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Hirose K, Li SZ, Gill R, Hartsock J. Pneumococcal Meningitis Induces Hearing Loss and Cochlear Ossification Modulated by Chemokine Receptors CX3CR1 and CCR2. J Assoc Res Otolaryngol 2024; 25:179-199. [PMID: 38472515 PMCID: PMC11018586 DOI: 10.1007/s10162-024-00935-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 01/12/2024] [Indexed: 03/14/2024] Open
Abstract
PURPOSE Pneumococcal meningitis is a major cause of hearing loss and permanent neurological impairment despite widely available antimicrobial therapies to control infection. Methods to improve hearing outcomes for those who survive bacterial meningitis remains elusive. We used a mouse model of pneumococcal meningitis to evaluate the impact of mononuclear phagocytes on hearing outcomes and cochlear ossification by altering the expression of CX3CR1 and CCR2 in these infected mice. METHODS We induced pneumococcal meningitis in approximately 500 C57Bl6 adult mice using live Streptococcus pneumoniae (serotype 3, 1 × 105 colony forming units (cfu) in 10 µl) injected directly into the cisterna magna of anesthetized mice and treated these mice with ceftriaxone daily until recovered. We evaluated hearing thresholds over time, characterized the cochlear inflammatory response, and quantified the amount of new bone formation during meningitis recovery. We used microcomputed tomography (microCT) scans to quantify cochlear volume loss caused by neo-ossification. We also performed perilymph sampling in live mice to assess the integrity of the blood-perilymph barrier during various time intervals after meningitis. We then evaluated the effect of CX3CR1 or CCR2 deletion in meningitis symptoms, hearing loss, macrophage/monocyte recruitment, neo-ossification, and blood labyrinth barrier function. RESULTS Sixty percent of mice with pneumococcal meningitis developed hearing loss. Cochlear fibrosis could be detected within 4 days of infection, and neo-ossification by 14 days. Loss of spiral ganglion neurons was common, and inner ear anatomy was distorted by scarring caused by new soft tissue and bone deposited within the scalae. The blood-perilymph barrier was disrupted at 3 days post infection (DPI) and was restored by seven DPI. Both CCR2 and CX3CR1 monocytes and macrophages were present in the cochlea in large numbers after infection. Neither chemokine receptor was necessary for the induction of hearing loss, cochlear fibrosis, ossification, or disruption of the blood-perilymph barrier. CCR2 knockout (KO) mice suffered the most severe hearing loss. CX3CR1 KO mice demonstrated an intermediate phenotype with greater susceptibility to hearing loss compared to control mice. Elimination of CX3CR1 mononuclear phagocytes during the first 2 weeks after meningitis in CX3CR1-DTR transgenic mice did not protect mice from any of the systemic or hearing sequelae of pneumococcal meningitis. CONCLUSIONS Pneumococcal meningitis can have devastating effects on cochlear structure and function, although not all mice experienced hearing loss or cochlear damage. Meningitis can result in rapid progression of hearing loss with fibrosis starting at four DPI and ossification within 2 weeks of infection detectable by light microscopy. The inflammatory response to bacterial meningitis is robust and can affect all three scalae. Our results suggest that CCR2 may assist in controlling infection and maintaining cochlear patency, as CCR2 knockout mice experienced more severe disease, more rapid hearing loss, and more advanced cochlear ossification after pneumococcal meningitis. CX3CR1 also may play an important role in the maintenance of cochlear patency.
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Affiliation(s)
- Keiko Hirose
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8115, St. Louis, MO, 63110, USA.
| | - Song Zhe Li
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8115, St. Louis, MO, 63110, USA
| | - Ruth Gill
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8115, St. Louis, MO, 63110, USA
- Department of Obstetric and Gynecology, Washington University, St. Louis, MO, USA
| | - Jared Hartsock
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8115, St. Louis, MO, 63110, USA
- Turner Scientific, Jacksonville, IL, USA
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Warner JD, Tilak AM, Manickavel S, Walsh E. Cochlear implantation after deafness from Pasteurella multocida meningitis. BMJ Case Rep 2022; 15:e248557. [PMID: 35428666 PMCID: PMC9013994 DOI: 10.1136/bcr-2021-248557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/05/2022] [Indexed: 11/04/2022] Open
Abstract
A woman in her late 40s who works as a veterinary technician represented to the emergency department with increasing headache, confusion, neck stiffness, subjective fevers and distorted hearing 2 days after diagnosis of viral infection at an outside emergency department.Diagnosis of Pasteurella multocida was made from blood cultures and lumbar puncture. Intravenous ceftriaxone was administered for 21 days. By the time of resolution of acute meningitis, she had become completely deaf bilaterally. MRI revealed faint early ossification/possible labyrinthitis ossificans of the basal cochlea, which was confirmed on surgical exploration during the placement of cochlear implants bilaterally 42 days later. We discuss how the atypical features of this infection lead to diagnostic delay and high morbidity, the unique imaging/surgical findings resulting from the infection, and the clinical utility of early and bilateral cochlear implantation in this and similar cases.
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Affiliation(s)
- Jeffrey Dewitt Warner
- Otolaryngology-Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Ashwini Milind Tilak
- Otolaryngology-Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Sudhir Manickavel
- Otolaryngology-Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Erika Walsh
- Otolaryngology-Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
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Yetiser S, Karaman K. Double challenge: cochlear implantation in the only hearing ear with progressive hearing loss following meningitis and vestibular dysfunction after implantation. J Otol 2020; 15:74-76. [PMID: 32440270 PMCID: PMC7231986 DOI: 10.1016/j.joto.2019.11.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 11/07/2019] [Accepted: 11/08/2019] [Indexed: 11/24/2022] Open
Abstract
Objective Vestibular dysfunction associated with cochlear implantation is rare. It is usually seen in patients with otosclerosis due to spread of electrical activity throughout the demineralized bone. A 17-year old female with progressive hearing loss 2 years after meningitis and vestibular dysfunction in the implanted ear is presented in this study. Findings The patient had mild hearing loss in the right ear and total hearing loss on the left side because of complete ossification of the cochlea following meningitis. She had to have cochlear implantation in the right ear because of progression of hearing loss. She had successful implantation but she experienced vestibular dysfunction following activation of cochlear electrodes. Closure of two electrodes caused disruption of auditory programming. Then the patient was subjected to long term vestibular rehabilitation program. Conclusion Timing for implantation before the completion of cochlear ossification is crucial not to miss the chance for hearing restoration. However, difficulties in hearing rehabilitation due to extensive ossification can be doubled by vestibular problems triggered by stimulation of the vestibular nerve by cochlear electrodes. Attempts to reduce the balance problem will complicate auditory programming. Vestibular rehabilitation for long term helps to carry on hearing progress.
