Improved Speech Intelligibility in Subjects With Stable Sensorineural Hearing Loss Following Intratympanic Dosing of FX-322 in a Phase 1b Study.

OBJECTIVES: There are no approved pharmacologic therapies for chronic sensorineural hearing loss (SNHL). The combination of CHIR99021+valproic acid (CV, FX-322) has been shown to regenerate mammalian cochlear hair cells ex vivo. The objectives were to characterize the cochlear pharmacokinetic profile of CV in guinea pigs, then measure FX-322 in human perilymph samples, and finally assess safety and audiometric effects of FX-322 in humans with chronic SNHL. STUDY DESIGNS: Middle ear residence, cochlear distribution, and elimination profiles of FX-322 were assessed in guinea pigs. Human perilymph sampling following intratympanic FX-322 dosing was performed in an open-label study in cochlear implant subjects. Unilateral intratympanic FX-322 was assessed in a Phase 1b prospective, randomized, double-blinded, placebo-controlled clinical trial. SETTING: Three private otolaryngology practices in the US. PATIENTS: Individuals diagnosed with mild to moderately severe chronic SNHL (≤70 dB standard pure-tone average) in one or both ears that was stable for ≥6 months, medical histories consistent with noise-induced or idiopathic sudden SNHL, and no significant vestibular symptoms. INTERVENTIONS: Intratympanic FX-322. MAIN OUTCOME MEASURES: Pharmacokinetics of FX-322 in perilymph and safety and audiometric effects. RESULTS: After intratympanic delivery in guinea pigs and humans, FX-322 levels in the cochlear extended high-frequency region were observed and projected to be pharmacologically active in humans. A single dose of FX-322 in SNHL subjects was well tolerated with mild, transient treatment-related adverse events (n = 15 FX-322 vs 8 placebo). Of the six patients treated with FX-322 who had baseline word recognition in quiet scores below 90%, four showed clinically meaningful improvements (absolute word recognition improved 18-42%, exceeding the 95% confidence interval determined by previously published criteria). No significant changes in placebo-injected ears were observed. At the group level, FX-322 subjects outperformed placebo group in word recognition in quiet when averaged across all time points, with a mean improvement from baseline of 18.9% (p = 0.029). For words in noise, the treated group showed a mean 1.3 dB signal-to-noise ratio improvement (p = 0.012) relative to their baseline scores while placebo-treated subjects did not (-0.21 dB, p = 0.71). CONCLUSIONS: Delivery of FX-322 to the extended high-frequency region of the cochlea is well tolerated and enhances speech recognition performance in multiple subjects with stable chronic hearing loss.

Anterior canal benign paroxysmal positional vertigo: an underappreciated entity.

OBJECTIVE: Evaluate the frequency and characteristics of benign paroxysmal positional vertigo (BPPV) arising from involvement of the anterior semicircular canal (AC) as compared with the posterior canal (PC) and horizontal canal (HC). STUDY DESIGN: Prospective review of patients with BPPV. SETTING: Tertiary referral center. PATIENTS: A total of 260 patients who were evaluated for vertigo were identified as experiencing BPPV. INTERVENTIONS: Standard vestibular assessment including the use of electrooculography (EOG) or video-oculography (VOG) was completed on all patients. Based on EOG/VOG findings, the BPPV origin was attributed to AC, PC, or HC involvement secondary to canalithiasis versus cupulolithiasis. Treatment was performed with canalith repositioning maneuvers (CRMs) appropriate for type of canal involvement. RESULTS: For the 260 patients, the positionally induced nystagmus patterns suggested the canal of origin to be AC in 21.2%, PC in 66.9%, and HC in 11.9%. Cupulolithiasis was observed in 27.3% of the AC, 6.3% of the PC, and 41.9% of the HC patients. Head trauma was confirmed in the history preceding the onset of vertigo in 36.4% of the AC, versus 9.2% of the PC and 9.7% of the HC patients (p < 0.001). The number of CRMs completed to treat the BPPV did not differ between canals involved (1.32 for AC, 1.49 for PC, and 1.34 for HC). CONCLUSION: The direction of subtle vertical-beating nystagmus underlying the torsional component is critical in differentiating AC versus PC origin; EOG/VOG aids in accurate assessment of the vertical component for the diagnosis of canal involvement. AC involvement may be more prevalent than previously appreciated, particularly if the examiner does not appreciate the vertical component of the nystagmus or the diagnosis is made without the assistance of EOG/VOG. Head trauma history is significantly more frequent in AC versus other forms of BPPV, and patients with a history of head trauma should be examined closely for AC involvement. CRM is as successful for treatment of AC BPPV as for other types of BPPV.

