Clinical characteristics of benign paroxysmal positional vertigo after traumatic brain injury.

INTRODUCTION: The aim of the present study was to evaluate the characteristics of brain injury and to assess the relationship between them and treatment outcomes in patients with traumatic benign paroxysmal positional vertigo (t-BPPV). MATERIALS AND METHODS: Sixty-three consecutive patients who were diagnosed with BPPV within 2 weeks after head trauma were included. RESULTS: Cerebral concussion, intracranial hemorrhages (ICH), skull fracture without ICH, and hemorrhagic contusion were observed in 68%, 24%, 5%, and 3% of t-BPPV patients, respectively. BPPV with single canal involvement was observed in 52 (83%) patients and that with multiple canal involvement was observed in 11 (17%) patients. The number of treatment sessions was not significantly different according to the cause of head trauma (p = 0.252), type of brain injury (p = 0.308) or location of head trauma (p = 0.287). The number of recurrences was not significantly different according to the cause of head trauma (p = 0.308), type of brain injury (p = 0.536) or location of head trauma (p = 0.138). CONCLUSION: The present study demonstrated that there were no significant differences in treatment sessions until resolution and the mean number of recurrences according to the type of brain injury.

Clinical diagnoses of patients showing caloric inversion.

OBJECTIVES: When air irrigation is used for caloric stimulation in patients with a perforated ear, warm irrigation may elicit a nystagmus that initially beats in the opposite direction of what is expected for warm irrigations, which is referred to as "caloric inversion". This study aimed to investigate the disease group in which caloric inversion appeared in patients who underwent caloric testing and to classify the patterns of caloric inversion. METHODS: We conducted a retrospective review of bithermal caloric test results that were collected in our dizziness clinic between 2005 and 2022. Caloric inversion was defined when nystagmus induced by caloric stimulation appeared in the opposite direction to that expected. The incidence of caloric inversion among all patients who underwent bithermal caloric tests was calculated. To confirm the clinical diagnoses of the patients with caloric inversion, their clinical records were reviewed. RESULTS: Out of 9923 patients who underwent bithermal caloric tests, 29 patients (0.29%) showed a caloric inversion. The most common clinical diagnosis was chronic otitis media (21 of 29, 72%). Of the 21 patients with chronic otitis media, 20 patients showed a caloric inversion by warm air irrigation and one patient showed caloric inversion by cold air stimulation. Patients with clinical diagnoses other than chronic otitis media such as sudden sensorineural hearing loss, benign paroxysmal vertigo of childhood and recurrent vestibulopathy showed caloric inversion by warm air irrigation. Caloric inversion by warm water irrigation was observed in patients with lateral semicircular canal cupulopathy and recurrent vestibulopathy. Two patients (one with Meniere's disease and one with age-related dizziness) showed caloric inversion by cold water irrigation. CONCLUSION: Caloric inversion can be observed in various diseases other than chronic otitis media with tympanic membrane perforation. Special care should be taken in the interpretation of caloric test results. LEVEL OF EVIDENCE: Level 4.

Targeting SARM1 improves autophagic stress-induced axonal neuropathy.

ABBREVIATIONS: AAV: adeno-associated virus; ATF3: activating transcription factor 3; ATG7: autophagy related 7; AVIL: advillin; cADPR: cyclic ADP ribose; CALC: calcitonin/calcitonin-related polypeptide; CMT: Charcot-Marie-Tooth disease; cKO: conditional knockout; DEG: differentially expressed gene; DRG: dorsal root ganglion; FE-SEM: field emission scanning electron microscopy; IF: immunofluorescence; NCV: nerve conduction velocity; PVALB: parvalbumin; RAG: regeneration-associated gene; ROS: reactive oxygen species; SARM1: sterile alpha and HEAT/Armadillo motif containing 1; SYN1: synapsin I.

Cerebellopontine angle tumor presenting as acute audiovestibular syndrome.

