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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 sub-
stantial body of evidence that now implicates cytokines and chemokines, proteolytic enzymes,
From the first description of meningococcemia and menin- and about half the survivors have neurologic and other sequelae
gococcal meningitis, before identification of the etiologic or- of the disease [4].
ganism (by Vieusseux in 1806) until the early twentieth century, Over the past four decades, clinical and neuropathologic
bacterial meningitis was considered a nearly uniformly fatal studies have documented the clear association between bacterial
disease, although some patients with meningococcal meningitis meningitis and brain edema formation, impairments of cere-
survived without antimicrobial therapy. The advent of various brospinal fluid (CSF) hydrodynamics, increased intracranial
experimental procedures followed by antisera therapy directed pressure, seizure activity, arterial and venous cerebral vascular
against meningococci reduced mortality rates during World insults (that may relate to death), and other neurologic sequelae.
War I, but the introduction of sulfonamides and penicillins Therefore, during the past 15–20 years, emphasis has been on
along with other antimicrobial agents heralded the reduction a greater understanding of the pathogenesis and pathophy-
in morbidity and survival possible with modern antimicrobial siology of bacterial meningitis in an attempt to improve out-
therapy. Despite these achievements and the introduction of come [5].
several new antimicrobial agents with in vitro activity against It is apparent that the host immune response is incapable of
the major meningeal pathogens plus some limited improvement controlling infection within the central nervous system (CNS),
in diagnostic assays, bacterial meningitis remains associated particularly the CSF within the subarachnoid space, and that
with unacceptably high morbidity and mortality [1]. this host inflammatory response may be responsible for many
Endemic meningitis is relatively unusual in developed coun-
adverse events during bacterial meningitis [6, 7]. A very complex
tries although epidemic meningitis occurs with considerable fre-
and integrated series of events involving host cytokines, che-
quency in resource-limited settings. Explosive epidemics of me-
mokines, proteolytic enzymes, and oxidants appears to be re-
ningococcal meningitis have continued to affect the so-called
sponsible for meningitis-induced brain dysfunction. This has
meningitis belt of sub-Saharan Africa. The most recent epi-
resulted in the search for adjunctive therapies for bacterial men-
demic, which began in 1996, has resulted in over 300,000 cases
ingitis, including corticosteroids.
and 30,000 deaths [2]. At present, exclusive of epidemics, about
In this brief review, we highlight recent epidemiologic trends
1.2 million cases of bacterial meningitis are estimated to occur
in bacterial meningitis worldwide and consider the current con-
annually worldwide with 135,000 deaths [3]. Bacterial menin-
cepts of the pathogenesis and pathophysiology of this syndrome
gitis is now a “top 10” infectious cause of death worldwide,
with an emphasis on the identification of promising targets for
adjunctive therapy. Some of these concepts have been reviewed
Reprints or correspondence: Dr. W. Michael Scheld, University of Virginia recently [8–10]. The pathogenesis of bacterial meningitis, in-
Health System, Dept. of Medicine, Division of Infectious Diseases, PO Box
cluding colonization of the nasopharynx by the pathogen, mi-
801342, Charlottesville, VA 22908 (wms@virginia.edu).
crobial invasion into the intravascular space and survival within
The Journal of Infectious Diseases 2002; 186(Suppl 2):S225–33
䉷 2002 by the Infectious Diseases Society of America. All rights reserved.
the bloodstream, microbial entry mechanisms into the CNS,
0022-1899/2002/18611S-0015$15.00 survival within the subarachnoid space, and host and/or en-
S226 Scheld et al. JID 2002;186 (Suppl 2)
vironmental factors contributing to susceptibility to invasive (particularly serotype C:2a:P1:2) into a population in which
disease are reviewed more extensively elsewhere [8]. serogroup B strains had been the predominant causes of en-
demic disease.
As documented in Scandinavia, susceptibility to invasive me-
Changing Epidemiology of Acute Bacterial Meningitis ningococcal disease is largely due to acquisition of a new vir-
ulent strain in a host without circulating bactericidal antibody
No bacterial infection worldwide has undergone a more spec-
tacular evolution in epidemiology than acute meningitis since against the causative organism [14]. The United Kingdom in
1990. The introduction of Haemophilus influenzae conjugate November 1999 was the first country to launch vaccination
vaccines (Hib) in the United States and western Europe has against group C meningococcal disease, and a rapid decrease
resulted in a decline in the incidence of invasive H. influenzae in the incidence of this syndrome (including clusters) is expected
infections by ⭓90% [1]. As a result, Streptococcus pneumoniae (see Public Health Laboratory Service [UK] annual report
and Neisseria meningitidis are the major causes of bacterial 1988–1999 and highlights 1999/2000). Infants and young adults
meningitis in these regions. Furthermore, a dramatic change in aged 15–17 years are targeted, and this strategy may be ap-
in 2001 in Ontario, Canada), but the impact on therapeutic of recent studies follow (for a more detailed discussion of path-
strategies is not known. ogenesis, see [8]).
