disease parallels that for benign paroxysmal positional vertigo. The similarity of age of onset spectrum for Ménière's disease and benign paroxysmal positional vertigo raises the possibility that the two conditions have the same fundamental cause.

A New Theory for Ménière's Disease: Detached Saccular Otoconia

Ménière's disease is an inner ear disorder characterized by vertigo attacks, fluctuating and progressive hearing loss, tinnitus, and aural fullness in the affected ear. The pathophysiology of Ménière's disease remains elusive. Theories so far are anatomical variation in the size or position of the endolymphatic sac and duct, viral inflammation or autoimmune involvement of the sac, or a genetically determined abnormality of endolymph control. Animal studies on blocking the ductus reuniens and endolymphatic duct have produced hydrops in the cochlea, saccule, and utricle. Cone beam computed tomography images show a similar pattern with apparent obstruction of the ductus reuniens, saccular duct, and endolymphatic sinus. New studies documenting the age of onset of Ménière's disease show a pattern similar to benign paroxysmal positional vertigo, raising the possibility that the fundamental cause of Ménière's disease might be detached saccular otoconia.

Mutation screening of the Otop1 gene in familial benign positional paroxysmal vertigo

Objectives: Benign paroxysmal positional vertigo (BPPV) is a sporadic disorder in the vast majority of cases, although a familial, benign, recurrent form, in which the disease segregates in an autosomal dominant fashion has been described. After the evidence for a role of a novel murine gene, Otop1, in knock-out tlt (tilted) and mlh (Mergulhador) mice, lacking the perception of gravity and linear motion and showing a vestibular disorder due to non-syndromic agenesis of both utricular and saccular otoconia, we aimed at verifying the role of the human analogue of the Otop1 gene in BPPV pathogenesis in familial cases of BPPV, collected in our tertiary university referral centre. Methods: Starting in 2007, families with at least two living members thought to have BPPV were considered for inclusion in the present study. The cases were both retrospectively and prospectively identified over the following two years. Results: Seven familial aggregations of BPPV were identified and Otop1 mutation screening showed the presence of a heterozygous mutation in one family, c.1013G> C p.Arg338Pro, which was considered possibly deleterious using the prediction software. It was absent in 100 control alleles, but was also found in two as yet unaffected relatives. Conclusions: The results of a mutation screening of the Otop1 gene in familial cases of BPPV do not support a major role of the gene in the pathogenesis of the disease.

Ex vivo visualization of the mouse otoconial layer compared with micro-computed tomography.

Micro-computed tomography (micro-CT) is useful for assessing the 3-dimensional (3D) morphology and age-related changes of the otoconial layer. Wriggle mouse Sagami (WMS) is a mutant of the plasma membrane Ca2+ ATPase type2 gene (Atp2b2) with deficits in the saccular otoconia. We examined the effectiveness of micro-CT in evaluating the otoconial layer of WMS and C57BL/6J mice. Otic capsules of C57BL/6J mice at different fixation time were examined using micro-CT to evaluate the effects of the fixation time on the otoconial layer. Otic capsules of Atp2b2(wri/wri), Atp2b2(wri/+), and Atp2b2(+/+) mice at P14, P21, and the age of 3 months were used to analyze age-related changes in the otoconial layer. A series of cross-section and 3D reconstructed images of the otoconial layer were obtained. The micro-CT findings were compared with the otic capsule findings cleared in methyl salicylate using stereomicroscopy. Micro-CT produced high-resolution images of the otoconial layer, thereby providing information regarding the spatial configuration and 3D curvature. There were no changes between the different fixation times. In the Atp2b2(wri/+) and Atp2b2(+/+) mice, the saccular and utricular otoconial layers were normal among all age groups. In the Atp2b2(wri/wri) mice, the saccular otoconial layer decreased on P14 and was absent on P21, whereas the utricular otoconial layer disappeared at 3 months of age. We obtained precise information regarding the mouse otoconial layer with minimum artifacts. This method is expected to improve our understanding of the physiologic function and age-related changes in otolith organs.

Typical and atypical benign paroxysmal positional vertigo: literature review and new theoretical considerations.

