Quantitative analysis and correlative evaluation of video-oculography, micro-computed tomography, and histopathology in Pendrin-null mice.

Patients with SLC26A4 mutations exhibit highly variable hearing loss and vestibular dysfunction. Although Slc26a4 mutant mice similarly exhibit vestibular deficits, including circling behavior, head tilting, and torticollis, the underlying pathogenesis of the vestibular symptoms remains unclear, hindering its effective management for patients with SLC26A4 mutations. In this study, we evaluated the equilibrium function using the inspection equipment, which can record eye movements against rotational, gravitational, and thermal stimulations. Moreover, we correlated the degree of functional impairment with the morphological alterations observed in Slc26a4Δ/Δ mice. The rotational stimulus and ice water caloric tests revealed considerable impairment of the semicircular canal, while the tilted gravitational stimulus test showed a severe functional decline of the otolithic system in Slc26a4Δ/Δ mice. Generally, the degree of impairment was more severe in circling Slc26a4Δ/Δ mice than in non-circling Slc26a4Δ/Δ mice. In non-circling Slc26a4Δ/Δ mice, the semicircular canal function was normal. Micro-computed tomography results showed enlargement of the vestibular aqueduct and bony semicircular canals but no correlative relationship between the severity of the caloric response and the size of bony labyrinths. Giant otoconia and a significant decrease in total otolith volume in the saccule and utricle were observed in Slc26a4Δ/Δ mice. However, the giant otoconia were not overly dislocated in the bony otolithic system and ectopic otoconia were absent in the semicircular canal. The number and morphology of the utricular hair cells in Slc26a4Δ/Δ mice were not significantly reduced compared to those in Slc26a4Δ/+ mice. Collectively, we can conclude that vestibular impairments are mainly associated with otoconia formation and morphology rather than hair cell degeneration. In addition, severe disturbances of semicircular canals cause circling behavior in Slc26a4Δ/Δ mice. Our comprehensive morphological and functional assessments apply to mouse models of other genetic diseases with vestibular impairment.

Clinical application of 3D-VOG analysis for quantitative evaluation of Otolith-Ocular reflex in the roll and pitch planes.

BACKGROUND: Management of vestibular falls requires precise evaluation of otolithic function and gravity recognition. Tilt of the head in the roll plane causes ocular counter rolling (OCR) with a gain of 5-10%, which can be a quantitative parameter related to the otolith-ocular reflex (OOR) in that plane. However, the OOR in the pitch plane is indiscernible because of our ability to voluntarily gaze and pursue. 3 D eye movements and its Listing's plane description can provide novel parameters with which to evaluate OOR, even in the pitch plane. OBJECTIVES: To evaluate the utility of 3 D eye movement analysis in video oculography (VOG) as a quantitative parameter reflecting otolithic function during head movements associated with daily life. MATERIALS AND METHODS: In healthy subjects, we analyzed the changes in 3 D eye movements and the Listing's plane that occur with static gravitational modification. RESULTS: OOR during head tilt in the roll plane revealed that OCR amplitude had a saturating/peaked conformation and was not fitted by a sine curve. OOR in the pitch plane revealed anteroposterior leaning of the Listing's plane. CONCLUSIONS: These novel tools for minimally invasive evaluation of OOR in a clinical setting could potentially enable us to quantitatively evaluate peripheral static disequilibrium.

Main sequence of torsional saccadic eye movement - analysis by three-dimensional video-oculography.

Background: Quantification of main sequence is required for three-dimensional recording and analysis of eye movement using video-oculography. However, the main sequence of torsional saccade has not been reported to the best of our knowledge. Aims/objectives: To obtain characteristics of torsional saccade using infra-red video-oculography, and to analyse the main sequence. Material and methods: Torsional saccades of 10 healthy subjects were extracted from torsional vestibulo-ocular reflex from voluntary head rotation. Angular velocities were plotted against amplitude of each saccade to obtain the main sequence of torsional saccade. Results: Main sequence of torsional saccade demonstrated non-linear characteristic. The adduction amplitude was significantly larger than abduction, while there was no significant difference in time constants. Conclusions and significance: Torsional saccade demonstrates non-linear characteristic, similar to main sequence of vertical and horizontal saccades.

The evaluation of gravitational recognition in patients with spinocerebellar degeneration using Listing's plane.

