The Severity of Infection Determines the Localization of Damage and Extent of Sensorineural Hearing Loss in Experimental Pneumococcal Meningitis

Abstract

Hearing loss is an important sequela of pneumococcal meningitis (PM), occurring in up to 30% of survivors. The role of the severity of infection on hearing function and pathomorphological consequences in the cochlea secondary to PM have not been investigated to date. Using a well-established model of PM, we systematically investigated the functional hearing outcome and the long-term fate of neurosensory cells in the cochlea, i.e., hair cells and spiral ganglion neurons (SGNs), with a focus on their tonotopic distribution. Intracisternal infection of infant rats with increasing inocula of Streptococcus pneumoniae resulted in a dose-dependent increase in CSF levels of interleukin-1␤, interleukin-6, tumor necrosis factor ␣, interleukin-10, and interferon-␥ in acute disease. The severity of long-term hearing loss at 3 weeks after infection, measured by auditory brainstem response recordings, correlated to the initial inoculum dose and to the levels of proinflammatory cytokines determined in the acute phase of PM. Quantitative cochlear histomorphology revealed a significant loss of SGNs and outer hair cells that strongly correlated to the level of infection, with the most severe damage occurring in the basal part of the cochlea. Inner hair cells (IHCs) were not significantly affected throughout the entire cochlea. However, surviving IHCs lost synaptic connectivity to remaining SGNs in all cochlear regions. These findings provide evidence that the inoculum concentration, i.e., severity of infection, is the major determinant of long-term morphological cell pathologies in the cochlea and functional hearing loss.

Histopathological changes to the peripheral vestibular system following meningitic labyrinthitis

“…Different studies have demonstrated the location of new bone formation in TB with labyrinthitis ossificans . Our findings are consistent with other studies that showed the presence of new bone formation beginning at the lower segments of the cochlea . We were able to find new bone formation (close the RWM or throughout the cochlea) in two (13.3%) TBs.…”

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

“…Inflammatory mediators (cytokines, chemokines, reactive oxygen and nitrogen species, MMPs) released from recruited neutrophils, endothelial cells, leptomeningeal macrophages and brain-resident microglia and astrocytes contribute to pathogen eradication but also act as neurotoxins and induce neuronal damage [107,116,119,120]. Moreover, PM induces damage to hair cells and spiral ganglion neurons in the inner ear [121][122][123] provoking sensorineural hearing impairments in up to 30% of survivors [108,124,125]. In an infant rat PM model, increased CSF levels of TNF-α during acute infection were positively correlated with increased hearing loss in surviving animals [122].…”

“…Moreover, PM induces damage to hair cells and spiral ganglion neurons in the inner ear [121][122][123] provoking sensorineural hearing impairments in up to 30% of survivors [108,124,125]. In an infant rat PM model, increased CSF levels of TNF-α during acute infection were positively correlated with increased hearing loss in surviving animals [122].…”

“…Bacterial meningitis induces sensorineural hearing loss by damaging hair cells and spiral ganglion neurons in the inner ear [122,123]. In PM, CSF levels of TNF-α during acute infection are positively correlated with increased hearing threshold after infection [122].…”

“…Bacterial meningitis induces sensorineural hearing loss by damaging hair cells and spiral ganglion neurons in the inner ear [122,123]. In PM, CSF levels of TNF-α during acute infection are positively correlated with increased hearing threshold after infection [122]. Treatment with doxycycline or Trocade plus daptomycin significantly reduces CSF levels of TNF-α and other pro-inflammatory cytokines and significantly improves hearing thresholds after PM [173,174].…”