Local pharmacological treatment of inner ear disorders

Hearing disorders are among the top 10 in terms of burden of disease in middle- and high-income countries, affecting 250 million people worldwide. During the last few decades researchers have made significant advances in understanding the basic mechanisms and molecular biology of inner ear diseases. The principal challenge in treatment of the inner ear is that the targets for pharmacological therapy are inaccessible due to the various barrier systems of the inner ear, and that the inner ear is embedded in the base of the skull. New technologies to provide safe and efficacious delivery of drugs to the inner ear are of great clinical interest. Local administration of medication to the inner ear would solve some of the problems associated with systemic delivery, such as drug interaction and systemic side effects. The aim of the research presented in this thesis was to elucidate different aspects of drug delivery to the inner ear using a local application technique. The round window membrane (RWM) is believed to be the main route for drug delivery to the inner ear when a drug is administered to the middle ear i.e. by an intratympanic injection. A morphological study of the round window performed on cynomolgus monkey described in Paper I showed the existence of a local defense system housed within the rim of the RWM. Previously undescribed gland-like structures were identified in the loose connective tissue of the mucosal layer near the bony insertion of the RWM. These findings could explain why labyrinthitis is rare despite the close proximity of the infection-prone middle ear. A local immunodefense system would also most likely affect the transport of drugs from the middle ear cavity to the inner ear and needs to be taken into consideration when developing new strategies for local drug administration in the middle ear. In the studies on which Paper II is based, the rheological and safety aspects of three candidate vehicles for intratympanic drug administration were investigated. The results speak in favor of sodium hyaluronate (HYA gel) which, in contrast to carboxymethyl cellulose and poloxamer 407, did not cause lasting or significant increases in hearing threshold after intratympanic injection in the guinea pig. Studies of vehicle elimination and morphological investigations support HYA gel as the most promising candidate for intratympanic administration. An important factor for local administration of drugs to the middle ear aimed for inner ear treatment is the adherence of the vehicle to the RWM. The distribution and elimination of HYA gel after intratympanic injection to the auditory bulla in guinea pig were investigated by magnetic resonance imaging in Paper III. HYA gel was distributed in a predictable way and filled the middle ear cavity well. The HYA gel remained close to the RWM for more than 24 hours. A myringotomy was needed before middle ear administration to allow air to escape and prevent trauma to the RWM. The hypothesis that higher concentrations of a drug in the inner ear could be achieved by local administration than through systemic administration was investigated in Paper IV and V using the antioxidant thiosulfate, which has previously been identified as a promising otoprotector against cisplatin-induced ototoxicity. The concentration of thiosulfate in scala tympani perilymph was much higher after intratympanic delivery to the guinea pig using an injection of a thiosulfate-containing HYA gel than after i.v. administration of a thiosulfate solution. The levels of thiosulfate in blood remained low after intratympanic administration, confirming that this delivery system will not risk decreased antitumoral effect due to cisplatin inactivation in tumor tissue. The final study, Paper V, demonstrated that ototoxicity in guinea pigs treated with the antineoplastic drug cisplatin was reduced by injection of thiosulfate-containing HYA gel three hours prior to the systemic cisplatin injection. This confirms the hypothesis of thiosulfate being a promising otoprotector for cisplatin induced hearing loss and also shows that drugs can be delivered locally to the inner ear by intratympanic injection using HYA gel as a vehicle

A pilot study on spatial hearing in children with congenital unilateral aural atresia

Despite normal hearing in one ear, individuals with congenital unilateral aural atresia may perceive difficulties in everyday listening conditions typically containing multiple sound sources. While previous work shows that intervention with bone conduction devices may aid spatial hearing for some children, testing conditions are often arranged to maximize any benefit and are not very similar to daily life. The benefit from amplification on spatial tasks has been found to vary between individuals, for reasons not entirely clear. This study has sought to expand on the limited knowledge on how children with unilateral aural atresia recognize speech masked by competing speech, and how horizontal sound localization accuracy is affected by the degree of unilateral hearing loss and by amplification using unilateral bone conduction devices when fitted before 3 years of age. In a within-subject, repeated measures design, including 11 children (mean age = 7.9 years), bone conduction hearing device (BCD) amplification did not negatively affect horizontal sound localization accuracy. The effect on speech recognition scores showed greater inter-individual variability. No benefit from amplification on a group level was found. There was no association between age at fitting and the benefit of the BCD. For children with poor unaided sound localization accuracy, there was a greater BCD benefit. Unaided localization accuracy increased as a function of decreasing hearing thresholds in the atretic ear. While it is possible that low sound levels in the atretic ear provided access to interaural localization cues for the children with the lowest hearing thresholds, the association has to be further investigated in a larger sample of children

The risk of cholesteatoma in individuals with first-degree relatives surgically treated for the disease

IMPORTANCE:  Cholesteatoma in the middle ear is not regarded as a hereditary disease, but case reports of familial clustering exist in the literature, as well as observed familial cases in the clinical work. However, the knowledge regarding cholesteatoma as a hereditary disease is lacking in the literature. OBJECTIVE To assess the risk of cholesteatoma in individuals with a first-degree relative surgically treated for the same disease. DESIGN, SETTING, AND PARTICIPANTS: In this nested case-control study in the Swedish population between 1987 and 2018 of first-time cholesteatoma surgery identified from the Swedish National Patient Register, 2 controls per case were randomly selected from the population register through incidence density sampling, and all first-degree relatives for cases and controls were identified. Data were received in April 2022, and analyses were conducted between April and September 2022. EXPOSURE: Cholesteatoma surgery in a first-degree relative. MAIN OUTCOMES AND MEASURES: The main outcome was first-time cholesteatoma surgery. The association between having a first-degree relative with cholesteatoma and the risk of cholesteatoma surgery in the index persons was estimated by odds ratios (ORs) and 95% CIs through conditional logistic regression analysis. RESULTS: Between 1987 and 2018, 10 618 individuals with a first-time cholesteatoma surgery (mean [SD] age at surgery, 35.6 [21.5] years; 6302 [59.4%] men) were identified in the Swedish National Patient Register. The risk of having a cholesteatoma surgery was almost 4 times higher in individuals having a first-degree relative surgically treated for the disease (OR, 3.9; 95% CI, 3.1-4.8), but few cases were exposed overall. Among the 10 105 cases with at least 1 control included in the main analysis, 227 (2.2%) had at least 1 first-degree relative treated for cholesteatoma, while the corresponding numbers for controls were 118 of 19 553 control patients (0.6%). The association was stronger for individuals under the age of 20 years at first surgery (OR, 5.2; 95% CI, 3.6-7.6) and for a surgery involving the atticus and/or mastoid region (OR, 4.8; 95% CI, 3.4-6.2). There was no difference in the prevalence of having a partner with cholesteatoma between cases and controls (10 cases [0.3%] and 16 controls [0.3%]; OR, 0.92; 95% CI, 0.41-2.05), which implies that increased awareness does not explain the association. CONCLUSIONS AND RELEVANCE:  In this Swedish case-control study using nationwide register data with high coverage and completeness, the findings suggest that the risk of cholesteatoma in the middle ear is strongly associated with a family history of the condition. Family history was nevertheless quite rare and can therefore only explain a limited number of all cases; these families could be an important source for information regarding the genetic background for cholesteatoma disease