Benign Paroxysmal Positional Vertigo (BPPV) is the most common and representative vestibular disease of peripheral origin. The three original monographs of BPPV are introduced and commented upon. In addition, a series of essential up-to-date papers are described, focusing particularly on the pathophysiology of BPPV: cupulolithiasis and canalolithiasis, the treatment of posterior canal BPPV, the characteristics of lateral canal BPPV and anterior canal BPPV.
A 60-year-old man had a hypertensive hemorrhage at the right side of the pontine tegmentum, which resulted in right facial palsy and left hemiparesis, and one-and-a-half syndrome. Eighty days after a stroke, he manifested progressively blurred vision and oscillopsia, corresponding to a vertical pendular nystagmus. Additionally, the abnormal rhythmic involuntary movements of his left upper extremity (brachial myoclonus) appeared simultaneously. In addition to the disturbances of the horizontal eye movements, the vertical gaze was also disturbed. The patient also complained of photophobia and often tried to close his eyes. Although his hearing acuities were within the normal range (right ear 28.8 dB, left ear 25.0dB), he always complained of hearing disturbance of his right ear which might suggest the involvements of the central auditory pathways at the pontine lesion. T1-weighted MRI findings showed a hemosiderin- and ferritin- lined cleft confined to the right side of the dorsal pontine tegmentum and the central tegmental tract. Furthermore, T2-weighted or FLAIR MRI revealed the enlargement of the right inferior olivary nuclei with high intensity signals, which is the typical appearance of hypertrophic olivary degeneration (HOD). Electronystagmography (ENG) showed the acquired vertical pendular nystagmus was prominent with a frequency of 2.5c/s and the amplitude of 5-7 degrees. Although the vertical eye movements were slightly recorded in the light, they could not be completely detected in the dark. However, the vertical “doll's eye phenomenon” was identified in the vertical plane, suggesting supranuclear vertical gaze palsy, with the convergence being additionally preserved. In the eye tracking test (ETT), the pursuit was dysmetric intermingled with a catch-up saccade both horizontally and vertically. Optokinetic nystagmus (OKN) could hardly be induced in both the horizontal and vertical stimulation, though the fast phase of nystagmus to the left could be slightly induced. Furthermore, the ice water caloric stimulation almost failed to induce caloric nystagmus, though the fast phase of nystagmus to the left was slightly induced. In the literature, to the best of our knowledge, disturbances of vertical eye movements in pontine tegmental lesions as in our case have been rarely reported. It is potentially conceivable that the medial longitudinal fasciculi (MLF) or neighboring tegmental tracts convey bidirectional signals for vertical eye movements such as smooth pursuit or VOR, and that the present pontine lesions are interrupting such pathways causing impairments of the vertical eye movements.
Positional down-beating nystagmus of peripheral origin (p-DBN) has been considered to be caused by Anterior-canal Benign Paroxysmal Positional Vertigo (A-BPPV). However, recently p-DBN was also described to be caused by a variant of Posterior-BPPV (v-P-BPPV). It has been difficult to make a differential diagnosis between A-BPPV and v-P-BPPV based on positional nystagmus findings alone, but this could be confirmed by the conversion from p-DBN to P-BPPV (canalolithiasis) presenting on the affected side. In this study, we examined a total of 18 conversion cases from P- or Lateral-BPPV (canalolithiasis) to p-DBN, in which the affected side was already identified. The conversion to p-DBN occurred within an average of 3 days after the repositioning maneuver. Based on the existence and the direction of torsional nystagmus, 12 cases were diagnosed as having v-P-BPPV and 6 cases were diagnosed as having probable A-BPPV. Hypothetically, free otoliths in the posterior- or lateral-canal may move towards the posterior-canal near the common crus, generating an inhibitory discharge of the posterior-canal, leading to p-DBN with torsional nystagmus. Furthermore, free otoliths may move through the common crus to the ampulla of the anterior-canal, touching or adhering to the cupula, generating an excitatory discharge of the anterior-canal, and leading to p-DBN with or without torsional nystagmus.
