Original Paper Audiology Neurotology

Audiol Neurotol 2013;18:392–405 DOI: 10.1159/000353582

Received: November 15, 2012 Accepted after revision: June 6, 2013 Published online: November 1, 2013

Effect of Both Local and Systemically Administered Dexamethasone on Long-Term Hearing and Tissue Response in a Guinea Pig Model of Cochlear Implantation Jason Lee a Hudaifa Ismail a Jun Ho Lee a, b Gordana Kel a Jonathan O’Leary a Amy Hampson a Hayden Eastwood a Stephen J. O’Leary a a

Department of Otolaryngology, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Vic., Australia; b Department of Otolaryngology, Seoul National University College of Medicine, Seoul, Korea

Key Words Cochlear implantation · Hearing protection · Dexamethasone · Fibrosis · Drug delivery to the ear

Abstract Dexamethasone administered prior to cochlear implantation has been shown to reduce the loss of residual hearing in experimental settings. However, its effect on the tissue response around the implant has not been extensively studied. In this study dexamethasone sodium phosphate was administered to guinea pigs via local delivery to the round window (2% dexamethasone for 120 min prior to surgery, ‘local 2/120’, or 20% dexamethasone for 30 min prior to surgery) or intravenously (2 mg/kg dexamethasone for 60 min) prior to implantation. Auditory brainstem responses (ABR) were monitored for 3 months, after which the cochleae were embedded in Spurr’s resin and sectioned. The extent of the tissue response and the survival of the neurosensory structures were analysed. Both local 2/120 and systemically delivered dexamethasone improved ABR thresholds when compared with control animals. Systemic dexamethasone also reduced the tissue response around the electrode. This suggests that

© 2013 S. Karger AG, Basel 1420–3030/13/0186–0392$38.00/0 E-Mail [email protected] www.karger.com/aud

whilst both locally and systemically administered dexamethasone can protect residual hearing after cochlear implantation, their effects upon the tissue response to implantation may differ. © 2013 S. Karger AG, Basel

Introduction

Cochlear implantation seeks to protect hearing and limit the extent of the tissue response surrounding the implanted electrode. Pharmacological treatment of the cochlea protects residual hearing in experimental settings. Previous studies show that dexamethasone significantly reduces hearing loss when applied as a single dose, either locally to the round window [James et al., 2008; Maini et al., 2009; Eastwood et al., 2010b] or systemically via intravenous injection [Connolly et al., 2011]. Nevertheless, the most effective route of administration in a clinical setting remains unclear. Local delivery is appealing as it distributes high concentrations of steroid to the inner ear, avoiding systemic complications. However, clinical application is complicated by slow rates of difProf. Stephen J. O’Leary Department of Otolaryngology, University of Melbourne Royal Victorian Eye and Ear Hospital 32 Gisborne Street, East Melbourne, VIC 3002 (Australia) E-Mail sjoleary @ unimelb.edu.au

fusion, necessitating long delays prior to implantation for maximal efficacy [Salt, 2005; Plontke and Salt, 2006; Plontke et al., 2007, 2008; Chang et al., 2009]. Systemic delivery has the advantage of flexible timing of drug delivery, preventing waiting periods in the operating theatre [Connolly et al., 2011]. Alternatively, direct drug elution from the implanted electrode may provide sufficient drug for therapeutic effect [Dinh et al., 2008a; Richardson et al., 2009; Farahmand Ghavi et al., 2010; Farhadi et al., 2013]. Whilst pharmaceuticals can ameliorate hearing loss associated with implant surgery, their effect on the tissue response has been less studied [Dinh et al., 2008a; James et al., 2008; Chang et al., 2009; Eastwood et al., 2010a, b]. Tissue response to implantation [Nadol and Eddington, 2004; James et al., 2008; Chang et al., 2009; Migirov et al., 2011] is characterised by fibrosis that may encapsulate the electrode and/or occupy an extensive area of the scala tympani. Macrophages and multi-nucleated foreign body giant cells (FBGCs) may surround the electrode. Additionally, osteoneogenesis may occur. An extensive tissue response may interfere with cochlear mechanics – and thus hearing – by impeding the movement of the basilar membrane or by obstructing the scala tympani [Choi and Oghalai, 2005]. Clinically, local delivery of steroids during surgery has been associated with reduced electrode impedance, suggesting that steroids may influence the tissue response [De Ceulaer et al., 2003; Paasche et al., 2006, 2009; Huang et al., 2007]. The anti-inflammatory and antioxidant effects of steroids could also reduce the tissue response [Satoh et al., 2006], via down-regulation of injury signalling and the subsequent immune response to implantation. We have previously found that the extent of the tissue response was independent of a 30-min local application of steroids to the round window membrane (RWM) [James et al., 2008]. Following systemic steroids, we observed a trend towards less fibrosis in the steroid-treated group [Connolly et al., 2011]. The failure to see a convincing reduction in the extent of the tissue response could reflect a complex relationship between fibrosis and intracochlear inflammation. Fibrosis in the presence of a foreign body can be dependent on its surface properties and does not always correlate with the degree of early inflammation in a wound-healing model [Anderson et al., 2008]. Alternatively, the failure to demonstrate a relationship between steroids and the tissue response could be due to previous experimental designs reported in the literature, particularly, a steroid dose too small to see an effect. In James et al. [2008], there was no effect on the extent of the

tissue response, but hearing was protected at 32 kHz only. Tissue response may be reduced in association with longer steroid application periods of 1–2 h, which are known to be associated with more extensive hearing protection. Here we compare local and systemic steroid administration over a period of 3 months to determine whether these are equivalent from the perspectives of both hearing preservation and their effects upon the tissue response to implantation.

