Howard W. Francis

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.

Impact of Cochlear Implants on the Functional Health Status of Older Adults

Objectives To assess the impact of cochlear implantation on quality of life changes in older adults aged 50 years and above.

Effects of deafferentation on the electrophysiology of ventral cochlear nucleus neurons

When cochlear pathology impairs the afferent innervation of the ventral cochlear nucleus (VCN), electrical responses of the auditory brainstem are altered and changes in cell and synaptic morphology are observed. However, the impact of deafferentation on the electrical properties of cells in the VCN is unknown. We examined the electrical properties of single neurons in the anterior and posterior VCN following bilateral cochlear removal in young rats. In control animals, two populations of cells were distinguished: those with a linear subthreshold current-voltage relationship and repetitive firing of action potentials with regular interspike intervals (type I), and those with rectifying subthreshold current-voltage relationships and phasic firing of 1-3 action potentials (type II). Measures of action potential shape further distinguished these two groups. Two weeks following cochlear removal, both electrical response patterns were still seen. Type I cells showed a higher input resistance. Deafferented single-spiking type II cells were slightly more depolarized, had smaller action potentials, smaller afterhyperpolarizations and shorter membrane time constants, whereas multiple-spiking type II cells were apparently unaffected. These changes in the electrical properties of VCN neurons following cochlear injury may adversely affect central processing of sounds presented acoustically or electrically by prostheses.

Synaptic alterations at inner hair cells precede spiral ganglion cell loss in aging C57BL/6J mice

Hearing deficits have often been associated with loss of or damage to receptor hair cells and/or degeneration of spiral ganglion cells. There are, however, some physiological abnormalities that are not reliably attributed to loss of these cells. The afferent synapse between radial fibers of spiral ganglion neurons and inner hair cells (IHCs) emerges as another site that could be involved in transmission abnormalities. We tested the hypothesis that the structure of these afferent terminals would differ between young animals and older animals with significant hearing loss. Afferent endings and their synapses were examined by transmission electron microscopy at approximately 45% distance from the basal end of the cochlea in 2-3 month-old and 8-12 month-old C57BL/6J mice. The number of terminals in older animals was reduced by half compared to younger animals. In contrast, there was no difference in the density of SGCs between the age groups. Older animals featured enlarged terminals and mitochondria and enlarged postsynaptic densities and presynaptic bodies. These morphological changes may be a combination of pathologic, adaptive and compensatory responses to sensory dysfunction. Improved knowledge of these processes is necessary to understand the role of afferent connectivity in dysfunction of the aging cochlea.

Immune-mediated inner ear disease

Immune-mediated inner ear disease (IMIED) is a syndrome that includes the subacute onset of sensorineural hearing loss, often accompanied by vertigo and tinnitus. This constellation of symptoms may occur as a primary disorder in which no other organ involvement is evident, or it may complicate certain systemic conditions, including Wegeners granulomatosis, Cogans syndrome, polyarteritis nodosa, and systemic lupus erythematosus. The precise disease mechanisms remain undefined, largely because of the difficulty obtaining relevant tissue specimens in untreated patients. However, if treated promptly with aggressive immunosuppression, the devastating sequelae of IMIED may be avoided. In this article, we review the pathophysiology, clinical evaluation, diagnostic testing, and therapy of IMIED.

Robot-Assisted Stapedotomy: Micropick Fenestration of the Stapes Footplate

OBJECTIVE: Micropick fenestration of the stapes footplate, a difficult step in stapedotomy, was selected for trials evaluating the potential for robotic assistance (RA) to improve clinical measures of surgical performance. STUDY DESIGN: In a surgical model of stapedotomy, we measured accuracy of fenestration to a desired point location and force applied to the stapes footplate. Performance variables were measured for 3 experienced and 3 less–experienced surgeons. RESULTS: RA significantly reduced the maximum force applied to the stapes footplate. For fenestration targeting, RA significantly improved accuracy for less–experienced surgeons and significantly worsened targeting for more-experienced surgeons. CONCLUSIONS: RA significantly improves performance for micropick fenestration in a surgical model of stapedotomy. For certain tasks, RA differentially affects performance for users of different experience levels. CLINICAL SIGNIFICANCE: These are the first results showing quantitative improvements in performance during simulated ear surgery using RA and differential effects of RA on performance for users of different experience levels.