In the United States of America, physiotherapists are involved in vestibular rehabilitation. With the aim of clarifying the degree of interest in Japanese physiotherapists regarding vestibular rehabilitation, this study used a questionnaire to survey physiotherapists who had previously been exposed to equilibrium research at workshops and physiotherapists who had not been exposed as a control group. Approximately 80% of those in the control group were interested in vestibular rehabilitation. However, most physiotherapists had very few opportunities to receive education regarding the pathophysiology of the vestibular system and related diseases in a clinical setting.
Physiotherapists who participated in workshops received this education from senior physiotherapists as their instructors. The small number of physiotherapists who were given such opportunities was engaged in vestibular system rehabilitation based on requests from otolaryngologists for a small number of cases.
A question regarding vestibular rehabilitation was on the national examination for physiotherapists in 2015. However, there are few opportunities for education regarding vestibular system before and after graduation.
Vestibular hair cells and vestibular ganglion cells are known to be important for the maintenance of balance systems. However they gradually decrease in number with age. In addition, a large amount of vestibular ganglion cells is lost after vestibular neuritis; meanwhile, the remaining cells degenerate. In addition, hair cells are damaged by ototoxic drugs and complete regeneration is difficult in mammals. In clinical situations, the loss of the bilateral vestibular systems impacts negatively and severely on an affected individual's quality of life. Unfortunately, to date, no fundamental therapy for vestibular disorders has been established. As such, there is an urgent need for new treatment breakthroughs.
Recently, transplantation of induced pluripotent stem cells (iPSCs) is an extremely promising tool for the treatment of presently incurable diseases. To replace damaged cells in transplanted tissues, transplanted cells must differentiate into target cells. We reported that co-cultures of otic progenitor cells derived from iPSCs with stromal tissues differentiated into vestibular hair cell like cells, and human neural stem cells (hNSCc) derived from iPSCs cultured in utricle tissues differentiated into cells resembling vestibular ganglion cells morphologically and functionally. We examined the potential of transplantation therapy using iPSC-derived cells in mouse utricles with the aim of replacing lost vestibular cells.
For clinical application, we made a mouse model of vestibular disorders to confirm the effect of cell transplantation in vivo. Administration of an ototoxic drug such as gentamicin into the mouse posterior semicircular canal induced a balance disorder and lowered the vestibulo ocular reflex (VOR) gain. Additionally, a few transplanted iPSCs survived in the mouse inner ear after iPSCs transplantation. These were preliminary data, but might be a first step to future regeneration therapy for vestibular disorders.
Genetic defects are a major cause of hearing loss in newborns. Numerous causative genes for genetic hearing loss have been identified. Most genes cause only hearing loss which is referred to as non-syndromic deafness. On the other hand, some genes cause not only congenital hearing loss but also vestibular dysfunction, etc., which is referred to as syndromic deafness. However, presently, there are no truly curative treatments for this condition. One of the feasible treatments for congenital inner ear disease is “gene therapy during the embryonic stages” before the expression of abnormal morphology and function of the inner ear. In 2008, Gubbles et al. reported on gene transfer by transuterine-mediated injection into the embryonic inner ear (otocyst) and electroporation at embryonic day 11.5 (E11.5). We also utilized those methods, and performed electroporation-mediated transuterine gene transfer into otocysts (EUGO) for two models of congenital inner ear disease. One is the Connexin (Cx) 30 knockout (KO) mouse in which GJB6 gene coding Cx30 is deleted. The other is the pendrin KO mouse in which the SLC26A4 gene coding pendrin is deleted. The former is the model of non-syndromic deafness, the latter is the model of syndromic deafness. EUGO caused the vast expression of normal genes in the inner ear and successfully improved the hearing and vestibular function in both models. Although we utilized the otocyst at E11.5, this method must be demonstrated before the beginning of gene expression in the inner ear. Thus, the timing of embryonic gene therapy is important, because each gene has a different timing of expression in the inner ear. Herein, we describe state-of-the-art research on genetic inner ear disease treatment through gene therapy and discuss the obstacles to overcome in curative treatments of genetic inner ear diseases in humans.
