Cochlear Implantation in Hereditary Hearing Loss and the Search for Predictive Factors From Genes to Hearing Outcomes Mirthe Fehrmann
From Genes to Hearing Outcomes Cochlear Implantation in Hereditary Hearing Loss and the Search for Predictive Factors Mirthe Fehrmann
The work presented in this thesis was carried out within the Donders Institute for Brain Cognition and Behaviour, and withing Hearing and Genes at the Department of Otorhinolaryngology of the Radboud University Medical Centre in Nijmegen, The Netherlands. ISBN: 978-94-6496-366-3 Cover design and layout: © evelienjagtman.com Printing: Gildeprint Enschede, gildeprint.nl Financial support for the publication of this thesis was provided by Cochlear Ltd. © Mirthe Fehrmann, 2025 All rights reserved. No parts of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior permission.
From Genes to Hearing Outcomes Cochlear Implantation in Hereditary Hearing Loss and the Search for Predictive Factors Proefschrift ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen op gezag van de rector magnificus prof. dr. J.M. Sanders, volgens besluit van het college voor promoties in het openbaar te verdedigen op dinsdag 3 juni 2025 om 10.30 uur precies door Mirthe Lynn Audrey Fehrmann geboren op 31 augustus 1994 te Scheemda
Promotoren: Prof. dr. E.A.M. Mylanus Prof. dr. R.J.E. Pennings Copromotoren: Dr. ir. C.P. Lanting Dr. W.J. Huinck Manuscriptcommissie: Prof. dr. B. Franke Prof. dr. C.C.W. Klaver (Erasmus Universiteit Rotterdam Prof. dr. V. Van Rompaey (Universiteit Antwerpen, België)
Table of Content Chapter 1 General Introduction and Thesis Outline 7 Chapter 2 Long-Term Outcomes of Cochlear Implantation in Usher Syndrome 29 Chapter 3 Good Cochlear Implantation Outcomes in Subjects With Mono-allelic WFS1Associated Hearing Loss – a Case Series 63 Chapter 4 Stable Long-term Outcomes after Cochlear Implantation in Subjects with TMPRSS3-associated Hearing Loss: a Retrospective Multicentre Study 85 Chapter 5 Cochlear Implantation Outcomes in Genotyped Subjects with Sensorineural Hearing Loss 113 Chapter 6 The potential of Electrocochleography in Explaining the Variability in Cochlear Implant Outcomes: a Scoping Review 151 Chapter 7 Evaluating Cochlear Implant Outcomes in DFNA9 Subjects: a Comprehensive Study on Cerebral White Matter Lesions and Vestibular Abnormalities 179 Chapter 8 General Discussion 203 Chapter 9 Summary 225 Appendices Nederlandse samenvatting 233 Research Data Management 240 List of Publications 242 Dankwoord 244 Over de auteur 249 PhD Portfolio 250
Chapter 1 General Introduction
General introduction 9 1 General Introduction It is said that hearing loss exists as long as there have been ears. Evidence of possible conductive hearing loss has been found in Neanderthal and early modern human remains dating back as far as 45.000 years ago. Significant ear canal exostoses were observed in these temporal bones, with probable hearing loss as a result (1, 2). Centuries later, around 1550 BCE, the Egyptians documented hearing loss in the ‘Ebers papyrus’, describing the first treatment for ‘an ear that hears badly` (3). This treatment involved injecting a mixture of olive oil, red lead, ant eggs, bat wings, and goat urine into the ears. Although it is known that a few drops of olive oil make ear wax more easily removable, the efficacy of the other ingredients has never been scientifically proven (4). The earliest description of hearing aids dates back to 1588 with Giambattista della Porta documenting curved animal horns as primitive hearing aids in his book ‘Magia Naturalis’(5). These horns laid the foundation for the ear trumpets, the first officially recognized hearing aids, in the 17th century. However, these instruments were limited in effectiveness as they could only funnel sound waves to the ear without amplifying them. It was not until the invention of the carbon microphone in 1878 that the first electric hearing devices capable of amplifying sound were developed in the early 20th century. This marked the beginning of a rapid acceleration in the development of hearing aids. Also, the development of the cochlear implant (CI) has roots that extend far back in history. Unlike traditional hearing aids, the CI does not amplify sound waves but instead electrically stimulates the cochlear nerve endings in the cochlea. The origins of this technique can be