BACKGROUND: Acute audiovestibular deficits may be a harbinger of vestibular schwannoma (VS). OBJECTIVE: To investigate clinical and laboratory features of 25 consecutive patients with VS presenting with acute audiovestibular deficits. METHODS: A symptomatic combination of acute audiovestibular deficits was investigated. Audiometric and vestibular function tests, and internal auditory canal magnetic resonance imaging (IAC MRI) results were evaluated. RESULTS: Varying combinations of symptoms may develop in VS patients with acute audiovestibular deficits, of whom sudden hearing loss (HL) without acute vertigo or acute facial nerve palsy (FNP) was most common. The most common audiometric configuration was high-tone hearing loss, and no patient showed low-tone hearing loss. IAC MRI demonstrated that the tumor had an intracanalicular portion and attachment to the bony IAC wall in all patients and widened the IAC wall in some patients. CONCLUSION: Different symptomatic combinations of acute audiovestibular deficits may develop in patients with VS. Awareness about the possibility of VS as a cause of sudden HL, acute vertigo, and acute FNP, as well as subsequent IAC MRI scanning is vital to earlier diagnosis of VS in these patients.

ßPix Guanine Nucleotide Exchange Factor Regulates Regeneration of Injured Peripheral Axons.

Axon regeneration is essential for successful recovery after peripheral nerve injury. Although growth cone reformation and axonal extension are crucial steps in axonal regeneration, the regulatory mechanisms underlying these dynamic processes are poorly understood. Here, we identify ßPix (Arhgef7), the guanine nucleotide exchange factor for Rac1 GTPase, as a regulator of axonal regeneration. After sciatic nerve injury in mice, the expression levels of ßPix increase significantly in nerve segments containing regenerating axons. In regrowing axons, ßPix is localized in the peripheral domain of the growth cone. Using ßPix neuronal isoform knockout (NIKO) mice in which the neuronal isoforms of ßPix are specifically removed, we demonstrate that ßPix promotes neurite outgrowth in cultured dorsal root ganglion neurons and in vivo axon regeneration after sciatic nerve crush injury. Activation of cJun and STAT3 in the cell bodies is not affected in ßPix NIKO mice, supporting the local action of ßPix in regenerating axons. Finally, inhibiting Src, a kinase previously identified as an activator of the ßPix neuronal isoform, causes axon outgrowth defects in vitro, like those found in the ßPix NIKO neurons. Altogether, these data indicate that ßPix plays an important role in axonal regrowth during peripheral nerve regeneration.

Posterior canal benign paroxysmal positional vertigo with long duration: Heavy or light cupula?

Objective: To investigate the characteristics of positional nystagmus in posterior semicircular canal (PSCC) benign paroxysmal positional vertigo (BPPV) patients with longer durations, and to discuss the possible underlying mechanism of this nystagmus. Methods: We conducted a retrospective review, and enrolled 118 consecutive patients with unilateral PSCC BPPV. The duration of nystagmus during a Dix-Hallpike test was classified into short (<1 min) and long (≥1 min) durations. For the identification of a neutral point in PSCC BPPV patients with long durations, the patient's head was turned 45° to the lesioned side to set the affected PSCC on the sagittal plane, and the disappearance of positional nystagmus was investigated in a pitch plane. Results: Among 118 patients with PSCC BPPV, positional nystagmus during a Dix-Hallpike test showed short durations (<1 min) in 112 patients and long durations (≥1 min) in 6 patients. Of 6 PSCC BPPV patients with a long duration, a neutral point was identified in 5 patients whose nystagmus lasted for longer than 2 min; interestingly, a neutral point was observed when the patient's head was slightly tilted backward in all 5 patients. Conclusion: Considering that a neutral position was identified when the patient's head was slightly tilted backward while keeping the head turned 45° to the right or left, we assume that the light cupula condition of the ipsilateral PSCC or the contralateral anterior semicircular canal, and not PSCC BPPV cupulolithiasis, could be responsible for the occurrence of persistent torsional-upbeating nystagmus in a Dix-Hallpike test. Level of Evidence: 4.