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Affiliation(s)
- Sertac Yetiser
- Anadolu Medical Center, Dept of ORL & HNS, Kocaeli, 41400, Turkey
| | - Kutlay Karaman
- Anadolu Medical Center, Dept of Radiology, Kocaeli, 41400, Turkey
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Erni ST, Fernandes G, Buri M, Perny M, Rutten RJ, van Noort JM, Senn P, Grandgirard D, Roccio M, Leib SL. Anti-inflammatory and Oto-Protective Effect of the Small Heat Shock Protein Alpha B-Crystallin (HspB5) in Experimental Pneumococcal Meningitis. Front Neurol 2019; 10:570. [PMID: 31244750 PMCID: PMC6573805 DOI: 10.3389/fneur.2019.00570] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 05/15/2019] [Indexed: 12/18/2022] Open
Abstract
Sensorineural hearing loss is the most common long-term deficit after pneumococcal meningitis (PM), occurring in up to 30% of surviving patients. The infection and the following overshooting inflammatory host response damage the vulnerable sensory cells of the inner ear, resulting in loss of hair cells and spiral ganglion neurons, ultimately leading to elevated hearing thresholds. Here, we tested the oto-protective properties of the small heat shock protein alpha B-crystallin (HspB5) with previously reported anti-inflammatory, anti-apoptotic and neuroprotective functions, in an experimental model of PM-induced hearing loss. We analyzed the effect of local and systemic delivery of HspB5 in an infant rat model of PM, as well as ex vivo, using whole mount cultures. Cytokine secretion profile, hearing thresholds and inner ear damage were assessed at predefined stages of the disease up to 1 month after infection. PM was accompanied by elevated pro-inflammatory cytokine concentrations in the cerebrospinal fluid (CSF), leukocyte and neutrophil infiltration in the perilymphatic spaces of the cochlea with neutrophils extracellular trap formation during the acute phase of the disease. Elevated hearing thresholds were measured after recovery from meningitis. Intracisternal but not intraperitoneal administration of HspB5 significantly reduced the levels of TNF-α, IL-6 IFN-γ and IL-10 in the acute phase of the disease. This resulted in a greater outer hair cell survival, as well as improved hearing thresholds at later stages. These results suggest that high local concentrations of HspB5 are needed to prevent inner ear damage in acute PM. HspB5 represents a promising therapeutic option to improve the auditory outcome and counteract hearing loss after PM.
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Affiliation(s)
- Silvia T Erni
- Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.,Cluster for Regenerative Neuroscience, DBMR, University of Bern, Bern, Switzerland.,Laboratory of Inner Ear Research, DBMR, University of Bern, Bern, Switzerland.,Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Gabriella Fernandes
- Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.,Cluster for Regenerative Neuroscience, DBMR, University of Bern, Bern, Switzerland.,Laboratory of Inner Ear Research, DBMR, University of Bern, Bern, Switzerland
| | - Michelle Buri
- Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.,Cluster for Regenerative Neuroscience, DBMR, University of Bern, Bern, Switzerland
| | - Michael Perny
- Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.,Cluster for Regenerative Neuroscience, DBMR, University of Bern, Bern, Switzerland.,Laboratory of Inner Ear Research, DBMR, University of Bern, Bern, Switzerland
| | | | | | - Pascal Senn
- Service d'oto-rhino-laryngologie (ORL) et de chirurgie cervico-faciale, Département des Neurosciences Cliniques, Hôpitaux Universitaires de Genève, Geneva, Switzerland
| | - Denis Grandgirard
- Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.,Cluster for Regenerative Neuroscience, DBMR, University of Bern, Bern, Switzerland
| | - Marta Roccio
- Cluster for Regenerative Neuroscience, DBMR, University of Bern, Bern, Switzerland.,Laboratory of Inner Ear Research, DBMR, University of Bern, Bern, Switzerland.,Department of Otorhinolaryngology, Head & Neck Surgery, Inselspital, Bern, Switzerland
| | - Stephen L Leib
- Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.,Cluster for Regenerative Neuroscience, DBMR, University of Bern, Bern, Switzerland
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Perny M, Solyga M, Grandgirard D, Roccio M, Leib SL, Senn P. Streptococcus pneumoniae-induced ototoxicity in organ of Corti explant cultures. Hear Res 2017; 350:100-109. [PMID: 28460251 DOI: 10.1016/j.heares.2017.04.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 04/11/2017] [Accepted: 04/23/2017] [Indexed: 12/20/2022]
Abstract
Hearing loss remains the most common long-term complication of pneumococcal meningitis (PM) reported in up to 30% of survivors. Streptococcus pneumoniae have been shown to possess different ototoxic properties. Here we present a novel ex vivo experimental setup to examine in detail the pattern of hair cell loss upon exposure to different S. pneumoniae strains, therefore recapitulating pathogen derived aspects of PM-induced hearing loss. Our results show a higher susceptibility towards S. pneumoniae-induced cochlear damage for outer hair cells (OHC) compared to inner hair cells (IHC), which is consistent with in vivo data. S. pneumoniae-induced hair cell loss was both time and dose-dependent. Moreover, we have found significant differences in the level of cell damage between tissue from the basal and the apical turns. This shows that the higher vulnerability of hair cells located at high frequency regions observed in vivo cannot be explained solely by the spatial organisation and bacterial infiltration from the basal portion of the cochlea. Using a wild type D39 strain and a mutant defective for the pneumolysin (PLY) gene, we also have shown that the toxin PLY is an important factor involved in ototoxic damages. The obtained results indicate that PLY can cause both IHC and OHC loss. Finally, we are reporting here for the first time a higher vulnerability of HC located at the basal and middle cochlear region to pneumolysin-induced damage. The detailed description of the susceptibility of hair cells to Streptococcus pneumoniae provided in this report can in the future determine the choice and the development of novel otoprotective therapies during pneumococcal meningitis.
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Affiliation(s)
- Michael Perny
- Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Switzerland; Inner Ear Research Laboratory, Department of Otorhinolaryngology, Head& Neck Surgery, Inselspital Bern and Department of Clinical Research, University of Bern, Switzerland; Cluster for Regenerative Neuroscience, Department of Clinical Research, University of Bern, Switzerland
| | - Magdalena Solyga
- Inner Ear Research Laboratory, Department of Otorhinolaryngology, Head& Neck Surgery, Inselspital Bern and Department of Clinical Research, University of Bern, Switzerland; Cluster for Regenerative Neuroscience, Department of Clinical Research, University of Bern, Switzerland
| | - Denis Grandgirard
- Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Switzerland; Cluster for Regenerative Neuroscience, Department of Clinical Research, University of Bern, Switzerland
| | - Marta Roccio
- Inner Ear Research Laboratory, Department of Otorhinolaryngology, Head& Neck Surgery, Inselspital Bern and Department of Clinical Research, University of Bern, Switzerland; Cluster for Regenerative Neuroscience, Department of Clinical Research, University of Bern, Switzerland
| | - Stephen L Leib
- Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Switzerland; Cluster for Regenerative Neuroscience, Department of Clinical Research, University of Bern, Switzerland.
| | - Pascal Senn
- Inner Ear Research Laboratory, Department of Otorhinolaryngology, Head& Neck Surgery, Inselspital Bern and Department of Clinical Research, University of Bern, Switzerland; Department of Otorhinolaryngology, Head & Neck Surgery, University Hospital Geneva (HUG), Genève, Switzerland; Cluster for Regenerative Neuroscience, Department of Clinical Research, University of Bern, Switzerland.
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Ge NN, Brodie SA, Tinling SP, Brodie HA. The Effects of Superoxide Dismutase in Gerbils with Bacterial Meningitis. Otolaryngol Head Neck Surg 2016; 131:563-72. [PMID: 15523427 DOI: 10.1016/j.otohns.2004.03.046] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
BACKGROUND: Inflammatory products, such as oxygen radicals generated during the course of bacterial meningitis, can damage nerve endings, hair cells, and/or supporting cells in the cochlea. Superoxide dismutase (SOD), an O2-scavenger, has been shown to play an important role in the protection against radical toxicity in various animal experiments. OBJECTIVE: To study the antioxidant effects of SOD on the inflammatory response of gerbils with bacterial meningitis. STUDY DESIGN: Meningitis was induced in three groups of 10 gerbils by intrathecal (IT) injection of Streptococcus pneumoniae into the cisterna magna. Group 1 received IT SOD, group 2 received intramuscular (IM) SOD, and group 3, the control group, received IM normal saline. Histologic data and auditory brainstem responses (ABR) were obtained from each gerbil. RESULTS: Fibrosis and/or neo-ossification were near absent in the IT SOD group and significantly less fibrosis occurred in the IM group (IT vs. IM: P = 0.010; IT vs. control group: P = 0.001). The amount of surviving spiral ganglion cells correlated inversely with the extent of fibrosis (r = −0.753, P < 0.00001). CONCLUSIONS: IT injection of SOD significantly reduced cochlear fibrosis and neo-ossification, reduced the spiral ganglion cell loss, and decreased damage of the cochlear components following bacterial meningitis.