traced back to 1747 when Giuseppe Veratti, a scientist from Bologna, achieved the first electrical stimulation of the inner ear, leading to the subjective perception of sound (6). Nearly two centuries later, in 1930, Wever and Bray observed electrical potentials within the cochlea that mirrored the waveform of sound stimuli, giving rise to the phenomenon known as the ‘Wever and Bray effect’ (7). This discovery sparked the intriguing idea that reproducing these potentials could restore lost or impaired hearing (8). This concept was realized in 1961 with the development and surgical implantation of the first electrode in the cochlea of two individuals. These individuals reported experiencing auditory perception and changes in loudness with varying levels of stimulation, laying the groundwork for the development of the cochlear implant in the 1980s (9). Ever since then, the field of otology has changed tremendously. For many years, effective treatments for individuals with deafness and severe hearing loss were lacking. However, introducing the CI made it possible for most of these individuals to (partially) regain the ability to hear and engage in conversations once again. Despite the overall success of cochlear implantation, there remains a wide variability in speech perception outcomes among CI recipients (10-12). Although factors such as the duration of hearing loss, age of onset of hearing loss, and duration of CI experience have been identified as
Chapter 1 10 contributors, the largest portion (~80 %) of this variability remains unexplained (13, 14). This makes it challenging for clinicians to provide CI candidates with accurate predictions of the benefits they might gain from the device. To improve pre-implantation counselling, it is crucial to better understand which factors contribute to the variability in CI outcomes. This thesis evaluates CI outcomes in individuals with hereditary hearing loss, specifically focusing on identifying factors contributing to the variability in speech perception outcomes. To interpret the findings presented in this thesis, it is first necessary to explain the basic concepts of hearing, hereditary hearing loss, cochlear implantation, and auditory outcome measurements. 1.1. Anatomy and physiology of the auditory pathway Anatomically and functionally, there is a distinction between the external, middle, and inner ear. The external ear collects sound waves and conducts them through the external auditory canal to the tympanic membrane (Figure 1A). From there, the tympanic membrane converts sound waves into mechanical vibrations, which are conducted along the ossicular chain in the middle ear, comprising the malleus, incus, and stapes. These vibrations are further conveyed to the oval window of the cochlea and subsequently into the inner ear via movements of the stapes footplate (15). The spiral-shaped cochlea comprises three fluid-filled ducts, including the scala vestibuli and scala tympani filled with perilymph, and the scala media filled with endolymph (Figure 1B). Reissner’s membrane divides the scala vestibuli and media, while the basilar membrane divides the scala tympani and media. Within the scala media, the organ of Corti rests upon the basilar membrane, serving as the primary sensory organ responsible for converting fluid vibrations into electrical signals. It comprises inner and outer hair cells, a tectorial membrane, various supporting cells, and efferent and afferent nerve fibres that synapse at the base of the hair cells. From here, peripheral fibres project to the cell bodies located within the modiolus, forming the spiral ganglion, from which the central fibres of these ganglion cells form the cochlear nerve (15). The lateral wall of the scala media contains the stria vascularis, which is crucial for maintaining the ion homeostasis of the endolymph through its sodium and potassium pumps (16, 17). These potassium pumps actively maintain a high potassium and low sodium concentration of the endolymph in the scala media, in contrast to the low potassium and high sodium concentration of the perilymph in the scala tympani (18). This distinct ionic composition generates a potential difference between the cochlear fluids, known as the endocochlear potential, which facilitates sound detection (19). The mechanical vibrations that reach the oval window cause the perilymph within the scala vestibuli and tympani to move, resulting in a vibration of the basilar membrane. This vibration causes the stereocilia of the hair cells to bend, mechanically opening potassium channels and allowing potassium ions from the scala media to enter the hair cell. This influx of potassium ions depolarizes the hair cells,
