Progression of Hearing Loss in Experimental Pneumococcal Meningitis: Correlation with Cerebrospinal Fluid Cytochemistry

Bhatt, Samir M.; Lauretano, Arthur M.; Cabellos, Carmen; Halpin, Chris; Levine, Robert A.; Xu, Wen Z.; Nadol, Joseph B.; Tuomanen, Elaine

doi:10.1093/infdis/167.3.675

Cited by 70 publications

(50 citation statements)

References 32 publications

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“…Hearing loss was correlated with the level of CSF inflammation in a rabbit model of pneumococcal meningitis (40), and intrathecal administration of TNF-␣ alone was sufficient to induce cochlear injury similar to that observed with bacterial meningitis (15). Furthermore, TLR and MyD88 knockout mice demonstrated less hearing loss following pneumococcal meningitis (247).…”

Section: Cochlear Damage and Hearing Lossmentioning

confidence: 72%

“…The underlying pathophysiology has been studied in several animal models (39,40,45,244,421,477) Cochlear involvement may result from direct spread of pneumococcal infection from the meninges, CSF, and cochlear perilymphatic system (40,227,244). Alternatively, a hematogenous route may occur following bacteremia or sepsis (227,244).…”

Section: Cochlear Damage and Hearing Lossmentioning

confidence: 99%

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Pathogenesis and Pathophysiology of Pneumococcal Meningitis

et al. 2011

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SUMMARY Pneumococcal meningitis continues to be associated with high rates of mortality and long-term neurological sequelae. The most common route of infection starts by nasopharyngeal colonization by Streptococcus pneumoniae , which must avoid mucosal entrapment and evade the host immune system after local activation. During invasive disease, pneumococcal epithelial adhesion is followed by bloodstream invasion and activation of the complement and coagulation systems. The release of inflammatory mediators facilitates pneumococcal crossing of the blood-brain barrier into the brain, where the bacteria multiply freely and trigger activation of circulating antigen-presenting cells and resident microglial cells. The resulting massive inflammation leads to further neutrophil recruitment and inflammation, resulting in the well-known features of bacterial meningitis, including cerebrospinal fluid pleocytosis, cochlear damage, cerebral edema, hydrocephalus, and cerebrovascular complications. Experimental animal models continue to further our understanding of the pathophysiology of pneumococcal meningitis and provide the platform for the development of new adjuvant treatments and antimicrobial therapy. This review discusses the most recent views on the pathophysiology of pneumococcal meningitis, as well as potential targets for (adjunctive) therapy.

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Section: Cochlear Damage and Hearing Lossmentioning

confidence: 72%

Section: Cochlear Damage and Hearing Lossmentioning

confidence: 99%

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

et al. 2011

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“…Hearing loss results from involvement of the inner ear due to inflammation as pneumococci and leukocytes extend from the CSF to the perilymph via the cochlear aqueduct (4,5,11). In a model of pneumococcal meningitis the severity of permanent hearing impairment as assessed by the increase in the ABR thresholds 2 weeks after (20).…”

Section: Discussionmentioning

confidence: 99%

“…The role of cytokines and MMPs in the pathophysiology of the cochlear damage associated with pneumococcal meningitis is still unknown. However, it has been demonstrated that MMPs are constitutively expressed at high levels in the cochlea (8) and that in meningitis pneumococci and polymorphonuclear leukocytes (PMNs) extend from the cerebrospinal fluid (CSF) to the perilymph via the cochlear aqueduct (5).…”