The inner ear consists of the cochlea and vestibule, both containing sensory hair cells, which possess strictly regulated actin organization to conduct sensitive mechanoelectrical transduction. Rho-GTPase is a family of small GTPases, known to play key roles in actin regulation. Cdc42 and Rac (Rac1, Rac2, Rac3) are major members of Rho-GTPase family and we have previously confirmed the expression of Cdc42, Rac1 and Rac3 in cochlear sensory epithelia. Recently we studied the function of Cdc42 and Rac in inner ears and the cerebellum using a gene-targeting strategy. We developed a Cdc42-conditional knock-out mouse (Cdc42-CKO mouse) using the Cre-loxP system under an Atoh1 promotor to establish a model of hair cell-specific deletion of Cdc42. The Cdc42-CKO mouse showed progressive hearing loss associated with hair bundle degeneration, structural abnormality of the apical cell junction and hair cell loss. On the other hand, the Rac1-CKO mouse, Rac3-KO mouse and their crossbred Rac1/Rac3 double knock-out (Rac1/3-DKO) mouse did not show this hearing phenotype. These data indicated that Cdc42 is essential for maintaining hearing function by regulation of actin dynamics in the hair cells, whereas Rac molecules are not necessary for hair cell function. Both the Cdc42-CKO mouse and Rac1/3-DKO did not show the vestibular phenotype, suggesting the existence of other Rho-GTPases compensating for the function of Cdc42 in the vestibular organ. Moreover, the Rac1/3-DKO mouse showed an ataxic gait and cerebellar hypoplasia, although these phenotypes are much more subtle in the Rac1-KO mouse and not observed in the Rac3-KO mouse. We found hypoplasia of the inner granular layer and dysfunction of neurite growth in the Rac1/3-DKO mouse, suggesting a compensatory function of Rac1 and Rac3 in the neurite extension and cellular migration of cerebellar granular cells. Further studies are needed to explore the function and compensatory mechanism of the Rho-GTPase family in the inner ears and cerebellum to elucidate fully the molecular regulation of the hearing and balance system.
The membranous labyrinth is composed of the endo and perilymphatic spaces. The endolymphatic space is filled with endolymph, a K-rich and positively polarized fluid, whereas the surrounding perilymphatic space is filled with perilymph, with a composition similar to the usual extracellular fluid. The homeostasis of the inner ear fluid is essential for maintenance of audio-vestibular function. Since the discovery of aquaporin water channels, it has become known that these channels play a crucial role in inner ear fluid homeostasis. In this paper, experimental evidence to support the above-mentioned hypothesis will be presented mainly based on our recent studies.
A typical abnormality in water transport in the inner ear is endolymphatic hydrops (EH), which is a critical component of Ménière's disease (MD). Regarding the flow of the endolymph, there are three aspects, i.e., the longitudinal flow theory, the radial flow theory, and the dynamic flow theory. The dynamic flow theory has both longitudinal flow and radical flow components. Maintenance of ion composition and resting potential is performed at each site (radial flow), and the flow from the cochlear, vestibule and semicircular canal to the endolymphatic sac (ES) (longitudinal flow) is necessary for absorption of endolymph and transport of polymeric substances. ES plays an important role for the water transport in the inner ear. The function of endolymph absorption is conventionally reported as a role for the ES. In recent years, it has been demonstrated that the ES actively regulates the homeostasis of the endolymphatic environment in response to changes in endolymphatic volume, pressure, and blood flow in the inner ear. EH is caused by impaired absorption of endolymph, overproduction, or both. Concerning the EH models, surgical obliteration of the ES sac and duct model is most promising, and various studies have been conducted on the pathology and treatment of MD using this model. On the other hand, EH can be induced by systemic administration of vasopressin (VP) as an overproduction mode. In this study, we compare the process of EH formation and features of each model using the obliteration model and the endolymph overproduction (VP administration) model. The results show that, in the obliteration model, severe EH occurs in all sites. In the overproduction model, the EH of the cochlea, utricle, and semicircular canals is severe, but is mild in the saccule. Overproduction of endolymph alone could not explain the severe saccular EH of MD, and it seemed that some inhibitory factors for absorption of endolymph are necessary in addition. Based on these results, the causes of MD and the relation with stress are discussed.