General introduction 11 1 activating calcium channels and triggering a calcium influx that leads to neurotransmitter release into the synaptic cleft at the base of the hair cell (20, 21). The neurotransmitter diffuses into the nerve terminal, causing an action potential in the spiral ganglion cells. Axons from the spiral ganglion neurons form the cochlear nerve (22, 23), which transmit the signal through the cochlear nucleus in the brainstem to the temporal cortex, where sound is interpreted and understood, enabling us to hear effectively (15). The stria vascularis actively reabsorbs the potassium ions used during this process, recycling them back to the scala media to sustain the endocochlear potential (21). 1 2 3 4 5 6 7 8 9 10 A B 1 2 3 4 10 5 6 7 8 9 C D Apex Base 200 Hz 400 Hz 500 Hz 800 Hz 1000 Hz 1500 Hz 2000 Hz 3000 Hz 4000 Hz 5000 Hz 7000 Hz 20.000 Hz 1 2 3 4 Figure 1. The peripheral hearing pathway A. Overview of the peripheral hearing pathway, showing 1. The ear canal, 2. Tympanic membrane, 3. Malleus, 4. Stapes, 5. Incus, 6. Cochlea, 7. Cochlear nerve, 8. Semicircular canals. 9. Vestibular nerve, 10. Eustachian tube. B. The transverse section through the middle turn of the cochlea shows 1. Scala vestibuli, 2. Scala media, 3. Scala tympani, 4. Stria vascularis, 5. Reissner’s membrane, 6. Tectorial membrane, 7. Basilar membrane, 8. Outer hair cells, 9. Inner hair cell, 10. Spiral ganglion neurons. C. detailed image of the organ of Corti, showing 1. Tectorial membrane, 2. Inner hair cell, 3. Outer hair cells, 4. Nerve fibres. D. Illustration of the tonotopic organization of the human cochlea. Figure created in BioRender. Fehrmann, M. (2025) https://BioRender.com/v91t683. Hair cells are essential for converting mechanical energy into electrical signals that can be transmitted to the central nervous system. They are divided into inner (IHC) and outer hair cells (OHC). Within the organ of Corti is one row of IHCs and three rows of OHCs, separated by supporting
Chapter 1 12 cells (Figure 1C) (24). IHCs primarily function as sensory cells, providing input to 95% of the cochlear nerve fibres (25). In contrast, OHCs play a supportive and modulating role in the hearing process due to their electromotility properties, which enable them to enhance or reduce the movements of the basilar and tectorial membranes, thereby amplifying soft sounds and diminishing excessively loud sounds (26-28). The hair cells are arranged such that their sensitivity to sound frequency changes systematically with their position in the cochlea, known as tonotopic distribution (Figure 1D). This phenomenon occurs because the basilar membrane’s stiffness is very high near the oval window and decreases exponentially toward the apex. Consequently, the propagation speed of the sinusoidal vibration of the membrane slows down towards the apex while the wave amplitude increases. At a certain point, the propagation speed is so low that energy accumulates, causing the wave to reach a maximum amplitude before fading out. At this maximum amplitude location, the hair cells are predominantly stimulated (29, 30). Due to the decreasing stiffness of the basilar membrane towards the apex, the maximum amplitude point for high-frequency sounds is at the base of the cochlea, whereas for lowfrequency sounds, it is at the apex. This tonotopic organization extends to other levels of the auditory pathway, including the auditory cortex (31). 1.2. Hearing loss Globally, more than 5% of the population, about 430 million individuals, require rehabilitation for disabling hearing impairment, including 34 million children. Predictions indicate that by 2050, this number will exceed 700 million, affecting roughly one in ten individuals (32). Hearing loss can be divided into three subtypes: conductive hearing loss, sensorineural hearing loss (SNHL), and mixed hearing loss. Conductive hearing loss arises from external and/or middle ear problems, while SNHL, the most prevalent type, originates from dysfunction of the cochlea or retrocochlear pathways. Mixed hearing loss involves a combination of both conductive and sensorineural components (15). Both conductive and mixed hearing loss are not covered in this thesis and will, therefore, not be discussed further. 