Atypical variants of benign paroxysmal positional vertigo (BPPV) are often encountered and frequently confusing. The authors present a hypothetical framework that accounts for all classical patterns of BPPV and several unusual variants such as BPPV without nystagmus, BPPV with downbeat nystagmus and BPPV with paradoxically direction-changing nystagmus. The authors introduce new concepts, such as "ipsicanal switch" and "horizontal short arm canalolithiasis" and suggest that their use may improve diagnosis and treatment in everyday clinical practice. The possible consequences of saccular otoconia detachment are reviewed according to the literature.

Three-dimensional cone beam computed tomography imaging of the membranous labyrinth in patients with Meniere’s disease

Conclusion: Three-dimensional cone beam computed tomography (3DCT) images revealed characteristic malformations of the membranous labyrinth of the inner ear in Meniere’s disease (MD). The morphology of the membranous region between the vestibular cecum of the cochlea and the saccule of ears with MD was compared to that of healthy ears. The present study supports the hypothesis proposed earlier that reuniting duct blockade is a result of the dislodgement of saccular otoconia. Objective: To visualize the membranous labyrinth using 3DCT and to investigate the pathology of MD. Methods: A preparatory study was conducted to determine the optimal 3DCT window settings for the detection of water, muscle, calcium carbonate (CaCO3), and bone. Based on this preparatory study, the ears of 13 healthy volunteers and 25 MD patients definitely diagnosed according to the criteria issued by the Committee on Hearing and Equilibrium of the American Academy of Otolaryngology, Head and Neck Surgery (AAO-HNS), were visualized. Results: The differences in the membranous labyrinth between MD ears and healthy ears could be visualized using 3DCT. The images were classified into three types based on their morphological pattern. The ears of patients with MD were different from normal ears in terms of this classification.

Assessment of Meniere's disease from a radiological aspect – saccular otoconia as a cause of Meniere's disease?

Conclusion: Significant reduced visualization of the reuniting duct (ductus reuniens; RD), saccular duct (SD) and endolymphatic sinus (ES) in Meniere's disease (MD) compared with normal control ears on three-dimensional (3D) CT imaging suggests the blockage of endolymphatic flow there with radiodense substances, which may be explained by dislodged otoconia from the saccule. These structures could be involved in the pathogenesis of MD. Objective: This study was designed to visualize and assess the RD, SD and ES in patients with MD using 3D CT. Methods: Sixty-two patients with a definite diagnose of unilateral MD, based on criteria proposed by the Committee on Hearing and Equilibrium of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS), were compared with contralateral ears and normal controls (26 ears) using 3D CT. The RD, SD and ES were scrutinized for patency on 3D CT images. Results: MD ears showed loss of continuity of the RD, SD and ES based on evaluation of 3D CT images, and differed significantly from normal healthy control ears (p < 0.01).

Saccular Otoconia as a Cause of Ménière Disease

Objective: Idiopathic endolymphatic hydrops can be caused by disturbance of the longitudinal flow of the endolymph in Ménière disease. This study investigated a possibility that the dislodged otoconia from the saccule could be a cause of Ménière disease by occluding the pathway of the endolymph. Method: We examined the ears of 65 patients with definitely diagnosed unilateral Ménière disease based on the criteria proposed by the AAO-HNS and the ears of normal control subjects and cadavers using three-dimensional (3D) cone beam CT by focusing on the vestibule. Results: The images of the reuniting duct and the saccular duct could be categorized by their patency. In the case of Ménière ears, both the reuniting duct and the saccular duct were occluded significantly compared with those of normal ears. The ears of the nonlesional side of Ménière patients also showed the occluded aspects of these ducts. The endolympatic sinus, which connects to the saccular duct, suggested relations with Ménière attack. Conclusion: Patients with Ménière disease often show a significantly higher incidence of blockage of the reuniting duct and saccular duct. There is a big probability that radiodense substances such as saccular otoconia falling into these ducts may be one of the etiologies of Ménière disease.