Tissue Response after Cochlear Implantation

Audiol Neurotol 2013;18:392–405 DOI: 10.1159/000353582

Methods Animals and Experimental Design All procedures were approved by the Animal Research and Ethics Committee of the Royal Victorian Eye and Ear Hospital (ethics approval No. 10/196). Anaesthesia for surgical procedures and ABR testing was inducted with intramuscular injection of ketamine (60 mg/kg) and xylazine (4 mg/kg). Inhalation anaesthesia using 0.5–1% isoflurane mixed with oxygen at a rate of 500 ml/min was used to maintain general anaesthesia for the duration of surgical procedures. A total of 35 Dunkin-Hartley guinea pigs were randomly assigned to 4 experimental groups: a control group (n = 8), receiving a normal saline-soaked RWM bead for 30 min prior to implantation (‘controls’); a high-dose local steroid group (n = 10), receiving dexamethasone sodium phosphate (20% w/v) with bead-RWM contact time of 30 min prior to surgery (‘local 20/30’); a low-dose local steroid group (n = 8), receiving dexamethasone sodium phosphate (2% w/v) with bead-RWM contact time of 120 min prior to surgery (‘local 2/120’), and a systemic steroid group (n = 9), receiving an intravenous injection of dexamethasone at 2 mg/kg 60 min prior to the surgery (‘systemic’). The local 20/30 group was introduced to determine if the length of time between applying drug and cochlear implantation required to protect hearing could be shortened by increasing the concentration of dexamethasone applied to the round window, as previous results have suggested [Chang et al., 2009]. Auditory Brainstem Response Recordings Prior to surgery (T = 0), all animals had click-evoked and puretone auditory brainstem response (ABR) thresholds estimated on the ear to be implanted in response to tone pips of 2–32 kHz. Only animals with a click-evoked threshold 0.4 μV. Implant Surgery All animals received a standardised implantation procedure and administration of the allocated drug. Surgical procedures, delivery of medication and evoked potential recording have been described in detail elsewhere [James et al., 2008; Chang et al., 2009; Connolly et al., 2011]. These techniques are designed to mirror human cochlear implantation as closely as possible, paying careful attention to the technique and the location of a basal cochleostomy, as well as the nature and characteristics of array insertion. Surgery was performed as atraumatically as possible, avoiding suction of the perilymph and injury to the spiral ligament or basilar membrane. All animals received analgesia immediately after surgery in the form of buprenorphine (0.03 mg/kg). Using an operating microscope, a 0.7-mm cutting burr was used to drill a cochleostomy near the RWM into the basal turn of the scala tympani. A non-stimulating electrode array comprising three platinum rings spaced 0.75 mm apart on a Silastic® carrier (MDX4-4210; Dow Corning Products, USA) was then inserted to a depth of 2.25 mm as guided by the third marker platinum ring and then left in situ. The electrodes were positioned along the extent of the lower basal turn of the cochlea. A temporalis fascial graft was placed around the implant to seal the cochleostomy and minimise any potential perilymph leak. Local dexamethasone delivery was achieved using a 2-mm-diameter bead of Seprapack® (hyaluronic acid and carboxymethylcellulose; Genzyme) which was pre-soaked in dexamethasone solution and then applied to the RWM prior to cochleostomy for the duration specified by the respective experimental group protocol. Systemic dexamethasone was administered into the jugular vein prior to the commencement of the implant surgery. Histopathological Analyses Upon completion of the experiments, animals were deeply anaesthetised and euthanised with an overdose of pentobarbitone (1.0 g/ml/kg), perfused with 10% neutral buffered formalin, and the cochleae were harvested and decalcified in 4% (w/v) EDTA (Sigma-Aldrich, USA). They were subsequently trimmed, dissected and orientated for resin (Spurr’s) sectioning as described by Xu et al. [1997]. Resin sections of 2 μm were taken every 125 μm from the round window through the cochlea and stained with haematoxylin and eosin. The histologist preparing and analysing slides was blinded to treatment group.

