Presence of corrective saccades in patients with normal vestibulo-ocular reflex gain in video head impulse test.

Background: The video head impulse test (vHIT) is a valuable clinical tool that can help identify dysfunction of the semicircular canals. While in cases with semicircular canal dysfunction, both decreased vestibulo-ocular reflex (VOR) gain and corrective saccades (CS) are usually observed, there are cases which show CS despite normal VOR gain in vHIT. Objective: This study aimed to investigate the clinical characteristics of patients who showed CS with normal VOR gain in vHIT. Materials and methods: Among 390 patients who underwent vHIT, 51 patients (20 males and 31 females, age 31-87 years, average 61.3 years old) who showed CS with normal VOR gain unilaterally during horizontal vHIT were included. All patients had normal vHIT (normal VOR gain and absent CS) on the contralateral side.The VOR gain of vHIT, the maximum slow phase velocity in the caloric test, and the amplitude of cervical and ocular vestibular evoked myogenic potentials (cVEMPs and oVEMPs) were analyzed. Results: The VOR gain on the affected side (0.95 ± 0.08) was significantly smaller than that on the contralateral side (1.03 ± 0.13) in horizontal vHIT (p < 0.001). The maximum slow phase velocity in the caloric test on the affected side (17.9 ± 17.8 degrees/s) was significantly smaller than that on the contralateral side (21.3 ± 16.6 degrees/s, p = 0.020). There were no significant differences in the amplitude of cVEMPs or oVEMPs between the affected side and the contralateral side (p = 0.096 for cVEMP; p = 0.770 for oVEMP). Conclusion: The side that showed CS with normal VOR gain in horizontal vHIT showed significantly smaller VOR gain as well as smaller caloric responses compared to the contralateral side. Having CS with normal VOR gain could be a sensitive indicator of mild dysfunction of the semicircular canals.

Assessment of semicircular canal function in benign paroxysmal positional vertigo using the video head impulse test and caloric test.

Objective: To assess semicircular canal function in benign paroxysmal positional vertigo (BPPV) using the video head impulse test (vHIT) and caloric test. Methods: We retrospectively reviewed 39 patients with idiopathic BPPV who underwent both vHIT and the caloric test. Twenty-one patients had posterior BPPV (p-BPPV) and eighteen had horizontal BPPV (h-BPPV). Vestibulo-ocular reflex (VOR) gain and corrective saccades (CS) were analyzed in vHIT and canal paresis (CP) was calculated in the caloric test. Results: The mean VOR gain of the posterior canal in p-BPPV was 0.75 ± 0.28 on the affected side, which was significantly smaller than that on the contralateral side (0.93 ± 0.24, p = .00738). On the other hand, there were no significant differences in the VOR gain of the horizontal canal in h-BPPV between the affected and the contralateral sides (p = .769). The rates of the presence of CS were not significantly different between the affected canal and the contralateral canal either in p-BPPV (p = .111) or h-BPPV (p = .0599). The mean CP value in h-BPPV patients (43.5 ± 31.3%) was significantly higher than that in p-BPPV patients (22.2 ± 22.9%; p = .0184). Conclusion: The VOR gain of vHIT in the affected canal was significantly smaller than that in the contralateral canal in p-BPPV, but not in h-BPPV. The caloric responses of the affected canal are reduced to a significantly larger extent in h-BPPV compared to p-BPPV. These results suggest that BPPV affects the semicircular canal function differently depending on which semicircular canal is involved.

Intratympanic steroid therapy for Bell's palsy with poor prognostic results.