mentioning

confidence: 99%

Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

et al. 2006

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Bacterial meningitis is characterized by an inflammatory reaction to the invading pathogens that can ultimately lead to sensorineural hearing loss, permanent brain injury, or death. The matrix metalloproteinases (MMPs) and tumor necrosis factor alpha-converting enzyme (TACE) are key mediators that promote inflammation, blood-brain barrier disruption, and brain injury in bacterial meningitis. Doxycycline is a clinically used antibiotic with anti-inflammatory effects that lead to reduced cytokine release and the inhibition of MMPs. Here, doxycycline inhibited TACE with a 50% inhibitory dose of 74 M in vitro and reduced the amount of tumor necrosis factor alpha released into the cerebrospinal fluid by 90% in vivo. In an infant rat model of pneumococcal meningitis, a single dose of doxycycline (30 mg/kg) given as adjuvant therapy in addition to ceftriaxone 18 h after infection significantly reduced the mortality, the blood-brain barrier disruption, and the extent of cortical brain injury. Adjuvant doxycycline (30 mg/kg given subcutaneously once daily for 4 days) also attenuated hearing loss, as assessed by auditory brainstem response audiometry, and neuronal death in the cochlear spiral ganglion at 3 weeks after infection. Thus, doxycycline, probably as a result of its anti-inflammatory properties, had broad beneficial effects in the brain and the cochlea and improved survival in this model of pneumococcal meningitis in infant rats. Pneumococcal meningitis has a high level of mortality (up to 30%), and brain and/or cochlear damage occurs in up to 50% of the survivors (2). Inflammatory mediators, such as tumor necrosis factor alpha (TNF-␣) and matrix metalloproteinases (MMPs), are produced during the host response to bacteria and contribute to the pathophysiology that can ultimately lead to death, brain damage, and hearing impairment (23,26,29,36). The role of cytokines and MMPs in the pathophysiology of the cochlear damage associated with pneumococcal meningitis is still unknown. However, it has been demonstrated that MMPs are constitutively expressed at high levels in the cochlea (8) and that in meningitis pneumococci and polymorphonuclear leukocytes (PMNs) extend from the cerebrospinal fluid (CSF) to the perilymph via the cochlear aqueduct (5).Tetracyclines are bacteriostatic agents with broad-spectrum antimicrobial activity (3). Doxycycline is a semisynthetic, longacting, second-generation tetracycline which is absorbed rapidly and penetrates well into the brain and CSF (48). Doxycycline has been shown to have anti-inflammatory effects that are separate and distinct from its antimicrobial action (13,16,35,43). These effects include the reduction of cytokine release and the inhibition of MMPs (7, 38). Experimental and clinical studies have indicated that treatment with doxycycline may be beneficial in inflammatory diseases associated with excessive MMP activity (7,13,35).In pneumococcal meningitis massive subarachnoid and ventricular space inflammation is triggered by the presence of bacteria in the CSF space (7,1...

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“…SNHL results from involvement of the inner ear due to inflammation as the cerebrospinal fluid (CSF) containing pneumococci and leukocytes extends from the subarachnoid space via the cochlear aqueduct to the perilymph (7)(8)(9). In an adult rat model of PM, the severity of permanent hearing impairment assessed 2 wk after the infection correlated significantly with the loss of type I spiral ganglion neurons (10).…”

mentioning

confidence: 99%

Limited Efficacy of Adjuvant Therapy with Dexamethasone in Preventing Hearing Loss Due to Experimental Pneumococcal Meningitis in the Infant Rat

2007

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Sensorineural hearing loss (SNHL) is the most common sequel of bacterial meningitis (BM) and is observed in up to 30% of survivors when the disease is caused by Streptococcus pneumoniae. BM is the single most important origin of acquired SNHL in childhood. Anti-inflammatory dexamethasone holds promises as potential adjuvant therapy to prevent SNHL associated with BM. However, in infant rats, pneumococcal meningitis (PM) increased auditory brainstem response (ABR) thresholds [mean difference ϭ 54 decibels sound pressure level (dB SPL)], measured 3 wk after infection, irrespective to treatment with ceftriaxone plus dexamethasone or ceftriaxone plus saline (p Ͻ 0.005 compared with mock-infected controls). Moreover, dexamethasone did not attenuate short-and long-term histomorphologic correlates of SNHL. At 24 h after infection, blood-labyrinth barrier (BLB) permeability was significantly increased in infected animals of both treatment groups compared with controls. Three weeks after the infection, the averaged number of type I neurons per square millimeter of the Rosenthal's canal dropped from 0.3019 Ϯ 0.0252 in controls to 0.2227 Ϯ 0.0635 in infected animals receiving saline (p Ͻ 0.0005). Dexamethasone was not more effective than saline in preventing neuron loss (0.2462 Ϯ 0.0399; p Ͼ 0.05). These results suggest that more efficient adjuvant therapies are needed to prevent SNHL associated with pediatric PM. (Pediatr Res 62: 291-294, 2007)

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Progression of Hearing Loss in Experimental Pneumococcal Meningitis: Correlation with Cerebrospinal Fluid Cytochemistry

Cited by 70 publications

References 32 publications

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

Limited Efficacy of Adjuvant Therapy with Dexamethasone in Preventing Hearing Loss Due to Experimental Pneumococcal Meningitis in the Infant Rat

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