Spontaneous Nystagmus in Patients With Posterior Semicircular Canal Benign Paroxysmal Positional Vertigo.

OBJECTIVE: This study aimed to investigate the incidence of spontaneous nystagmus (SN) in posterior semicircular canal (PSCC) benign paroxysmal positional vertigo (BPPV) and its effect on treatment outcomes. STUDY DESIGN: Retrospective case series. SETTING: Tertiary referral center. METHODS: This study included 50 patients with idiopathic unilateral PSCC BPPV between July 2021 and May 2022. The presence of SN was investigated, and the results of the bithermal caloric test and video head impulse test (vHIT) were compared. RESULTS: SN was observed in 13 (26%) of the 50 patients presenting PSCC BPPV. The direction of SN was mainly unidirectional and horizontal in 12 of the 13 patients with a slow-phase velocity ranging from 2 to 4°/s. One patient presented an upbeating torsional SN at the initial evaluation. The mean vHIT gain of the PSCC on the affected side was significantly lower in patients with SN than those without SN (p = .004, Mann-Whitney U test). The proportion of patients who recovered within 2 sessions of the repositioning maneuver was significantly higher in those without SN than that in those with SN (p < .001, Fisher's exact test). CONCLUSION: This study demonstrated that the treatment outcomes of PSCC BPPV were significantly worse in patients with SN than those without SN. Examining the presence of SN in patients with PSCC BPPV may be helpful in counseling the patients on prognosis, and it is expected that more sessions of canalith repositioning maneuver may be required to treat PSCC BPPV in patients with SN than those without SN.

Adaptive autophagy reprogramming in Schwann cells during peripheral demyelination.

The myelin sheath is an essential structure for the rapid transmission of electrical impulses through axons, and peripheral myelination is a well-programmed postnatal process of Schwann cells (SCs), the myelin-forming peripheral glia. SCs transdifferentiate into demyelinating SCs (DSCs) to remove the myelin sheath during Wallerian degeneration after axonal injury and demyelinating neuropathies, and macrophages are responsible for the degradation of myelin under both conditions. In this study, the mechanism by which DSCs acquire the ability of myelin exocytosis was investigated. Using serial ultrastructural evaluation, we found that autophagy-related gene 7-dependent formation of a "secretory phagophore (SP)" and tubular phagophore was necessary for exocytosis of large myelin chambers by DSCs. DSCs seemed to utilize myelin membranes for SP formation and employed p62/sequestosome-1 (p62) as an autophagy receptor for myelin excretion. In addition, the acquisition of the myelin exocytosis ability of DSCs was associated with the decrease in canonical autolysosomal flux and was demonstrated by p62 secretion. Finally, this SC demyelination mechanism appeared to also function in inflammatory demyelinating neuropathies. Our findings show a novel autophagy-mediated myelin clearance mechanism by DSCs in response to nerve damage.

Regulation of the V-ATPase subunit ATP6V0D2 and its role in demyelination after peripheral nerve injury.

After peripheral nerve injury, demyelinating Schwann cells discharge myelin debris and macrophages execute myelin degradation, leading to demyelination of degenerating axons, which is essential for efficient nerve regeneration. In this study, we show that vacuolar-type proton ATPase subunit d2 (Atp6v0d2) is among the most highly upregulated genes in degenerating mouse sciatic nerves after nerve injury using microarray analysis. ATP6V0D2 is mostly expressed in macrophages of injured nerves. Atp6v0d2 knockout mice display delayed peripheral nerve demyelination and significantly attenuated myelin lipid digestion after nerve injury. However, macrophage recruitment and Schwann cell dedifferentiation are unaffected by loss of Atp6v0d2 expression. Taken together, these data demonstrate that ATP6V0D2 in macrophages is specifically required for demyelination during Wallerian degeneration.

Direction-changing spontaneous nystagmus in patients with dizziness.

