The effect of radiotherapy in aminoglycoside ototoxicity and noise induced hearing loss

Background: Radiotherapy remains a vital component in treatment protocols for patients with head and neck cancers. While some radiation-induced complications are transient, sensorineural hearing loss is characterized as late and permanent. To date there are no studies assessing the effect of fractionated radiotherapy on sensorineural hearing loss using an animal model. Moreover, the combined effect of radiotherapy and other hearing stressors such as aminoglycoside ototoxicity or acoustic trauma have not been delineated.Objective: The purpose of the present thesis is to characterize the relationship between radiotherapy dosage and the time course of possible hearing loss, to examine the relationship between radiotherapy and Gentamicin induced ototoxicity and to examine the relationship between radiotherapy and noise induced hearing loss.Methods: First, a unilateral fractionated radiotherapy scheme was used to examine the effect radiotherapy in an in vivo animal model. Second, a 10-day Gentamicin treatment was administered subcutaneously (40 mg/kg/day or 80 mg/kg/day). Third, Animals were exposed to acoustic trauma by a continuous pure tone of 6 kHz at 120 dB SPL for 60 minutes bilaterally. Outcome measures included auditory brainstem responses assessed at baseline, throughout and after treatments, distortion of production of otoacoustic emission and post-mortem cochlear morphology using light and scanning electron microscopy.Results: Radiation induced sensorineural hearing loss is permanent, dose dependent and caused by an initial sensorial damage followed by an important neural component primarily responsible for its progression. A syngersitic effect was identified with both low and high doses of Gentamicin and radiotherapy. Ears subjected to radiation did not show a delay in recovery after the noise exposure. However, morphology results of cochleae suggested synergistic damage to auditory hair cells that were not detected by auditory testing. Conclusion: The results of this thesis prove that previous exposure to radiotherapy in the temporal bone region can develop hearing loss long after the end of treatment, therefore long term follow ups in clinical and audiology settings are strongly recommended. Furthermore, cochleae previously exposed to radiotherapy are more susceptible to aminoglycoside ototoxicity and the damages associated with acoustic trauma. This raises an important concern for aminoglycoside treatments of patients with previous radiation exposure and highlights the importance of protecting the ears of these patients to future potential stressors such as acoustic trauma.Avant-propos: La radiothérapie demeure un composant majeur dans les protocoles de traitements chez les patients atteints de cancers au niveau de la tête et du cou. Alors que la plupart des complications causées par la radiothérapie sont temporaires, la perte d’audition sensorielle elle, est tardive et définitive. À ce jour, aucune étude n’a abordé les effets de la radiothérapie fractionnelle sur la perte de l’ouïe sensorielle sur un modèle animal. De plus, la combinaison des effets qu’engendrent la radiothérapie et d’autres stimulis auditifs tels que l’ototoxicité des aminoglycosides ou des traumatismes acoustiques n’a pas été reportée dans la littérature scientifique.Objectif : L’objectif de cette thèse vise à définir la relation entre différents dosages radiothérapeutiques et le lapse de temps pouvant s’écouler avant une éventuelle perte d’audition. Aussi, cette thèse examinera la corrélation entre la radiothérapie et l’ototoxicité provoquée par Gentamicine en plus d’examiner le lien entre la radiothérapie et la perte d’ouïe provoquée par quelconque traumatisme sonore.Méthodologie : D’abord, un traitement unilatéral radiothérapeutique en fractions a été utilisé pour examiner les effets de la radiothérapie sur un model animal. En second lieu, durant 10 jours consécutifs, un traitement sous-cutané de Gentamicine (40 mg/kg/jr or 80 mg/kg/jr) a été administré au cobaye. Enfin, les animaux ont été exposés à un traumatisme sonore entrainé par un son continuel de 6 kHz à 120 dB SPL pour 60 minutes bilatéral. Les mesures d’évaluation des résultats étaient calculées selon les réponses auditives du tronc cérébral mesurées au début, pendant et à la fin des traitements, la distorsion de production d’émission otoacoustique, post-mortem morphologie cochléaire utilisant la microscopie optique ainsi que la microscopie électronique à balayage.Résultats : La perte auditive causée par la radiothérapie est permanente. Le dégrée de perte auditive varie selon le dosage administré. Elle résulte d’un traumatisme au niveau sensoriel de l’ouïe. Les dommages engendrés par ce traumatisme évoluent ensuite au niveau cérébral, ce dernier étant responsable de sa progression. Un effet de synergie combinant la radiothérapie et la Gentamicine à forte et faible dose a été identifié. Les oreilles exposées à la radiothérapie n’ont pas démontré un délai de reprise des fonctions auditives suite à un traumatisme sonore. Par contre, les résultats histologiques des cochlées révèlent un dommage des cellules ciliées auditives non détecté par les testes auditifs.Conclusion : Les résultats provenant de cette thèse prouvent qu’avoir été exposé à des traitements de radiothérapie au niveau de la tête et du cou peuvent entrainer des déficiences auditives, et ce, longtemps après la fin des traitements. Pour ce, des suivis en clinique et en audiologie à long terme sont fort recommandés. De plus, les cochlées exposées à la radiothérapie sont plus susceptibles à l’ototoxicité causé par des aminoglycosides ainsi que les traumatismes sonores

