Cochlear Implants: Fundamentals and Application - part 3 pdf

136 3. Surgical Pathology F IGURE 3.15. A photomicrograph of the basal turn of the cat cochlea where the electrode entry through the round window membrane was grafted with fascia, and an otitis media was induced with Streptococcus pneumoniae. This has formed a fibrous tissue sheath or type 1 seal. ET—electrode track. mococcal otitis media, but there was a reduced incidence of infection when the entry point was grafted. Therefore, for safety it is essential to place a graft around the electrode where it enters the cochlea. Although there was no statistically significant difference between fascia and Gelfoam, it is recommended that fascia and not Gelfoam be used. Gelfoam was used in the animal models to produce otitis media as described previously. If bacteria are introduced at surgery with Gelfoam around the elec- trode entry point, it could act as a home (nidus) for infection (Clark and Shepherd 1997). These experimental results apply to the Nucleus free-fitting array only. It must be stressed that a two-element array with members close to each other should not pass from the middle to the inner ear. A space between them is a conduit for infection, a home to allow pathogens to multiply, as well as a site to increase the pathogenicity of the organisms and reduce the ingress of antibodies and anti- biotics. This is especially important considering the above studies showing the invasiveness of S. pneumoniae. Host Factors and Foreign Bodies Implanted foreign bodies, as discussed above (see Biocompatibility of Materials), are not totally inert, and should be evaluated for tissue toxicity. Foreign bodies markedly increase the pathogenic potential of organisms of low virulence, for Infection 137 example, Staphylococcus epidermidis (Lowy and Hammer 1983). Many studies have shown that a bacterial inoculum that is normally “subinfective” will lead to a severe infection in the presence of implanted material such as devitalized and crushed muscle and gelatin (Vaudaux et al 1994). Finally on the basis of the above evidence it is apparent that any dead space between the two members of a dual element array would not only be a pathway for infection to enter the inner ear and a home for the pathogens to multiply, but also would allow them to become more virulent. The effect of a dead space either within a foreign body or between two bodies has been investigated by Zimmerli et al (1982) using Teflon perforated cylinders (tissue cages). With this and other implants producing a dead space (Bergan 1981; Marchant et al 1986), an inflammatory exudate accumulated within the cages within 2 to 4 weeks. If these tissue cages were infected with an organism at levels much below those normally causing infection, there would be a virulent inflam- mation with the ingress of polymorphonucleocytes and the formation of pus. This demonstrated that a dead space could make organisms more virulent. Further- more, the tissue cage model also showed that parenteral antibiotics were ineffec- tive against the organisms in the cage if administered more than 12 hours after the inoculation. This inefficacy of antibiotic therapy is commonly observed in the clinical context of foreign body infections (Vaudaux et al 1994). Furthermore, it was shown that the phagocytic activity of neutrophils in the cages was markedly deficient and lower than observed with neutrophils from acute and chronic peritoneal exudates or blood. This suggested the neutrophils could be damaged through contact with the surface of foreign bodies, and this would reduce their antibacterial activity (Zimmerli et al 1982). Or alternatively it was associated with a reduced level of opsonins and complement in the tissue cages (Zimmerli et al 1982). In a later phase of infection, complement-mediated opsonic activity was reduced, and this too limited the ability of body to handle infection. Thus any dead space created within and across the inner ear is not only likely to be a path or home for infection, but also will increase the virulence of the organism and reduce the body’s ability to deal with the infection either through phagocytic action or complement-mediated responses. It has also been shown with dead space that the access for antibiotics is significantly reduced. In addition, the studies with the infected tissue cages showed there was no associated bacter- emia or spread by the bloodstream. The penetration of antibiotics to infected locations almost always depends on passive diffusion. The rate is proportional to the concentrations of a drug in the plasma or extracellular fluid. Drugs that are extensively bound to protein may not penetrate to the same extent as those with lesser links. Drugs that are highly protein