Ben J. Balough

NAC for noise: from the bench top to the clinic.

Noise-induced hearing loss (NIHL) is an important etiology of deafness worldwide. Hearing conservation programs are in place and have reduced the prevalence of NIHL, but this disorder is still far too common. Occupational and recreational pursuits expose people to loud noise and ten million persons in the US have some degree of noise-induced hearing impairment. It is estimated that 50 million in the US and 600 million people worldwide are exposed to noise hazards occupationally. Noise deafness is still an important and frequent cause of battlefield injury in the US military. A mainstay of hearing conservation programs is personal mechanical hearing protection devices which are helpful but have inherent limitations. Research has shown that oxidative stress plays an important role in noise-induced cochlear injury resulting in the discovery that a number of antioxidant and cell death inhibiting compounds can ameliorate deafness associated with acoustic trauma. This article reviews one such compound, N-acetylcysteine (NAC), in terms of its efficacy in reducing hearing loss in a variety of animal models of acute acoustic trauma and hypothesizes what its therapeutic mechanisms of action might be based on the known actions of NAC. Early clinical trials with NAC are mentioned.

Characterizing and treating dizziness after mild head trauma.

Objective: The objectives of this study were to characterize patterns of dizziness seen after mild head trauma and to examine the diagnosis and treatment of this disorder. Study Design: Prospective patient registry. Setting: Tertiary referral center. Patients: Fifty-eight cases of active duty and retired military personnel who sustained mild head trauma and had resultant dizziness. Interventions: Vestibular evaluation, characterization by group, and treatment. Main Outcome Measures: Outcome measures include characterization of diagnosis types, patient distribution by diagnosis type, and patient outcome. Results: Individuals suffering from dizziness after mild head injury were divided into three diagnostic groups. Forty-one percent of the individuals suffered from posttraumatic vestibular migraines, 28% of the individuals had posttraumatic positional vertigo, and 19% of the individuals were classified as posttraumatic spatial disorientation. The remaining 12% of the patients could not be characterized. The positional group had objective physical examination findings, which cleared with treatment in all cases. The migraine group of patients and the disorientation group of patients had distinct abnormalities of the vestibulo-ocular reflex (VOR) and the vestibulo-spinal reflex (VSR). Eighty-four percent of the migraine group demonstrated an improvement of these test results as compared with 27% of the disorientation group. Mean time to return to work was less than 1 week for the positional group, 3.8 weeks for the migraine group, and greater than 3 months for the disorientation group. Conclusions: Using our patient registry of individuals suffering from dizziness after mild head trauma, we were able to characterize the majority of these cases into one of three more specific diagnostic groups. We present diagnostic criteria, suggested treatment guidelines, and our prognostic data.

Blast exposure: vestibular consequences and associated characteristics.

Objective: To characterize vestibular and related symptoms seen after blast exposure. Study Design: Prospective single-subject design. Settings: Tertiary care facility and military field hospital. Patients: Active-duty US Military personnel exposed to blast(s) in Iraq and/or Afghanistan. Interventions: Vestibular function tests, auditory tests, and a structured history and physical examination. Results: Blast exposure induced vestibular disorders, and related symptoms are significantly different than those seen in blunt head trauma. The vestibular characteristics and objective tests of vestibular function significantly worsen in blast-exposed patients as a function of time between injury and presentation. Conclusion: Blast exposure produces a unique set of vestibular disorders and associated symptoms that progress over time. Understanding the characteristics of these symptoms as they vary over time may be critical in designing treatment strategies that modify long-term outcome.