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Audiol Neurotol 2013;18:392–405 DOI: 10.1159/000353582

Detailed histological analyses were performed on the lower basal turn of the cochlea, where the electrode was implanted and a tissue response was apparent. The electrode’s position was inferred from its impression on the tissue reaction (prior to its removal), typified by a circumferential or semilunar space in the tissue. Area measurements were made in Amira 5.4 image analysis software (Massachusetts, USA) by importing and orientating the cochlear sections and then segmenting the scala tympani and the tissue response. To estimate the extent of the tissue reaction, the area occupied by the tissue response and the percentage of scala tympani that it occupied was measured on each section (in 125-μm steps) from the cochleostomy onwards. Several measures were used to summarise the extent of the tissue response in each cochlea. The cumulative area occupied by the tissue response was determined by summing the areas calculated from the sequential (125-μmstepped) sections. Additionally, the percentage of scala tympani occupied by fibrosis was averaged across all sections where the electrode was reasonably thought to have been present – all sections from the cochleostomy to the last section exhibiting a tissue response, typically 10–20 sections. Outer hair cells (OHCs) were counted and averaged across all of these 10–20 sections. Osseous spiral lamina (OSL) injury was evaluated on all sections and was deemed to have been present if seen on any section. The extent of osteoneogenesis (new bone growth) was estimated by visual inspection on a scale of 0–3 on each section and averaged, as for the OHC counts. To evaluate the cell types present, 6 sequential sections displaying a tissue response – extending from the mid-modiolar region basally towards the round window in 125-μm steps – were examined. The presence of red blood cells, macrophages, FBGCs, agranulocytes (leucocytes or monocytes) and granulocytes was analysed qualitatively, where the occurrence of each cell type across the 6 sections was expressed on a scale of 0–3. In order to correlate ABR thresholds and the cochleotopic condition of the organ of Corti, cochlear reconstruction was undertaken. The corresponding cochlear place for each ABR frequency analysed was identified following the principles of cochlear reconstruction proposed by Guild [1921] and adopted by Schuknecht [1953], where the cochlear sections are placed over a frequency place map, in this case of the guinea pig [Viberg and Canlon, 2004]. The cochleae were orientated for sectioning so that the round window was encountered first, and this led to the sections being approximately orthogonal to the lower basal cochlear turn. In this orientation the hair cells were counted (from a single section) in the lower basal, upper basal and lower second turn, corresponding with 32, 16, 8 and 2 kHz, respectively. Spiral ganglion cell (SGC) densities were estimated from the mid-modiolar sections of the lower two cochlear turns, corresponding with 32, 8 and 2 kHz for the three lower half-turns respectively, by counting all type I cells within Rosenthal’s canal in which a nucleus was clearly visible and dividing this count by the canal area using Mirax Viewer software (Carl Zeiss, Germany). Statistical Analyses Statistical analyses were performed on IBM® SPSS® Statistics 19. ABR threshold shifts were analysed using ANOVA. Post hoc testing reported the Fisher least significant difference, including the mean difference (M), standard error (SE) and probability (p). Student’s t tests and Pearson’s correlations were performed where appropriate.

Lee /Ismail /Lee /Kel /O’Leary /Hampson / Eastwood /O’Leary  

 

 

 

 

 

 

 

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Fig. 1. Threshold shifts after cochlear implantation. Frequency-specific threshold shifts for the 3 dexamethasone treatment groups compared to controls at various time points after surgery. a 1 week. b 4 weeks. c 8 weeks. d 12 weeks.

Table 1. Cohort pre-implant ABR thresholds (dB SPL)

Control Systemic dexamethasone Local 20/30 dexamethasone Local 2/120 dexamethasone

2 kHz

8 kHz

16 kHz

24 kHz

32 kHz

threshold SEM

threshold SEM

threshold SEM

threshold SEM

threshold SEM

35.6 36.1 36.1 38.9

24.2 25.3 26.0 32.4

28.5 29.2 26.4 28.5

38.1 38.6 40.7 41.4

48.3 47.0 50.6 53.4

3.0 3.0 2.8 4.3

2.3 2.1 2.1 6.6

4.7 4.8 2.6 3.7

1.8 1.8 2.5 2.9

2.8 2.5 3.3 4.2

SPL = Sound pressure level.

ABR and Steroid Treatment We estimated ABR thresholds in response to tone pips (2, 8, 16, 24 and 32 kHz) prior to surgery and again at 1, 4, 8 and 12 weeks after implantation (fig. 1; table 1). Postoperative thresholds were elevated most at frequencies

≥8 kHz. The influence of treatment over 12 weeks following implantation was explored by performing a mixed ANOVA with ABR threshold shifts across time as a repeated measure (1, 4, 8 and 12 weeks) and treatment groups and stimulus frequency as fixed factors. Mauchly’s test of sphericity indicated that the assumption of sphericity for time had been violated – χ2(2) = 21.8, p =

Tissue Response after Cochlear Implantation

Audiol Neurotol 2013;18:392–405 DOI: 10.1159/000353582

Results

395

Color version available online

a

Fig. 2. Basal turn tissue response 3 months after cochlear implantation. a, b The tissue response in 2 different saline control cochleae, both close to the point of cochleostomy (i 125 μm, ii 375 μm, iii 625 μm from the round window) and at mid-modiolar region (iv). Thick arrow – the site of the cochleostomy; thin ar-

b

black arrowhead – osteoneogenesis; white arrowheads – loose areolar fibrosis; asterisk – a fibrous sheath arising from the margin of the scala tympani; cross – damage to the OSL. b iii A bridge of tissue extending from the scalar margin to the electrode sheath (bar = 200 μm).

row – a dense fibrous tissue sheath surrounding the electrode tract;