In Bell's palsy, electrodiagnosis by electroneurography (ENoG) is widely used to predict a patient's prognosis. The therapeutic options for patients with poor prognostic results remain controversial. Here, we investigated whether early intervention with intratympanic steroid therapy (ITST) is an effective treatment for Bell's palsy patients with poor electrodiagnostic test results (≤ 10% electroneurography value). Patients in the concurrent ITST group (n = 8) received the standard systemic dose of prednisolone (410 mg total) and intratympanic dexamethasone (16.5 mg total) and those in the control group (n = 21) received systemic prednisolone at the standard dose or higher (average dose, 605 ± 27 mg). A year after onset, the recovery rate was higher in the ITST group than in the control group (88% vs 43%, P = 0.044). The average House-Brackmann grade was better in the concurrent ITST group (1.13 ± 0.13 vs 1.71 ± 0.16, P = 0.035). Concurrent ITST improves the facial nerve outcome in patients with poor electroneurography test results, regardless of whether equivalent or lower glucocorticoid doses were administered. This may be ascribed to a neuroprotective effect of ITST due to a higher dose of steroid reaching the lesion due to dexamethasone transfer in the facial nerve.

Postnatal expression and possible function of RANK and RANKL in the murine inner ear.

The bone encasing the inner ear, known as the otic capsule, is unique because it remodels little postnatally compared to other bones in the body. Previous studies established that osteoprotegerin (OPG) in the inner ear inhibits otic capsule remodeling. OPG acts as a decoy receptor of receptor activator of nuclear factor κB ligand (RANKL) to disrupt the interaction between RANKL and RANK, the primary regulators of bone metabolism. Here we studied the expression and function of RANK and RANKL in the murine cochlea. Using a combination of in situ hybridization, real-time quantitative RT-PCR, and western blot, we demonstrate that Rankl and Rank genes and their protein products are expressed in the intracochlear soft tissues and the otic capsule in a developmentally regulated manner. Using a culture of neonatal murine cochlear neurons, we show that the interaction between RANK and RANKL inhibits neurite outgrowth in these neurons, and is associated with upregulation of NOGO-A expression. Taken together, our results suggest that, in addition to regulating otic capsule bone remodeling, RANK and RANKL expressed by intracochlear soft tissues may also regulate spiral ganglion neuron function by affecting neurite outgrowth.

Regeneration of Cochlear Synapses by Systemic Administration of a Bisphosphonate.

Sensorineural hearing loss (SNHL) caused by noise exposure and attendant loss of glutamatergic synapses between cochlear spiral ganglion neurons (SGNs) and hair cells is the most common sensory deficit worldwide. We show here that systemic administration of a bisphosphonate to mice 24 h after synaptopathic noise exposure regenerated synapses between inner hair cells and SGNs and restored cochlear function. We further demonstrate that this effect is mediated by inhibition of the mevalonate pathway. These results are highly significant because they suggest that bisphosphonates could reverse cochlear synaptopathy for the treatment of SNHL.

Data for temporal facial nerve recovery in Ramsay Hunt syndrome following intratympanic steroid therapy.

This article contains data related to the research article entitled "Concurrent treatment with intratympanic dexamethasone improves facial nerve recovery in Ramsay Hunt syndrome" (Akira Inagaki, Toshiya Minakata, Schiyo Katsumi, Shingo Murakami) [1]. This data article reports the protocol for a clinical trial investigating the benefit of intratympanic steroid therapy on facial recovery in Ramsay Hunt syndrome and temporal facial recovery. The data included in this article are as follows: inclusion and exclusion criteria, the treatment protocol of steroids and antiviral therapies, facial recovery as assessed by the House-Brackmann scale in all enrolled patients, House-Brackmann scores in patients with a poor electrophysiological result, and House-Brackmann scores after propensity score matching. This article will be useful for related investigations or clinical practices in the future by serving as a model and benchmark.

Concurrent treatment with intratympanic dexamethasone improves facial nerve recovery in Ramsay Hunt syndrome.

OBJECTIVE: To determine whether early intervention with intratympanic steroid injections, known as concurrent intratympanic steroid therapy (ITST), is an effective supplement to systemic steroid therapy for moderately-severe to severe Ramsay Hunt syndrome. METHODS: Forty-six patients with Ramsay Hunt syndrome (House-Brackmann grade IV or higher) who received either concurrent ITST with standard systemic steroid therapy (ITST group, n = 12) or standard systemic therapy alone (control group, n = 34) with antivirals starting within 7 days of onset. Patients in the concurrent ITST group received the standard systemic dose of prednisolone (410 mg in total) and intratympanic dexamethasone (16.5 mg in total) over 10 consecutive days. Patients in the control group received systemic prednisolone at the standard dose or higher (average dose, 581 ± 25 mg). RESULTS: The recovery rate was higher in the concurrent ITST group than in the control group (93% vs 47%, P = .013). The adjusted odds ratio was 22.2 (95% confidence interval 1.32-373.58, P = .031). CONCLUSIONS: The recovery rate was higher after concurrent systemic and intratympanic steroid therapy than after standard systemic steroid therapy, regardless of whether the steroid used had lower or equivalent glucocorticoid potency. This finding suggests that concurrent intratympanic steroid therapy is a beneficial supplement in patients with Ramsay Hunt syndrome.