Predictors of Vestibular Schwannoma Growth and Clinical Implications

Objective: Vestibular schwannomas exhibit variable and unpredictable patterns of growth. We evaluated the extent to which tumor growth influences the management of these benign tumors, and we explored symptom markers present at diagnosis that may be predictive of tumor growth. Study Design: Retrospective case review. Setting: Tertiary care hospital center. Patients: One hundred eighty patients with unilateral vestibular schwannomas diagnosed between 1997 and 2007 who were initially managed conservatively by serial observation. Intervention(s): Serial observation versus eventual microsurgical or radiosurgical treatment. Main Outcome Measure(s): Tumor growth, defined as a 1 mm/year or greater increase in tumor size. Results: We observed that tumor growth was the most important predictor of a change in treatment strategy from serial observation to microsurgical or radiosurgical treatment. We further noted in multivariate analyses that larger tumor size at diagnosis was associated with higher odds of tumor growth, such that each 1-mm increment in tumor size at presentation increased the odds of growth by 20%. We also found that the symptom marker of tinnitus at diagnosis significantly increased the odds of tumor growth nearly 3-fold. Conclusion: Tumor growth plays a significant role in guiding the management of vestibular schwannomas. Assessment of tumor size at diagnosis and for the presence of tinnitus may allow for risk stratification of patients with newly diagnosed vestibular schwannomas and for a more rational application of the conservative management approach.

Pilot testing of an assessment tool for competency in mastoidectomy

To determine the feasibility, validity, and reliability of an evaluation tool for the assessment of competency in mastoid surgery. This study tests the hypothesis that residents of dissimilar training levels differ in their technical performance as measured by this tool.

Cochlear implantation in patients with neurofibromatosis type 2 and bilateral vestibular schwannoma.

Objective: To investigate the results of cochlear implantation in patients with neurofibromatosis Type 2 (NF2) and bilateral vestibular schwannoma. Study Design: Retrospective case review. Setting: Three academic tertiary referral centers. Patients: Seven patients with NF2 and bilateral vestibular schwannoma who lost hearing in at least one ear after treatment of their tumor (surgery or radiation therapy). Intervention: Cochlear implantation after treatment of their vestibular schwannoma. Main Outcome Measure: Postimplantation audiometric scores (pure-tone average thresholds, consonant-nucleus-consonant (CNC) words/phonemes, Central Institute for the Deaf (CID) sentences, Hearing in Noise Test (HINT) quiet/noise, and Monosyllable, Trochee, Spondee (MTS) recognition/category tests), patient satisfaction, and device use patterns. Results: The average age at implantation was 40 years (range, 16-57 yr). Follow-up ranged from 6 to 88 months after implantation. Three patients were implanted with residual useful hearing in the contralateral ear, whereas four patients had no hearing in the contralateral ear. Hearing loss was due to surgical excision of tumor (n = 5) or gamma-knife radiotherapy (n = 2). Postactivation pure-tone average thresholds in the implanted ear ranged from 30 to 55 dB (average, 32.5 dB), although speech reception testing varied considerably among subjects. Despite this variability, all patients continue to use the device on a daily basis. Conclusion: In selected cases of deafness in patients with NF2 where there has been anatomic preservation of the auditory nerve after acoustic neuroma resection or radiation therapy, cochlear implantation may offer some improvement in communication skills, including the possibility of open-set speech communication in some patients. These results compare favorably to the auditory brainstem implant offering an alternative for hearing rehabilitation in patients with NF2.

Revision cochlear implantation surgery in adults: indications and results.

Objective: To assess the efficacy, risks, and indications of revision cochlear implantation (RCI) and to identify the clinical, audiologic, and device-related characteristics that predict outcome. Study Design: Retrospective case series. Setting: Academic tertiary referral center. Patients: Adults (≥18 yr) who underwent RCI at Johns Hopkins University. Intervention: Revision cochlear implant surgery. Main Outcome Measures: Speech perception by open-set testing and patient report and patient report of symptom resolution. Results: During the 16-year period of this study, 4.8% of all adults implanted at our center have required 1 or more RCI surgeries. A total of 48 RCIs have been performed. The indications for RCI included infection (12%), electrode extrusion (15%), hard failure (23%), suspected device failure (42%), and isolated facial nerve stimulation (8%). Overall, successful resolution of the implant-related or medical condition was achieved with RCI in 83% of cases. Speech perception was lower in only 1 (2.1%) of 48 cases. Satisfactory preoperative speech recognition was preserved or surpassed in 5 of 6 infection cases and 8 cases with progressive symptoms of tinnitus and facial nerve stimulation. All cases of hard failure regained or surpassed previous peak performance. Improved speech recognition was experienced by 75% of cases with suspected device failure. Of cases in which RCI failed to restore previous functional benefit, there was a significant association with advanced age (>70 yr). Whereas an abnormal integrity test was predictive of favorable outcome after RCI, a negative test was not predictive of outcome. A similar pattern of results was observed with respect to ex vivo device analysis. Conclusion: Revision cochlear implantation can be safely performed to restore lost benefit in appropriately selected cases. When properly performed after medical and audiologic options have been exhausted, RCI rarely compromises previous function and, in most cases, can resolve functional complaints and distracting symptoms. When positive, integrity testing is a useful screen for the presence of a device defect. In cases in which device integrity is uncertain, clinical judgment guided by longitudinal assessment can help determine whether RCI is likely to be beneficial.