PURPOSE: The present study aimed to investigate the clinical features of patients with direction-changing spontaneous nystagmus (DCSN) and gain insight into its underlying mechanisms. METHODS: Medical records and vestibular function test results collected in our dizziness clinic between February 2013 and February 2020 were retrospectively reviewed. Spontaneous nystagmus was recorded while sitting upright using videonystagmography for 2 min to confirm the spontaneous changes in nystagmus direction. Causative disease diagnoses were based on the patients' clinical history, audiometry results, vestibular function tests, and imaging studies. RESULTS: Of 4786 patients, DCSN was observed in 41 (0.86%). Causative disease diagnoses included vestibular neuritis (n = 9), lateral semicircular canal cupulopathy (n = 9), cerebellopontine angle tumor (n = 8), vestibular paroxysmia (n = 2), vestibular migraine (n = 2), vestibular nucleus infarction (n = 1), sudden sensorineural hearing loss with vertigo (n = 2), Meniere's disease (n = 2), Ramsay Hunt syndrome (n = 1), labyrinthine fistula due to middle ear cholesteatoma (n = 1), lateral semicircular canal dysplasia (n = 1), post tympanomastoidectomy dizziness (n = 1), and head trauma (n = 2). CONCLUSIONS: Although the periodicity of DCSN could not be determined because of insufficiently long observation times, it was observed in various central and peripheral vestibulopathies. Careful examination of spontaneous nystagmus over a sufficient period may ensure the detection of DCSN when evaluating dizziness.

An in silico method to assess antibody fragment polyreactivity.

Antibodies are essential biological research tools and important therapeutic agents, but some exhibit non-specific binding to off-target proteins and other biomolecules. Such polyreactive antibodies compromise screening pipelines, lead to incorrect and irreproducible experimental results, and are generally intractable for clinical development. Here, we design a set of experiments using a diverse naïve synthetic camelid antibody fragment (nanobody) library to enable machine learning models to accurately assess polyreactivity from protein sequence (AUC > 0.8). Moreover, our models provide quantitative scoring metrics that predict the effect of amino acid substitutions on polyreactivity. We experimentally test our models' performance on three independent nanobody scaffolds, where over 90% of predicted substitutions successfully reduced polyreactivity. Importantly, the models allow us to diminish the polyreactivity of an angiotensin II type I receptor antagonist nanobody, without compromising its functional properties. We provide a companion web-server that offers a straightforward means of predicting polyreactivity and polyreactivity-reducing mutations for any given nanobody sequence.

Analysis of the Microbiome of the Ear Canal in Normal Individuals and Patients with Chronic Otitis Externa.

BACKGROUND: Recently, microbiome research has been actively conducted for various skin areas. However, no study has yet compared the microbiome of bacteria and fungi in the ear canal of healthy individuals and patients with chronic otitis externa in Korea. OBJECTIVE: This study aimed to investigate the difference in the distribution of fungal and bacterial microbial communities in ear canal samples of healthy individuals and patients with chronic otitis externa. METHODS: In 24 patients with bilateral chronic otitis externa and 24 healthy controls, cotton swabs were used to obtain samples from the bilateral ear canal. To characterize the fungal and bacterial communities, we sequenced and analyzed the 16S rRNA V4-V5 and ITS1 regions using Quantitative Insights into Microbial Ecology 2, respectively. RESULTS: The alpha diversity analysis for bacteria and fungi confirmed that both richness and evenness decreased in the patient group. The beta diversity analysis for bacteria confirmed that these parameters differed between the control and patient groups. The beta diversity analysis for fungi showed no difference between the groups. CONCLUSION: We observed different skin microbiomes in the patients with chronic otitis externa compared with those in the healthy individuals.

Change in Diagnosis of Benign Paroxysmal Positional Vertigo During COVID-19 Pandemic.