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MESH Headings
- Animals
- Anti-Inflammatory Agents/therapeutic use
- Evoked Potentials, Auditory, Brain Stem
- Fibrosis/etiology
- Fibrosis/prevention & control
- Free Radical Scavengers/administration & dosage
- Gerbillinae
- Hearing Loss, Sensorineural/etiology
- Hearing Loss, Sensorineural/physiopathology
- Hearing Loss, Sensorineural/prevention & control
- Inflammation/etiology
- Inflammation/prevention & control
- Injections, Intramuscular
- Injections, Spinal
- Labyrinth Diseases/drug therapy
- Labyrinth Diseases/etiology
- Labyrinth Diseases/pathology
- Labyrinth Diseases/prevention & control
- Male
- Meningitis, Bacterial/drug therapy
- Meningitis, Bacterial/microbiology
- Models, Animal
- Ossification, Heterotopic/etiology
- Ossification, Heterotopic/prevention & control
- Reactive Oxygen Species/adverse effects
- Streptococcal Infections/complications
- Streptococcal Infections/drug therapy
- Superoxide Dismutase/administration & dosage
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Affiliation(s)
- Norman N Ge
- Department of Otolaryngology-Head and Neck Surgery, University of California, Davis Medical Center, Davis, CA 98517, USA
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7
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Tan WJT, Thorne PR, Vlajkovic SM. Noise-induced cochlear inflammation. World J Otorhinolaryngol 2013; 3:89-99. [DOI: 10.5319/wjo.v3.i3.89] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Revised: 08/08/2013] [Accepted: 08/20/2013] [Indexed: 02/06/2023] Open
Abstract
Hearing loss is the most common sensory disability with considerable social and economic implications. According to recent World Health Organization estimates, 360 million people worldwide suffer from moderate to profound hearing loss. Exposure to excessive noise is one of the major causes of sensorineural hearing loss, secondary only to age-related hearing loss (presbyacusis). Since cochlear tissues have limited abilities of repair and regeneration, this damage can be irreversible, leading to cochlear dysfunction and permanent hearing loss. Recent studies have shown that cochlear inflammation can be induced by noise exposure and contribute to the overall pathogenesis of cochlear injury and hearing loss. The cochlea is separated from the systemic circulation by the blood-labyrinth barrier, which is physiologically similar to the blood-brain barrier of the central nervous system. Because of this feature, the cochlea was originally considered an immunologically privileged organ. However, this postulate has been challenged by the evidence of an inflammatory response in the cochlea in the presence of bacterial or viral pathogens or antigens that can cause labyrinthitis. Although the main purpose of the inflammatory reaction is to protect against invading pathogens, the inflammatory response can also cause significant bystander injury to the delicate structures of the cochlea. The cochlear inflammatory response is characterised by the generation of proinflammatory mediators (cytokines, chemokines and adhesion molecules), and the recruitment of inflammatory cells (leukocytes). Here, we present an overview of the current research on cochlear inflammation, with particular emphasis on noise-induced cochlear inflammation. We also discuss treatment strategies aimed at the suppression of inflammation, which may potentially lead to mitigation of hearing loss.
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8
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Teissier N, Doehring I, Noel-Petroff N, Elmaleh-Bergès M, Viala P, François M, Faye A, Van Den Abbeele T, Lorrot M. Implants cochléaires dans les surdités après méningite bactérienne : suivi audiologique de 16 enfants. Arch Pediatr 2013; 20:616-23. [DOI: 10.1016/j.arcped.2013.03.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2012] [Revised: 01/26/2013] [Accepted: 03/10/2013] [Indexed: 10/26/2022]
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Demel C, Hoegen T, Giese A, Angele B, Pfister HW, Koedel U, Klein M. Reduced spiral ganglion neuronal loss by adjunctive neurotrophin-3 in experimental pneumococcal meningitis. J Neuroinflammation 2011; 8:7. [PMID: 21261959 PMCID: PMC3038911 DOI: 10.1186/1742-2094-8-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2010] [Accepted: 01/24/2011] [Indexed: 12/20/2022] Open
Abstract
Background Hearing loss is a frequent long-term complication of pneumococcal meningitis (PM). Its main pathological correlate is damage to the organ of Corti and loss of spiral ganglion neurons. The only current treatment option is cochlear implants which require surviving neurons. Here, we investigated the impact of systemically applied neurotrophin-3 (NT-3) on long-term hearing loss and the survival of neurons. Methods Eighteen hours after infection with S. pneumoniae, C57BL/6 mice were treated with a combination of ceftriaxone with NT-3 or dexamethasone or placebo. Hearing, cochlear damage, and brain damage were assessed by audiometry and histology. Results The main findings from immunohistochemical visualization of neurotrophins (NT-3, BDNF) and their receptors (TrkB, TrkC, and p75) in the cochlea were (i) enhanced staining for the cell survival-promoting receptor TrkB and (ii) increased NT-3 staining in NT-3 treated mice, showing that systemically applied NT-3 reaches the cochlea. The major effects of adjunctive NT-3 treatment were (i) a reduction of meningitis-induced hearing impairment and (ii) a reduction of spiral ganglion neuronal loss. The efficacy of NT-3 therapy was comparable to that of dexamethasone. Conclusion Systemically applied NT-3 might be an interesting candidate to improve hearing outcome after pneumococcal meningitis.
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Affiliation(s)
- Cornelia Demel
- Department of Neurology, Klinikum Grosshadern, Ludwig Maximilians University Munich, Marchioninistrasse 15, 81377 Munich, Germany
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Intratympanic Steroid Prevents Long-Term Spiral Ganglion Neuron Loss in Experimental Meningitis. Otol Neurotol 2010; 31:394-403. [DOI: 10.1097/mao.0b013e3181d2796c] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Stocco C, Leite MDL, Labiak VB, Virgens Filho JSD, Nascimento É. Influência de variáveis climáticas sobre a incidência de meningite e sua distribuição espacial no município de Ponta Grossa - PR, 2001-2005. SAUDE E SOCIEDADE 2010. [DOI: 10.1590/s0104-12902010000100007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Os elementos climáticos têm destacada influência sobre a manifestação de muitas doenças nos seres humanos. Assim, o objetivo deste estudo foi avaliar a influência de variáveis climáticas locais sobre a incidência mensal de meningite no Município de Ponta Grossa, Paraná, no período de 2001 a 2005, assim como distribuir espacialmente sua ocorrência na área urbana. A amostra inicial foi composta de 401 casos notificados e confirmados de indivíduos residentes nesse município. Verificou-se forte correlação entre a incidência média mensal de meningite e as variáveis climáticas temperatura média do ar, precipitação pluviométrica e umidade relativa do ar na maioria dos meses. A distribuição espacial dos casos em estudo revelou maior concentração nas porções centro-oeste e centro-norte da cidade.
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Sellner J, Täuber MG, Leib SL. Pathogenesis and pathophysiology of bacterial CNS infections. HANDBOOK OF CLINICAL NEUROLOGY 2010; 96:1-16. [PMID: 20109671 DOI: 10.1016/s0072-9752(09)96001-8] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Johann Sellner
- Department of Neurology, Technische Universität München, Germany
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Allegro J, Papsin BC, Harrison RV, Campisi P. Acoustic analysis of voice in cochlear implant recipients with post-meningitic hearing loss. Cochlear Implants Int 2009; 11:100-16. [PMID: 19810023 DOI: 10.1002/cii.417] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
The objective of this study was to evaluate the critical time period between the onset of sensorineural hearing loss and cochlear implantation with respect to normal voice production in children with post-meningitic hearing loss. Acoustic measures of voice production were obtained from ten paediatric cochlear implant recipients with post-meningitic hearing loss. Acoustic measures were obtained utilising the Multi-Dimensional Voice Program and Computerized Speech Laboratory (Kay Elemetrics Corp.). Measures were based on sustained phonation of the vowel /a/. Acoustic parameters included fundamental frequency, short- and long-term frequency perturbation, and short- and long-term amplitude perturbation. Measures of fundamental frequency and short-term frequency and amplitude perturbation were comparable to values of children with normal hearing. Long-term control of frequency was within normal limits for subjects with a period of auditory deprivation of less than four months. Measures of long-term amplitude perturbation were normal for all patients except those with cochlear ossification. Early restoration of auditory feedback with cochlear implantation, the absence of cochlear ossification, residual aided hearing following meningitis, and auditory-verbal therapy were identified as factors in preserving the long-term control of frequency and amplitude in the setting of post-meningitic hearing loss.
