Intralabyrinthine schwannomas mimic cochleovestibular disease: symptoms from tumor mass effect in the labyrinth.

OBJECTIVE: To describe symptoms from intralabyrinthine schwannomas specific from more common vestibular schwannomas of the internal auditory canal or cerebellopontine angle resulting from mass effect from the tumor within the labyrinth. PATIENTS: Eight patients diagnosed as having intralabyrinthine schwannomas from 2000 to 2014 were examined retrospectively from two tertiary neurotologic centers. INTERVENTIONS: Diagnosis of intralabyrinthine schwannoma was made with gadolinium-enhanced magnetic resonance imaging scans. Heavily T2-weighted sequences were used to verify mass within the fluid-filled labyrinth. Patients then underwent audiometric and vestibular testing when appropriate. Treatment consisted of observation or surgical resection. MAIN OUTCOME MEASURES: Clinical symptoms, magnetic resonance imaging scans, audiometric and videonystagmography data, and operative findings were reviewed. RESULTS: Five of the eight patients had positional vertigo or nystagmus on testing. One patient's only complaint was positional vertigo without auditory symptoms. Three of the patients demonstrated mixed hearing loss. Two patients underwent resection of their tumors, one because of tumor growth and the other because of intractable vertigo. CONCLUSION: These data show that a high proportion within our series displayed symptoms of positional vertigo and mixed hearing loss, which are symptoms not typical of nonintralabyrinthine schwannomas. One patient's only reported symptom was positional vertigo. These symptoms may arise from the effect of the tumor's mass exerted on the cochlear and vestibular end organs.

Cisplatin exposure damages resident stem cells of the mammalian inner ear.

BACKGROUND: Cisplatin is a widely used chemotherapeutic agent that can also cause ototoxic injury. One potential treatment for cisplatin-induced hearing loss involves the activation of endogenous inner ear stem cells, which may then produce replacement hair cells. In this series of experiments, we examined the effects of cisplatin exposure on both hair cells and resident stem cells of the mouse inner ear. RESULTS: Treatment for 24 hr with 10 µM cisplatin caused significant loss of hair cells in the mouse utricle, but such damage was not evident until 4 days after the cisplatin exposure. In addition to killing hair cells, cisplatin treatment also disrupted the actin cytoskeleton in remaining supporting cells, and led to increased histone H2AX phosphorylation within the sensory epithelia. Finally, treatment with 10 µM cisplatin appeared to have direct toxic effects on resident stem cells in the mouse utricle. Exposure to cisplatin blocked the proliferation of isolated stem cells and prevented sphere formation when those cells were maintained in suspension culture. CONCLUSION: The results suggest that inner ear stem cells may be injured during cisplatin ototoxicity, thus limiting their ability to mediate sensory repair.

Vestibular tests for rehabilitation: applications and interpretation.

Vestibular function testing plays a critical role in understanding balance disorders. These tests augment a well-performed history and physical exam in providing quantitative information regarding vestibular reflexes, central oculomotor function and postural control strategies. Video-oculography (VOG) and caloric stimulation play a major role in evaluation of both peripheral vestibular and central oculomotor disorders. Rotational chair testing and, more recently the Dynamic Visual Acuity Test (DVAT) and Gaze Stabilization Test (GST) provide information regarding higher frequency vestibulo-ocular reflex (VOR) function. Computerized Dynamic Posturography (CDP) explores the interaction of the vestibular, visual and proprioceptive systems for posture control. Finally, the cervical Vestibular Evoked Myogenic Potential (cVEMP) test and the Dynamic Subjective Visual Vertical (DSVV) test provide information regarding saccular and utricular function, respectively. New techniques and applications continue to provide knowledge both of disease processes and potential medical, surgical and rehabilitative interventions.

Practical guide to choosing an appropriate data display.

The primary objective of graphing research data is to communicate key information visually in a rapid, accurate, and concise way. Graphs might be considered visual take-home lessons of the major point(s) of the manuscript. In choosing a graph, it is tempting to concentrate only on ways of illustrating summary statements characterizing the group(s). However, individual patients are unique, and their characteristics or outcomes may not be predicted by a group summary. Consequently, if possible, graphs should demonstrate individual responses as well as group summaries. "Graphical literacy," "graphical excellence," and "graphical acumen" are achievable with work and collaboration. To produce a well-designed graph, a combination of by-subject detail and overall results should be the goal within the same illustration. The practice gap addressed in this article is that little attention from authors, reviewers, editors, and publishers seems to be paid to graphical literacy. The purpose of this article is to present some practical guidelines for choosing or evaluating more appropriate data displays.

A practical guide to surveys and questionnaires.

