A mouse model for benign paroxysmal positional vertigo with genetic predisposition for displaced otoconia

Abnormal formation of otoconia, the biominerals of the inner ear, results in balance disorders. The inertial mass of otoconia activates the underlying mechanosensory hair cells in response to change in head position primarily during linear and rotational acceleration. Otoconia associate exclusively with the two gravity receptors, the utricle and saccule. The cristae sensory epithelium is associated with an extracellular gelatinous matrix known as cupula, equivalent to otoconia. During head rotation, the inertia of endolymphatic fluids within the semicircular canals deflects the cupula of the corresponding crista and activates the underlying mechanosensory hair cells. It is believed that detached free‐floating otoconia particles travel ectopically to the semicircular canal and cristae and are the culprit for benign paroxysmal positional vertigo (BPPV). The Slc26a4 mouse mutant harbors a missense mutation in pendrin. This mutation leads to impaired transport activity of pendrin and to defects in otoconia composition and distribution. All Slc26a4 ^loop/loop homozygous mutant mice are profoundly deaf but show inconsistent vestibular deficiency. A panel of behavioral tests was utilized in order to generate a scoring method for vestibular function. A pathological finding of displaced otoconia was identified consistently in the inner ears of mutant mice with severe vestibular dysfunction. In this work, we present a mouse model with a genetic predisposition for ectopic otoconia with a clinical correlation to BPPV. This unique mouse model can serve as a platform for further investigation of BPPV pathophysiology, and for developing novel treatment approaches in a live animal model.     

Quantitative analysis of benign paroxysmal positional vertigo fatigue under canalithiasis conditions

In our daily life, small flows in the semicircular canals (SCCs) of the inner ear displace a sensory structure called the cupula which mediates the transduction of head angular velocities to afferent signals. We consider a dysfunction of the SCCs known as canalithiasis. Under this condition, small debris particles disturb the flow in the SCCs and can cause benign paroxysmal positional vertigo (BPPV), arguably the most common form of vertigo in humans. The diagnosis of BPPV is mainly based on the analysis of typical eye movements (positional nystagmus) following provocative head maneuvers that are known to lead to vertigo in BPPV patients. These eye movements are triggered by the vestibulo-ocular reflex, and their velocity provides an indirect measurement of the cupula displacement. An attenuation of the vertigo and the nystagmus is often observed when the provocative maneuver is repeated. This attenuation is known as BPPV fatigue. It was not quantitatively described so far, and the mechanisms causing it remain unknown. We quantify fatigue by eye velocity measurements and propose a fluid dynamic interpretation of our results based on a computational model for the fluid–particle dynamics of a SCC with canalithiasis. Our model suggests that the particles may not go back to their initial position after a first head maneuver such that a second head maneuver leads to different particle trajectories causing smaller cupula displacements.     

A mathematical model for top-shelf vertigo: the role of sedimenting otoconia in BPPV

Benign paroxysmal positional vertigo (BPPV) is a mechanical disorder of the vestibular system in which calcite particles called otoconia interfere with the mechanical functioning of the fluid-filled semicircular canals normally used to sense rotation. Using hydrodynamic models, we examine the two mechanisms proposed by the medical community for BPPV: cupulolithiasis, in which otoconia attach directly to the cupula (a sensory membrane), and canalithiasis, in which otoconia settle through the canals and exert a fluid pressure across the cupula. We utilize known hydrodynamic calculations and make reasonable geometric and physical approximations to derive an expression for the transcupular pressure DeltaPc exerted by a settling solid particle in canalithiasis. By tracking settling otoconia in a two-dimensional model geometry, the cupular volume displacement and associated eye response (nystagmus) can be calculated quantitatively. Several important features emerge: (1) a pressure amplification occurs as otoconia enter a narrowing duct; (2) an average-sized otoconium requires approximately 5 s to settle through the wide ampulla, where DeltaPc is not amplified, which suggests a mechanism for the observed latency of BPPV; and (3) an average-sized otoconium beginning below the center of the cupula can cause a volumetric cupular displacement on the order of 30 pL, with nystagmus of order 2 degrees/s, which is approximately the threshold for sensation. Larger cupular volume displacement and nystagmus could result from larger and/or multiple otoconia.     