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Affiliation(s)
- J Allegro
- Centre for Paediatric Voice and Laryngeal Function and Department of Communication Disorders, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
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Cayé-Thomasen P, Worsøe L, Brandt CT, Miyazaki H, Ostergaard C, Frimodt-Møller N, Thomsen J. Routes, dynamics, and correlates of cochlear inflammation in terminal and recovering experimental meningitis. Laryngoscope 2009; 119:1560-70. [PMID: 19504554 DOI: 10.1002/lary.20260] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
OBJECTIVES/HYPOTHESIS To examine the routes, dynamics and correlates of cochlear inflammation in meningitis to provide information on the pathogenesis of the associated hearing loss and indications for rational pharmacotherapeutical intervention. STUDY DESIGN A well-established rat model of Streptococcus pneumoniae meningitis was employed. METHODS Eight rats were inoculated intrathecally and not treated, whereas 26 were inoculated and treated with ceftriaxone. Six rats were sham-inoculated, making a total of 40 rats. The rats were sacrificed when reaching terminal illness or after 7 days, followed by light microscopy. Routes of cochlear inflammatory infiltration were examined. The volume fraction of inflammatory infiltration was estimated and correlated to bacterial and leukocyte counts in cerebrospinal fluid (CSF) and blood. RESULTS The perilymphatic space was infiltrated with inflammatory cells via cochlear aqueduct, whereas the endolymphatic space was infiltrated from the spiral ligament. Rosenthal's canal was infiltrated through osseous spiral lamina canaliculi. In the untreated group, the degree of inflammation correlated with time of death, whereas antibiotic treatment reversed this development. Perilymphatic inflammation correlated significantly with the CSF leukocyte count, whereas endolymphatic inflammation correlated with spiral ligament inflammation. CONCLUSIONS Meningogenic inflammation of the rat cochlea occurs via the cochlear aqueduct and the spiral ligament capillary bed. The spiral ganglion is infiltrated through the osseous spiral lamina. The degree of inflammation correlates positively with time of death in untreated meningitis, whereas antibiotic treatment leads to subsiding infiltration during recovery.
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Affiliation(s)
- Per Cayé-Thomasen
- Department of Otorhinolaryngology, Head and Neck Surgery, Copenhagen University Hospital Gentofte, Denmark.
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des Portes V. Quel suivi à long terme pour quels patients ? Séquelles des méningites bactériennes chez l’enfant et chez l’adulte : incidence, types, modes d’évaluation. Med Mal Infect 2009; 39:572-80. [DOI: 10.1016/j.medmal.2009.02.019] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2009] [Accepted: 02/20/2009] [Indexed: 11/29/2022]
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16
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Wolff M, Decazes JM. [Degree of emergency for antibiotherapy in patients with presumed bacterial meningitis: experimental and clinical data]. Med Mal Infect 2009; 39:493-8. [PMID: 19403252 DOI: 10.1016/j.medmal.2009.02.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2009] [Accepted: 02/20/2009] [Indexed: 10/20/2022]
Abstract
No prospective randomized clinical studies are available to determine exactly how much time should be spent on investigation before initiating antibiotherapy in a patient with presumed bacterial meningitis. Experimental models show that antibiotics should be administered before the inflammatory response, but at this time the patient's symptoms are often unspecific. Models also demonstrate that a gain of time is beneficial at any time, in terms of inflammation, magnitude of bacteremia, or loss of hearing. Very few clinical studies address the acceptable delay between admission and administration of antibiotics and two of these show a correlation with outcome in adult meningitis. The available data supports the recommendation that hospital investigation of a patient with presumed bacterial meningitis should be conducted in such a way that efficient antimicrobial chemotherapy will be initiated within one hour after arrival.
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Affiliation(s)
- M Wolff
- Service de réanimation médicale et des maladies infectieuses, hôpital Bichat - Claude-Bernard, 46, rue Henri-Huchard, 75018 Paris, France.
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Beijen J, Casselman J, Joosten F, Stover T, Aschendorff A, Zarowski A, Becker H, Mylanus E. Magnetic resonance imaging in patients with meningitis induced hearing loss. Eur Arch Otorhinolaryngol 2009; 266:1229-36. [PMID: 19221779 PMCID: PMC2704951 DOI: 10.1007/s00405-009-0921-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2008] [Accepted: 01/26/2009] [Indexed: 11/25/2022]
Abstract
The aim of this multicentre study was to compare T1 with T2 weighted MRI scans of the labyrinth after meningitis and to investigate whether waiting with scanning improved the reliability of diagnosing an ongoing process such as cochlear osteogenesis. Forty-five patients were included who suffered from meningitis induced hearing loss (radiological imaging <1 year after meningitis). Twenty-one gadolinium enhanced T1 and 45 T2 weighted MRI scans were scored by two radiologists regarding the condition of the labyrinth. These radiological observations were compared with the condition of the cochlea as described during cochlear implantation. A higher percentage of agreement with surgery was found for T2 (both radiologists 73%) than for T1 weighted MRI scans (radiologist 1: 62%, radiologist 2: 67%), but this difference is not significant. There was no significant difference between early (0–3 months) and late (>3 months) scanning, showing that radiological imaging soon after meningitis allows early diagnosis without suffering from a lower agreement with surgical findings.
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Affiliation(s)
- J Beijen
- Department of Otorhinolaryngology, Radboud University Medical Centre, Nijmegen, The Netherlands.
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Long-Term Hearing Loss in Gerbils With Bacterial Meningitis Treated With Superoxide Dismutase. Otol Neurotol 2008; 29:1061-7. [DOI: 10.1097/mao.0b013e31818b6479] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Nitrogen and oxygen molecules in meningitis-associated labyrinthitis and hearing impairment. Infection 2007; 36:2-14. [PMID: 18084715 DOI: 10.1007/s15010-007-7153-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2007] [Accepted: 09/12/2007] [Indexed: 12/16/2022]
Abstract
Pneumococcal meningitis remains a serious disease with a case fatality rate of 15%-25%. Furthermore, long-term residues affect up to 50% of survivors. One of the most frequent sequelae is sensorineural hearing loss, which occurs in 26% of survivors of pneumococcal meningitis. Unfortunately, sufficient treatment regimens are still missing. New insights into the pathology and pathophysiology of meningitis-associated hearing loss have come from animal models of bacterial meningitis. Most likely, bacteria reach the cochlea through the cochlear aquaeduct. Once arrived in the perilymphatic spaces, they induce a severe suppurative labyrinthitis. The blood-labyrinth barrier breaks, hair cells are damaged, and neurons in the spiral ganglion undergo cell death, leading to meningitis-associated hearing loss. Reactive oxygen and nitrogen species, in particular peroxynitrite, seem to be among the crucial mediators of cochlear damage and hearing loss during meningitis. In our rat model of pneumococcal meningitis, adjunctive therapy with the antioxidants and peroxynitrite scavengers Mn(III)tetrakis(4-bencoic acid)-porphyrin (MnTBAP) and N-Acetyl-L-Cystein (NAC) significantly attenuated acute and long-term hearing loss. In several other animal studies of pneumococcal meningitis, adjunctive antioxidant therapy also protected infected animals from intracranial complications. Therefore, the use of antioxidants seems to be a promising future treatment option in pneumococcal meningitis.