Surveys with questionnaires play a vital role in decision and policy making in society. Within medicine, including otolaryngology, surveys with questionnaires may be the only method for gathering data on rare or unusual events. In addition, questionnaires can be developed and validated to be used as outcome measures in clinical trials and other clinical research architecture. Consequently, it is fundamentally important that such tools be properly developed and validated. Just asking questions that have not gone through rigorous design and development may be misleading and unfair at best; at worst, they can result in under- or overtreatment and unnecessary expense. Furthermore, it is important that consumers of the data produced by these instruments understand the principles of questionnaire design to interpret results in an optimal and meaningful way. This article presents a practical guide for understanding the methodologies of survey and questionnaire design, including the concepts of validity and reliability, how surveys are administered and implemented, and, finally, biases and pitfalls of surveys.

Cisplatin ototoxicity blocks sensory regeneration in the avian inner ear.

Cisplatin is a chemotherapeutic agent that is widely used in the treatment of solid tumors. Ototoxicity is a common side effect of cisplatin therapy and often leads to permanent hearing loss. The sensory organs of the avian ear are able to regenerate hair cells after aminoglycoside ototoxicity. This regenerative response is mediated by supporting cells, which serve as precursors to replacement hair cells. Given the antimitotic properties of cisplatin, we examined whether the avian ear was also capable of regeneration after cisplatin ototoxicity. Using cell and organ cultures of the chick cochlea and utricle, we found that cisplatin treatment caused apoptosis of both auditory and vestibular hair cells. Hair cell death in the cochlea occurred in a unique pattern, progressing from the low-frequency (distal) region toward the high-frequency (proximal) region. We also found that cisplatin caused a dose-dependent reduction in the proliferation of cultured supporting cells as well as increased apoptosis in those cells. As a result, we observed no recovery of hair cells after ototoxic injury caused by cisplatin. Finally, we explored the potential for nonmitotic hair cell recovery via activation of Notch pathway signaling. Treatment with the gamma-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester failed to promote the direct transdifferentiation of supporting cells into hair cells in cisplatin-treated utricles. Taken together, our data show that cisplatin treatment causes maintained changes to inner ear supporting cells and severely impairs the ability of the avian ear to regenerate either via proliferation or by direct transdifferentiation.

Epigenetic influences on sensory regeneration: histone deacetylases regulate supporting cell proliferation in the avian utricle.

The sensory hair cells of the cochlea and vestibular organs are essential for normal hearing and balance function. The mammalian ear possesses a very limited ability to regenerate hair cells and their loss can lead to permanent sensory impairment. In contrast, hair cells in the avian ear are quickly regenerated after acoustic trauma or ototoxic injury. The very different regenerative abilities of the avian vs. mammalian ear can be attributed to differences in injury-evoked expression of genes that either promote or inhibit the production of new hair cells. Gene expression is regulated both by the binding of cis-regulatory molecules to promoter regions as well as through structural modifications of chromatin (e.g., methylation and acetylation). This study examined effects of histone deacetylases (HDACs), whose main function is to modify histone acetylation, on the regulation of regenerative proliferation in the chick utricle. Cultures of regenerating utricles and dissociated cells from the utricular sensory epithelia were treated with the HDAC inhibitors valproic acid, trichostatin A, sodium butyrate, and MS-275. All of these molecules prevent the enzymatic removal of acetyl groups from histones, thus maintaining nuclear chromatin in a "relaxed" (open) configuration. Treatment with all inhibitors resulted in comparable decreases in supporting cell proliferation. We also observed that treatment with the HDAC1-, 2-, and 3-specific inhibitor MS-275 was sufficient to reduce proliferation and that two class I HDACs--HDAC1 and HDAC2--were expressed in the sensory epithelium of the utricle. These results suggest that inhibition of specific type I HDACs is sufficient to prevent cell cycle entry in supporting cells. Notably, treatment with HDAC inhibitors did not affect the differentiation of replacement hair cells. We conclude that histone deacetylation is a positive regulator of regenerative proliferation but is not critical for avian hair cell differentiation.

Mutations in a novel gene encoding a CRAL-TRIO domain cause human Cayman ataxia and ataxia/dystonia in the jittery mouse.

Cayman ataxia is a recessive congenital ataxia restricted to one area of Grand Cayman Island. Comparative mapping suggested that the locus on 19p13.3 associated with Cayman ataxia might be homologous to the locus on mouse chromosome 10 associated with the recessive ataxic mouse mutant jittery. Screening genes in the region of overlap identified mutations in a novel predicted gene in three mouse jittery alleles, including the first mouse mutation caused by an Alu-related (B1 element) insertion. We found two mutations exclusively in all individuals with Cayman ataxia. The gene ATCAY or Atcay encodes a neuron-restricted protein called caytaxin. Caytaxin contains a CRAL-TRIO motif common to proteins that bind small lipophilic molecules. Mutations in another protein containing a CRAL-TRIO domain, alpha-tocopherol transfer protein (TTPA), cause a vitamin E-responsive ataxia. Three-dimensional protein structural modeling predicts that the caytaxin ligand is more polar than vitamin E. Identification of the caytaxin ligand may help develop a therapy for Cayman ataxia.