Changing trends in the surgical treatment of Ménière's disease: results of a 10-year survey.

In order to discern trends in surgical procedures used to treat Ménière's disease in the United States during the 1990s, we mailed a questionnaire to 700 members of the American Otological Society and the American Neurotology Society. These physicians were asked about the frequency, results, and complications of surgical procedures for Ménière's disease that they had performed between Jan. 1, 1990, and Dec. 31, 1999. Questionnaires were returned by 137 surgeons (19.6%). Their responses indicated that the number of vestibular neurectomies, labyrinthectomies, and endolymphatic sac surgeries all decreased during 1999. Meanwhile, the use of office-administered intratympanic gentamicin therapy increased rapidly throughout the entire 10-year period, and by 1999 it had become the most frequently used invasive treatment for Ménière's disease. Surgeons now seem to reserve inpatient procedures for cases where intratympanic gentamicin fails to control vertigo.

Direct application of dexamethasone for the treatment of chronic eustachian tube dysfunction.

We undertook a prospective study to determine the safety and effectiveness of the direct administration of a steroid to the eustachian tube via the Silverstein MicroWick in 11 patients with chronic eustachian tube dysfunction, including two who had Samter's triad. All patients had previously been treated with medical therapy and surgical middle ear ventilation without resolution. The MicroWick was placed directly in the eustachian tube orifice through a pressure-equalization tube. Patients received 3 drops of dexamethasone 4 mg/ml three times a day. The drops were discontinued after 4 weeks, and the MicroWick and ventilation tube were removed after 3 months. At study's end, eight patients (72.7%) reported subjective improvement in terms of a reduction in aural pressure and fullness. Audiometric testing demonstrated a 55% reduction in the mean air-bone gap and a 3% increase in the mean speech discrimination score. Bone pure-tone averages remained stable. Tympanometry showed that five patients (45.5%) converted from type B or C tympanograms to type A. Four patients (36.4%) had persistent perforations. Both patients with Samter's triad improved with therapy. These preliminary results suggest that direct dexamethasone administration to the eustachian tube is safe and effective for the treatment of chronic eustachian tube dysfunction. Long-term studies to confirm these findings are under way.

Gentamicin perfusion vestibular response and hearing loss.

OBJECTIVE: To compare hearing results as a function of vestibular ablation in the treatment of Ménière's Disease, using gentamicin perfusion. STUDY DESIGN: A retrospective review of patients with Ménière's Disease treated by gentamicin perfusion of the inner ear via the MicroWick device. SETTING: A tertiary otologic referral center. PATIENTS AND INTERVENTIONS: The charts of patients treated with gentamicin perfusion via the MicroWick between the years 1998 and 2000 were reviewed. The results for patients with functional hearing in the affected ear were analyzed and were compared with the results in patients without functional hearing. MAIN OUTCOME MEASURES: Audiologic and vestibular test results as well as subjective symptoms. RESULTS: There were 45 patients who met the inclusion criteria. The averages for speech discrimination score and pure tone average before treatment were 92% and 38 dB, and after treatment were 82% and 47 dB. Patients were divided into two groups: Group 1 (20 patients), less than 75% ice air caloric reduced vestibular response (RVR); Group 2 (25 patients), those who reached greater than 75% ice air caloric RVR. There were 8 patients (17.6%) with persistent vertigo; 7 were from Group 1, and 1 was from Group 2, which was statistically significant (p = 0.007)wwww. The pure tone average dropped an average of 3 dB for Group 1 and 15 dB for Group 2. The difference in hearing loss between the two groups was statistically significant (p = 0.01). CONCLUSION: This study suggests that there is a correlation between the degree of vestibular ablation, the control of vertigo, and the risk of hearing loss. Patients with functional hearing seem to have a similar success rate for vertigo control, compared with patients who already had lost functional hearing before treatment. Future investigation may determine if less than 100% RVR, but greater than 75% RVR, is an alternative end point with adequate vertigo control and reduced risk of hearing loss.

Chemical perfusion of the inner ear.