1.3. Hereditary hearing loss This thesis focuses on hereditary hearing loss, the main cause of SNHL, since 50-70% of cases are attributable to genetic causes (33). It can be classified as syndromic, comprising ~30% of cases, or non-syndromic, which accounts for the remaining ~70% of cases (34). Hereditary SNHL is highly heterogeneous, involving hundreds of genes encoding proteins with specific roles in various parts of the auditory system. It may present as either syndromic or non-syndromic. Non-syndromic hearing loss entails hearing loss without accompanying signs or symptoms. Syndromic hearing loss, on the other hand, occurs alongside other medical conditions, like retinitis pigmentosa (i.e., Usher syndrome), goitre (i.e., Pendred syndrome), or pigmentary anomalies of skin, hair, and eyes (i.e., Waardenburg
General introduction 13 1 syndrome) (35). Currently, ~150 genes have been linked to non-syndromic SNHL, and many more are associated with syndromic SNHL (36). Pathogenic variants in these genes can be identified through whole exome sequencing (WES). Since the introduction of this technique in 2015, there has been a substantial increase in solved cases of hereditary hearing loss (37, 38). Hereditary hearing loss can be inherited in different ways, with autosomal recessive inheritance requiring pathogenic variants on both alleles of the involved gene for SNHL to occur, while autosomal dominant inheritance results in SNHL with a pathogenic variant present on just one allele. In cases of non-syndromic hearing loss, approximately 80% follow a recessive inheritance pattern, while about 19% are due to dominant inheritance. The remaining percentage comprises the rare X-linked, Y-linked, or mitochondrial inheritance patterns (33, 34, 39). The DFN-classification is used to denote deafness loci, further classified by modes of inheritance. DFN indicates DeaFNess, followed by a letter indicating the inheritance mode and a number that reflects the order of gene discovery. Thus, DFNA represents an autosomal dominantly inherited locus, DFNB represents autosomal recessive inheritance, DFNX denotes X-linked inheritance, and DFNY signifies Y-linked inheritance (34). 1.4. Cochlear implantation For many people with hearing loss, a conventional hearing aid is an effective solution. Current hearing aid fitting methods, such as the NAL (National Acoustic Laboratories) and DSL (Desired Sensation Level) prescription rules, focus primarily on optimizing speech intelligibility and ensuring audibility across different frequencies. However, these methods become less effective as hearing loss progresses to severe or profound levels (40). Given the progressive nature of many forms of SNHL, individuals often start with conventional hearing aids for rehabilitation. Yet, as their hearing loss progresses, hearing aids may no longer provide sufficient amplification for effective speech recognition, leading to communication and safety concerns. For these individuals, cochlear implantation becomes the next step in rehabilitation. Conversely, individuals born with severe to profound SNHL typically begin their rehabilitation with cochlear implantation at an early age. Additionally, nowadays, an increasing number of adults with congenital hearing loss are becoming eligible for cochlear implantation, not primarily to improve speech perception but to serve as a signalling tool. This is particularly important for individuals with severe vision loss. A CI consists of an external and internal component. The external component comprises the speech processor and transmitting coil (Figure 2A). The processor captures sound via multiple microphones and converts it into an electrical signal. This signal is then transmitted via the transmitting coil to a receiving coil in the surgically placed internal component, the implant. Magnets in both external and internal parts keep the coils aligned. The internal component consists of a receiving coil connected to the electrode array inserted into the scala tympani of the cochlea (Figure 2B). The electrode array features multiple leads connected to individual electrode contacts arranged sequentially.