bound may have reduced activity because there is a smaller fraction to react with its target. For example, the drugs cefotaxime and ceftriaxone, both third-generation cephalosporins and the treatment of choice for H. influenzae and S. pneumoniae infections, have different degrees of binding. Ceftriaxone is used for adults and Cefotaxime in children. Ceftriaxone, however, is 90% to 95% protein bound, and that greatly reduces its efficacy. On the other hand, cefotaxime 138 3. Surgical Pathology is only 36%. Vancomycin should be added to the therapy if the minimum inhib- itory concentration (MIC) for these antibiotics is greater than 0.12 mg/L. Thus if there is a dead space as seen with a two-element array, the penetration of the antibiotics could be considerably reduced. In addition, in preventing infection spreading to the meninges many antibiotics that are polar and at a physiological pH do not cross the blood–brain barrier at all well. Some such as penicillin G are even actively transported out of the CSF by active transport mechanisms in the choroid plexus. The concentrations of penicillin and cephalosporins in the CSF are usually only 0.5% to 5% of the steady-state level in the plasma (Quag- liarello et al 1986). The integrity of the blood–brain barrier, however, is dimin- ished during bacterial infection. With infections from S. pneumoniae and other pathogens, there is also the added problem of their developing a biofilm, a slime on the surface of the foreign material, and this will allow them to resist antibiotics and antibodies. Bacteria that adhere to implant materials by encasing themselves in a hydrated matrix of polysaccharide protein form a slimy layer known as a biofilm (Stewart and Cos- terton 2001). Bacteria in the biofilm are resistant to antibiotics. For example, a b-lactimase negative strain of Klebsiella pneumoniae had a MIC of 2 lg/mL of ampicillin in aqueous suspension, but when grown as a biofilm the organism was scarcely affected by 4 hours’ treatment with 5000 lg/mL of ampicillin, a dose that would eradicate free-floating bacteria. The antibiotic resistance that normally occurs due to efflux pumps, modifying enzymes, and target mutations does not seem to apply to this mechanism of drug resistance with biofilms. Furthermore, because active and inactive microbes are closely situated and because surviving bacteria can use dead ones as nutrients, the new cells remaining after antibiotic therapy can restore the biofilm to its original state in a matter of hours. Single-Component Array and the Natural Defenses Against Infection A single component array that is surrounded with a fibrous tissue sheath can, as described above, effectively work with the body’s three defense mechanisms to prevent the ingress of infection from an otitis media to the cochlea and thence the meninges. The above studies demonstrated that the sheath around the single component array enabled three lines of defense to be used against the spread of infection. The first line of defense is the surface activity of mucus-secreting cells, and their extension around the electrode. The second line of defense is the mo- bilization of phagocytes in and around the sheath. The third line of defense is the mobilization of type B lymphocytes, and type T lymphocytes to the sheath and between the sheath and the electrode. With the first line of defense against the spread of infection from otitis media, the surface cells around the electrode entry changed into mucus-secreting cells and extended around and along the electrode array. They produced mucus that is bacteriostatic, and the hairs of the mucous cells beat to and fro to sweep the bacteria away. Their growth around the electrode is illustrated in Figure 3.8. Infection 139 F IGURE 3.16. Phagocytosis of bacteria—the second line of defense. Photomicrograph shows granulocytes and debris in apposition to mucous lining cells. The second line of defense operates when the bacteria release toxins into the sheath. The blood vessels dilate and bring the phagocytes to the site so they can digest the bacteria. This is illustrated in Figure 3.16. The third line of defense is the production of type B and T lymphocytes, in response to the bacterial surface antigen. The B lymphocytes produce antibodies and the T lymphocytes are killer cells that pierce cells. Note that in Figure 3.11 the lymphocytes not only lie in the connective tissue around the sheath, but also enter between the sheath and the array. Clinical Protocol The results obtained from animal studies indicate that there is a risk of otitis media extending into the inner ear after implantation during the first few weeks, a period of increased vulnerability due to the increased permeability of the tissues and the need for