Age‐Related Changes on the Morphology of the Otoconia

Although there are numerous reports on otoconial morphology using field-emission scanning electron microscopy (FESEM), there are few reports regarding the changes of otoconial morphology with aging. The aim of the current study was to investigate changes in otoconial morphology in rats according to age, using FESEM. Laboratory study using experimental animals. We investigated age-related changes in otoconial morphology using FESEM in three groups of rats: young (1 wk old), middle-aged (6 mo old), and aged (23 mo old). There was great size variation in utricular otoconia in the young and aged rats, but we found no clear regional separation of saccular otoconia in all groups based on size. In the oldest rats, the bodies of many otoconia in both maculae were pitted, fissured, penetrated, and eventually broken into several fragments. However, the terminal facets were smooth and the lines of intersection of facets were sharp, despite the degenerated bodies of the otoconia in this group. Giant otoconia were discovered frequently on the outer margin of the utricular maculae in aged rats. We directly observed weakened or broken linking filaments and otoconial fragments in the aged group. The oldest rats showed the most degeneration of otoconia and linking filaments with otoconial fragments. This study of age-related morphologic changes in otoconia might help us understand the origin of idiopathic benign paroxysmal positional vertigo.

Histomorphologische Untersuchung bei experimentell induzierter Kanalolithiasis

Free otoconia in the posterior semicircular canal (pSCC) are regarded as the main reason for benign paroxysmal positional vertigo. We investigated the distribution of otoconia in the membranous labyrinth of guinea pigs (n = 34) after a defined rotatory/angular kinetic acceleration. The angular kinetic energy of the rotatory experiment produced a dislocation of the otoconia and sometimes of the complete gelatinous otolithic membrane of the utricular and saccular macula. The otoconia could be observed in all three semicircular canals but predominated in the dark cell areas of the utricular side of the lateral SCC. A total obstruction of the semicircular canal could never be seen. Close to the lateral crista, perilymphatic hemorrhage could frequently be observed. The saccular otoconia were located in the amalgamation between endolymphatic membrane and saccule. The results of this histological study can form the basis for different theories about the genesis of canalolithiasis and cupulolithiasis and the vertigo which accompanies them.

Gravity receptor function in mice with graded otoconial deficiencies

The purpose of the present study was to examine gravity receptor function in mutant mouse strains with variable deficits in otoconia: lethal milk ( lm), pallid ( pa), tilted ( tlt), mocha ( mh), and muted ( mu). Control animals were either age-matched heterozygotes or C57BL/6J (abbr. B6) mice. Gravity receptor function was measured using linear vestibular evoked potentials (VsEPs). Cage and swimming behaviors were also documented. Temporal bones were cleared to assess the overall otoconial deficit and to correlate structure and function for lm mice. Results confirmed the absence of VsEPs for mice that lacked otoconia completely. VsEP thresholds and amplitudes varied in mouse strains with variable loss of otoconia. Some heterozygotes also showed elevated VsEP thresholds in comparison to B6 mice. In lm mice, which have absent otoconia in the utricle and a variable loss of otoconia in the saccule, VsEPs were present and average P1/N1 amplitudes were highly correlated with the average loss of saccular otoconia ( R=0.77, p<0.001). Cage and swimming behavior were not adversely affected in those animals with recordable VsEPs. Most, but not all, mice with absent VsEPs were unable to swim. Some animals were able to swim despite having no measurable gravity receptor response. The latter finding underscores the remarkable adaptive potential exhibited by neurobehavioral systems following profound sensory loss. It also shows that behavior alone may be an unreliable indicator of the extent of gravity receptor deficits.