0.001; so the results are reported with the GreenhouseGeisser correction (ε = 0.911). Threshold shifts improved over time (F2.73, 420.7 = 67.215, p < 0.001; fig. 1), with the first month after surgery displaying the greatest reduction in threshold shift. The interaction between frequency and time was not significant (F10.928, 420.7 = 0.373, p = 0.966). There was a significant interaction between time and treatment group on ABR threshold (F8.20, 420.7 = 2.56, p = 0.007), so the simple main effects for treatment group at each time point were reported. At 1 week after surgery, ABR threshold shifts were statistically significantly lower in the local 2/120 (M = –19.5, SE = 4.48 dB, p < 0.001) and systemic (M = –21.1, SE = 4.37 dB, p < 0.001) groups than controls. These differences persisted at 4 weeks, where ABR threshold shifts in the local 2/120 (M = –14.0, SE = 4.34 dB, p = 0.002) and systemic (M = –13.1, SE = 4.24 dB, p = 0.002) groups remained lower than the controls. At 8 weeks after surgery, both the local 2/120 (M = –21.1, SE = 4.75 dB, p < 0.001) and the systemic groups (M = –14.4, SE = 4.24 dB, p = 0.001) continued to have smaller threshold shifts than the control group. At 12 weeks, local 2/120 threshold shifts remained lower than for controls (M = –14.1, SE = 4.76 dB, p = 0.004), but the difference in threshold shifts between systemic and controls was not significantly different (M = –8.75, SE = 4.65, p = 0.062) unless only the lowest and highest frequencies (2 and 32 kHz) were considered, where a statistically significant difference remained (M = –13.5, SE = 6.29, p = 0.032). Threshold shifts did not differ significantly between local 396

Audiol Neurotol 2013;18:392–405 DOI: 10.1159/000353582

2/120 and systemic treatment at any time point. Over 12 weeks, threshold shifts for local 2/120 remained lower than for local 20/30 (week 1: M = –14.2, SE = 4.25, p = 0.001; week 12: M = –13.6, SE = 4.52, p = 0.003), but the latter did not differ from controls. Tissue Response and Steroid Group The presence of macrophages and/or FBGCs adjacent to the electrode tract (fig. 2a iii, thin arrow) typified the tissue response (fig. 2a i–iv). Additionally, a dense layer of fibrocytes (fig. 2b i, asterisk) and/or a loose areolar network of fibrocytes (fig. 2a i, b iv, white arrowheads) that extended to the adjacent scalar wall surrounded the electrode tract. Osteoneogenesis was sometimes present, either within the fibrotic reaction (fig. 2a iv, black arrowhead) or extending from a region where the scalar wall or OSL had been injured (fig. 2a iv, cross). A sleeve of tissue usually extended from the site of the cochleostomy (fig. 2a i, thick arrow) along the electrode for several hundred microns. Further into the cochlea, the extent of the tissue response varied between specimens; it was greater when the electrode tract was in close proximity to the scalar wall or when there was evidence that the electrode had traumatised the endosteum. Small numbers of red blood cells were present in most temporal bones, either interspersed amongst areolar fibrous tissue (fig. 3a, d, arrows) or seen lining the endosteum of the scala tympani in cochleae where the tissue response was minimal. Angiogenesis was apparent within the tissue response (fig. 3b, asterisk), and Lee /Ismail /Lee /Kel /O’Leary /Hampson / Eastwood /O’Leary  

 

 

 

 

 

 

 

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macrophages were seen in most temporal bones. These were usually incorporated into the electrode sheath but could sometimes be seen adjacent to bony fragments present within the tissue response (fig.  3c). Similarly, FBGCs were most often encountered within the electrode sheath (fig. 4, thick arrow). Figure 4 also exhibits an example of a denser fibrosis (fig. 4, thin arrow) within an otherwise loose areolar tissue response. The total area of the tissue response across the cochlea – when measured across all cochlear sections where the electrode was present – was greatest in the controls and least in the systemic group (fig. 5a). Similarly, the percentage of scala tympani occupied by tissue response was found to be less than either controls (U = 3, z = –2.571, p = 0.010) or the local 2/120 groups (U = 9, z = –2.199, p = 0.028; fig. 5b). Further analysis was performed, considering tissue response areas on each section from the site of the cochleostomy. Tissue response areas did not differ significantly (Mann-Whitney U tests) between groups 125–375 μm from the cochleostomy site. However, the tissue response areas were significantly reduced (p < 0.05, U tests) in the systemic group compared with controls in 8 of the 11 subsequent sections up to 1.75 mm from the cochleostomy. This difference between groups is exemplified in figure 6, which shows micrographs exhibiting varying degrees of tissue response in local 2/120 (fig. 6a), systemic (fig. 6b) and control (fig. 6c) cochleae. To further examine whether the architecture of the tissue response varied between the groups, an analysis of the cell types present within the tissue response was undertaken. FBGCs were seen in 31% of systemically treated animals, but were more frequently observed in the other groups (63, 56 and 56% for local 2/120, local 20/30 and control groups, respectively). The proportion of cochleae exhibitTissue Response after Cochlear Implantation

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Fig. 3. Aspects of the tissue response. a Red blood cells (arrow) adjacent to the tissue response, which is largely loose areolar tissue; a macrophage is seen within this tissue – systemic treatment. b New blood vessels (asterisk) within loose areolar fibrosis – control animal. c A bone fragment surrounded by macrophages – systemic treatment. d Red blood cells (arrow) within areolar fibrous tissue – control animal (bar = 50 μm).

