Pathophysiology of Bacterial Meningitis: Mechanism(s) of Neuronal Injury

Abstract

No bacterial disease has undergone a more dramatic change in epidemiology during the past decade than acute bacterial meningitis. This review describes the changing epidemiology and considers some important recent observations that contribute to our understanding of the pathogenesis and pathophysiology of meningitis. The major focus is on the mechanisms of neuronal injury and the pathophysiologic concepts responsible for death and neurologic sequelae. In recent years, experimental studies have amplified our understanding of the substantial body of evidence that now implicates cytokines and chemokines, proteolytic enzymes, and oxidants in the inflammatory cascade leading to tissue destruction in bacterial meningitis. The molecular mechanisms responsible for oxidant-induced neuronal injury in meningitis are explored in some depth. Genetic targeting and/or pharmacologic blockade of the implicated pathways may be a future strategy for therapeutic adjunctive measures to improve outcome and may hold substantial promise, in concert with antimicrobial agents, in humans with acute bacterial meningitis.

Concepts and Mechanisms: Crossing Host Barriers

“…Clinical and neuropathologic studies have clearly documented the complications of bacterial meningitis, which are brain edema, increased intracranial pressure, seizure, arterial and venous cerebral vascular insults, and other motor, sensitive, sensorial, and cognitive sequelae (Scheld et al 2002). Host immune responses are frequently inadequately tuned to control infection within the CNS, either insufficient and unable to control microbial burden, or excessive and associated with excessive inflammation and irreversible tissue damages (Tunkel and Scheld 1995;Pfister and Scheld 1997).…”

Pathophysiology of acute meningitis caused by Streptococcus pneumoniae and adjunctive therapy approaches

“…Brain resident cells produce O 2 -, H 2 O 2 as part of the host immune response to invasive bacterial infection, in addition, S. pneumoniae itself is also an important source of H 2 O 2 , which is not only able to cause direct cytotoxic damage but also reacts with the host's NO to form the highly reactive species ONOO 56 . Peroxynitrite can crosses membranes, activate the MMPs, leads to DNA damage, protein carbonylation and cause lipid peroxidation 52 , leading to a membrane integrity loss, energy depletion, contributing to cell injury during pneumococcal meningitis 57 .…”

Modulation of connexin expression and gap junction communication in astrocytes by the gram‐positive bacterium S. aureus

“…However, the functional consequences resulting from changes in the extent of astrocyte coupling remain an area of debate and are likely influenced by the context of CNS damage (Farahani et al, 2005;Perez Velazquez et al, 2003). Neuroinflammation is a hallmark of various CNS pathologies such as trauma, bacterial meningitis, brain abscess, Alzheimer's disease, and multiple sclerosis, which share a general feature of reactive gliosis characterized, to varying degrees, by the proliferation and hypertrophy of activated astrocytes (Eikelenboom et al, 2002;Griffin and Mrak, 2002;Kielian, 2004;Koedel et al, 2002;McGeer and McGeer, 2002;Nau and Bruck, 2002;Scheld et al, 2002). When activated by an appropriate stimulus, astrocytes have the capacity to produce robust amounts of proinflammatory mediators which may have profound effects on GJC (Dong and Benveniste, 2001;Esen et al, 2004;Kim et al, 2005;Smits et al, 2001).…”