Purpose: The present study investigated the impact of coronavirus disease 2019 (COVID-19) pandemic on benign paroxysmal positional vertigo (BPPV). Patients and Methods: The medical records of BPPV patients who were evaluated in the outpatient department (OPD) and emergency room (ER) during (435 patients) and before (517 patients) the COVID-19 pandemic were retrospectively reviewed. Dix-Hallpike and supine head-roll tests were used to classify the subtype of BPPV as posterior semicircular canal (PSCC), geotropic lateral semicircular canal (geotropic LSCC), or apogeotropic lateral semicircular canal (apogeotropic LSCC) BPPV. Results: More patients with PSCC BPPV were diagnosed at the OPD compared with those who were diagnosed at the ER both before and during the COVID-19 pandemic; however, more patients with LSCC BPPV were diagnosed at the ER compared with those who were diagnosed at the OPD during the same periods. The mean time interval between vertigo onset and initial evaluation was remarkably longer during the pandemic in patients with PSCC BPPV. Conclusion: This study demonstrated that the incidences of BPPV subtypes according to hospital visit type were not significantly different before and during the COVID-19 pandemic. Because hospital visits were delayed in patients with PSCC BPPV during the COVID-19 pandemic, telemedicine or e-health could be suitable alternatives to face-to-face medical care for these patients.

New Therapeutic Maneuver for Horizontal Semicircular Canal Cupulolithiasis: A Prospective Randomized Trial.

BACKGROUND: There are debates on whether mastoid oscillation has any benefit or harm in treating horizontal semicircular canal (HSCC) cupulolithiasis. The goal of this study was to investigate the therapeutic effects of the new maneuver using only inertia and gravity and compare it with the previously reported cupulolith repositioning maneuver using mastoid vibration (CuRM). METHODS: We enrolled 57 patients diagnosed with HSCC cupulolithiasis. Patients were randomly allocated to the previously reported CuRM or the new maneuver (briefly, 30° head rotation to the affected side and thereafter bidirectional side-lying) using simply inertia and gravity, and their immediate and short-term effects were evaluated. RESULTS: The immediate success rate did not differ significantly between the CuRM (8 of 22, 36.4%) and the new maneuver (10 of 35, 28.6%) groups (p = 0.538, Pearson's chi-square test). The late resolution rates at the first follow-up of the CuRM (75%, 9 of 12) and new maneuver groups (82.6%, 19 of 23) were very high, and there was no statistical difference between them (p = 0.670, Fisher's exact test). CONCLUSIONS: This study showed that the new maneuver was effective for treating HSCC cupulolithiasis with an immediate success rate of 28.6% (10 of 35). Although it did not show better results than the existing maneuver using vibration, there was no statistical difference. Considering the debate on the effectiveness of oscillation, we believe our new maneuver is a conservative alternative that uses only inertia and gravity, and it can be easily performed in clinics where oscillation equipment is not available.

Downbeat Nystagmus and Bilateral Sudden Hearing Loss by Suicidal Aspirin Intoxication.

Ototoxic side effects such as sensorineural hearing loss and tinnitus can be caused by acute salicylate intoxication. Bilateral symmetric sensori- neural hearing loss involving all tested frequencies is a typical pattern of hearing loss in acute salicylate intoxication, which usually resolves within 2 or 3 days without any specific treatment for ototoxicity. Herein, we report a case of suicidal aspirin intoxication resulting in sudden bilateral hearing loss and vertigo. The patient exhibited spontaneous downbeat nystagmus, and the mechanism underlying this characteristic nystagmus is discussed.

The PINK1 Activator Niclosamide Mitigates Mitochondrial Dysfunction and Thermal Hypersensitivity in a Paclitaxel-Induced Drosophila Model of Peripheral Neuropathy.