Fig. 4. Detail of the fibrous sheath surrounding an electrode. Example of an FBGC (thick arrow) within the fibrous sheath surrounding an electrode. There was primarily loose areolar fibrosis surrounding this sheath but also some denser hyaline fibrosis (thin arrow) – local 2/120 group.

ing other cell types, including macrophages (100, 69, 75 and 81% for local 2/120, systemic, local 20/30 and control, respectively), fibrocytes (100, 75, 75 and 94%), agranulocytes (81, 50, 63 and 63%) and granulocytes (0, 0, 6.3 and 0%) was similar between groups. In all groups, occasional agranulocytes (primarily leucocytes) were encountered across most sections, but granulocytes could be identified in just 1 cochlea. In 6 animals Reissner’s membrane was bowed outwards, away from the basilar membrane, becoming convex in shape as is generally associated with endolymphatic hydrops (fig.  7i–iv, arrow in 7i). The convexity of Reissner’s membrane was graded subjectively to be mild, moderate, severe or very severe with membrane tearing. Bowing of at least mild severity was observed in 1 local 2/120, 2 local 20/30, 2 control and 2 systemic animals in the lower second turn. In 4 animals, bowing was seen Audiol Neurotol 2013;18:392–405 DOI: 10.1159/000353582

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Fig. 5. Extent of tissue response after cochlear implantation. a Cumulative tissue response (μm2) for each treat-

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ment group. The systemic group was the only group to display a significantly reduced tissue response compared to the control. b The percentage of scala tympani occupied by the tissue response for each treatment group. Again, the systemic group was the only group to display a significantly reduced tissue response compared to the control. (* p < 0.05, Student’s t test).

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Fig. 6. Comparison of extent of tissue response adjacent to the lateral cochlear wall of the scala tympani. The indicative tissue responses are presented from animals treated with local 2/120 (a), animals treated systemically (b) and the control group (c). Note that the area of the tissue response is smaller in the systemic group (bar = 100 μm).

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Audiol Neurotol 2013;18:392–405 DOI: 10.1159/000353582

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Fig. 7. Evidence of endolymphatic hydrops.

Mid-modiolar scala media sections of the 4 lower turns (i lower basal, ii upper basal, iii lower second, iv upper second) in 1 saline control cochlea displaying a bowing of Reissner’s membrane that is suggestive of endolymphatic hydrops (bar = 200 μm).

across the 2, 8, 16, 24 and 32-kHz regions – which included turns apical to the electrode – while in 1 of the systemically treated animals the bowing was confined to the 2and 8-kHz regions. Similarly, in 1 control animal at least mild convexity was seen at 2, 8 and 32 kHz.

Table 2. Correlations of various tissue responses in the basal turn

OHC OSL injury New bone

OSL injury

New bone

Tissue

–0.164

–0.534** 0.128

–0.436* –0.040 0.709**

Relationships between Histological Features in the Basal Turn and Hearing throughout the Cochlea When considering all cohorts, the tissue response volume was greater when more extensive osteoneogenesis occurred (r = 0.72, p < 0.01; table 2). Poorer OHC survival in the basal turn was associated with greater tissue response volume and more extensive osteoneogenesis (table 2). In this series, the extent of OSL injury did not correlate with the tissue response volume or the amount of osteoneogenesis. Poorer ABR thresholds were seen ≥24 kHz in association with greater OSL injury (table 3). Similarly, poorer ABR thresholds at 8, 24 and 32 kHz were associated with both osteoneogenesis and greater tissue response volumes in the basal turn. The best hearing observed reduced as the extent of the tissue response increased. Figure 8 illustrates this for 8 kHz threshold shifts 8 weeks

after implantation, where all data points were seen to lie below the diagonal in the lower right half of the plot. A similar pattern was seen across the other frequencies.

Tissue Response after Cochlear Implantation

Audiol Neurotol 2013;18:392–405 DOI: 10.1159/000353582

New bone growth and cumulative tissue response were significantly correlated with a decrease in OHC, while new bone growth was significantly correlated with an increase in cumulative tissue. * p < 0.05 significant; ** p < 0.01 significant.

SGC Counts, Hair Cell Counts and Cochlear Place We observed no tissue response above the lower basal turn of the cochlea. However, as shown in figure 1, ABR threshold shifts derived from the upper basal turn (8 kHz) were elevated. In addition, ABR thresholds derived from the lower second turn (2 kHz) were elevated in control 399

Table 3. Correlations of various tissue responses to increase in hearing threshold

ABR threshold shift at 4 weeks

OHC OSL fracture New bone Tissue (cumulative)

2 kHz

8 kHz

16 kHz

24 kHz

32 kHz

–0.164 0.162 0.302 0.393*

–0.452* 0.316 0.405* 0.565**

–0.267 0.438* –0.013 0.099

–0.662** 0.500** 0.434* 0.409*

–0.607** 0.442* 0.433* 0.487**

At the high frequencies (24 and 32 kHz) an increase in threshold was significantly correlated with a reduction in OHC counts and an increase in OSL injury, new bone growth and cumulative tissue response. * p < 0.05 significant; ** p < 0.01 significant.