Background: The thickness of Listing's plane accurately reflects gravitational recognition, constructed through the integration of visual, vestibular, and proprioceptive sensory input in the neural integrator of the central nervous system. Spinocerebellar degeneration (SCD) is a progressive degenerative disease mainly involving the cerebellum and brainstem that leads to destabilize the gravitational recognition, and may thicken thickening of Listing's plane. Objective: The aim of this study is to evaluate the gravitational recognition in response to positional change in patients with SCD, using the thickness of Listing's plane as a parameter. Materials and methods: In this prospective study, we evaluated the thickness of Listing's plane in 21 consecutive patients with SCD and 32 healthy subjects in the seated and supine positions, and investigated the association with other neuro-otological examinations (electronystagmography including caloric test and posturography). Results: We detected significant thickening of Listing's plane in SCD patients only when they were in the seated position. The thickness of Listing's plane correlated with neither the caloric response nor Romberg's ratio or the total center of the pressure path length. Conclusions and significance: The thickness of Listing's plane could be a useful parameter for assessing a gravity-oriented internal model in SCD patients.

Effectiveness of laryngotracheal separation in neurologically impaired pediatric patients.

CONCLUSION: Laryngotracheal separation (LTS) can prevent aspiration pneumonia, improve the respiratory condition, and offer the possibility of home care for neurologically impaired children. OBJECTIVES: This study aimed to evaluate the effectiveness of LTS in neurologically impaired pediatric patients from the viewpoint of postoperative success of pneumonia prevention, improvement in the respiratory condition, and postoperative success rate of home-based care. METHODS: The medical records of 21 children who underwent LTS at an academic medical center from September 2004 to March 2013 were retrospectively investigated. Pre- and postoperative data, including the frequency of pneumonia treatment, the frequency of sputum suctioning, the respiratory condition, the nutrition method, and the outcome after LTS were assessed. We also used the scoring system for patients with severe motor and intellectual disabilities, medical care dependent group (SMID-MCDG) in Japan for evaluating the usefulness of LTS. RESULTS: The frequency of pneumonia treatment and that of suctioning decreased considerably after LTS. Furthermore, the respiratory condition improved at a rate of 63.19%. The SMID-MCDG score significantly reduced after LTS. No significant complications were observed and two-thirds of the patients were successfully discharged for home care after the procedure.

Periodic alternating nystagmus caused by a medullary lesion in acute disseminated encephalomyelitis.

OBJECTIVE: To document a patient with periodic alternating nystagmus (PAN) caused by acute disseminated encephalomyelitis (ADEM) and suggest a mechanism to explain her PAN. PATIENT: A 34-year-old woman with PAN caused by ADEM. INTERVENTION: Diagnostic. RESULTS: The patient complained of severe disequilibrium from the disease onset. Four years after onset, when she visited us, the patient exhibited prominent PAN consisting of alternating rightward and leftward components, which cycled about every 90 seconds and were accompanied by a 5-second translating phase with downbeating nystagmus. Eye movement analysis that separated the horizontal and vertical components revealed the presence of downbeating movements throughout all phases of the PAN. ENG recordings revealed slightly saccadic pursuit, slightly impaired optokinetic eye movement and an absence of visual suppression of the caloric response. MRI recorded at the onset of the disease revealed lesions in the medulla, the spinal cord at the C2 level, and the frontal horn of the left lateral ventricle, but not the cerebellum. CONCLUSION: We attribute this patient's PAN to impairment of the nucleus prepositus hypoglossi in the medulla, which plays a role in the velocity storage system. In addition, cerebellar dysfunction is indicated by the occurrence of PAN while fixating.

Massively parallel DNA sequencing successfully identifies new causative mutations in deafness genes in patients with cochlear implantation and EAS.

Genetic factors, the most common etiology in severe to profound hearing loss, are one of the key determinants of Cochlear Implantation (CI) and Electric Acoustic Stimulation (EAS) outcomes. Satisfactory auditory performance after receiving a CI/EAS in patients with certain deafness gene mutations indicates that genetic testing would be helpful in predicting CI/EAS outcomes and deciding treatment choices. However, because of the extreme genetic heterogeneity of deafness, clinical application of genetic information still entails difficulties. Target exon sequencing using massively parallel DNA sequencing is a new powerful strategy to discover rare causative genes in Mendelian disorders such as deafness. We used massive sequencing of the exons of 58 target candidate genes to analyze 8 (4 early-onset, 4 late-onset) Japanese CI/EAS patients, who did not have mutations in commonly found genes including GJB2, SLC26A4, or mitochondrial 1555A>G or 3243A>G mutations. We successfully identified four rare causative mutations in the MYO15A, TECTA, TMPRSS3, and ACTG1 genes in four patients who showed relatively good auditory performance with CI including EAS, suggesting that genetic testing may be able to predict the performance after implantation.