Chapter 1 14 In contrast to hearing aids, which amplify sound, CIs directly interact with the auditory system to enable hearing. A CI detects sound within a specific frequency band and activates the corresponding electrode in the cochlea which directly stimulates the spiral ganglion neurons matching this frequency band. The signal then reaches the cochlear nerve, transmitting it to the brain and mimicking the natural hearing process. This coordination between frequency bands and electrodes mimics the tonotopic organization of a healthy cochlea, in which higher frequencies are perceived at the cochlear base and lower frequencies at the apex. By electrically stimulating various frequency ranges, the CI provides the recipient with a perception of sound across different frequencies (15). 2 4 A B 1 2 3 1 Figure 2. External and internal components of the cochlear implant A. External components of the cochlear implant showing 1. Speech processor, and 2. Transmitting coil. B. External and internal parts of the cochlear implant showing: 1. Speech processor, 2. Transmitting coil, 3. Receiving coil, 4. Electrode array. Figure created in BioRender. Fehrmann, M. (2025) https://BioRender.com/h88u065. 1.5. Auditory outcome measures Various methods are available to evaluate hearing loss and CI outcomes. Before interpreting the hearing outcomes presented in this thesis, it is important to explain the basic concepts of some auditory outcome measurements. Auditory outcome measures can be divided into behavioural and objective measurements. With behavioural measurements, hearing performance is evaluated based on an individual’s subjective response to an acoustic stimulus. In this thesis, the following two behavioural outcome measurements are used to evaluate pre- and post-implantation hearing performance: Pure tone audiometry Pure tone audiometry assesses hearing loss, its severity, and its nature (conductive, sensorineural, or mixed). During the test, the minimum level at which a pure tone is just audible in a quiet environment is determined across various frequencies (125, 250, 500, 1000, 2000, 4000, 8000 Hz). These sound levels
General introduction 15 1 form the hearing threshold and can be measured both aided and unaided (41). To compare hearing thresholds pre- and post-implantation, the pure tone average (PTA) can be calculated. In this thesis, the PTA is calculated using thresholds at 500, 1000, 2000, and 4000 Hz (PTA0.5-4kHz). Speech recognition Assessing speech recognition involves evaluating the discriminatory ability of hearing, indicating an individual’s capacity to differentiate between different speech patterns, and providing insights into the impact of hearing loss. This test presents words at various sound levels for the individual to repeat, with the percentage of correct repetitions determined for each sound level. Speech recognition tests can be conducted in both quiet and noise (42). In this thesis, speech perception was evaluated in quiet using standard monosyllabic (consonant-vowel-consonant) Dutch word lists (43), presented at 65 dB SPL, with scores based on the correct repetition of phonemes and assessed both aided and unaided. In contrast to behavioural measurements, objective measures involve assessments and tests that provide information about the auditory system without relying solely on an individual’s subjective responses. These measurements are typically based on physiological responses to auditory or electrical stimuli and are unaffected by the individual’s perception or interpretation. Examples of objective measures include otoacoustic emissions (OAE’s), auditory brainstem responses (ABR), Auditory Steady-State Response (ASSR), and electrocochleography (ECochG). In the Netherlands, OAE measurements are used during the initial two screening sessions of the newborn hearing screening (NHS), while automated ABR is used during the third and final session (44). The use of ECochG in clinical practice has declined with the rise of the non-invasive ABR (45). However, interest in this objective measurement has recently resurged due to its potential in explaining some of the variability in CI outcomes. In addition to the outcome measures mentioned above, various other assessments can be utilized to evaluate CI outcomes. These include, for example, sound localization, cortical measurements, and interactions between bilateral CIs or a CI and a hearing aid (bimodal stimulation). Evaluations of quality of life (QOL) and patient-related outcomes are also common, with tools such as the Nijmegen Cochlear Implantation questionnaire (NCIQ), 36-Item Short Form Survey (SF-36), and Health Utilities Index Mark 3 (HUI3). Although these outcomes are relevant in CI-related research, they are not addressed in this thesis and will not be further discussed. 2. Cochlear implantation outcomes With the basic concepts of hearing, hereditary hearing loss, cochlear implantation, and auditory outcome measurements explained, it is time to delve into the aims of this thesis, which is divided into two parts. The first aim is to assess CI outcomes in individuals with hereditary hearing loss, while the second aim focusses on exploring three potential factors that may account for some of the variability in CI outcomes within this study population.