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10.5 Cumulative area occupied by tissue reaction (×106 μm2)

animals. Better survival of the SGCs and the organ of Corti was observed in these regions than in the lower basal turn (fig. 9). On ANOVA, OHC counts were statistically different between treatment groups (F3, 143 = 4.37, p = 0.006) but not frequency (F4, 143 = 1.27, p = 0.28) and the interaction between these factors was not significant. OHC counts were statistically significantly higher for local 2/120 than controls (M = 0.66, SE = 0.262, p = 0.013) or systemically treated animals (M = 0.89, SE = 0.262, p = 0.001). OHC counts in the local 20/30 group were significantly higher than in systemically treated animals (M = 0.55, SE = 0.255, p = 0.033). On ANOVA, inner hair cell (IHC) counts were statistically different between frequencies (F4, 143 = 3.35, p = 0.012) but not treatment group (F3, 143 = 1.48, p = 0.222) and the interaction between these factors was not significant. As figure 9 reveals, IHC counts were reduced in the lower basal turn, but near normal at and above 8 kHz, although survival in the controls was more variable than for other groups. Similarly, on ANOVA SGC counts differed significantly between frequencies (F2, 74 = 14.4, p < 0.001) but not treatment groups (F3, 74 = 0.60, p = 0.62). SGC counts were significantly lower in the 32 kHz region (i.e. the lower basal turn) than more apical regions at either the 8 kHz region (M = 336, SE = 882 cells/mm2, p < 0.001) or the 2 kHz region (M = 434, SE = 882 cells/mm2, p < 0.001). At both 2 and 8 kHz, neither the IHC, OHC nor SGC counts correlated significantly with either the extent of the tissue response in the lower basal turn or the corresponding ABR threshold shift (correlations not shown). However, at each frequency above 8 kHz, the loco-regional IHC, OHC and SGC counts all correlated with each other and also with their corresponding ABR threshold shift.

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Fig. 8. Tissue response and ABR thresholds. Total tissue response

(μm2) for all animals compared to 8-kHz threshold shifts 8 weeks after implantation. All data points fall in the lower right half of the graph, meaning that the best possible hearing was limited by the extent of the tissue response. When the tissue response was more extensive, ABR thresholds were elevated.

Discussion

Local and Systemic Steroids In summary, the three major conclusions drawn from this study are the following: (1) both local 2/120 and systemic steroid treatments were similarly effective in reducing the loss of residual hearing after implantation. However, the extent of the tissue response in the basal turn was lower in systemic than other groups, including Lee /Ismail /Lee /Kel /O’Leary /Hampson / Eastwood /O’Leary  

 

 

 

 

 

 

 

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Fig. 9. Effect of treatment on the inner ear hearing elements. The mean IHC counts (a, range 0–1 cells), OHC counts (b, range 0–3 cells) and SGC density (c, cells/mm2) for all treatment groups at specific frequency positions

within the cochlea. Note that for SGC counts, these were made at half-turns only, so these data were available for 32-, 8- and 2-kHz regions, representing the lower and upper basal turns and the lower second turn, respectively.

the local 2/120 group; (2) considering all cohorts, a more extensive tissue response in the basal turn of the cochlea was associated with poorer hearing in both the upper and lower basal turns, while greater injury of the OSL led to reduced ABR thresholds in the lower basal turn only, and (3) OHC counts were lower after systemic steroids compared with the local 2/120 treatment group, while IHC and SGC counts were dependent upon frequency (being poorer in the lower basal turn) but not the treatment group. The hearing results support previous research from our laboratories that a single dose of either local or systemic steroids, when delivered prior to implantation, can protect hearing. Here we establish that application of 2% dexamethasone to the round window for 120 min prior to implantation is as effective for hearing protection as 2 mg/kg systemic dexamethasone injected 60 min prior to implantation. However, the pattern of hearing loss observed here differed from that reported in our previous work. Here, ABR thresholds were elevated at 2 kHz, but in our previous studies they were not. In the present study there was little hearing protection at 8–16 kHz in the treatment groups, while in our previous work protection was maximal at these frequencies [James et al., 2008; Chang et al., 2009; Connolly et al., 2011]. We suspect that these differences may have resulted from there being different surgeons involved in the present studies (J.L. and H.I.); presumably the implantation techniques of these