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20
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Franco-Vidal V, Beurg M, Darrouzet V, Bébéar JP, Skinner LJ, Dulon D. Zinc protection against pneumolysin toxicity on rat cochlear hair cells. Audiol Neurootol 2007; 13:65-70. [PMID: 17890859 DOI: 10.1159/000108763] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2007] [Accepted: 07/04/2007] [Indexed: 11/19/2022] Open
Abstract
Streptococcus pneumoniae can induce local and systemic diseases such as meningitis, otitis media, and pneumonia. One third of these meningitis cases can be associated with irreversible sensorineural hearing loss whose mechanisms likely involves the exotoxin pneumolysin (PLY) that irreversibly damages cochlear hair cells (HCs). In the respiratory system and in neuron it has been demonstrated that zinc deficiency increases severity and mortality of such infections in animal models and in children. Moreover, zinc supplementation can decrease the severity of pneumococcal respiratory infections. The aim of our study was to assess the potential protective effect of zinc against PLY toxicity on HCs in culture. Our results showed that in the presence of zinc at concentration as low as 1 microM, the toxicity of PLY was largely reduced by about 50% for both inner and outer HCs. At 300 microM of zinc, protection significantly increased with 62 and 55.2% for IHCs and OHCs, respectively. Our results suggest that the protective effect of zinc is likely due to an inhibition of the toxin incorporation and aggregation into the plasma membrane, thus preventing calcium influx through the toxin pores. Our findings raise the possibility that treatments with zinc may help to prevent debilitating otological sequelae from pneumococcal infection.
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Affiliation(s)
- Valérie Franco-Vidal
- Otolaryngology and Skull Base Surgery Department, University of Bordeaux 2 Victor Segalen, Bordeaux, France.
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Wei BPC, Shepherd RK, Robins-Browne RM, Clark GM, O'Leary SJ. Pneumococcal meningitis: development of a new animal model. Otol Neurotol 2007; 27:844-54. [PMID: 16936571 PMCID: PMC1839842 DOI: 10.1097/01.mao.0000231603.25961.f1] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
HYPOTHESIS The rat is a suitable animal to establish a model for the study of pneumococcal meningitis postcochlear implantation. BACKGROUND There has been an increase in the number of cases of cochlear implant-related meningitis. The most common organism identified was Streptococcus pneumoniae. Whether cochlear implantation increases the risk of pneumococcal meningitis in healthy subjects without other risk factors remains to be determined. Previous animal studies do not focus on the pathogenesis and risk of pneumococcal meningitis postimplantation and are based on relatively small animal numbers, making it difficult to assess the cause-and-effect relationship. There is, therefore, a need to develop a new animal model allowing direct examination of the pathogenesis of meningitis in the presence of a cochlear implant. METHODS Eighteen nonimplanted rats were infected with 1 x 10 and 1 x 10 colony-forming units (CFU) of a clinical isolate of S. pneumoniae via three different inoculation routes (middle ear, inner ear, and i.p.) to examine for evidence of meningitis during 24 hours. Six implanted rats were infected with the highest amount of bacteria possible for each route of inoculation (4 x 10 CFU i.p., 3 x 10 CFU middle ear, and 1 x 10 CFU inner ear) to examine for evidence of meningitis with the presence of an implant. The histological pattern of cochlear infections for each of the three different inoculating routes were examined. RESULTS Pneumococcal meningitis was evident in all 6 implanted animals for each of the three different routes of inoculation. Once in the inner ear, bacteria were found to enter the central nervous system via either the cochlear aqueduct or canaliculi perforantes of the osseous spiral lamina, reaching the perineural and perivascular space then the internal acoustic meatus. The rate, extent, and pattern of infection within the cochleae depended on the route of inoculation. Finally, there was no evidence of pneumococcal meningitis observed in 18 nonimplanted rats inoculated at a lower concentration of S. pneumoniae when observed for 24 hours postinoculation. CONCLUSION Meningitis in implanted rats after inoculation with a clinical isolate of S. pneumoniae is possible via all three potential routes of infection via the upper respiratory tract. The lack of meningitis observed in the 18 nonimplanted rats suggests that longer postinoculation monitoring periods are required to ensure whether or not meningitis will develop. Based on this work, we have developed a new animal model that will allow quantitative risk assessment of meningitis postcochlear implantation, and the assessment of the efficacy of potential interventional strategies in future studies.
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Affiliation(s)
- Benjamin P C Wei
- Bionic Ear Institute, Department of Otolaryngology, University of Melbourne, Royal Victorian Eye & Ear Hospital, Melbourne, Victoria, Australia.
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Kim HH, Addison J, Suh E, Trune DR, Richter CP. Otoprotective Effects of Dexamethasone in the Management of Pneumococcal Meningitis: an Animal Study. Laryngoscope 2007; 117:1209-15. [PMID: 17603319 DOI: 10.1097/mlg.0b013e318058195f] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE To determine whether treating pneumococcal meningitis with a combined antibiotic and steroid regime will prevent cochlear damage, a common pneumococcal meningitis side effect. STUDY DESIGN Prospective animal study. METHODS Gerbils were randomly assigned to three experimental groups. Animals in group 1 received intrathecal saline injections. Animals in groups 2 and 3 received intrathecal injections of Streptococcus pneumoniae to induce meningitis. Group 2 was treated for 7 days with intraperitoneal penicillin injections (48,000 units). Animals from group 3 received intraperitoneal dexamethasone (0.5 mg/kg) injections for 4 days in addition to 7 days of intraperitoneal penicillin. Three months after the meningitis was induced, the animals' cochlear functions were determined using auditory brainstem responses (ABRs). After measuring cochlear function, the animals were sacrificed for cochlear histopathology. Spiral ganglion cell densities at Rosenthal's canal were determined. RESULTS ABR thresholds were significantly elevated in animals from group 2 when compared with the animals in groups 1 and 3 (P < .05). ABR thresholds for animals from group 3 and group 1 were similar (P > .05). Damage of cochlear structures was detected in animals from group 2. The degree of the damage varied: one animal in group 2 had no identifiable hair cells and pillar cells and showed damage of the tectorial membrane. Spiral ganglion density in the basal turn was significantly less in animals from group 2 when compared with controls (P < .05). Although spiral ganglion cell density was less in the dexamethasone-treated group (group 3) when compared with group 1 (control group), but greater than observed in animals treated with antibiotics only (group 2), the differences were statistically not significant (P > .5). Nuclear diameters of the spiral ganglion cells decreased on average from 7.24 +/- 0.48 microm (group 1) to 6.28 +/- 0.76 microm (group 3, animals that received dexamethasone) to 5.57 +/- 0.82 microm (group 2, animals that received antibiotics only). Differences were significant (P < .05). Differences in stria vascularis thickness were not significant among the animals. CONCLUSION Dexamethasone has a protective effect on the cochlea when given together with antibiotics in the treatment of pneumococcal meningitis.
