Lawrence R. Lustig

Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice.

The KvLQT1 gene encodes a voltage-gated potassium channel. Mutations in KvLQT1 underlie the dominantly transmitted Ward-Romano long QT syndrome, which causes cardiac arrhythmia, and the recessively transmitted Jervell and Lange-Nielsen syndrome, which causes both cardiac arrhythmia and congenital deafness. KvLQT1 is also disrupted by balanced germline chromosomal rearrangements in patients with Beckwith-Wiedemann syndrome (BWS), which causes prenatal overgrowth and cancer. Because of the diverse human disorders and organ systems affected by this gene, we developed an animal model by inactivating the murine Kvlqt1. No electrocardiographic abnormalities were observed. However, homozygous mice exhibited complete deafness, as well as circular movement and repetitive falling, suggesting imbalance. Histochemical study revealed severe anatomic disruption of the cochlear and vestibular end organs, suggesting that Kvlqt1 is essential for normal development of the inner ear. Surprisingly, homozygous mice also displayed threefold enlargement by weight of the stomach resulting from mucous neck cell hyperplasia. Finally, there were no features of BWS, suggesting that Kvlqt1 is not responsible for BWS.

Dehiscence of bone overlying the superior canal as a cause of apparent conductive hearing loss.

Objective To identify patients with superior semicircular canal dehiscence and apparent conductive hearing loss and to define the cause of the air-bone gap. Study Design Prospective study of patients with superior canal dehiscence. Setting Tertiary referral center. Patients Vestibular and/or auditory findings indicative of canal dehiscence and demonstration of superior canal dehiscence on computed tomography of the temporal bone. Intervention Vestibular-evoked myogenic potentials, three-dimensional eye movement recordings, and surgical resurfacing of the superior canal. Outcome Measure Association of superior canal dehiscence with an air-bone gap on audiometry. Results Four patients with dehiscence of bone overlying the superior canal were found to have air-bone gaps in the affected ears that were greatest at lower frequencies and averaged 24 ± 7 dB over the frequency range of 250 to 4,000 Hz. Three of these patients had undergone stapedectomy before the identification of superior canal dehiscence. The air-bone gap was unchanged postoperatively. Each patient had an intact vestibular-evoked myogenic potential (VEMP) response from the affected ear, a finding that would not have been expected based on a middle ear cause of conductive hearing loss. One patient underwent resurfacing of the superior canal through a middle fossa approach. Postoperatively, his vestibular symptoms were relieved, and his air conduction thresholds were improved by 20 dB. Conclusions Superior canal dehiscence can result in apparent conductive hearing loss. The third mobile window created by the dehiscent superior canal results in dissipation of acoustic energy and is a cause of inner ear conductive hearing loss.

Sensorineural Deafness and Seizures in Mice Lacking Vesicular Glutamate Transporter 3

The expression of unconventional vesicular glutamate transporter VGLUT3 by neurons known to release a different classical transmitter has suggested novel roles for signaling by glutamate, but this distribution has raised questions about whether the protein actually contributes to glutamate release. We now report that mice lacking VGLUT3 are profoundly deaf due to the absence of glutamate release from hair cells at the first synapse in the auditory pathway. The early degeneration of some cochlear ganglion neurons in knockout mice also indicates an important developmental role for the glutamate released by hair cells before the onset of hearing. In addition, the mice exhibit primary, generalized epilepsy that is accompanied by remarkably little change in ongoing motor behavior. The glutamate release conferred by expression of VGLUT3 thus has an essential role in both function and development of the auditory pathway, as well as in the control of cortical excitability.

Lemierre's syndrome: two cases of postanginal sepsis.

Lemierres disease consists of suppurative thrombophlebitis of the IJV in the presence of oropharyngeal infection and can be complicated by septic pulmonary emboli. If a patient has an oropharyngeal or deep neck infection and neck pain suspicious for IJV thrombosis, a CT or MRI is warranted to establish the diagnosis. Blood cultures should be obtained to establish the responsible organism. In most cases F. necrophorum, an anaerobic bacterium, is responsible for the sepsis. Once the diagnosis of Lemierres disease is made, long-term, high-dose intravenous antibiotics with beta-lactamase anaerobic activity should be initiated. In cases with persistent sepsis and emboli despite appropriate medical management, ligation or excision of the IJV should be performed. Finally, if there is clinical or radiologic evidence of retrograde cavernous sinus thrombosis, the use of anticoagulants should be considered.