Numerical modeling of the cupular displacement and motion of otoconia particles in a semicircular canal

Balance is achieved and maintained by a balance system called a labyrinth that is composed of three semicircular canals and the otolith organs that sense linear gravity and acceleration. Within each semicircular canal, there is a gelatinous structure called the cupula, which is deformed under the influence of the surrounding endolymph. One of the balance disorders is benign paroxysmal positional vertigo, and one of the pathological conditions that have been identified as possible causes of this syndrome is canalithiasis—disturbance of the endolymph flow and cupular displacement caused by the free-moving otoconia particles within the lumen of the canal. Analysis of phenomena occurring within the semicircular canal can help to explain some balance-related disorders and the response of the vestibular system to external perturbations under various pathological conditions. Numerical simulations allow a study of the influence of a wide range of factors, without the need to perform experiments and clinical examinations. In case of canalithiasis, an accurate explanation and tracking of the motion of otoconia particles in vivo is obviously nearly impossible. In this study, a numerical model was developed to predict the motion of otoconia particles within the semicircular canal and the effect of the endolymph flow and particles on the deformation of the cupula.     

Benign Paroxysmal Positional Vertigo after Dental Procedures: A Population-Based Case-Control Study

BackgroundBenign paroxysmal positional vertigo (BPPV), the most common type of vertigo in the general population, is thought to be caused by dislodgement of otoliths from otolithic organs into the semicircular canals. In most cases, however, the cause behind the otolith dislodgement is unknown. Dental procedures, one of the most common medical treatments, are considered to be a possible cause of BPPV, although this has yet to be proven. This study is the first nationwide population-based case-control study conducted to investigate the correlation between BPPV and dental manipulation.MethodsPatients diagnosed with BPPV between January 1, 2007 and December 31, 2012 were recruited from the National Health Insurance Research Database in Taiwan. We further identified those who had undergone dental procedures within 1 month and within 3 months before the first diagnosis date of BPPV. We also identified the comorbidities of the patients with BPPV, including head trauma, osteoporosis, migraine, hypertension, diabetes, hyperlipidemia and stroke. These variables were then compared to those in age- and gender-matched controls.ResultsIn total, 768 patients with BPPV and 1536 age- and gender-matched controls were recruited. In the BPPV group, 9.2% of the patients had undergone dental procedures within 1 month before the diagnosis of BPPV. In contrast, only 5.5% of the controls had undergone dental treatment within 1 month before the date at which they were identified (P = 0.001). After adjustments for demographic factors and comorbidities, recent exposure to dental procedures was positively associated with BPPV (adjusted odds ratio 1.77; 95% confidence interval 1.27–2.47). This association was still significant if we expanded the time period from 1 month to 3 months (adjusted odds ratio 1.77; 95% confidence interval 1.39–2.26).ConclusionsOur results demonstrated a correlation between dental procedures and BPPV. The specialists who treat patients with BPPV should consider dental procedures to be a risk factor, and dentists should recognize BPPV as a possible complication of dental treatment.     

Vestibular postural control model

Current models for physiological components and a posture control experiment conducted with three normal subjects form the basis for a model which seeks to describe quantitatively the control of body sway when only vestibular motion cues are used. Emphasis is placed on delineating the relative functional roles of the linear and the angular acceleration sensors and on modeling the functional interface between these sensors and the initiation of compensatory responses at the ankle joint.The model predicts the form of the postural response to a small sway disturbance; including initial detection of sway, characteristics of the transient correction, and maintenance of stability. The model suggests that postural stability requires a short time constant integration of semicircular canal output. Separation of semicircular canal and utricular otolith function into sway motion detector and static reference sensors respectively is demonstrated.This work was supported by NASA under Grant NGR-22-009-156.     