Chapter 1 16 Cochlear implantation is a highly successful type of rehabilitation for individuals with severe to profound SNHL that improves hearing, speech recognition, and quality of life (46). Studies evaluating CI outcomes specifically in genotyped recipients have also reported generally favourable outcomes (47-51). However, despite the overall success, outcomes vary across CI recipients (12). It is known that performance following CI can be influenced by multiple factors such as cochlear anatomy, age of implantation, duration of hearing loss, residual hearing and pre-implantation speech recognition, and cognitive performance (13, 14, 52, 53). Lazard et al. described a model that included nine factors that accounted for 22% of the variance in CI outcomes (14). The four factors with the strongest influence on CI outcomes, accounting for 10% of the total variance, included duration of severe/profound hearing loss, age of onset of severe/profound hearing loss, duration of CI experience, and aetiology (13). This thesis focuses on three additional potential factors impacting CI outcomes: the cochlear siteof-lesion, electrocochleography (ECochG) measurements, and cerebral white matter lesions (WML). While the cochlear site-of-lesion and ECochG measurements focus on the influence of peripheral components of the auditory pathway (pre- and postsynaptic regions of the cochlea and cochlear nerve), the impact of central factors on CI outcomes is evaluated through the assessment of cerebral WML. 2.1. Genetic factors and cochlear implantation outcomes The first potential factor to be explored in this thesis regarding variability in CI outcomes in individuals with hereditary SNHL is the cochlear site-of-lesion. This specifically examines how the different parts of the cochlea affected by genetic defects contribute to the variability in CI outcomes. This concept, proposed by Eppsteiner et al., is central to the spiral ganglion hypothesis (54). According to this hypothesis, CI outcomes are influenced by the specific location of damage within the cochlea. They divide the cochlea into a pre-synaptic part (e.g., the organ of Corti, the stria vascularis, and the tectorial membrane) and a postsynaptic part (encompassing the SGNs and the cochlear nerve; Figure 3). Since CIs directly stimulate SGNs, poor outcomes are anticipated when the post-synaptic part is affected. Conversely, favourable CI performance is expected when damage occurs in structures within the presynaptic part, such as hair cells or the stria vascularis (54). To support their hypothesis, Eppsteiner et al. examined subjects with hereditary SNHL and correlated the underlying genetic defects with CI performance. They conducted genetic testing in 29 adult CI recipients with idiopathic SNHL and evaluated their speech perception outcomes. A genetic cause of SNHL was identified in three individuals. Two individuals had bi-allelic pathogenic variants in TMPRSS3, a gene they associated with SGN pathology. In contrast, the third subject had causative variants in LOXHD1, a gene expressed in the pre-synaptic part of the cochlea. Their observation that the two subjects with TMPRSS3-associated SNHL had poor outcomes, while the subject with LOXHD1associated SNHL had favourable outcomes, substantiated their hypothesis (54).
General introduction 17 1 Figure 3. Pre- and post-synaptic components of the cochlea The transverse section through the middle turn of the cochlea shows the pre-synaptic components of the cochlea in blue, including the stria vascularis and organ of Corti, and the post-synaptic parts in red, including the spiral ganglion neurons that eventually form the cochlear nerve. Figure created in BioRender. Fehrmann, M. (2025) https://BioRender.com/e54j431. Also, other research supports the hypothesis that individuals with SNHL associated with post-synaptic pathology have less beneficial CI outcomes. Suboptimal CI outcomes are observed in cases of lower SGN survival (55), cochlear nerve deficiency (56), cochlear nerve hypoplasia (57), and vestibular schwannoma (58, 59). In contrast, overall beneficial CI outcomes are reported for aetiologies linked to pre-synaptic pathologies. For example, successful CI outcomes are seen in individuals with sudden deafness (60) and SNHL induced by ototoxic drugs (61), both of which are associated with hair cell pathology (62, 63). Additionally, cochlear implantation is reported to be a beneficial rehabilitation option for individuals with an enlarged vestibular aqueduct (64). Although previous research proposes the intriguing hypothesis that the cochlear site-of-lesion correlates with CI outcomes, there is currently limited evidence to support it. This underlines the need for further research, which will be addressed in this thesis. To do so, all genotyped individuals who underwent cochlear implantation in the Radboud University Medical Center between 2003 and 2021 were assembled in a study cohort. Within this cohort, CI outcomes in three distinct, each with a different cochlear site-of-lesion, are evaluated, including