U.S. Phase I preliminary results of use of the Otologics MET Fully-Implantable Ossicular Stimulator

OBJECTIVES: The safety of the Otologics Fully-Implantable MET Ossicular Stimulator was assessed in adult patients with bilateral moderate to severe sensorineural hearing loss. METHODS: Surgical implantation of the ossicular stimulator was performed. A repeated-measure, within-subjects design assessed safety and aided sound field thresholds and speech performances with the subjects own, appropriately fitted, walk-in hearing aid(s) and the Otologics Fully-Implantable MET Ossicular Stimulator. RESULTS: Twenty patients were implanted and activated as part of the Phase I clinical trial. Results demonstrated 10–20 dB of functional gain across audiometric frequencies. Pure tone averages and monaural word recognition scores were slightly better for the walk-in—aided condition, while patient benefit scales favored the postoperative implant-aided conditions. CONCLUSION/SIGNIFICANCE: Although monaural word scores and aided thresholds favored the walk-in—aided condition, preliminary results indicate that the Otologics MET Fully-Implantable Ossicular Stimulator is an alternative to currently available hearing aids in patients with sensorineural hearing loss.

Distribution of PLGA nanoparticles in chinchilla cochleae

Objectives To study the distribution of polylactic/glycolic acid–encapsulated iron oxide nanoparticles (PLGA-NPs) in chinchilla cochleae after application on the round window membrane (RWM). Study Design and Setting Six chinchillas (12 ears) were equally divided into controls (no treatments) and experimen-tals (PLGA-NP with or without magnetic exposure). After 40 minutes of PLGA-NP placement on the RWM, perilymph was withdrawn from the scala tympani. The RWM and cochleae were fixed with 2.5% glutaraldehyde and processed for transmission electron microscopy. Results Nanoparticles were found in cochleae with or without exposure to magnet forces appearing in the RWM, perilymph, endolymph, and multiple locations in the organ of Corti. Electron energy loss spectroscopy confirmed iron elements in nanoparticles. Conclusion The nanoparticles were distributed throughout the inner ear after application on the chinchilla RWM, with and without magnetic forces. Significance PLGA-NP applied to the RWM may have potential for sustained therapy to the inner ear.

Kinetics of gentamicin uptake in the inner ear of Chinchilla langier after middle-ear administration in a sustained-release vehicle

The search for a safe, effective treatment for the vertigo associated with Menieres disease has long been an important topic in otolaryngology. In recent years many groups have begun using intratympanic gentamicin to treat this vertigo. Although reported cure rates are as high as 90%, many questions remain regarding this type of treatment. Current limitations are the necessity for repeated treatments and a lack of clear dosing guidelines. In addition, the gentamicin must be delivered in a manner that allows maximal vestibulotoxic effect without injury to hearing. Until investigators can control the exact amount of medicine that is placed in the ear and have an understanding of the kinetics of gentamicin absorption, adequate dosing guidelines will be difficult to establish, and therapy will continue to rely on empiric data. We describe the use of a fibrin-based sustained-release vehicle, impregnated with gentamicin, injected into the middle ear of chinchillas. This allows for a prolonged effect without repeated dosing. Using this model, we studied the absorption kinetics of gentamicin at time points ranging from 8 hours to 1 week after injection. We used our findings to create a kinetics curve of gentamicin absorption. We discuss the shape and characteristics of this kinetics curve and examine the effects of the fibrin-based sustained-release vehicle and gentamicin on the middle ear. We noted no absorption in the contralateral (untreated ear) or blood. Through better understanding of the actions of gentamicin in this animal model, we hope to facilitate safer use of intratympanic medicines in our patient population and initiate programs for the use of this sustained-release vehicle in human beings.

Morphologic Changes in the Inner Ear of Chinchilla Laniger after Middle Ear Administration of Gentamicin in a Sustained-Release Vehicle

The use of transtympanic gentamicin has become a popular method of treating Menieres disease; nevertheless, many questions still remain regarding this therapy. Until investigators can control the exact amount of medicine that is administered to the ear and have an understanding of the kinetics of gentamicin, therapy will continue to rely on empirical data. Previously we described the use of a fibrin-based sustained-release vehicle impregnated with gentamicin in the middle ears of chinchillas. With this model a kinetics curve of gentamicin was defined. The inner ears of these animals were submitted for immunohistochemical and histologic analysis. We discuss the ultrastructural changes seen and correlate this to our kinetics data. We also examine measurement of hair cell damage with heat shock protein levels. By better understanding the actions of gentamicin in this animal model, we hope to facilitate safer use of intratympanic medicines in our patient population.