Morphometry of otoconia in the utricle and saccule of developing Japanese quail

The development of otoconia in the utricular and saccular maculae from initial embryonic formation to adult stages was examined in Japanese quails. Both the morphology and size of the otoconia were quantified at different developmental stages. It was observed that the otoconia were initially formed on embryologic stage E5 in the saccule and E6 in the utricle. Otolith mass areas increased in a sigmoidal growth pattern, with saccular otolith areas being smaller than the utricular mass areas. Saccular otolith masses reached adult values at embryonic stage E12 and utricular areas reached adult values at post-hatch day 7. Mature individual otoconia were characterized by a barrel shape with two trihedral faceted ends. However, initial formation of otoconia at E5 (saccular) and E6 (utricular) maculae was characterized by a double fluted morphology that consisted of an hourglass shape with extended fins forming trihedral angles of 120°. Double fluted otoconia rapidly filled, so that by embryonic day 8 mature otoconia dominated the maculae for the remainder of development through adulthood. Thus, a progression from double fluted to mature forms was noted. Mature utricular otoconia in adult quails averaged 11 μm in length and 5 μm in width, with length/width ratios of approximately 2.5:1, for all size ranges. Saccular otoconia were smaller, having about 70% the size of utricular otoconia in both length and width. During development, the average size and range of individual otoconia increased nearly linearly for both otolith organs. In the utricular macula, large otoconia were concentrated in the lateral regions of the epithelium. In contrast, otoconia of various sizes were distributed uniformly across the surface of the saccular macula.

Appearance and evolution of calcitic and aragonitic otoconia during Pleurodeles waltl development

The aim of this study is to determine the stages of appearance, morphology, crystallographic structure and chemical composition of otoconia during the inner ear development of an urodele amphibian, Pleurodeles waltl. The first otoconia are detected in the otocyst. Near hatching, calcitic otoconia are polyhedral in the saccule and cylindrical in the utricle. During the following stages, the saccular otoconia agglomerate and constitute a polyhedral calcitic otolith. At larval stage 44, aragonitic fusiform otoconia appear on the otolithic surface. At stage 52, X-ray diffraction analysis shows calcite and aragonite patterns. In adults, all the saccular otoconia are aragonitic. In contrast, the utricular otoconia do not show any modification up to adulthood. In the endolymphatic sac, otoconia appear at stage 45 and in the lagena at stage 49. They remain aragonitic up to adulthood. Energy dispersive X-ray spectroscopy (EDXS) elemental analysis of the otoconia reveals a high quantity of calcium with trace quantities of sodium, magnesium, phosphorus, sulfur, chlorine and potassium. However, magnesium and sulfur have a lower concentration in lagenar aragonitic otoconia than in utricular and saccular calcitic ones. As in adults, trace amounts of strontium are only found in aragonitic otoconia.

Characterization of otoconin-95, the major protein of murine otoconia, provides insights into the formation of these inner ear biominerals.

During the course of a study aimed at identifying inner ear-specific transcripts, a 1,906-bp murine cDNA predicted to encode a secreted 469-aa protein with two domains of homology with the secreted phospholipases A2 was isolated. This transcript is specifically expressed in the inner ear from embryonic day 9.5. The encoded 95-kDa glycoprotein is the major protein of the utricular and saccular otoconia and thus was named otoconin-95. By immunohistofluorescence, otoconin-95 also was detected in the cupulae of the semicircular canals and in previously undescribed transient granular structures of the cochlea. Otoconin-95 was found to be synthesized by various nonsensory cell types, but not by the supporting cells of the sensory epithelia, which produce the otoconial precursor vesicles. In addition, multiple isoforms generated by differential splicing were observed in different combinations during development. Based on the present results, we propose a model for the formation of the otoconia.

Why Do Benign Paroxysmal Positional Vertigo Episodes Recover Spontaneously?

It is well known that most episodes of benign paroxysmal positional vertigo (BPPV), even in untreated, recover spontaneously in 2 to 6 weeks. In the present study, we put forward the hypothesis that this is mainly due to the fact that endolymph, owing to its low calcium content (20 microM) is able to dissolve otoconia. To support this, the fate of frog saccular otoconia immersed in normal endolymph (Ca2+ content 20 microM) and in Ca2+-rich endolymphatic fluids (up to 500 microM) was studied by observing the crystals at regular intervals for 3 weeks. The results demonstrated that normal endolymph can dissolve otoconia very rapidly (in about 20 hours). When the endolymphatic Ca2+ content was increased (50 to 200 microM) otoconia dissolution time was slowed down (about 100 to 130 hours, respectively) and completely stopped when the endolymphatic Ca2+ content was of 500 microM. The present results therefore suggest that the major process involved in the spontaneous recovery of BPPV episodes is the capability of the endolymph to dissolve dislodged otoconia.