Paclitaxel is a widely used anticancer drug that induces dose-limiting peripheral neuropathy. Mitochondrial dysfunction has been implicated in paclitaxel-induced neuronal damage and in the onset of peripheral neuropathy. We have previously shown that the expression of PINK1, a key mediator of mitochondrial quality control, ameliorated the paclitaxel-induced thermal hyperalgesia phenotype and restored mitochondrial homeostasis in Drosophila larvae. In this study, we show that the small-molecule PINK1 activator niclosamide exhibits therapeutic potential for paclitaxel-induced peripheral neuropathy. Specifically, niclosamide cotreatment significantly ameliorated the paclitaxel-induced thermal hyperalgesia phenotype in Drosophila larvae in a PINK1-dependent manner. Paclitaxel-induced alteration of the dendrite structure of class IV dendritic arborization (C4da) neurons was not reduced upon niclosamide treatment. In contrast, paclitaxel treatment-induced increases in both mitochondrial ROS and aberrant mitophagy levels in C4da neurons were significantly suppressed by niclosamide. In addition, niclosamide suppressed paclitaxel-induced mitochondrial dysfunction in human SH-SY5Y cells in a PINK1-dependent manner. These results suggest that niclosamide alleviates thermal hyperalgesia by attenuating paclitaxel-induced mitochondrial dysfunction. Taken together, our results suggest that niclosamide is a potential candidate for the treatment of paclitaxel-induced peripheral neuropathy with low toxicity in neurons and that targeting mitochondrial dysfunction is a promising strategy for the treatment of chemotherapy-induced peripheral neuropathy.

FK506-binding protein-like and FK506-binding protein 8 regulate dual leucine zipper kinase degradation and neuronal responses to axon injury.

The dual leucine zipper kinase (DLK) is a key regulator of axon regeneration and degeneration in response to neuronal injury; however, regulatory mechanisms of the DLK function via its interacting proteins are largely unknown. To better understand the molecular mechanism of DLK function, we performed yeast two-hybrid screening analysis and identified FK506-binding protein-like (FKBPL, also known as WAF-1/CIP1 stabilizing protein 39) as a DLK-binding protein. FKBPL binds to the kinase domain of DLK and inhibits its kinase activity. In addition, FKBPL induces DLK protein degradation through ubiquitin-dependent pathways. We further assessed other members in the FKBP protein family and found that FK506-binding protein 8 (FKBP8) also induced DLK degradation. We identified the lysine 271 residue in the kinase domain as a major site of DLK ubiquitination and SUMO3 conjugation and was thus responsible for regulating FKBP8-mediated proteasomal degradation that was inhibited by the substitution of the lysine 271 to arginine. FKBP8-mediated degradation of DLK is mediated by autophagy pathway because knockdown of Atg5 inhibited DLK destabilization. We show that in vivo overexpression of FKBP8 delayed the progression of axon degeneration and suppressed neuronal death after axotomy in sciatic and optic nerves. Taken together, this study identified FKBPL and FKBP8 as novel DLK-interacting proteins that regulate DLK stability via the ubiquitin-proteasome and lysosomal protein degradation pathways.

Direction-changing spontaneous nystagmus in cerebellopontine angle tumour.

The most common symptoms of tumours involving the cerebellopontine angle (CPA) are unilateral sensorineural hearing loss, dizziness, and asymmetric tinnitus. While the clinical manifestations have been well documented in previous studies, the nystagmus findings in these patients have not been thoroughly investigated yet. This study aimed to investigate the incidence of direction-changing spontaneous nystagmus in patients with CPA tumours, evaluate their radiologic characteristics, and gain insight into the mechanisms underlying nystagmus. Direction-changing spontaneous nystagmus was observed in 6 out of 83 patients (7%) with CPA tumours during the 7-year period. Temporal bone magnetic resonance imaging findings revealed the presence of an intrameatal mass in CPA tumours in all six patients with direction-changing spontaneous nystagmus. Vestibular schwannomas were confined within the internal auditory meatus in four patients, and petroclival meningiomas extended into the internal auditory meatus in two patients. The mechanism of direction-changing spontaneous nystagmus may be explained as paroxysmal secondary central hyperactivity in the vestibular nucleus due to the long-standing pressure effect in the vestibular nerve by tumours, or by ephaptic discharges in the vestibular nerve.