the seal to form. To minimize the risk of infection spreading into the inner ear during or after implantation, it is recommended that surgery should be carried out under strict aseptic conditions, preferably using a laminar flow of filtered sterile air. Systemic antibiotics should be administered at the beginning and conclusion of the operation to eradicate organisms introduced during the procedure that could invade the inner ear during the period of increased vulner- ability when the electrode seal is being established. As a further safeguard the operative wound should be irrigated with an antibiotic solution of ampicillin and 140 3. Surgical Pathology cloxacillin. Although not the first-line antibiotics for the treatment of S. pneu- moniae infections, they have a broad spectrum of activity. In the U.S., of the children who had meningitis, one child with a ventriculoperitoneal shunt devel- oped the infection within a day or two of having the implant, and two with normal cochleae developed it within 24 hours. It is likely that the causal S. pneumoniae could have been introduced into the perilymph and thence the CSF. For this reason irrigation seems warranted. This is especially desirable as unpublished studies by Black and Clark showed that antibiotic concentrations were very low in the peri- lymph of the cat unless the cochlea was infected; furthermore the blood–brain barrier does not allow antibiotics to easily enter the CSF in the uninflammed condition. In children with the Mondini syndrome, special care should be taken as there can be a wide dehiscence between the scala tympani or the scala vestibuli and internal auditory canal. The data in the experimental animal presented in the sections above also demonstrate the necessity of a fascial autograft, which should be placed around the electrode in the cochleostomy. I have experimental unpub- lished data to suggest that if there are gaps between strips of fascia, they could be a passage for pathogens to enter the cochlea. If there is a “perilymph gusher” at surgery, then the fascia will need to be compressed quite firmly. The fascial autograft can be taken from the temporalis fascia. It is not desirable to use crushed muscle, as it can become necrotic and a home for infection. Bone pate´ provides spicules of bone that are not absorbed and may also be a nidus for infection, as may Gelfoam. Furthermore, as stated above, there are serious risks associated with the use of a two-element electrode array. After the tissue around a cochleostomy or the implanted round window has healed, the response to infection appears similar to that of a nonimplanted cochlea. However, certain microorganisms could have a detrimental impact as seen with S. pneumoniae or P. aeruginosa. Improving the seal at the entry point still requires further research with other biocompatible materials and techniques. Deafness and the Central Auditory Pathways Spiral Ganglion With the loss of hair cells there is a rapid and extensive reduction of the unmy- elinated peripheral processes in the organ of Corti (Terayama et al 1977), and a more gradual degeneration of the myelinated portion of the peripheral processes within the spiral lamina as well as the spiral ganglion cells (Webster and Webster 1981; Spoendlin 1984; Leake and Hradek 1988; Shepherd and Javel 1997). Some surviving cells and processes may be demyelinated. These changes as discussed above are due to the loss of trophic factors from the hair cells, and vary according to the type of lesion and animal species. In the human there is better preservation of the spiral ganglion cells over longer periods of time than in other animals, for example, the guinea pig. Otte et al (1978) found 45% of cochleae from profoundly deaf people had at least a third or more of the number of ganglion cells found in Deafness and the Central Auditory Pathways 141 the normal population. In 93 cochleae from profoundly deaf people Nadol et al (1989) found the main spiral ganglion population was half the normal. The loss was greater in older subjects, for longer durations of hearing loss, and in the basal turn. Etiology had the greatest impact and the depletion was most extensive in people with viral labyrinthitis, congenital or genetic deafness, or bacterial men- ingitis. The least extensive loss occurred after aminoglycosides and sudden id- iopathic deafness (Nadol et al 1989; Nadol 1997). The physiological effects of these pathological changes and their impact on electrical stimulation with a co- chlear implant are discussed in Chapter 5. Cochlear Nucleus Pathological changes in the central auditory pathways, as well as in the spiral ganglion, can follow loss of cochlear function. As distinct from spiral ganglion cell loss, occurring at any stage