Optokinetic stimulation can break Listing's law without induction of eye movement.

OBJECTIVE: Pseudo-images of three-dimensional eye movements captured on an infrared video oculogram can be translated onto a rotational expression around axial vector. This provides a subject's Listing's plane, which moves according to the head's orientation relative to gravity. Optokinetically induced changes in the cognitive gravitational reference frame will affect the context of Listing's plane. The purpose of this study was to estimate the effect of OKS on Listing's plane. METHODS: In this study, we presented vertical optokinetic visual stimulation with fixation targets, which are thought to induce pseudo-inclination of the head, and evaluated changes in the subjects' Listing's plane. RESULTS: We observed no stimulus-induced movement of Listing's plane that corresponded to the assumed pseudo-recognition of a change in verticality. On the other hand, we did observe vergence movement of Listing's plane (in the yaw plane), which corresponded to exposure to diminished and increased gravitational circumstance. In addition, the thickness of Listing's plane significantly increased with the load of each stimulation. CONCLUSION: Vertical OKS leads to a rotation of Listing's plane mainly around a vertical axis. This may represent false exhibition of central compensatory re-weighting with respect to inherent otoconial mass asymmetry resulting from the OKS-mediated loss of the gravity reference. In addition, a OKS-mediated thickening of Listing's plane suggests to us that confusing visual input can reduce the stability of the internal model, which would likely manifest itself as a thickening of Listing's plane. In other words, fluctuation between the build-up and drop-out of vection induced by optokinetic stimulation will cause a thickening of Listing's plane. The thickness of Listing's plane could be a novel clinical parameter for quantitatively evaluating static vestibular function and accuracy of the internal model.

Time course of the recovery of three-dimensional eye position in patients with acute cerebellitis.

Listing's plane is a construction derived from eye position and reflects gravitational orientation. The cerebellum plays a key role in orienting and integrating sensory input concerning gravity from visual, vestibular and proprioceptive apparatuses. This suggests that the thickness of Listing's plane could serve as a novel parameter for evaluating the accuracy of the constructed gravity-oriented internal model. We report a case with acute cerebellitis along with data on Listing's plane, calculated from consecutive infrared video-oculogram recordings. We found thickening of Listing's plane at the early stage of the disease, and a gradual reduction of the thickness into normal range in parallel with the recovery of the patient's posture and gate. Notably, clinical improvement of the patient's posture was delayed relative to the normalization of the thickness of Listing's plane. The thickness of Listing's plane reflects the stability of the cerebellar-mediated cognitive gravitational reference frame. This thickness value could serve as a parameter to quantitatively evaluate the function of the constructed internal model. Recovery from cerebellar ataxia (manifested as normalization of the thickness of Listing's plane) was followed by recovery of muscular strength lost during the period the patient was by his disease forced to assume a lying position.

Changes in Listing plane thickness caused by vestibular schwannoma: a parameter for evaluating the accuracy of the gravity-oriented internal model.

OBJECTIVE: Three-dimensional analysis of video-oculograms can be used to calculate Listing plane for patients and experimental subjects. Listing plane reflects the head's orientation with respect to gravity, which suggests that the plane is derived from otolithic vestibular input, itself, or from a gravity-oriented internal model constructed through integration of visual, vestibular, and proprioceptive sensory inputs. The goal of this study was to determine whether the Listing plane can serve as a parameter for evaluating static (peripheral or central) vestibular function. STUDY DESIGN: Prospective study. SETTING: Tertiary referral center. PATIENTS: Healthy subjects and patients with unilateral vestibular schwannoma without any previous treatment. INTERVENTION: Diagnostic. MAIN OUTCOME MEASURES: Video-oculograms were recorded from healthy subjects (aged 36.8 ± 6.3 yr) and from patients (aged 60.3 ± 7.5 yr) during voluntary gaze with the head in an upright or each-side-down orientation, and the thicknesses of the calculated Listing planes were then compared. RESULTS: Results revealed thickening of the Listing plane in patients only when the head was in an impaired-side-down orientation (1.250 ± 0.795 and 1.074 ± 0.759 degrees in the right- and left-side-down head orientations in healthy subjects versus 2.222 ± 1.237 degrees in the impaired-side-down orientation in patients), and this thickening correlated with caloric weakness. By contrast, neither the sensation of postural instability nor postural disturbance in force platform recordings contributed to the thickness of Listing plane. CONCLUSION: The thickness of the Listing plane could be a novel parameter for quantitatively evaluating static vestibular (otolithic) function, although central compensation might exist.