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Brandt CT, Cayé-Thomasen P, Lund SP, Worsøe L, Ostergaard C, Frimodt-Møller N, Espersen F, Thomsen J, Lundgren JD. Hearing loss and cochlear damage in experimental pneumococcal meningitis, with special reference to the role of neutrophil granulocytes. Neurobiol Dis 2006; 23:300-11. [PMID: 16798006 DOI: 10.1016/j.nbd.2006.03.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2005] [Revised: 03/03/2006] [Accepted: 03/10/2006] [Indexed: 11/21/2022] Open
Abstract
Hearing loss is a well-known sequelae from meningitis, affecting up to 25% of survivors. However, the principal components of the infectious and inflammatory reaction responsible for the sensorineural hearing loss remain to be identified. The present study aimed to investigate the impact of an augmented neutrophil response on the development of hearing loss and cochlear damage in a model of experimental pneumococcal meningitis in rats. Hearing loss and cochlear damage were assessed by distortion product oto-acoustic emissions (DPOAE), auditory brainstem response (ABR) and histopathology in rats treated with ceftriaxone 28 h after infection. Rats were treated with Granulocyte Colony Stimulating Factor (G-CSF) initiated prior to infection, 28 h after infection or with ceftriaxone only. Rats were followed for 7 days, and assessment of hearing was performed before infection and 24 h and day 8 after infection. Pretreatment with G-CSF increased hearing loss 24 h after infection and on day 8 compared to untreated rats (Mann-Whitney, P = 0.012 and P = 0.013 respectively). The increased sensorineural hearing loss at day 8 was associated with significantly decreased spiral ganglion cell counts (P = 0.0006), increased damage to the organ of Corti (P = 0.007), increased areas of inflammatory infiltrates (P = 0.02) and increased white blood cell (WBC) counts in cerebrospinal fluid on day 8 after infection (P = 0.0084). Initiation of G-CSF 28 h after infection did not significantly affect hearing loss or cochlear pathology compared to controls. In conclusion, the inflammatory host reaction contributes significantly to the development of hearing loss in experimental meningitis.
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Affiliation(s)
- C T Brandt
- National Center for Antimicrobials and Infection Control, Division of Microbiology, Statens Serum Institut, Copenhagen, Denmark.
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Klein M, Koedel U, Pfister H, Kastenbauer S. Morphological correlates of acute and permanent hearing loss during experimental pneumococcal meningitis. Brain Pathol 2006; 13:123-32. [PMID: 12744466 PMCID: PMC8095810 DOI: 10.1111/j.1750-3639.2003.tb00012.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
In patients with acute bacterial meningitis, hearing loss can be transient but is often permanent. The mechanisms underlying meningitis-associated hearing loss are not fully understood. Therefore, we investigated the morphological correlates of hearing loss in a rat model of pneumococcal meningitis. Transcutaneous intracisternal injection of Streptococcus pneumoniae resulted in a dose-dependent hearing loss (determined by auditory brainstem response audiometry), which was partially reversible during the acute stage. Nevertheless, a severe permanent hearing loss persisted until 2 weeks after infection. Suppurative labyrinthitis was accompanied by blood-labyrinth barrier disruption (determined by cochlear Evans blue extravasation), which correlated closely with hearing loss during the acute stage but not after recovery. Two weeks after infection, spiral ganglion neuronal density was markedly decreased and correlated with the severity of permanent hearing loss. Neuronal loss can be explained by the new finding of meningitis-associated spiral ganglion neuronal necrosis rather than apoptosis (determined by morphology, TUNEL staining, and immunohistochemistry).
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Affiliation(s)
- Matthias Klein
- Department of Neurology, Klinikum Grosshadern, Ludwig‐Maximilians‐University, Munich, Germany
| | - Uwe Koedel
- Department of Neurology, Klinikum Grosshadern, Ludwig‐Maximilians‐University, Munich, Germany
| | - Hans‐Walter Pfister
- Department of Neurology, Klinikum Grosshadern, Ludwig‐Maximilians‐University, Munich, Germany
| | - Stefan Kastenbauer
- Department of Neurology, Klinikum Grosshadern, Ludwig‐Maximilians‐University, Munich, Germany
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Abstract
PURPOSE OF REVIEW The mortality of bacterial meningitis can reach 30%, and up to 50% of survivors suffer from persisting neurological deficits as a consequence of the disease. The incidence of neurological sequelae of bacterial meningitis has not improved over the last decade. Adjunctive therapeutic options are limited, and ongoing research into the pathophysiology of brain damage in bacterial meningitis aims at providing the scientific basis for future development of more efficient adjunctive options. RECENT FINDINGS In a population with good access to health care, dexamethasone given before or at the time of initiation of antibiotic therapy acts beneficially in paediatric pneumococcal meningitis, but not in meningococcal meningitis. In experimental animal models, brain-derived neurotrophic factor protected against brain injury and improved hearing while melatonin, which has antioxidant properties among other effects, reduced neuronal death. Transgene technology can be used to provide new insights into the pathophysiology of the disease and to identify potential therapeutic targets. SUMMARY Although dexamethasone improves outcome of bacterial meningitis under defined circumstances, the morbidity of bacterial meningitis still remains unacceptably high. Experimental models may help to identify new therapeutic strategies to further improve the neurological outcome in young children suffering from bacterial meningitis.
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Beurg M, Hafidi A, Skinner L, Cowan G, Hondarrague Y, Mitchell TJ, Dulon D. The mechanism of pneumolysin-induced cochlear hair cell death in the rat. J Physiol 2005; 568:211-27. [PMID: 16051626 PMCID: PMC1474774 DOI: 10.1113/jphysiol.2005.092478] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Streptoccocus pneumoniae infection can result in local and systemic diseases such as otitis media, pneumonia and meningitis. Sensorineural hearing loss associated with this infection is mediated by the release of an exotoxin, pneumolysin. The goal of the present study was to characterize the mechanisms of pneumolysin toxicity in cochlear hair cells in vitro. Pneumolysin induced severe damage in cochlear hair cells, ranging from stereocilia disorganization to total cell loss. Surprisingly, pneumolysin-induced cell death preferentially targeted inner hair cells. Pneumolysin triggered in vitro cell death by an influx of calcium. Extracellular calcium appeared to enter the cell through a pore formed by the toxin. Buffering intracellular calcium with BAPTA improved hair cell survival. The mitochondrial apoptotic pathway involved in pneumolysin-induced cell death was demonstrated by the use of bongkrekic acid. Binding of pneumolysin to the hair cell plasma membrane was required to induce cell death. Increasing external calcium reduced cell toxicity by preventing the binding of pneumolysin to hair cell membranes. These results showed the significant role of calcium both in triggering pneumolysin-induced hair cell apoptosis and in preventing the toxin from binding to its cellular target.
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MESH Headings
- Animals
- Animals, Newborn
- Apoptosis/drug effects
- Bacterial Proteins/genetics
- Bacterial Proteins/toxicity
- Bongkrekic Acid/pharmacology
- Calcium/metabolism
- Calcium/pharmacology
- Calcium Channels/drug effects
- Calcium Channels/metabolism
- Cell Survival/drug effects
- Chelating Agents/pharmacology
- Cochlea/drug effects
- Cochlea/metabolism
- Egtazic Acid/analogs & derivatives
- Egtazic Acid/pharmacology
- Green Fluorescent Proteins/genetics
- Hair Cells, Auditory, Inner/drug effects
- Hair Cells, Auditory, Inner/metabolism
- Hair Cells, Auditory, Inner/ultrastructure
- Hair Cells, Auditory, Outer/drug effects
- Hair Cells, Auditory, Outer/metabolism
- Hair Cells, Auditory, Outer/ultrastructure
- Mitochondria/drug effects
- Mitochondria/metabolism
- Mitochondrial ADP, ATP Translocases/antagonists & inhibitors
- Organ Culture Techniques
- Rats
- Rats, Wistar
- Recombinant Fusion Proteins/metabolism
- Streptolysins/genetics
- Streptolysins/toxicity
- Time Factors
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Affiliation(s)
- Maryline Beurg
- EA-3665 Université Victor Segalen Bordeaux 2, Laboratoire de Biologie Cellulaire et Moléculaire de l'Audition, Hôpital Pellegrin, Bat PQR, 33076 Bordeaux, France.