A Systematic Review on Complications of Tissue Preservation Surgical Techniques in Percutaneous Bone Conduction Hearing Devices

OBJECTIVE:: To investigate skin-related postoperative complications from tissue preservation approaches in percutaneous bone conduction device (BCD) implantations. DATA SOURCES:: PubMed, Embase, and Cochrane Library. STUDY SELECTION:: We identified studies on BCDs including the opted surgical technique and derived complications. Retrieved articles were screened using predefined inclusion criteria. Critical appraisal included directness of evidence and risk of bias. Studies that successfully passed critical appraisal were included. DATA EXTRACTION:: Outcome measures included patient demographics, surgery time, follow-up time, and complications reported by Holgers classification. DATA SYNTHESIS:: We selected 18 articles for data extraction; encompassing 381 BCDs implanted using non-skin thinning approaches. Four studies reported an implantation technique using the punch method (81 implants), 13 studies applied the linear incision technique without soft tissue reduction (288 implants) and one study used the Weber technique (12 implants). Holgers 3 was described in 2.5% following the punch technique, in 5.9% following the linear incision technique, and in no implants following the Weber technique. One patient was mentioned having Holgers 4, skin overgrowth was reported in 6 patients, and 10 studies compared their non-skin thinning technique with a skin-thinning technique. Overall, the soft tissue preservation technique had a similar or superior complication rate, shorter surgical time, and better and faster healing, compared with the soft tissue reduction technique. CONCLUSION:: Tissue preservation surgical techniques for percutaneous BCDs have limited postoperative skin complication rates. Moreover, these techniques are suggested to have at least similar complications rates compared with skin-thinning techniques

A Systematic Review on Complications of Tissue Preservation Surgical Techniques in Percutaneous Bone Conduction Hearing Devices

OBJECTIVE:: To investigate skin-related postoperative complications from tissue preservation approaches in percutaneous bone conduction device (BCD) implantations. DATA SOURCES:: PubMed, Embase, and Cochrane Library. STUDY SELECTION:: We identified studies on BCDs including the opted surgical technique and derived complications. Retrieved articles were screened using predefined inclusion criteria. Critical appraisal included directness of evidence and risk of bias. Studies that successfully passed critical appraisal were included. DATA EXTRACTION:: Outcome measures included patient demographics, surgery time, follow-up time, and complications reported by Holgers classification. DATA SYNTHESIS:: We selected 18 articles for data extraction; encompassing 381 BCDs implanted using non-skin thinning approaches. Four studies reported an implantation technique using the punch method (81 implants), 13 studies applied the linear incision technique without soft tissue reduction (288 implants) and one study used the Weber technique (12 implants). Holgers 3 was described in 2.5% following the punch technique, in 5.9% following the linear incision technique, and in no implants following the Weber technique. One patient was mentioned having Holgers 4, skin overgrowth was reported in 6 patients, and 10 studies compared their non-skin thinning technique with a skin-thinning technique. Overall, the soft tissue preservation technique had a similar or superior complication rate, shorter surgical time, and better and faster healing, compared with the soft tissue reduction technique. CONCLUSION:: Tissue preservation surgical techniques for percutaneous BCDs have limited postoperative skin complication rates. Moreover, these techniques are suggested to have at least similar complications rates compared with skin-thinning techniques