Chapter 1 18 individuals with Usher syndrome (hair cells), WFS1-associated SNHL (ion homeostasis), and TMPRSS3associated SNHL (SGN). Subsequently, CI outcomes of the entire study cohort are analysed. In this study, outcomes will be correlated with the cochlear site-of-lesion and other known factors influencing CI outcomes, such as duration of SNHL, degree of SNHL, age at implantation, and duration of CI experience. Additionally, in all four studies, poor performers are identified and evaluated in more detail to identify factors associated with poor performance. 2.2. Electrocochleography and cochlear implantation outcomes Secondly, ECochG measurements, as a potential indicator of cochlear and neural health, may help unravel factors influencing the variability in CI outcomes explored in this thesis. In line with the cochlear site-of-lesion, ECochG can assess the function of specific regions of the peripheral auditory pathway, both pre- and post-synaptic. This technique can, therefore, be used to evaluate how the function of different affected areas within the peripheral auditory pathway influences CI outcomes. ECochG is an electrophysiological technique that records electrical potentials generated by different components of the cochlea and peripheral cochlear nerve in response to an acoustic stimulus (65). It reflects hair cell function through the cochlear microphonic (CM) and summating potential (SP), while neural function is assessed via the compound action potential (CAP) and auditory nerve neurophonics (ANN) (66). ECochG responses can be recorded using various techniques at different sites, including extra-tympanic, trans-tympanic, intra-tympanic, and intra-cochlear electrode positioning. In these measurements, closer to the generator site yields better-quality ECochG responses (67-71). Historically, ECochG measurements served as an objective method for assessing hearing loss. However, its role has diminished with the rise of the non-invasive auditory brainstem response (ABR) (45), particularly due to the invasive nature of ECochG. Performing ECochG measurements in an outpatient setting requires a transtympanic approach, as extra-tympanic measurements often lack sufficient accuracy (68). Despite transtympanic promontory ECochG measurements being proven feasible since the early 1950s and associated with a low complication rate, they can be uncomfortable for subjects, even with local anaesthesia (67, 68, 72, 73), and thus pose a potential burden. In recent years, there has been renewed interest in applying ECochG to cochlear implantation. Intraoperative ECochG measurements, specifically CM responses, are therefore used to monitor cochlear trauma during electrode insertion and provide real-time feedback to preserve residual hearing (74). Studies have shown that drops in ECochG responses during electrode insertion are associated with significantly poorer hearing preservation post-implantation (75-78).
General introduction 19 1 Furthermore, there is an increasing interest in ECochG’s potential role in explaining some of the variability in CI outcomes (70, 79-82). Since CIs directly stimulate SGNs, the integrity of both SGNs and the cochlear nerve is crucial for achieving adequate speech perception with a CI. Therefore, Eppsteiner et al. hypothesized that favourable CI outcomes are linked to the neural health of the spiral ganglion neurons (SGNs) and cochlear nerve (54). ECochG measurements can provide valuable insights into the health and integrity of the sensory and neural components of the auditory pathway, which can be correlated with CI outcomes. Previous studies have explored the correlation between ECochG responses and speech perception outcomes following cochlear implantation. Some studies reported promising results, indicating that ECochG responses could account for up to 59% of the variability in speech perception outcomes (70, 79-82). However, other studies found no correlation between ECochG responses and speech perception outcomes following CI (83-86). This disparity underscores the need for further research to determine the extent to which ECochG measurements can explain the variability in speech perception outcomes following cochlear implantation. To address this gap, this thesis conducted a scoping review to explore the relationship between ECochG measurements and speech perception outcomes following cochlear implantation. This scoping review catalogues the current literature on the correlation between various ECochG responses and speech perception with CI, including ECochG total response (ECochG-TR) and its underlying components such as the CAP, the ANN, SP, and CM. 2.3. Cerebral white matter lesions and cochlear implantation outcomes The third potential factor contributing to variability in CI outcomes investigated in this thesis is cerebral WML, which can serve as an indicator of cognitive performance. While the cochlear site-oflesion and ECochG measurements address the peripheral auditory pathway, cerebral WML affects the central auditory pathway, offering a different perspective on the factors influencing CI outcomes. Unlike simple sound perception, accurate speech understanding is a complex process requiring both auditory perception and cognitive skills (87). Consequently, cognitive factors are increasingly acknowledged for their influence on CI outcomes (53, 87-90). Cognition is ‘the mental action of acquiring knowledge and understanding through thought, experience, and senses’ (91). It includes various aspects of high-level intellectual functions and processes, typically conceptualized in terms of functional domains. The Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM5) identifies six key domains of cognitive function, including perceptual-motor function, language, learning and memory, social cognition, complex attention, and executive function (92). Cognitive impairment refers to any disease or condition that significantly hinders an individual’s mental abilities, with Alzheimer’s disease being the most well-known (91).