surgeons differed from those of surgeons involved in our previous studies. Over the 12 week post-operative observation period, it became apparent that the mean ABR threshold shifts decreased over time in all treatment groups. The magnitude of the hearing recovery was greatest in the controls, leading to a reduction in the difference in ABR thresholds between steroid-treated cohorts and control animals over time. The aetiology of the recovery in ABR thresholds over time is not yet known, but our observation that endolymphatic hydrops was present in some animals (fig. 7) identifies this as a plausible explanation, as discussed below. It is thought that an extensive waiting time between steroid application and implantation for local therapy is required in order for the drug to diffuse sufficiently far into the cochlea to provide protection. Diffusion is a passive process, largely due to the slow longitudinal flow of perilymph along the cochlea [Salt and Plontke, 2009]. The distribution of a drug already present in the scala tympani is not changed by cochlear implantation, as observed in an MRI study where gadolinium distribution was evaluated [King et al., 2011; Yamazaki et al., 2012]. We found in the present study that the long waiting times required to afford protection from local delivery could not be shortened by increasing the concentration of drug applied to the inner ear. Our previous work suggested that this approach might show promise because ABR thresholds from the lower basal turn, assessed 1 week after implantation, were

Tissue Response after Cochlear Implantation

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found to be similar to those when there was a 10-fold increase in drug concentration applied for half the waiting time [Chang et al., 2009]. The long-term observation provided here does not support this approach. Modelling of drug diffusion within the cochlea predicts that the extent of drug distribution is primarily determined by its application time as opposed to concentration [Plontke et al., 2002, 2008; Salt, 2005; Salt and Plontke, 2005, 2009]. The results of the present study are consistent with this, and suggest that long delays cannot be avoided when round window delivery is used to administer hearing protection drugs. There is evidence that elution from an electrode has the advantage of distributing steroid as far as the implant is inserted into the cochlea, without incurring intra-operative delays [Dinh et al., 2008a; Farahmand Ghavi et al., 2010; Farhadi et al., 2013]. Although this approach is not protection per se – because the steroid is not present within the inner ear prior to injury – its efficacy in some experiments suggests that rapid distribution to the cochlea immediately after surgery can still be effective in rescuing hearing even after the surgical insult. Biological Response of the Cochlea to Implantation and Steroids The difference in the extent of the tissue response between local and systemic steroid delivery implies that even though both techniques may protect hearing, the biological response of the cochlea may differ with the route of administration. Prior to exploring this possibility, our current understanding of how steroids may protect hearing, and the biology of the tissue response to implantation, are reviewed. Glucocorticoid receptors are found in the mammalian cochlea in the IHCs, OHCs, spiral ligament, stria vascularis, Reissner’s membrane, SGCs and cochlear nerve [Terakado et al., 2011]. In experimental cochlear implantation, glucocorticosteroids applied locally to the cochlea act through anti-inflammatory, anti-apoptotic and antioxidant pathways, with direct effects upon the IHCs and OHCs observed [Dinh et al., 2008a, b; Haake et al., 2009; van De Water et al., 2010; Eshraghi et al., 2011]. Systemically administered glucocorticosteroids also act at the cochlear level [Connolly et al., 2011] but in addition are thought to reduce the activation of circulating immunecompetent cells [Souter et al., 2012]. The tissue response observed weeks to months after cochlear implantation is probably the result of both surgical stress to the cochlea and a foreign body response to the implant itself. It is not possible to distinguish between these, as they proceed in concert and could potentially in402

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fluence each other. Early after implantation, injury signalling is thought to lead to local production of inflammatory cytokines that attract immune-competent cells to the surgical site [Yamamoto et al., 2009; van De Water et al., 2010; Bas et al., 2012]. These are initially endogenous to the cochlea [Shi, 2010], but will also be recruited from the circulation after up-regulation of cell adhesion molecules, such as I-CAM1, on the endothelium of cochlear venules [Suzuki and Harris, 1995; Tornabene et al., 2006]. Soon after its introduction to the cochlea, the electrode becomes coated with proteins, including fibrin and other products of the complement cascade, creating a surface permissive of cell adhesion [Nadol and Eddington, 2004]. Macrophages (which under normal circumstances are present transiently to eliminate damaged tissue) will, in the presence of an implant, adhere to this foreign body and/or coalesce into FBGCs. Macrophages on the surface of a prosthesis signal resolution of the foreign body reaction through fibrosis. Similarly, the response of the cochlea to inflammation (independent of implantation) may be either through resolution, fibrosis or osteoneogenesis (the role of the macrophage in inflammation is reviewed in Duffield et al. [2013]). It is at this point that any attempt to differentiate between the cochlear response to surgical trauma and the foreign body response becomes problematic. In light of these considerations, we speculate that the reduction in tissue response volume and extent following systemic administration of steroids may result from a decrease in the recruitment of circulating immune-competent cells into the cochlea. This could arise because activation levels of leucocytes are expected to be lower following parenteral steroid treatment, so these may be less responsive to cochlear injury signalling. Systemic steroids have in other systems been shown to inhibit leucocyte adhesion in post-capillary venules [Tailor et al., 1999], including in the central nervous system where this effect appears to be mediated by the regulation of metalloproteinases [Harkness et al., 2000; Forster et al., 2007]. These effects are also expected to decrease the recruitment of circulating immunecompetent cells. Interestingly, despite their protective effects upon hearing, local steroids did not reduce tissue volumes significantly. This may suggest that any reduction in cochlear injury signalling through the intracochlear action(s) of steroids is insufficient to prevent the recruitment of immune-competent cells into the inner ear. It was found that OHC counts across the lower two cochlear turns were greater in the local 2/120 than the systemic steroid group. This too would be consistent with local and systemic steroids having different effects upon the cochlear response to implantation. Lee /Ismail /Lee /Kel /O’Leary /Hampson / Eastwood /O’Leary  