of life, transneuronal degeneration of higher order neurons only develops with the loss of cochlear function at a critical period early in life. Ablation of the cochlea in the experimental animal during a narrow time window near the onset of hearing is the only period when significant cell death is demonstrated in the anteroventral cochlear nucleus (AVCN) (Tierney et al 1997; Mostafapour et al 2000). With cochlear destruction in 6-day-old mice, the co- chlear nucleus (CN) population was reduced to 34% of normal (Trune 1982). The changes were not due solely to ablation of the cochlea, but also to the loss of activity in the auditory nerve. Born and Rubel (1988) found transneuronal cell death and reduction in soma size also occurred when a sodium channel blocker was applied (Pasic and Rubel 1989). These changes could be prevented by elec- trical stimulation of the auditory nerve, but not by direct excitation of the neurons in the CN (Hyson and Rubel 1989; Zirpel and Rubel 1996). They were the result of presynaptic release of the transmitter shown to be glutamate (Zirpel and Rubel 1996). The effects were associated with reduced protein synthesis (Sie and Rubel 1992), and increased intracellular Ca 2ם (Zirpel et al 1995). Mostafapour et al (2000) found evidence that suggested neuronal death was due to the inactivation of an antiapoptotic (anti–cell death) gene bcl-2. Early loss of hearing also led to a significant decrease in the expression of messenger RNA (mRNA)-encoded receptors to glutamate (Marianowski et al 2000). In addition, there was an increase in the expression of receptors to c-aminobutyric acid, a major inhibitor (Mari- anowski et al 2000), as well as a long-term deficiency in glycinergic synaptic inhibition. In mammals the changes were most marked in the CN, but higher order effects could be observed. The significance of these events is not clear, but they presumably affect both place and temporal frequency codes, as discussed in Chapters 5 and 6. It is also unclear when and whether these changes occur in humans. They do, however, suggest the importance of early electrical stimulation of the auditory nerve. If animals are deafened after the onset of hearing, there is no transneuronal degeneration, but a shrinkage in the soma size associated with downregulation of 142 3. Surgical Pathology its metabolism, and a reduction in the neuropil (a complex mesh of terminal axons, dendrites, and neuroglial processes). The reduction in soma size was first dem- onstrated by Powell and Erulkar (1962), who destroyed the cochlea in mature cats, and reported neuronal shrinkage in the CN and superior olivary complex (SOC). In another study, a reduction in soma size by a third occurred within 1 week of the hearing loss (Pasic and Rubel 1989). The deafening had a marked effect on the metabolic activity (Wong-Riley et al 1978; Durham et al 1993). There was also a loss of the neuropil or axon terminals innervating the ventral cochlear nucleus (VCN) (Powell and Erulkar 1962; Trune 1982). This may have been due to a loss of spiral ganglion cells, and a reduction in the number of their axons converging on the AVCN cells. It resulted, too, in an increase in the packing density in the AVCN. Cochlear ablation in adult experimental animals also led to a loss of synapses in the AVCN. This too could be related to the loss of auditory neurons converging on the AVCN cells. This was followed by the generation of synapses over a long period from the remaining afferent input (Benson et al 1997). The loss of hearing also affected the terminal boutons. For example, the end bulbs terminating on the globular bushy cells were smaller as were the end bulbs of Held terminating on spherical bushy cells (Ryugo et al 1997; Redd et al 2000). This effect could have been the result of a downregulation in the metabolism of the remaining spiral ganglion cells. The above changes were accompanied by a temporary reduction in the expression of mRNA receptors to glutamate (Sato et al 2000), the main excitatory neurotransmitter in the auditory pathway. There was also a deficiency in glycinergic synaptic inhibition (Willott et al 1997). As the sensorineural hearing loss led to a loss of the terminal axons and syn- apses on the cells in the AVCN as well as soma size, this would limit the pro- cessing of temporal and place information as discussed in Chapter 5. As these effects were secondary to the loss of spiral ganglion cells it makes it essential to stimulate these cells electrically as soon as possible after deafening to preserve the input to the AVCN. The connections could thus be preserved for improved strategies that may be developed later to provide fine temporal spatial patterns of excitation for the temporal coding of frequency. Chouard