A model of Alexander's law of vestibular nystagmus

The observation that the amplitude of vestibular nystagmus grows as gaze is increased in the direction of the nystagmus fast phase and diminished with gaze in the opposite direction is known as Alexander's law. We have developed an analog computer model to simulate Alexander's law in nystagmus secondary to dysfunction of a semicircular canal. The model utilizes relevant brainstem anatomy and physiology and includes gaze modulation of vestibular signals and push-pull integration to create eye positition commands. When simulating normally functioning semicircular canals, the model produced no nystagmus. When simulating total impairment of the canal on one side with gaze directed maximally in the opposite direction, the model produced a large amplitude nystagmus with linear slow phases directed toward the affected side. As gaze was changed from far contralateral to ipsilateral, the nystagmus gradually diminished to zero. When simulating partial impairment of one canal, the nystagmus was smaller in amplitude and absent in ipsilateral gaze.     

Awareness of benign paroxysmal positional vertigo in central Israel

Background

Despite its frequent occurrence and effective treatment options, benign paroxysmal positional vertigo (BPPV) still remains under-estimated in the community.

Methods

We reviewed referral letters and medical records of 120 patients who were treated for BPPV at our Dizziness Clinic during the years 2006–2008 and searched for factors that possibly contribute to missing this entity.

Results

The referral diagnosis could be clustered into four groups: BPPV (25.6%), further unspecified vertigo (36.6%), dizziness (27.5%) and other (10%). BPPV was recognized more frequently by ENT doctors than by other specialists. Patients referred with the correct diagnosis of BPPV were significantly younger and the duration of their symptoms shorter than in other referral groups. Patients in the distinct referral groups did not differ in the presence of autonomic symptoms or a history of another serious disease. A history typical of BPPV could be obtained in all but 11 patients, but position dependence was noted by the referring physician only in 55 patients, 31 of them correctly assigned as possible BPPV. Only in two patients was the Dix-Hallpike test performed. Thirty two patients were diagnosed with BPPV in the past, but this did not influence the recognition of the recurrence of this clinical entity. About 40% of patients had an audiogram and/or brainstem auditory evoked potentials. Electronystagmography was performed in 7.5% and brain imaging in 14% of patients before referral.

Conclusion

Our results show that BPPV is still an under-recognized entity. Education and the demand on specialists to learn how to treat BPPV, could improve the situation.     

Mechanics of Coriolis stimulus and inducing factors of motion sickness.

To specify inducing factors of motion sickness comprised in Coriolis stimulus, or cross-coupled rotation, the sensation of rotation derived from the semicircular canal system during and after Coriolis stimulus under a variety of stimulus conditions, was estimated by an approach from mechanics with giving minimal hypotheses and simplifications on the semicircular canal system and the sensory nervous system. By solving an equation of motion of the endolymph during Coriolis stimulus, rotating angle of the endolymph was obtained, and the sensation of rotation derived from each semicircular canal was estimated. Then the sensation derived from the whole semicircular canal system was particularly considered in two cases of a single Coriolis stimulus and cyclic Coriolis stimuli. The magnitude and the direction of sensation of rotation were shown to depend on an angular velocity of body rotation and a rotating angle of head movement (amplitude of head oscillation when cyclic Coriolis stimuli) irrespective of initial angle (center angle) of the head relative to the vertical axis. The present mechanical analysis of Coriolis stimulus led a suggestion that the severity of nausea evoked by Coriolis stimulus is proportional to the effective value of the sensation of rotation caused by the Coriolis stimulus.     

A mathematical model of the response of semicircular canal and otolith to head rotation under gravity

The mathematical model of the system composed of two sensors: semicircular canal and sacculus, is presented. The system is described by three series of blocks: biomechanical block, mechanoelectrical transduction mechanism and hair cell ionic currents and membrane potential dynamics. The response of the aforecited system to various stimuli (head rotation under gravity and falling) was investigated. The identification of the model parameters was fulfilled for the experimental data, obtained for the axolotle (Ambystoma tigrinum) in Institute of Physiology, Autonomous University of Puebla, Mexico. The comparative analysis of canal and sacculus membrane potential was realized.     