Concurrent Treatment With Intratympanic Dexamethasone for Moderate-Severe Through Severe Bell's Palsy.

OBJECTIVE: To determine whether early intervention with intratympanic steroid injection, known as concurrent intratympanic steroid therapy, is effective as a supplement to systemic steroid therapy for treating moderate-severe to severe Bell's palsy. DESIGN: An open-label historical control trial. SETTING: Tertiary referral center. PARTICIPANTS: A total of 35 Bell's palsy patients presenting with House-Brackmann grade IV or higher were treated with intratympanic steroid therapy concurrent with standard systemic treatment and compared with 108 patients treated with standard systemic therapy alone started within 7 days of onset. INTERVENTIONS: In the concurrent intratympanic steroid therapy group, patients received both 410 mg of prednisolone (standard dose) and 1.65 mg of intratympanic dexamethasone for 10 consecutive days. Patients in the control group received the standard dose, or more, of systemic prednisolone. Both groups were additionally treated with valacyclovir. MAIN OUTCOMES AND MEASURES: The primary outcome measure was restoration of a House-Brackmann score of grade I. RESULTS: The rate of recovery to House-Brackmann Grade I was higher for the concurrent intratympanic steroid therapy group than for the control group (94% vs 73%, p = 0.008). The adjusted odds ratio was 5.47 (95% confidence interval: 1.18-25.21, p = 0.029). CONCLUSIONS: The recovery rate was higher for concurrent intratympanic steroid therapy treatment than for standard-of-care control treatment, regardless of whether steroid with lower or equivalent glucocorticoid action was administered. This result suggests that concurrent treatment with intratympanic steroid therapy is a potentially beneficial supplement to systemic steroid administration.

Intracochlear Perfusion of Tumor Necrosis Factor-Alpha Induces Sensorineural Hearing Loss and Synaptic Degeneration in Guinea Pigs.

Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine that plays a prominent role in the nervous system, mediating a range of physiologic and pathologic functions. In the auditory system, elevated levels of TNF-α have been implicated in several types of sensorineural hearing loss, including sensorineural hearing loss induced by vestibular schwannoma, a potentially fatal intracranial tumor that originates from the eighth cranial nerve; however, the mechanisms underlying the tumor's deleterious effects on hearing are not well-understood. Here, we investigated the effect of acute elevations of TNF-α in the inner ear on cochlear function and morphology by perfusing the cochlea with TNF-α in vivo in guinea pigs. TNF-α perfusion did not significantly change thresholds for compound action potential (CAP) responses, which reflect cochlear nerve activity, or distortion product otoacoustic emissions, which reflect outer hair cell integrity. However, intracochlear TNF-α perfusion reduced CAP amplitudes and increased the number of inner hair cell synapses without paired post-synaptic terminals, suggesting a pattern of synaptic degeneration that resembles that observed in primary cochlear neuropathy. Additionally, etanercept, a TNF-α blocker, protected against TNF-α-induced synaptopathy when administered systemically prior to intracochlear TNF-α perfusion. Findings motivate further investigation into the harmful effects of chronically elevated intracochlear levels of TNF-α, and the potential for etanercept to counter these effects.

Transplantation of Olfactory Stem Cells with Biodegradable Hydrogel Accelerates Facial Nerve Regeneration After Crush Injury.