et al (1983) found the soma size of octopus cells in the VCN of the guinea pig was preserved with electrical stimulation. In a study by Xu et al (1990), kittens were deafened 37 to 40 days after birth with ototoxic drugs. The animals were stimulated 80 to 90 days after birth on one side. The mean soma areas in the AVCN were significantly greater than the unstimulated control side. There was a weaker trend for the cells to be larger in the posteroventral cochlear nucleus on the stimulated side. Pons and Midbrain A bilateral sensorineural hearing loss at the onset of hearing resulted in a signifi- cant reduction in synaptic density in the central nucleus of the inferior colliculus Deafness and the Central Auditory Pathways 143 (ICC) (Hardie et al 1998). In view of the loss of neurons in the AVCN discussed above, this would lead to a loss of input and synaptic connections at the IC. A unilateral loss, however, did not lead to a loss in density. This was associated with an increase in the proportion of neurons projecting from the ipsilateral side (Nordeen et al 1983; Moore and Kitzes 1985). This suggests that the relative level of neural activity in the pathway from each VCN determines the success of each side in forming or retaining synapses in the auditory midbrain (Moore 1990). A sensorineural loss after the onset of hearing also affected the higher brain centers in the pons and midbrain. There was a reduction in the soma area of neurons in the trapezoid body (Pasic et al 1994), the SOC and nucleus of the lateral lemniscus (Powell and Erulkar 1962), and ICC (Nishiyama et al 2000). Human Brainstem There are few studies on the human central auditory pathways following a pro- found hearing loss. A reduction in the soma area was found in the CN by Clark, Shepherd et al. (1988) Seldon and Clark (1991), and Moore et al (1997), but also in the medial superior olive (MSO) and IC (Moore et al 1997). There was also a reduction in the volume of the CN, especially the VCN, in the studies by Clark, Shepherd et al (1988) and Seldon and Clark (1991). These findings, also discussed in Chapter 4, were essentially consistent with those from experimental animals. The brainstem and temporal bone of the first University of Melbourne/Bionic Ear Institute patient to have a bilateral cochlear implant were also studied (Yu- kawa et al 2001a,b). The sections were compared with those from a second person who had a cochlear implant on one side. The bilateral patient died at the age of 59 years. He went profoundly deaf in the left ear at 31 years due to a head injury, and became profoundly deaf in the right ear at 36 years. At 46 years he had a right cochlear implant and a left cochlear implant at 51 years. Thus the right ear was implanted for 13 years and the left for 8 years. He had only fair speech discrimination with the right implant and satisfactory results with the left. Bin- aural psychophysical studies showed there was a marked reduction in the inter- aural temporal discrimination difference limens for electrical stimulation. It was well below that for normal hearing, as discussed in Chapter 6. The unilateral subject died at the age of 62 years. She suffered a hearing loss due to mumps and then had a 27-year history of a slow progressive loss and had a profound hearing loss for 5 years prior to implantation. She had the implant for 1.5 years in the left ear. The brainstems were sectioned and the MSO analyzed, as it is considered an important nucleus for coding interaural time differences (see Chapter 5). The trigeminal nucleus was also examined as a control for tissue fixation and pro- cessing artifacts. The cell density and volume were determined for each nucleus. Cell numbers and volume were determined by a technique in which a criterion was established to ensure that the cells were not counted twice. The results are shown in the Table 3.1 for cell density and volume, and statis- tical significance was determined with the Mann-Whitney U test. There was a 144 3. Surgical Pathology T ABLE 3.1. The cell density and volume measures for the right and left medial superior olive from one patient with a bilateral and another with a unilateral cochlear implant. Side Cell density (ן10 מ5 /lm 3 ) Mean Bilateral Right 1.23 1.17* Left 1.1 Unilateral Right 2.2 1.96 Left 1.71 *p Ͻ .05, Mann-Whitney U test. Side Cell volume (lm 3 ) Mean Bilateral Right 2241 2005** Left 1693* Unilateral Right 2688 2577 Left 2511* *p Ͻ .05, **p Ͻ .0001, Mann-Whitney U test. significant difference between the bilateral and the unilateral subjects. For the combined right and left sides there was a lower cell density and volume for the bilateral compared with the unilateral subject. This suggests that the MSO was affected by the hearing loss