Motion from the past. A new method to infer vestibular capacities of extinct species

The vestibular system detects head movement in space and maintains visual and postural stability. The semicircular canal system is responsible for registering head rotation. How it responds to head rotation is determined by the rotational axis and the angular acceleration of the head, as well as the sensitivity and orientation of each semicircular canal. The morphological parameters of the semicircular canals are supposed to allow an optimal detection of head rotations induced by some behaviours, especially locomotor. We propose a new method of semicircular canal analysis, based on the computation of central streamlines of virtually reconstructed labyrinths. This method allows us to ascertain the functional structure of the semicircular canal system and to infer its capacity to detect particular head rotations, induced by particular behaviours. In addition, this method is well-suited for datasets provided by any kind of serial sectioning methods, from MRI to μCT scanning and even mechanical serial sectioning, of extant and extinct taxa.     

Performance of DHI Score as a Predictor of Benign Paroxysmal Positional Vertigo in Geriatric Patients with Dizziness/Vertigo: A Cross-Sectional Study

Background

Dizziness/vertigo is one of the most common complaint and handicapping condition among patients aged 65 years and older (Geriatric patients). This study was conducted to assess the impact of dizziness/vertigo on the quality of life in the geriatric patients attending a geriatric outpatient clinic.

Settings and Design

A cross-sectional study was performed in a geriatric outpatient clinic of a rural teaching tertiary care hospital in central India.

Materials and Methods

In all consecutive geriatric patients with dizziness/vertigo attending geriatric outpatient clinic, DHI questionnaire was applied to assess the impact of dizziness/vertigo and dizziness associated handicap in the three areas of a patients’ life: physical, functional and emotional domain. Later, each patient was evaluated and underwent Dix-Hallpike maneuver by the physician who was blind of the DHI scoring of the patient.

Statistical Analysis Used

We compared means and proportions of variables across two categories of benign paroxysmal positional vertigo (BPPV) and non-BPPV. For these comparisons we used Student’s t-test to test for continuous variables, chi-square test for categorical variables and Fisher’s exact test in the case of small cell sizes (expected value<5).

Results

The magnitude of dizziness/vertigo was 3%. Of the 88 dizziness/vertigo patients, 19 (22%) and 69(78%) cases, respectively, were attributed to BPPV and non-BPPV group. The association of DHI score ≥50 with the BPPV was found to be statistically significant with x² value = 58.2 at P<0.01.

Conclusion

DHI Score is a useful tool for the prediction of benign paroxysmal positional vertigo. Correct diagnosis of BPPV is 16 times greater if the DHI Score is greater than or equal to 50. The physical, functional and emotional investigation of dizziness, through the DHI, has demonstrated to be a valuable and useful instrument in the clinical routine.     

Morphology of the mammalian vestibulo-ocular reflex: the spatial arrangement of the human fetal semicircular canals and extraocular muscles

The vestibulo-ocular reflex is the system of compensatory ocular movements in response to stimulation of the kinetic labyrinth seen in all vertebrates. It allows maintenance of a stable gaze even when the head is moving. Perhaps the simplest influence on the VOR is the spatial orientation of the planes of the semicircular canals relative to the extraocular muscles. It is hypothesized that the extraocular muscles are in parallel alignment with their corresponding semicircular canals in order to reduce the amount of neural processing needed and hence keep reflex times to a minimum. However, despite its obvious importance, little is known of this spatial arrangement. Moreover, nothing is known about any ontogenetic changes in the relative orientations of the extraocular muscles and semicircular canals. The morphologies of fetal and adult specimens of Homo sapiens were examined using magnetic resonance (MR) images. Three-dimensional co-ordinate data were taken from the images and used to calculate vector equations of the extraocular muscles and planes of best fit for the semicircular canals. The relative orientations of the muscles and canals were then calculated from the vectors and planes. It was shown that there are significant correlations between both the anterior and lateral semicircular canals and their corresponding extraocular muscles during ontogeny. In the case of the lateral canal with the medial rectus, the lateral canal with the lateral rectus, and the anterior canal with the inferior oblique, the trend is towards, though never reaching, alignment, whereas the anterior canal and the superior rectus muscle move out of alignment as age increases. Furthermore, it was noted that none of the six muscle-canal pairs is in perfect alignment, either during ontogeny or in adulthood. It was also shown that the three semicircular canals are not precisely orthogonal, but that the anterior and posterior canals form an angle of about 85 degrees , while the anterior and lateral canals diverge by approximately 100 degrees . Overall, it was shown that there is significant reorientation of the extraocular muscles and semicircular canals during ontogeny, but that, in most cases, there is little realignment beyond the fetal period.     