Olfactory mucosa contains neural stem cells, called olfactory stem cells (OSCs), which produce trophic support required for promoting axonal regeneration after nerve injury. However, the local tissue environment can reduce the viability/function of transplanted cells when placed directly on the injury. Although gelatin hydrogels have been shown to aid cell survival during transplantation, such OSC-hydrogel combinations have not been extensively tested, particularly during recovery from facial nerve palsy. In this study, OSCs were isolated from the olfactory mucosae of newborn mice and were shown to express neural stem cell markers before differentiation, as well as cell-type specific markers after differentiation, confirming their multipotency. The OSCs also secrete growth factors and various cytokines that promote nerve regeneration. To test the effects of OSC transplantation in vivo, Medgel, a biodegradable hydrogel sponge, was applied to retain OSCs around the injury site and to lessen the detrimental effects of the local environment in an established facial nerve palsy mouse model. When OSCs were transplanted into the injury site, accelerated recovery was observed for 1 week. When OSCs were transplanted with Medgel, a higher level and duration of accelerated recovery was observed. OSCs in Medgel also increased peripheral nerve function and increased the number of regenerated nerve fibers. These results suggest that OSCs implanted with Medgel accelerate and enhance recovery from facial palsy in mice. Because human OSCs can be easily obtained from olfactory mucosa biopsies with limited risk, this OSC-Medgel combination is a candidate treatment option for accelerating recovery after facial nerve injury. Stem Cells Translational Medicine 2019;8:169&10.

Quantitative analysis of facial palsy using a three-dimensional facial motion measurement system.

OBJECTIVE: The prognosis for facial nerve palsy (FNP) depends on its severity. Currently, many clinicians use the Yanagihara, House-Brackmann, and/or Sunnybrook grading systems to assess FNP. Although these assessments are performed by experts, inter- and intra-observer disagreements have been demonstrated. The quantitative and objective analyses of the degree of FNP would be preferred to monitor functional changes and to plan and evaluate therapeutic interventions in patients with FNP. Numerous two-dimensional (2-D) assessments have been proposed, however, the limitations of 2-D assessment have been reported. The purpose of this study was to introduce a three-dimensional (3-D) image generation system for the analysis of facial nerve palsy (FNP) and to show the correlation between the severity of FNP assessed by this method and two conventional systems. METHODS: Five independent facial motions, resting, eyebrow raise, gentle eye closure, full smile with lips open and whistling were recorded with our system and the images were then analyzed using our software. The regional and gross facial symmetries were analyzed. The predicted scores were calculated and compared to the Yanagihara and H-B grading scores. We analyzed 15 normal volunteers and 42 patients with FNP. RESULTS: The results showed that 3-D analysis could measure mouth movement in the anteroposterior direction, whereas two-dimensional analysis could not. The system results showed good correlation with the clinical results from the Yanagihara (r(2)=0.86) and House-Brackmann (r(2)=0.81) grading scales. CONCLUSION: This objective method can produce consistent results that align with two conventional systems. Therefore, this method is ideally suited for use in a routine clinical setting.

Facial nerve palsy after reactivation of herpes simplex virus type 1 in diabetic mice.

OBJECTIVES/HYPOTHESIS: Bell's palsy is highly associated with diabetes mellitus (DM). Either the reactivation of herpes simplex virus type 1 (HSV-1) or diabetic mononeuropathy has been proposed to cause the facial paralysis observed in DM patients. However, distinguishing whether the facial palsy is caused by herpetic neuritis or diabetic mononeuropathy is difficult. We previously reported that facial paralysis was aggravated in DM mice after HSV-1 inoculation of the murine auricle. In the current study, we induced HSV-1 reactivation by an auricular scratch following DM induction with streptozotocin (STZ). STUDY DESIGN: Controlled animal study. METHODS: Diabetes mellitus was induced with streptozotocin injection in only mice that developed transient facial nerve paralysis with HSV-1. Recurrent facial palsy was induced after HSV-1 reactivation by auricular scratch. RESULTS: After DM induction, the number of cluster of differentiation 3 (CD3)(+) T cells decreased by 70% in the DM mice, and facial nerve palsy recurred in 13% of the DM mice. Herpes simplex virus type 1 deoxyribonucleic acid (DNA) was detected in the facial nerve of all of the DM mice with palsy, and HSV-1 capsids were found in the geniculate ganglion using electron microscopy. Herpes simplex virus type 1 DNA was also found in some of the DM mice without palsy, which suggested the subclinical reactivation of HSV-1. CONCLUSIONS: These results suggested that HSV-1 reactivation in the geniculate ganglion may be the main causative factor of the increased incidence of facial paralysis in DM patients.