The Role of Vestibular Rehabilitation in the Treatment of Meniere’s Disease

OBJECTIVE: To study the role of vestibular rehabilitation is treating patients with Menieres disease. METHODS: We examined all Menieres patients presenting to our tertiary care specialized vestibular clinic during a 1-year period. All patients underwent a standardized history and physical examination, a complete auditory-vestibular test battery, and a set of physical therapy tools to measure balance function. RESULTS: A subset of patients suffered from disequilibrium or unsteadiness between attacks. Once the acute fluctuating symptoms of Menieres were controlled in this group of individuals, all of them underwent vestibular physical therapy and demonstrated significant improvement in balance function on both objective and self-report tests. CONCLUSIONS: Due to the fluctuating nature of the disorder, vestibular physical therapy has had a limited role in the treatment of Menieres disease. In general, rehabilitation has been used only as a postoperative treatment for the acute vertigo seen after vestibular neurectomy or labyrinthectomy. This is the first report advocating the role of vestibular physical therapy in a group of patients receiving medical therapy of intraear medicines (other that gentamicin).

Humanitarian otologic missions: long-term surgical results.

Objective: The purpose of this study was to determine the efficacy of treating chronic ear disease by performing a single surgical intervention in the austere environment of a developing nation. Subjects and Methods: Data were collected from retrospective chart reviews on 121 patients who underwent surgical treatment of chronic ear disease during humanitarian surgical missions in South and Central America. Surgical outcomes and clinical course were assessed at 10 to 12 months after the initial surgery. Results: A total of 117 patients were included in the study. Follow-up records were available for 75 patients (64%). A total of 20 surgeries were performed for dry perforations (group 1), 30 for chronically draining ears (group 2), and 25 for cholesteatomas (group 3). Surgical success was determined as 60 percent, 74 percent, and 92 percent for groups 1, 2, and 3, respectively. Conclusions: Surgical results during international otologic outreach missions to developing nations fall within the results expected in developed nations.

Low-Dose D-Methionine and N-Acetyl-L- Cysteine for Protection from Permanent Noise-Induced Hearing Loss in Chinchillas

Objective. Despite efforts at public health awareness and stringent industrial standards for hearing protection, noise-induced hearing loss (NIHL) remains a formidable public health concern. Although many antioxidants have proven to be beneficial in the laboratory for prevention of permanent NIHL, low-dose combinations of compounds with different biochemical mechanisms of action may allow long-term administration with fewer side effects and equal efficacy. The mixture of D-methionine and N-acetyl-L-cysteine administered at levels less than 10% of standard dosing has not been previously reported. Study Design. Twenty-six female adult Chinchilla laniger were placed in 4 study groups, consisting of (1) a group receiving combination 12.5 mg/kg each D-methionine and N-acetyl-L-cysteine (DMET/NAC group), (2) a group receiving 12.5 mg/kg D-methionine (DMET-only group), (3) a group receiving 12.5 mg/kg N-acetyl-L-cysteine (NAC-only group), and (4) saline controls. Setting. Laboratory. Subjects and Methods. All groups received twice-daily intraperitoneal injections 2 days prior to noise exposure, 1 hour before and after exposure on day 3, and for 2 days subsequently, totaling 10 doses of 125 mg/kg for each antioxidant over 5 days. Results. Although NAC-only animals paralleled saline control recovery during 3 weeks, the DMET-only group revealed gradual improvement with statistically significant recovery in the middle frequencies. The DMET/NAC group showed significant improvement at most frequencies compared with controls (P < .001 and P < .05). Conclusion. Significant recovery of hearing was observed following continuous noise exposure with either DMET only or a combination of low-dose DMET/NAC, demonstrating a considerably lower dose of antioxidants required than previously reported for hearing recovery following acoustic trauma.