The clinical outcome of acute bacterial meningitis depends
on multiple factors including the socioeconomic status of the
patient (developed vs. developing countries), age, pathogen, Pathophysiology of Bacterial Meningitis
and the clinical characteristics and laboratory manifestations
Various bacteria including the major meningeal pathogens
of the acute infection. For example, the case fatality rate for
(e.g., S. pneumoniae) undergo autolysis under harsh conditions
H. influenzae type B meningitis in recent reviews has been about
such as exposure to antimicrobial agents and/or growth to sta-
5%, [1], a figure similar to that of meningococcal meningitis in
tionary phase. Autolysis consists of self-digestion of the cell
the same report. Conversely, the mortality rate associated with
wall by peptidoglycan hydrolyases termed autolysins. At least
pneumococcal meningitis is about 20% versus 15%–30% for
3 autolysins are recognized in pneumococci, but the major au-
Listeria monocytogenes in recent years [1]. About 30% of the
tolysin is the N-acetyl-muramoyl-l-alanine amidase (LytA) [24].
survivors of pneumococcal meningitis develop long-term se-
Activation of LytA and autolysis result in the release in sub-
molysin stimulates the production of inflammatory mediators in and ERK-2/ERK-1 MAPK activities [38]. These same MAPKs
vitro including tumor necrosis factor (TNF)-a, interleukin (IL)- are also activated when rat or human astrocytes are stimulated
1b, and IL-6 [28]. Pneumolysin is also an inducer and/or activator with various pneumococcal cell wall fragments. In addition,
of enzymes such as phospholipase A2, COX-2, and inducible pneumococci activate NF-kB in undifferentiated human and
nitric oxide synthase (iNOS). However, in a rabbit meningitis mature murine monocytes [39]. Although the signaling path-
model, a pneumolysin-deficient pneumococcal strain resulted in ways involved in immune inactivation only recently became a
an inflammatory response similar to that induced by injection of major focus of research activity, a rat model of pneumococcal
the wild type strain, suggesting that pneumolysin is not essential meningitis showed a marked increase in NF-kB activity. Phar-
for the induction of meningeal inflammation [29]. macologic inhibition of NF-kB led to a significant reduction of
Another potential trigger of immune activation during acute host inflammatory responses as evidenced by lower CSF leu-
meningitis is bacterial DNA released during bacterial autolysis. kocyte and IL-6 concentrations [40]. It appears that NF-kB is
Bacterial DNA has substantial immune stimulatory effects on a central transcriptional activator of many genes that encode
B, NK, and dendritic cells and on monocytes and macrophages proteins, host factors, or both involved in the pathophysiology
ficiency and the pathophysiology of acute bacterial meningitis. ering, triggering, firm adhesion, and emigration) are involved
The role of caspase (Casp)-1 in the pathophysiology of pneu- in this adhesion cascade. The selectin family of adhesion mol-
mococcal meningitis has been the subject of recent experiments. ecules (P-, E-, L-selectin) mediates tethering and promotes leu-
Casp-1 plays a central role in the generation of mature IL-1b kocyte rolling under flow conditions.
and IL-18 [46]. Casp-1 mRNA and protein expression is up- Firm adhesion of leukocytes to the endothelium is mediated
regulated in the brain during experimental pneumococcal men- by a family of integrins. Integrin activation requires a triggering
ingitis; this up-regulated activation is associated with increased step mediated by a proinflammatory cytokine (e.g., IL-1b) and
levels of IL-1b [8]. Furthermore, depletion of the Casp-1 gene chemokines (e.g., IL-8), complement products, and bacterial
and/or pharmacologic blockade of Casp-1 attenuates the men- cell wall components. Leukocyte integrins, once activated, bind
ingitis-induced increase in IL-1b. A significant reduction in NF- to endothelial cell count receptors. Macrophage antigen 1
kB activity, brain TNF-a, MIP-1a, and MIP-2 expression, and (MAC-1; CD11b/CD18) is the predominant integrin involved
CSF pleocytosis was also observed [8]. The Casp-1–IL-1b sig- in neutrophil binding to the activated endothelial cell. Inter-
naling pathways play a crucial role in the induction and am- cellular adhesion molecule (ICAM)-1, an immunoglobulin-like
central mechanisms of oxidant-induced brain damage, and come related to penicillin susceptibility and dexamethasone use. Pediatrics
1998; 102:1087–97.
pharmacologic interference with these biochemical pathways
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