occurring well after the onset of hearing, and this is the reason the patient did not have satisfactory interaural temporal difference limens. It is also of interest that for both patients the cell volume was lower on the left side. This is consistent with the fact that the first patient received more help from the left implant, and the second unilateral patient had a left implant. In both cases there would have been more contralateral stimulation to the right, thus helping to preserve its function. This is consistent with the experimental animal studies showing that electrical stimulation maintains cell viability and size (Miller and Altschuler 1995). Prenatal (Congenital) and Postnatal Hearing Loss Deafness may occur before or during birth (prenatal and perinatal, respectively) when it is referred to as congenital. It can also occur after birth (postnatal). Con- genital deafness may arise from genetic causes, chromosomal abnormalities, or diseases affecting the mother during pregnancy. In about two thirds of children with prelinguistic severe or profound sensorineural deafness without syndromes (before language develops), the cause is thought to be genetic (Morton 1991). Postnatal deafness is mostly from disease or injury, but may also be the result of delayed genetic effects. Genetic and Chromosomal Body cells contain 46 chromosomes, and the genes are located at different points along the chromosomes. In the male the body cell divides into two germ cells; PreNatal (Congenital) and Postnatal Hearing Loss 145 the sperms each contain 23 chromosomes. The same occurs in the female for the ova. When the two germ cells containing 23 chromosomes unite, they form a new cell with 46 chromosomes. Two chromosomes determine the sex of the individual. In the male, one of the two sex chromosomes is small (Y chromosome) and inherited from the father, and the other, the X chromosome, is inherited from the mother. The female has two X chromosomes, one being inherited from the father and one from the mother. The other 22 chromosomes are referred to as autosomes. If a parent passes on a dominant gene causing deafness, it only requires one chromosome of the pair to have the deafness gene for the child to be affected. If it is a recessive gene, the child needs to have one on each chromosome pair. A sex-linked inheritance may occur in the male when the X gene is affected, and thus without protective effects from the Y or male chromosome. Genetic deafness may be classified thus as dominant or recessive. Most genetic deafness presenting congenitally is transmitted as a recessive, and about half those with recessive deafness have no accompanying abnormalities. Congenital, Genetic Deafness Nonsyndromic As stated, genetic deafness frequently occurs alone without other abnormalities (nonsyndromic). In about 80% of children with nonsyndromic deafness, the in- heritance is autosomal recessive (Dahl et al 2001). Using DNA markers, genetic linkage studies have shown over 20 genes for nonsyndromic deafness (Van Camp and Smith 2002). A mutation of the connexin 26 gene has been found to account for up to 50% of cases of nonsyndromic deafness in children of European descent (Maw et al 1995; Denoyelle et al 1997). In addition 50% to 90% of chromosomes on which a connexin 26 mutation has been determined have the same specific mutation (deletion of a guanine nucleotide at position 35, i.e., 35delG) (Denoyelle et al 1997). A similar incidence to the European data was found for a group of Australian deaf children (Dahl et al 2001). Furthermore, over 40 connexin 26 mutations have been reported (Denoyelle et al 1999). On the other hand, the incidence of connexin mutations is very low in Asian-American and African- American populations (Morell et al 1998). Connexin 26 belongs to a family of proteins that mediate the exchange of molecules between adjacent cells. The number refers to the size of the protein in thousands of daltons. Connexin is highly expressed in the cells lining the cochlear duct and the stria vascularis. It is thought that it is important for the recycling of (K ם ) ions from sensory hair cells into the endolymph in the process of transduc- tion of sound to electrical signals. The slope of the hearing loss (over 2000 to 8000 Hz) was greater than in children without connexin 26 mutant alleles (Wilcox et al 2000). It is not known to what extent cochlear implants benefit children with connexin 26 and other genetic disorders. Nonsyndromic deafness has variable anatomical and histological features. First, there may be total lack of development of the inner ear, and the x-ray will show complete absence. It can be difficult to distinguish this condition from bony laby- [...]... 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