Diabetic mice show an aggravated course of herpes-simplex virus-induced facial nerve paralysis.

HYPOTHESIS: Bell's palsy is highly associated with diabetes mellitus. BACKGROUND: The cause of Bell's palsy in diabetes mellitus is not completely understood. Diabetic mononeuropathy or reactivation of herpes simplex virus type 1 (HSV-1) may be responsible for the facial paralysis seen in diabetic patients. We previously reported transient and ipsilateral facial paralysis in mice inoculated with HSV-1. In this study, we examined the neuropathogenesis of HSV-1 in diabetic mice to clarify the relationship between Bell's palsy and diabetes mellitus. METHODS: We compared the incidence and course of facial paralysis after HSV-1 inoculation in diabetic and nondiabetic mice groups. Diabetic mice were prepared by intraperitoneal streptozotocin injection. Facial nerve damage was assessed by electrophysiologic and histopathologic examinations. RESULTS: Compared with the nondiabetic group, the incidence of facial nerve paralysis was significantly increased in the diabetic mice. Electrophysiologic examinations and histopathologic changes also revealed that the facial nerve damage was more severe in the diabetic group. CONCLUSION: The aggravated course of HSV-1 infection in diabetes suggests that HSV-1 may be the main causative factor for the increased incidence of facial paralysis in diabetic patients.

Auditory and vestibular defects induced by experimental labyrinthitis following herpes simplex virus in mice.

CONCLUSION: Our herpes simplex virus (HSV) labyrinthitis mouse model suggests that HSV infection induces vestibular neuritis and sudden deafness. OBJECTIVE: Viral labyrinthitis has been postulated to play a role in vestibular neuritis and sudden deafness. We established a mouse model to investigate the pathogenesis of HSV-induced labyrinthitis. The relationship between HSV infection and apoptosis in the labyrinth was assessed. METHODS: HSV types 1 and 2 were inoculated into the middle ear of mice, and the function of the cochlear and vestibular nerves was assessed. Histopathological changes were examined with hematoxylin and eosin staining. Anti-HSV immunohistochemistry staining and TUNEL staining were done to investigate the relationship between HSV-infected cells and apoptotic cells. RESULTS: Hearing loss and vestibular dysfunction were observed in all mice after inoculation of HSV type 1 or 2. In the cochlear duct, columnar epithelial cells in the stria vascularis were infected with HSV, but only a portion of the infected cells underwent apoptosis. In contrast, many uninfected cells in the spiral organ of Corti were apoptotic. Vestibular dysfunction was observed when vestibular ganglion cells were largely infected, but not apoptotic. These findings recapitulate sudden deafness and vestibular neuritis described in patients.

Apoptosis induction after herpes simplex virus infection differs according to cell type in vivo.

We compared apoptosis induction in mice following three routes of infection. After intravenous infection, wild-type herpes simplex virus (HSV) types 1 and 2 and US3Delta mutants infected the adrenal gland and caused apoptosis. Corneal infection with wild-type virus resulted in apoptosis in a fraction of infected epithelium cells. Interestingly, many uninfected cells were apoptotic in the retina. Although neurons in the trigeminal ganglion were heavily infected, no apoptotic neurons were observed. Intracranial infection with wild-type virus resulted in HSV-infected cells inside the brain; however, most of the infected neurons escaped apoptosis. In contrast, infection with US3Delta and gamma(1)34.5Delta mutants caused apoptosis in infected neurons. Cleaved caspase-8 and p53 were detected in apoptotic cells in the adrenal gland and the brain; however, phospho-JNK was detected only in apoptotic cells of the brain. These results suggest that the activation of apoptotic signaling proteins differs depending on the host cell type and modulates the induction of apoptosis in HSV-infected cells.