Chapter 1 20 Multiple studies have shown that hearing impairment is linked to cognitive decline (93-96). The elderly with peripheral hearing loss experience cognitive decline 30-40% faster than those without hearing loss and have a 24% higher risk of cognitive impairment (97). Additionally, hearing loss leads to atrophy in various cerebral regions, including the primary auditory cortex in the temporal lobe and regions associated with speech memory (98-100). In older adults, hearing loss might even reduce total brain volume, mainly due to white matter damage (101). This raises the question of whether these structural cerebral changes affect speech recognition outcomes following cochlear implantation. This thesis assesses whether cerebral WML can explain some of the variability in CI outcomes, using WML as an indicator of cognitive decline. Since cognitive skills depend on various cerebral grey matter regions, effective information transfer between these regions is crucial, a process facilitated by white matter (102). Therefore, WML can disrupt central processing and impair speech understanding. The Fazekas scoring system is frequently used to localize and grade cerebral WML (Figure 4). This score distinguishes between periventricular white matter lesions (PVWM) and deep white matter lesions (DWL). The Fazekas score is the sum of the PVWM and DWM scores and ranges from zero to six. Periventricular white matter Deep white matter Score 0 Score 1 Score 2 Score 3 Score 0 Score 1 Score 2 Score 3 Figure 4. The Fazekas scoring system The Fazekas scoring system is divided into the periventricular white matter (PVWM) score and the deep white matter (DWM) score. The PVWM is scored as follows: 0=absent, 1=caps or pencil-thin lining, 2=smooth halo, 3=irregular periventricular signal extending into the deep white matter. The DWM is scored as follows: 0=absent, 1=punctate foci, 2=beginning confluence, 3=large confluent areas. The Fazekas total score is the sum of the PVWM and DWM scores. Figure from Wu et al. (103), adapted figure reprinted with permission from Editor-in-Chief Aging and Disease.
General introduction 21 1 Previous studies have linked increased cerebral WML to lower speech recognition in normal-hearing individuals under 70 years of age (104) and those with cardiovascular disease (105). Additionally, individuals with more cerebral WML were less likely to regain normal auditory function after an episode of sudden deafness (106). Only one prior study has explored the correlation between cerebral WML and speech perception outcomes following cochlear implantation. This study found that the PVWM score explained approximately 27.4% of the variance in speech perception in quiet two years post-implantation in subjects aged 50-70 years at the time of implantation (53). However, as this study was limited by its small and heterogeneous cohort, a new study assessing the correlation between WML and CI outcomes in individuals with DFNA9 was initiated as part of this thesis. 3. Scope and outline of this thesis The research conducted in this thesis aims to address two objectives: The first aim of this thesis is to assess CI outcomes in individuals with hereditary hearing loss. Therefore, the CI outcomes in three distinct syndromes or genes are initially evaluated. Chapter 2 examines CI outcomes in subjects with Usher syndrome. Due to the considerable variability in phenotype observed among the three subtypes, each subtype was analysed separately. In Chapter 3, CI outcomes in subjects with mono-allelic WFS1-associated SNHL are investigated, associated with both Wolfram-like syndrome and DFNA6/14/38. Chapter 4 evaluates CI outcomes in individuals with TMPRSS3-associated SNHL linked to both DFNB8 and DFNB10. Finally, Chapter 5 assesses CI outcomes in a large cohort of subjects with hereditary SNHL associated with multiple genes. The second aim of this thesis is to investigate three potential factors that may account for some of the variability in CI outcomes among individuals with hereditary hearing loss, including the cochlear siteof-lesion, cerebral white matter lesions, and ECochG measurements. The role of the cochlear site-oflesion is examined in Chapters 4 and 5, which not only evaluated CI outcomes in TMPRSS3-associated SNHL and SNHL associated with multiple genes, but also correlate CI performance with the underlying cochlear site-of-lesion. Furthermore, Chapter 6 presents a scoping review that evaluates the extent to which ECochG measurements can help to understand the variability in speech perception outcomes following cochlear implantation. Additionally, in Chapter 7, the potential role of WML in explaining some of the variability in CI outcomes following cochlear implantation is explored among subjects with DFNA9. To finish up, Chapter 8 presents a general discussion that reviews the key findings and explores their significance and impact. It also offers insights into potential improvements and suggestions for future research to better understand the variability of CI outcomes, specifically in individuals with hereditary SNHL.
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