Effect of Ninjin-yoei-to (Rensheng-Yangrong-Tang) on olfactory behavior after olfactory nerve transection.

Ninjin-yoei-to (NYT), a Japanese traditional medicine, is used to treat athrepsia due to surgery, anorexia, cold constitution, and anemia. There are reports of the effects of NYT on the nervous system; however, there have been no behavioral studies of the effect of NYT on olfactory function. The olfactory system undergoes continuous replacement of sensory neurons. Morphologic and behavioral studies have shown that the olfactory system recovers after bilateral olfactory nerve transection (BNX). However, in the humans, olfactory function does not always recover. In this study, we examined the effect of oral NYT on behavioral recovery after BNX. Fourteen mice were subjected to BNX. The regular diet was mixed with 2% NYT (NYT diet). Mice were separated into two groups; seven mice were fed the regular diet (control group), and seven mice were fed the NYT diet (NYT group). NYT was administered beginning 7 days prior to BNX and continuing for 35 days after BNX. Mice in both groups had free access to food and water. Olfactory function was evaluated by testing each mouse's ability to avoid cotton balls treated with acetic acid. After BNX, mice lost their ability to avoid cotton balls treated with acetic acid. In the control group, the time for behavioral recovery after BNX was 28 days. In the NYT group, the time for behavioral recovery after BNX was 21 days. NYT hastened behavioral recovery after BNX. NYT may have therapeutic benefits for patients with olfactory disorders.

Effect of microgravity on spatial orientation and posture regulation during Coriolis stimulation.

OBJECTIVE: To elucidate spatial orientation and posture regulation under conditions of microgravity. MATERIAL AND METHODS: Coriolis stimulation was done with five normal subjects on the ground (1 g) and onboard an aircraft (under conditions of microgravity during parabolic flight). Subjects were asked to tilt their heads forward during rotation at speeds of 0, 50, 100 and 150 degrees/s on the ground and 100 degrees/s during flight. Body sway was recorded using a 3D linear accelerometer and eye movements using an infrared charge-coupled device video camera. Flight experiments were performed on 5 consecutive days, and 11-16 parabolic maneuvers were done during each flight. Two subjects boarded each flight and were examined alternately at least five times. RESULTS: Coriolis stimulation at 1 g caused body sway, nystagmus and a movement sensation in accordance with inertial inputs at 1 g. Neither body sway, excepting a minute sway due to the Coriolis force, nor a movement sensation occurred in microgravity, but nystagmus was recorded. CONCLUSIONS: Posture, eye movement and sensation at 1 g are controlled with reference to spatial coordinates that represent the external world in the brain. Normal spatial coordinates are not relevant in microgravity because there is no Z-axis, and the posture regulation and sensation that depend on them collapse. The discrepancy in responses between posture and eye movement under conditions of microgravity may be caused by a different constitution of the effectors which adjust posture and gaze.

Protective effect of edaravone against streptomycin-induced vestibulotoxicity in the guinea pig.

This study investigated alleviation of streptomycin-induced vestibulotoxicity by edaravone in guinea pigs. Edaravone, a free radical scavenger, has potent free radical quenching action and is used in clinical practice to treat cerebral infarction. Streptomycin was administered to the inner ear by osmotic pump for 24 h, and edaravone (n=8) or saline (n=6) was intraperitoneally injected once a day for 7 days. We observed horizontal vestibulo-ocular reflex as a marker of postoperative vestibular function. Animals injected with saline showed statistically smaller gains than those injected with edaravone. These results suggest that edaravone suppresses streptomycin-induced vestibulotoxicity.