Changes in the cat cochlear nucleus following neonatal deafening and chronic intracochlear electrical stimulation

The effects of chronic intracochlear electrical stimulation on the cochlear nucleus (CN) were studied in eight cats that were neonatally deafened by daily intramuscular injections of neomycin. Profound hearing loss was confirmed in each animal by auditory brainstem response (ABR) and frequency following response (500 Hz) testing. Five of the kittens were implanted unilaterally with a scala tympani electrode array at ages 8-16 weeks. These kittens were stimulated daily for four hours at 2 dB above the evoked ABR threshold, over a period of three months, and subsequently euthanized for histological analysis at 26-32 weeks of age. The three remaining deaf kittens were maintained without stimulation over prolonged periods in order to study the long-term consequences of neonatal deafening, and were euthanized at 66-133 weeks of age. This study compares the CN of these deafened experimental animals and the CN of normal adult cats. Three experimental parameters were examined: CN volume, cross-sectional area of spherical cells in the rostral anteroventral cochlear nucleus (AVCN), and spherical cell density in this same region. The CN in animals that received electrical stimulation showed significant bilateral degenerative changes in all three measured parameters. Total nuclear volume was reduced by 35-36%, spherical cell size was reduced by 20-26%, and spherical cell density decreased by 36-42%, as compared to the normal cat CN. Comparisons were also made in the stimulated animals between CN ipsilateral to the stimulated cochlea and the contralateral, unstimulated CN.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of the Copper Transporter, CTR1, in Platinum-Induced Ototoxicity

The goal of this study was to determine the role of an influx copper transporter, CTR1, in the ototoxicity induced by cisplatin, a potent anticancer platinum analog used in the treatment of a variety of solid tumors. As determined through reverse transcriptase-PCR (RT-PCR), quantitative RT-PCR, Western blot, and immunohistochemistry, mouse CTR1 (Ctr1) was found to be abundantly expressed and highly localized at the primary sites of cisplatin toxicity in the inner ear, mainly outer hair cells (OHCs), inner hair cells, stria vascularis, spiral ganglia, and surrounding nerves in the mouse cochlea. A CTR1 substrate, copper sulfate, decreased the uptake and cytotoxicity of cisplatin in HEI-OC1, a cell line that expresses many molecular markers reminiscent of OHCs. Small interfering RNA-mediated knockdown of Ctr1 in this cell line caused a corresponding decrease in cisplatin uptake. In mice, intratympanic administration of copper sulfate 30 min before intraperitoneal administration of cisplatin was found to prevent hearing loss at click stimulus and 8, 16, and 32 kHz frequencies. To date, the utility of cisplatin remains severely limited because of its ototoxic effects. The studies described in this report suggest that cisplatin-induced ototoxicity and cochlear uptake can be modulated by administration of a CTR1 inhibitor, copper sulfate. The possibility of local administration of CTR1 inhibitors during cisplatin therapy as a means of otoprotection is thereby raised.

Repair of Chronic Tympanic Membrane Perforations Using Epidermal Growth Factor

Perforation of the tympanic membrane (TM) is a frequent cause of conductive hearing loss. Persistent TM perforations often require surgical repair with an autologous tissue graft to restore hearing and prevent recurrent infection. While highly efficacious, this method of closure requires a relatively complex and expensive microsurgical procedure. We have recently developed a chronic TM perforation model in the chinchilla for use in the exploration of novel methods of TM repair.

A meta-analysis of the complications associated with osseointegrated hearing aids.