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Barkdull GC, Vu C, Keithley EM, Harris JP. Cochlear microperfusion: experimental evaluation of a potential new therapy for severe hearing loss caused by inflammation. Otol Neurotol 2005; 26:19-26. [PMID: 15699715 DOI: 10.1097/00129492-200501000-00005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
HYPOTHESIS Cochlear microperfusion will be a useful treatment of severe sensorineural hearing loss caused by inflammation. BACKGROUND Viruses, bacteria, and autoimmunity can initiate inflammation in the inner ear. The acute phase is associated with elevations in cytokines, nitrous oxide, and cellular infiltrates and the breakdown of the blood-labyrinthine barrier. The chronic phase leads to irreversible ossification of the labyrinth. METHODS The authors developed cochlear microperfusion to facilitate removal of inflammatory cells and their byproducts during the acute phase of inflammation. Using a ventral approach to the guinea pig cochlea, the authors displaced resident perilymph by delivering perfusate into the scala vestibuli and collecting the effluent from the scala tympani. The authors evaluated the benefit of the procedure in an animal model of severe hearing loss caused by inflammation. RESULTS Healthy controls undergoing cochlear microperfusion with phosphate-buffered saline incurred a mean hearing loss of 16 dB (n=4). This hearing loss was associated with the creation of two cochleostomies and not the perfusion itself. Sterile labyrinthitis (n=5) generated by perfusion of the cochlea with antigen consistently produced severe hearing loss over the initial 48 hours, and this hearing loss persisted for the subsequent 7 days. Therapeutic cochlear microperfusion, performed within the first 24 hours of developing severe hearing loss (n=9), immediately restored on average 24 dB (p <0.007) of hearing. CONCLUSION Cochlear microperfusion is a promising new technique for treating severe deafness caused by inflammation. The benefit may be sustained when combined with local delivery of immunosuppressive agents to the inner ear.
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Affiliation(s)
- Gregory C Barkdull
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California, San Diego, School of Medicine, 92103-8895, USA
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Tinling SP, Nabili V, Brodie HA. Fine structure histopathology of labyrinthitis ossificans in the gerbil model. Ann Otol Rhinol Laryngol 2005; 114:161-6. [PMID: 15757198 DOI: 10.1177/000348940511400214] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Labyrinthitis ossificans (LO) is the pathological deposition of new bone within the lumen of the cochlea and labyrinth. This process occurs most commonly as a result of infection or inflammation affecting the otic capsule. Trauma and vascular compromise can also lead to neo-ossification within the otic capsule. The mechanism that regulates this process remains unestablished. This study details the end-stage histopathology in high-resolution plastic thin sections. Twenty Mongolian gerbils were infected by intrathecal injection of Streptococcus pneumoniae type 3 followed by subcutaneous penicillin G procaine (8 days) and were painlessly sacrificed 3 months later. The cochleas were serially divided and sectioned for light and electron microscopy. Sixteen of 20 animals (27 of 40 cochleas) demonstrated LO. Cochlear damage was most extensive in the vestibule and basal turn and decreased toward the apex, which often appeared normal. The histopathologic findings consisted of 1) new bone, calcospherites, osteoid, and fibrosis without dense connective tissue or osteoblasts extending from the endosteal wall into the lumen of the vestibule and scala tympani; 2) areas of dense connective tissue and osteoid enclosed by epithelial cells conjoined with the organ of Corti, stria vascularis, spiral ligament, and vestibular (Reissner's) membrane; and 3) partial to complete loss of the organ of Corti, spiral ligament cell bodies, stria vascularis, and spiral ganglion cells. Osteoblastic activity was not demonstrated in end-stage ossification in LO in the gerbil model. Neo-ossification appears to occur by calcospherite deposition along collagen-like fibrils within osteoid. The destruction of the organ of Corti, spiral ganglion cells, stria vascularis, and cells of Reissner's membrane and the spiral ligament occurs even in the absence of ossification of the cochlear duct.
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Affiliation(s)
- Steven P Tinling
- Department of Otolaryngology, University of California, Davis, School of Medicine, Davis, California, USA
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Li L, Shui QX, Li X. Neuroprotective effects of brain-derived neurotrophic factor (BDNF) on hearing in experimental pneumococcal meningitis. J Child Neurol 2005; 20:51-6. [PMID: 15791923 DOI: 10.1177/08830738050200010801] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Bacterial meningitis is still one of the most common causes of acquired profound sensorineural deafness in children despite antibiotic treatment. We investigated the neuroprotective effects of brain-derived neurotrophic factor on hearing function in experimental bacterial meningitis. We implanted stainless steel tubes into both cerebral ventricles of Sprague-Dawley rats aged 21 days. Bacterial meningitis was induced by inoculating a strain of serotype III Streptococcus pneumoniae into the cisterna magna. Six micrograms per day of brain-derived neurotrophic factor (groups 1 and 3) or albumin (groups 2 and 4) was injected into the cerebral ventricles 24 hours after or before infection, respectively, for a duration of 7 days. Additionally, all rats received antibiotic subcutaneous treatment starting 24 hours after infection for 7 days. Brainstem auditory evoked potentials were recorded 24 hours before and 24 hours after infection and after 7 days of treatment with brain-derived neurotrophic factor or placebo and antibiotics, respectively, to determine hearing threshold. Our results showed that the hearing thresholds of animals in each group increased significantly 24 hours after infection compared with the results recorded 24 hours before infection (P < .01). After 7 days of treatment with brain-derived neurotrophic factor, brainstem auditory evoked potential responses recurred in 16 ears when stimulated at 75 dB hearing level in groups 1 and 3. Their hearing thresholds significantly decreased compared with the control group 2 (P < .05) and group 4 (P < .01). However, 13 of 14 ears absent brainstem auditory evoked potential responses could still not be identified at 75 dB hearing level in control groups 2 and 4. The improvement of the hearing thresholds in group 3 (treated before infection) was greater than that of group 1 (treated after infection) (P < .05), but there was no significant difference found between the control groups before and after infection (P > .05). Our study supports the hypothesis that the administration of exogenous brain-derived neurotrophic factor can be effective in preventing or treating hearing loss following bacterial meningitis.
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Affiliation(s)
- Ling Li
- Department of Pediatric Neurology, the First People's Hospital of Yunnan Province, Kunming, Affiliated Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
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Anjos LP, Queirós F, Pereira MC, Brandão M, Melo A, Lucena R. Prognóstico audiológico tardio relacionado à meningite em lactentes. ARQUIVOS DE NEURO-PSIQUIATRIA 2004; 62:635-40. [PMID: 15334222 DOI: 10.1590/s0004-282x2004000400013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
INTRODUÇÃO: Déficit auditivo tem sido considerado uma das principais manifestações tardias das meningites, sobretudo quando esta ocorre nos dois primeiros anos de vida. No país, poucos são os estudos relatando a evolução de crianças acometidas por meningite e a percentagem e gravidade dos transtornos auditivos e seqüelas neurológicas após a alta hospitalar. OBJETIVO: Caracterizar as principais seqüelas auditivas e neurológicas, delineando o perfil do comprometimento auditivo encontrado cinco anos após a infecção do sistema nervoso central. MÉTODO: Foram incluídas crianças com idade entre 5 e 7 anos, admitidas no Hospital Couto Maia no ano de 1997, e que tiveram diagnóstico de meningite com idade inferior a dois anos. RESULTADOS: 19 crianças passaram pela avaliação neurológica e auditiva. A idade média foi 6 anos e 68,42% eram do sexo masculino. Quanto à etiologia, 52,63% piogênica, 42,1%viral, 5,26% tuberculosa. Alterações auditivas ocorreram em 26,31% da população. CONCLUSÃO: Distúrbios auditivos trazem implicações acadêmicas e sociais às crianças afetadas, especialmente aquelas em idade escolar. Destacamos a necessidade de monitoramento audiológico de todas as crianças com história prévia de meningite.