In general, chemical perfusion therapy of inner ear disease is safe, inexpensive, and easy to perform. High inner ear medication concentrations can be achieved while minimizing systemic side effects. Most delivery methods are minimally invasive and can be performed in the office. The treatment is usually well accepted by patients. Vertigo control rates for Meniere's disease have been excellent--rivaling other prominent surgical treatments--allowing intratympanic therapy to become the most prominent first-line treatment for Meniere's disease. Side effects of ototoxicity occurring in approximately 30% of patients remain as one of the primary hurdles to overcome. Most patients who experience hearing loss, however, do not complain of the loss and are simply happy to be free of their vertigo attacks. The use of oral steroids to rescue and preserve hearing during gentamicin perfusion remain promising, and complete recovery and even hearing improvement have been observed [30]. Steroid perfusion of the inner ear also is variably effective for the treatment of SSHL, and is particularly indicated when oral steroids fail or are contraindicated due to other health reasons. Many inner ear perfusion methods and philosophies of treatment exist. Each technique has its associated advantages and disadvantages, and the individual surgeon must decide which technique to use in concordance with the patient's disease and expectations. In the future, new medications likely will be developed to treat certain types of inner ear disease, including SSHL, tinnitus, and various forms of vertigo. These medications can be administered by direct chemical perfusion of the inner ear.

Vestibular nerve section.

When the vertigo of Meniere's disease becomes refractory to medical management, a variety of surgical options are available. If intratympanic gentamicin has failed or is not recommended and serviceable hearing is present, sectioning the vestibular nerve is an excellent option in terms of vertigo control, hearing preservation, and postoperative quality of life. Transection of the vestibular nerve has gone through a metamorphosis since attempted by Krause over a century ago. The microsurgical posterior fossa vestibular neurectomy has undergone an evolution, resulting in the combined RRVN. This is essentially a retrosigmoid approach with exposure of the lateral venous sinus to allow forward retraction of the sinus and better exposure. This technique has the advantages of minimization of required mastoid and suboccipital bone work, elimination of the need for cerebellar retraction, improved exposure, ability to achieve watertight dural closure to minimize incidence of CSF leakage, low incidence of postoperative headache, and low overall complication rate. If a cleavage plain cannot be readily identified, then the superior half of the eighth nerve is sectioned near the brainstem. The results are essentially the same whether the vestibular nerve is cut in the IAC or the posterior fossa. Vertigo has been completely controlled in 85% and hearing has been preserved at the preoperative level in 80% of patients. Combined RRVN is a direct and safe technique, with high success in properly selected patients.

Laser stapedotomy minus prosthesis (laser STAMP): absence of refixation.

OBJECTIVE: To determine what percentage of patients with otosclerosis could successfully undergo a laser stapedotomy minus prosthesis over a 5-year period, and to determine the percentage of patients in whom refixation develops during follow-up. STUDY DESIGN: Retrospective case review of 136 patients (137 ears) who underwent primary surgery for otosclerosis. SETTING: An otology/neurotology tertiary referral center. PATIENTS: Patients were chosen if they had clinical evidence of otosclerosis without a history of otologic surgery. INTERVENTIONS: A standard stapes approach was used for all patients. For the laser stapedotomy minus prosthesis, a hand-held laser probe was used to vaporize the anterior crus of the stapes and perform a linear stapedotomy across the anterior one third of the footplate. If otosclerosis was confined to the fissula ante fenestram, the stapes became completely mobile. The stapedotomy opening was sealed with an adipose tissue graft from the ear lobe. MAIN OUTCOME MEASURES: Pure-tone audiometry with appropriate masking and auditory discrimination testing was performed before surgery, 6 weeks after surgery, and every year thereafter. RESULTS: Of the 137 cases, favorable anatomy and minimal otosclerosis allowed 46 (33.6%) of these patients to undergo laser stapedotomy minus prosthesis. Fifty-seven patients (41.6%) could not undergo the procedure because of extensive otosclerosis. The remaining 34 patients (24.8%) did not receive laser stapedotomy minus prosthesis because of other anatomic or technical difficulties. Of the 34 patients in the laser stapedotomy minus prosthesis group with more than 4 months follow-up, the average air-bone gap was closed from a mean of 22 dB (SD 10 dB) to 6 dB (SD 4 dB) 6 weeks postoperatively. Follow-up periods ranged from 5 months to 53 months (mean 767 days, SD 437 days). The long-term air-bone gap improved slightly to an average of 5 dB (SD 6 dB) in comparison with the sixth postoperative week value. CONCLUSION: Laser stapedotomy minus prosthesis is a minimally invasive procedure, which over the follow-up period has a very low incidence of refixation, as evidenced by a lack of progressive conductive hearing loss. The success of this procedure depends on the correct selection of cases. This procedure has been successfully performed on 33.6% of patients undergoing primary stapes surgery. Laser stapedotomy minus prosthesis seems to be a viable alternative to conventional stapedotomy that yields good results without evidence of refixation over an extended time.