Objective To summarize available peer-reviewed literature to describe the range and rate of complications related to osseointegrated hearing aids in adult and pediatric patients. Methods We searched PubMed using the terms bone-anchored hearing aid for articles published in English between 2000 and 2011. We included all articles reporting complications rates, except those that were case reports, general review (not systematic review), or commentary, as well as those that did not include patient outcomes, that reported outcomes associated with nonstandard implantation (e.g., 8.5-mm abutment) or were of poor study or reporting quality. Results After excluding articles that did not meet criteria, 20 articles were identified, comprising 2,134 patients who underwent a total of 2,310 osseoimplants. Complications reported in the literature were typically minor in nature. Skin reactions from Holgers Grade 2 to 4 ranged from 2.4% to 38.1%. Failure of osseointegration ranged from 0% to 18% in adult and mixed populations, and 0% to 14.3% in pediatric populations. The rate of revision surgery ranges from 1.7% to 34.5% in adult and mixed populations and 0.0% to 44.4% in pediatric patients, whereas the total rate of implant loss ranged from 1.6% to 17.4% in adult and mixed populations and from 0.0% to 25% in pediatric patients. Conclusion Overall, the quality of large scale and/or prospective studies reporting the incidence of complications after osseointegrated hearing aid surgery is poor and lacks uniformity. However, based on available data, which shows a lack of major complications, osseointegrated implantation is a safe procedure in both adult and pediatric populations. Well-designed, prospective studies with uniform reporting standards would allow greater comparison between techniques and more reliable analysis of complications of osseointegration surgery of the temporal bone for cochlear stimulation.

Contemporary Presentation and Management of a Spectrum of Mastoid Abscesses

Background: The incidence of complications resulting from suppurative otitis media has significantly decreased since the introduction of antibiotics. At the start of the 20th century 50% of all cases of otitis media developed a coalescent mastoiditis. By 1959, the incidence had fallen to 0.4%. Recent studies suggest a current incidence of only 0.24%. Additionally, during the time of Friedrich Bezold (1824‐1908), 20% of patients with mastoiditis developed subperiosteal abscess. Interestingly, this has incidence increased; today nearly 50% of patients diagnosed with coalescent mastoiditis have subperiosteal abscess.

Cochlear implantation in patients with bilateral Ménière's syndrome.

Objective To evaluate the indications and clinical outcomes (audiologic and vestibular) in patients with Ménières syndrome who have undergone cochlear implantation. Study Design This is a retrospective review of patients at a large tertiary academic medical center. Patients Nine patients were included in the study with AAO-HNS criteria for diagnosis of Ménières syndrome as well as bilateral severe to profound sensorineural hearing loss as an indication for undergoing cochlear implantation. Audiologic criteria for implantation were considered in the context of speech recognition performance with well-fit, powerful hearing aids noting large fluctuations in performance levels in some patients. In all cases, the poorer hearing ear was implanted. Seven subjects had bilateral disease and had progressed to profound sensorineural hearing loss. The average age of the patients was 61 years. Six patients had undergone previous surgery to control vertigo, including endolymphatic shunt surgery and vestibular nerve section. No patient had received previous treatment with intra-tympanic gentamicin. Symptoms of Ménières syndrome had been present in all patients for at least 10 years before implantation. Intervention Cochlear Implantation. Main Outcome Measures Pre- and Postoperative audiometric scores (monosyllable words/phonemes, Central Institute for the Deaf (CID) sentences, Hearing in Noise Test (HINT) in quite/noise (+10 db)), pre- and postoperative vestibular symptoms (number of vestibular attacks, aural fullness, tinnitus). Results Follow-up after implantation ranged from 1 to 5 years. Average 6 month postimplantation scores were: monosyllable words/phonemes = 52%/65%, CID sentences = 82%, HINT in quiet/noise = 70%/50%. Average 1-year postimplant scores were: monosyllable words/phonemes = 60%/76%, CID sentences = 97%, HINT in quiet/noise = 89%/78%. Postoperative speech recognition scores were, on average, substantially greater than preoperative scores. While there were few complications associated with implantation, some patients experienced alterations in their implant performance in association with fluctuations in vestibular symptoms. Conclusions Patients with advanced binaural involvement with Ménières Disease may present a challenge to conventional criteria for cochlear implant candidacy because of fluctuating symptoms. We observed significant benefit over baseline in a consecutive series of patients with Ménières syndrome who progressed to bilateral, severe-to-profound sensorineural hearing loss and underwent cochlear implantation. Further, previous vestibular surgery, including labyrinthectomy, does not contraindicate cochlear implantation.