Can floseal™ be applied safely during otologic surgery? Assessment of ototoxicity in a chinchilla animal model

Abstract Background In otologic surgery good visualization is paramount, and patients with bleeding diatheses or who need to be anti-coagulated can present a significant challenge. Here, we determine whether Floseal™, a hemostatic matrix, is ototoxic in a validated animal model. Methods Nine chinchillas housed in the animal care facilities of the Montreal Children’s Hospital Research Institute were used for the study. After a myringotomy incision was made in each tympanic membrane, baseline auditory brainstem response measurements were performed at 8, 20, and 25 kHz. In each animal one ear was randomized to receive Floseal™ to the middle ear cavity, whereas the other ear served as the control and received 0.9% sodium chloride. Outcome measures included early (day 7) and late (day 30) auditory brainstem response, clinical evidence of facial nerve or vestibular disturbance and histological evidence of ototoxity. Results There was no significant hearing threshold shift on auditory brainstem response across all tested frequencies for both experimental and control ear. No animals receiving Floseal™ developed facial or vestibular nerve dysfunction and there was no histological evidence of ototoxicity. Conclusion Based on the preliminary ototoxicity assessment on nine chinchillas, transtympanic Floseal™ does not appear to be ototoxic. More studies are warranted to assess the safety and applicability of the product in humans

Safety of transtympanic application of probiotics in a chinchilla animal model

Abstract Background Chronic suppurative otitis media can be recalcitrant and difficult to treat, particularly with the increasing occurrence of antibiotic resistance. Lactobacillus plantarum is a probiotic that has been shown to decrease S. aureus and P. aeruginosa growth in wounds, making it a good candidate for the treatment of chronic suppurative otitis media. However, before it can be applied in the ear, its ototoxicity potential must be evaluated. Methods A prospective controlled trial was conducted in a chinchilla animal model at the Animal care research facilities of the Montreal Children’s Hospital Research Institute to determine whether Lactobacillus plantarum is ototoxic when applied transtympanically. Ten chinchillas each had one ear randomly assigned to receive 109 CFU/mL of Lactobacillus plantarum solution, while the contralateral ear received saline. Auditory brainstem responses were measured bilaterally at 8, 20, 25 kHz before, at 7–10 days after application, and at 28 days after application of probiotic or saline. Facial nerve and vestibular function were assessed clinically. Results There were no statistically significant differences in hearing thresholds between control and experimental ears at 28 days after application. A difference of 11 dB was noted in the 25 kHz range at day 7–10, but resolved by day 28. No animals receiving probiotics developed vestibular nerve dysfunction. There was no histologic evidence of auditory hair cell damaged evidenced by scanning electron microscopy. Conclusion Our study suggests that a single application of Lactobacillus plantarum at 109 CFU/mL does not cause ototoxicity in a chinchilla animal model. These preliminary safety evaluations and the pathogen inhibitory effects of L. plantarum demonstrated by previous studies present this probiotic as a candidate of interest for further investigation

Scar formation in mice deafened with kanamycin and furosemide

In mammals, hair cell loss is irreversible and leads to hearing loss. To develop and test the functioning of different strategies aiming at hair cell regeneration, animal models of sensorineural hearing loss are essential. Although cochleae of these animals should lack hair cells, supporting cells should be preserved forming an environment for the regenerated hair cells. In this study, we investigated how ototoxic treatment with kanamycin and furosemide changes the structure of cochlear sensory epithelium in mice. The study also compared different tissue preparation protocols for scanning electron microscopy (SEM). Cochleae were collected from deafened and nondeafened mice and further processed for plastic mid modiolar sections and SEM. For comparing SEM protocols, cochleae from nondeafened mice were processed using three protocols: osmium-thiocarbohydrazide-osmium (OTO), tannic acid-arginine-osmium, and the conventional method with gold-coating. The OTO method demonstrated optimal cochlear tissue preservation. Histological investigation of cochleae of deafened mice revealed that the supporting cells enlarged and ultimately replaced the lost hair cells forming types 1 and 2 phalangeal scars in a base towards apex gradient. The type 3 epithelial scar, flattened epithelium, has not been seen in analysed cochleae. The study concluded that mice deafened with kanamycin and furosemide formed scars containing supporting cells, which renders this mouse model suitable for testing various hair cell regeneration approaches