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Affiliation(s)
- Luzia Poliana Anjos
- Departamento de Ciências da Vida, Universidade do Estado da Bahia, Salvador, BA, Brazil
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Tinling SP, Colton J, Brodie HA. Location and Timing of Initial Osteoid Deposition in Postmeningitic Labyrinthitis Ossificans Determined by Multiple Fluorescent Labels. Laryngoscope 2004; 114:675-80. [PMID: 15064623 DOI: 10.1097/00005537-200404000-00015] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVES/HYPOTHESIS Variable amounts of fibrosis and neo-ossification fill the cochlea following bacterial meningitis. The purpose of the study was to delineate the timing and location of initial ossification following pneumococcal meningitis, as well as subsequent remodeling and resorption, over the 3-month period after infection. STUDY DESIGN Randomized, double-blind study. METHODS Fluorochromes are compounds that specifically incorporate into ossifying bone. Sequential addition of different colored fluorochromes during osteoneogenesis define the timing and location of osteoid deposition and mineralization. Mongolian gerbils were infected by intrathecal injection of Streptococcus pneumoniae type 3, and control gerbils received saline. Both groups were injected with calcein on postoperative day 3, followed by xylenol orange, oxytetracycline, and alizarin red on days 7, 14, and 28 respectively. Ten experimental gerbils were killed 24 hours after each label, and an additional group at 84 days after infection. Two groups of 10 control gerbils were killed at 29 and 84 days after treatment. The temporal bones and tibias were harvested, embedded in plastic, and sliced with a diamond saw. Wafers at a thickness of 200 microm were mounted in sequence and examined. RESULTS Sixteen of 49 experimental animals (33%) were positive for at least one of the fluorescent labels. Fluorescent labeled osteoid was present at all sampling times. Label extended from the endosteal wall into the lumen of the scala tympani between the vestibule and the round window membrane. Discrete sites of fluorescence varied among specimens and were associated with the opening of the cochlear aqueduct, the scala tympani, organ of Corti, and the stria vascularis and spiral ligament in all turns from base to apex. CONCLUSION The results indicate that osteoid is deposited and begins mineralization by day 3 after infection, at least, and continues, at least, through the first 28 days after infection. There was no apparent resorption of new bone and remodeling by 84 days after infection.
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Affiliation(s)
- Steven P Tinling
- Department of Otolaryngology, University of California, Davis, Davis, California, U.S.A
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Klein M, Koedel U, Pfister HW, Kastenbauer S. Meningitis-associated hearing loss: Protection by adjunctive antioxidant therapy. Ann Neurol 2003; 54:451-8. [PMID: 14520656 DOI: 10.1002/ana.10684] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Hearing loss is the most frequent long-term complication of pneumococcal meningitis, affecting up to 40% of survivors. Unfortunately, adjuvant therapy with dexamethasone has failed to satisfactorily reduce its incidence. Therefore, we evaluated the use of antioxidants for the adjunctive therapy of meningitis-associated deafness. Eighteen hours after intracisternal injection of 7.5 x 10(5) colony-forming units of Streptococcus pneumoniae, rats were treated systemically either with ceftriaxone and the antioxidants and peroxynitrite scavengers Mn(III)tetrakis(4-benzoic acid)-porphyrin (MnTBAP) or N-acetyl-L-cysteine (NAC) or placebo (1 ml phosphate-buffered saline) for 4 days. Hearing was assessed by auditory brainstem response audiometry. Adjunctive antioxidant therapy significantly reduced the long-term hearing loss (14 days after infection) for square wave impulses (mean hearing loss +/- SD: ceftriaxone and placebo, 45+/-26 dB; ceftriaxone and MnTBAP, 9+/-23 dB; ceftriaxone and NAC, 19+/-30 dB) as well as 1 kHz (ceftriaxone and placebo, 28+/-19 dB; ceftriaxone and MnTBAP, 10+/-16 dB; ceftriaxone and NAC, 10+/-17 dB), and 10 kHz tone bursts (ceftriaxone and placebo, 62+/-27 dB; ceftriaxone and MnTBAP, 16+/-13 dB; ceftriaxone and NAC, 25+/-26 dB). Furthermore, both antioxidants attenuated the morphological correlates of meningogenic hearing loss, namely, long-term blood-labyrinth barrier disruption, spiral ganglion neuronal loss, and fibrous obliteration of the perilymphatic spaces. Adjuvant antioxidant therapy is highly otoprotective in meningitis and therefore is a promising future treatment option.
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Affiliation(s)
- Matthias Klein
- Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany
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Kastenbauer S, Klein M, Koedel U, Pfister HW. Reactive nitrogen species contribute to blood-labyrinth barrier disruption in suppurative labyrinthitis complicating experimental pneumococcal meningitis in the rat. Brain Res 2001; 904:208-17. [PMID: 11406118 DOI: 10.1016/s0006-8993(01)02164-3] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Sensorineural hearing damage is a frequent complication of bacterial meningitis, affecting as many as 30% of survivors of pneumococcal meningitis. There is a substantial body of evidence that oxidants, such as reactive nitrogen species (RNS), are central mediators of brain damage in experimental bacterial meningitis. In the present study, we investigated whether RNS also contribute to the pathophysiology of suppurative labyrinthitis in our well-established rat model of pneumococcal meningitis. In all infected rats, but not in uninfected controls, we observed suppurative labyrinthitis. Cochlear inflammation was accompanied by severe blood-labyrinth barrier (BLB) disruption as evidenced by increased Evans Blue extravasation. Furthermore, increased cochlear expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) was detected by immunohistochemistry. Colocalization of iNOS and tyrosine nitration (a marker of RNS attack) indicated that nitric oxide (NO) produced by iNOS contributes to oxidative cochlear damage through the action of RNS. To determine the pathophysiological role of RNS in BLB disruption, rats were treated with peroxynitrite scavengers (MnTBAP and uric acid, UA). Six h after adjunctive treatment with 300 mg/kg i.p. UA or 15 mg/kg i.p. MnTBAP+100 mg/kg i.p. ceftriaxone, BLB disruption was significantly reduced compared with that in infected animals treated only with ceftriaxone. Therefore, we conclude that RNS are involved in the breaching of the BLB during meningogenic pneumococcal labyrinthitis.
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Affiliation(s)
- S Kastenbauer
- Department of Neurology, Klinikum Grossetahadern, Ludwig-Maximilians University, Munich, Germany
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Stöver T, Yagi M, Raphael Y. Transduction of the contralateral ear after adenovirus-mediated cochlear gene transfer. Gene Ther 2000; 7:377-83. [PMID: 10694819 DOI: 10.1038/sj.gt.3301108] [Citation(s) in RCA: 89] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Cochlear gene transfer is a promising new approach for inner ear therapy. Previous studies have demonstrated hair cell protection with cochlear gene transfer not only in the inoculated, but also in the uninoculated ear. To characterize the kinetics of viral spread, we investigated the extent of transgene expression in the contralateral (uninoculated) cochlea after unilateral adenoviral cochlear gene transfer. We used a lacZ reporter gene vector, and demonstrated spread of the adenovirus into the cerebrospinal fluid (CSF) after cochlear inoculation of 25 microl viral vector. Direct virus application into the CSF resulted in transduction of both cochleae, whereas virus inoculation into the bloodstream did not. The cochlear aqueduct was identified as the most likely route of virus spread to the contralateral cochlea. These data enhance our understanding of the kinetics of virus-mediated transgene expression in the inner ear, and assist in the development of clinical applications for inner ear gene therapy. Our results showed a functional communication between the CSF and the perilymphatic space of the inner ear, that is not only of importance for otological gene transfer, but also for CNS gene transfer. Gene Therapy (2000) 7, 377-383.
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Affiliation(s)
- T Stöver
- Kresge Hearing Research Institute, Department of Otolaryngology, The University of Michigan Medical School, Ann Arbor, MI, USA
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