 

 

 

 

 

 

 

Relationships between the Tissue Response and Hearing A more extensive foreign body response was associated with both greater osteoneogenesis and poorer OHC counts within the lower basal turn of the cochlea. We have observed this previously in animals receiving lower doses of medications where there was minimal impact upon hearing [O’Leary et al., 2013]. In this study, osteoneogenesis was commonly seen in association with endosteal trauma, but it is also known to occur in the cochlea after non-surgical damage such as meningitis, infection and autoimmune disease [Hoistad et al., 1998; Tinling et al., 2004; Durisin et al., 2010], so endosteal trauma appears not to be a prerequisite for its development. Therefore, the correlation between osteoneogenesis and the extent of the tissue response in this study presumably reflects the intensity of the inflammatory response to implantation. This too would explain why OHC counts in the lower basal turn are poorer when there is a more extensive tissue response present (table  2): inflammation can lead to apoptosis of hair cells through an oxidative stress pathway [Abi-Hachem et al., 2010]. Inflammation could also explain why 2 and 8 kHz ABR thresholds arising from the upper basal turn (i.e. apical to the electrode) correlated with the extent of the tissue response in the lower basal turn (table 3). Oxidative stress and apoptosis of hair cells has been shown to extend apical to the site of the electrode insertion in experimental cochlear implantation [Eshraghi et al., 2005], and this is consistent with our observation that a full complement of OHC counts were not seen in this region (fig. 9). However, in the 8 kHz region the IHC counts were normal, and neither the OHC nor the SGC counts correlated with the extent of the tissue response or the ABR threshold shifts. This is in contrast to hearing >8 kHz, where OHC, IHC and SGC counts were correlated with each other, the ABR thresholds and the extent of the tissue response. Therefore, it would appear that the mechanism(s) of hearing loss at 8 kHz may differ from those at higher frequencies; the hair cell counts were higher here, yet the ABR thresholds were poorer, indicating that hearing loss may be less dependent upon hair cell integrity than in the lower basal turn. A possible mechanism of hearing impairment that would fit with these findings is excitotoxic injury to the peripheral dendrites of the auditory neurons, leading to deafferentation of the IHC. This has been associated with cochlear inflammation and oxidative stress. Another mechanism may be a disturbance of cochlear mechanics caused by the tissue response damping fluid movements within the scala tympani [Choi and Oghalai, 2005]. One Tissue Response after Cochlear Implantation

result that would be consistent with this interpretation was that the best threshold observed decreased with the extent of the tissue response in an almost (log-) linear relationship (fig. 8). Further experimentation is required to resolve the cause of hearing loss in regions apical to the cochlear electrode. The finding that some cochleae exhibited a bowing of Reissner’s membrane, as is expected with endolymphatic hydrops, suggests that this too may be a factor contributing to hearing loss after cochlear implant surgery. Slowly resolving endolymphatic hydrops may provide an explanation for the gradual improvement of ABR thresholds seen over the 12 weeks since implantation. It is necessary to perform similar histological analyses at earlier time periods after surgery to determine the prevalence of hydrops early on and whether it resolves over time. Endolymphatic hydrops has long been associated with other forms of ear surgery, most notably stapedectomy, where it is one of the mechanisms proposed to explain sudden hearing loss in the weeks after surgery. It has previously been associated with cochlear implantation in cochleae from profoundly deaf individuals [Handzel et al., 2006], and the majority of experiences both clinically and experimentally have been with severe-to-profound deafness, so effects on hearing would have been harder to detect and may easily have been overlooked. In conclusion, it appears that dexamethasone application prior to implantation can both protect residual hearing and influence the tissue response. Locally applied dexamethasone appears better suited for protecting the inner ear structures from surgical trauma, while systemically applied dexamethasone, as well as protecting hearing, also appears to reduce the tissue response around the electrode. In a clinical setting where both the protection of inner ear structures and a reduced tissue response are desired for the optimal performance of the implant, a strategy of combining both local and systemic delivery could warrant investigation.

Acknowledgements The authors wish to acknowledge the generous assistance of the Rodney Williams and Garnett Passe Memorial Foundation and NHMRC project grant for funding this project, The Royal Victorian Eye and Ear Hospital for providing facilities, Maria Clarke and Prudence Nielsen for preparation of histological slides, Dr. James Fallon for providing the ABR analysis program (NIDCD contract HHS-N-263-2007-00053-C; PI: R.K. Shepherd) and Helen Feng for manufacturing the electrode arrays.

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Copyright: S. Karger AG, Basel 2013. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.

Effect of both local and systemically administered dexamethasone on long-term hearing and tissue response in a Guinea pig model of cochlear implantation.

Dexamethasone administered prior to cochlear implantation has been shown to reduce the loss of residual hearing in experimental settings. However, its...
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