Intraspecific variation in the domestic cat bony labyrinth revealed by different measurement techniques

The knowledge of intraspecific variation is important to make assumptions on an interspecific level. To study intraspecific variation in the bony labyrinth morphology of the domestic cat, eleven specimens of Felis silvestris catus and two additional subspecies (F. s. lybica, F. s. ornata) were investigated. The sample comprises skulls of adult males and females, as well as juvenile cats. Each bony labyrinth endocast was virtually reconstructed based on µCT scans. To estimate the radius of curvature of each inner ear semicircular canal, three different approaches were tested. The comparison of the different methods resulted in different absolute values for the measured radii. The assumed best structure to precisely characterize the size of a semicircular canal is the inner perimeter. Within the tested sample, the anterior semicircular canal is always the largest, while the posterior semicircular canal is the second largest and the lateral semicircular canal the smallest in most cases. The coefficient of variation lies below 10% for all bony labyrinth measurements within the sample. The inner perimeter values of each semicircular canal are similar within all investigated specimens, even though the skull length of adult cats is twice as long as that of juvenile cats. Thus, inner ear biometry of the domestic cat seems stable throughout growth series and can therefore be used for systematic and ecological studies and the inclusion of juvenile individuals is reasonable. It is noteworthy that the inner perimeter values of the semicircular canals do not vary as much as the values of the angles spanned between the three canals within the sample. The inner ear within the cat skull is oriented about 25° to 31° to the palate (angle between the plane anchored to the lateral semicircular canals (SC) and the plane anchored to the palate). The cochlea coils between 3.00 and 3.25 turns in the investigated sample.     

The effects of biological rhythms and sleep quality on benign paroxysmal positional vertigo and reflux symptom severity

Recently, there has been increased interest in chronotypes and clinical differences between them. However, there is limited information about the potential influence of the chronotypes on clinical manifestations and symptom intensity of somatic diseases. The aim of this study is to evaluate the impact of biological rhythm differences and sleep quality on benign paroxysmal positional vertigo (BPPV) and larengo pharyngeal reflux (LPR) severity. Forty-four LPR patients, 43 BBPV patients and 42 controls were included in the study. The morningness–eveningness questionnaire was used to determine chronotypes, and the Pittsburgh Sleep Quality Index was used to assess subjective sleep quality. Both patient groups reported a significantly greater tendency to eveningness diurnal preferences compared to healthy controls. As with the circadian preferences, patients with BPPV or LPR characterized by poorer sleep quality and worse insomnia than non-patient individuals. It can be concluded that the circadian rhythm and sleep quality are related to the severity of LPR and BPPV.     

Semicircular duct and ampulla dimensions in cat,guinea pig and man

Predictions from the classic theory of semicircular canal operation, the torsion pendulum model, depend upon labyrinthine dimensions and the physical properties of the endolymph. The dimensions of the semicircular canal, duct and ampulla in cat, guinea pig and man were determined from measurements of magnified sections of decalcified temporal bones. Estimates of the effect of shrinkage were obtained from measures in fresh material and it appears shrinkage is probably only a fairly small factor. The dimensions so obtained were used to provide new estimates of the short time constant and other mechanical parameters of the torsion pendulum model in the three species.     

Co-morbidities of vertiginous diseases

Background  

Co-morbidities of vertiginous diseases have so far not been investigated systematically. Thus, it is still unclear whether the different vertigo syndromes (e.g. benign paroxysmal positional vertigo (BPPV), Meniere's disease (MD), vestibular migraine and phobic vertigo (PPV)) have also different spectrums of co-morbidities.