Pathophysiology and Treatment of Bacterial Meningitis PDF

Therapeutic Advances in Neurological Disorders Review Ther Adv Neurol Disord Pathophysiology and treatment o...

Therapeutic Advances in Neurological Disorders Review Ther Adv Neurol Disord Pathophysiology and treatment of (2009) 2(6) 401—412 DOI: 10.1177/ bacterial meningitis 1756285609337975 ! The Author(s), 2009. Reprints and permissions: Olaf Hoffman and Joerg R. Weber http://www.sagepub.co.uk/ journalsPermissions.nav Abstract: Bacterial meningitis is a medical emergency requiring immediate diagnosis and immediate treatment. Streptococcus pneumoniae and Neisseria meningitidis are the most common and most aggressive pathogens of meningitis. Emerging antibiotic resistance is an upcoming challenge. Clinical and experimental studies have established a more detailed understanding of the mechanisms resulting in brain damage, sequelae and neuropsychological deficits. We summarize the current pathophysiological concept of acute bacterial meningitis and present current treatment strategies. Keywords: bacterial meningitis, meningoencephalitis, pneumococci, meningococci, dexamethasone Correspondence to: Introduction resources presents an equally important issue Joerg R. Weber, MD Department of Cell Despite modern antibiotics and improved critical beside the scientific and medical challenges in Biology and Neurobiology, care, bacterial meningitis (BM) is still an unre- unraveling the molecular basis of bacterial Charité — Universitaetsmedizin solved problem in clinical medicine. Although meningitis, developing new treatments and meet- Berlin, Berlin, Germany highly effective antibiotics kill bacteria efficiently, ing new upcoming challenges such as increasing and Department of Neurology, LKH mortality rates are still up to 34% [van de Beek resistance of pathogens to currently used antibio- Klagenfurt, Klagenfurt, et al. 2006]. Up to 50% of the survivors suffer tics; for example, pneumococci up to 35% Austria [email protected] from long-term sequelae [Weisfelt et al. 2006; de [Richter et al. 2002; Doern et al. 2001; Whitney Olaf Hoffman Gans and van de Beek, 2002; Schuchat et al. et al. 2000]. It is important to state that the pro- Department of Neurology, 1997; Bohr et al. 1984]. This review focuses portion of resistant isolates is extremely depen- Charité - Universitaetsmedizin mostly on the typical and most common causes dent on geographical and other factors. Berlin, Berlin, Germany of community acquired bacterial meningitis such as meningococci and pneumococci. Definition of bacterial meningitis Bacterial meningitis is an inflammation of the Two landmark studies suggested an approach to meninges, in particular the arachnoid and the improve the outcome of acute BM by decreasing pia mater, associated with the invasion of bacteria inflammation using dexamethasone as an adjunc- into the subarachnoid space, principles known tive treatment to antibiotics [de Gans and van de for more than 100 years [Flexner, 1907]. The Beek, 2002; Odio et al. 1991]. In contrast to these pathogens take advantage of the specific features clinical data collected in the USA or Western of the immune system in the CNS, replicate and Europe, several studies performed in resource induce inflammation [Simberkoff et al. 1980]. poor countries did not detect any positive effect. A hallmark of bacterial meningitis is the Potential reasons for this difference may include recruitment of highly activated leukocytes into other underlying diseases, in particular AIDS the CSF. Beside bacteria, viruses, fungi and non- [Scarborough et al. 2007; Molyneux et al. 2002], infectious causes as in systemic and neoplastic tuberculosis [Nguyen et al. 2007], malnutrition disease as well as certain drugs can induce and the fact that patients in these studies presented meningeal inflammation. Usually the inflamma- to emergency rooms at more advanced stages of the tory process is not limited to the meninges disease [Scarborough and Thwaites, 2008]. surrounding the brain but also affects the brain parenchyma (meningoencephalitis) [Swartz, Consequently, the widening gap between weal- 1984], the ventricles (ventriculitis) and spreads thier societies and countries with limited along the spinal cord [Kastenbauer et al. 2001]. http://tan.sagepub.com 401 Therapeutic Advances in Neurological Disorders 2 (6) In recent years the damage of neurons, particu- The highest incidence is observed in the sub- larly in hippocampal structures, has been Sahara meningitis belt where cyclic epidemics identified as a potential cause of persistent neu- occur at least once per decade. ropsychological deficits in survivors [Zysk et al. 1996; Nau et al. 1999b]. Bacterial meningitis is a Pathogenesis medical emergency requiring immediate diagno- sis and subsequent treatment. Bacterial invasion The current assumption is that high-grade bac- Epidemiology teremia precedes meningitis and that bacteria During the last 20 years, the epidemiology of invade from the blood stream to the central ner- bacterial meningitis has dramatically changed. vous system (CNS). Alternatively, direct accesses Haemophilus influenzae, formerly a major cause to the CNS through dural defects or local infec- of meningitis, has disappeared in developed tions are potential entrance routes. In the clinical countries and serves as a remarkable example of setting, such defects should be identified by CCT a successful vaccination campaign. Nowadays, or MRI scans. pneumococci are the most important cause of bacterial meningitis in children and adults in The anatomical site of bacterial invasion from the the US as well as in Europe. The incidence of bloodstream remains unidentified. Experimental the disease varies from 1.1 to 2 in the US evidence suggests that the choroid plexus may be [Schuchat et al. 1997; Wenger et al. 1990] and a site of invasion [Daum et al. 1978]. Meningo- in Western Europe [Berg et al. 1996] up to 12 in cocci are found in the choroid plexus as well as 100 000 per year in Africa [O’Dempsey et al. in the meninges [Pron et al. 1997] and pneumo- 1996]. The risk of disease is highest in individuals cocci infiltrate the leptomeningeal blood vessels younger than 5 years and older than 60 years. [Zwijnenburg et al. 2001; Rodriguez et al. 1991] Some predisposing factors such as a former sple- in meningitis. These data suggest that several nectomy, malnutrition or sickle cell disease are highly vascularized sites are potential entry known [Kastenbauer and Pfister, 2003; Fraser locations. In order to cross the blood—brain et al. 1973]. The use of conjugate pneumococcal or the blood—CSF barrier and to overcome vaccines has led to a significant decline in invasive sophisticated structures such as tight junctions, pneumococcal disease, including meningitis, in meningeal pathogens must carry effective molec- those regions promoting this approach [Hsu ular tools. et al. 2009; Whitney et al. 2003]. An emerging problem is the growing prevalence of pneumo- Streptococcal proteins such as CbpA interact cocci resistant to beta-lactam antibiotics [Stanek with glycoconjugate receptors of phosphorylcho- and Mufson, 1999]. Prolonged persistence of line with platelet activating factor (PAF) on the pneumococci in the cerebrospinal fluid (CSF) eukaryotic cells and promote endocytosis and may result in higher mortality as well as in pro- crossing the blood—brain barrier [Radin et al. nounced neurological damage in survivors [Fiore 2005; Orihuela et al. 2004; Ring et al. 1998; et al. 2000; McCullers et al. 2000]. These effects Cundell et al. 1995]. Meningococci’s PilC1 adhe- of living bacteria urge us to understand in detail sin interacts with CD46 and the outer membrane the effects of bacterial toxins and released cell protein connects to vitronectin and integrins wall and surface components and their contribu- [Unkmeir et al. 2002; Kallstrom et al. 1997]. tion to neuronal damage. Bacteria causing meningitis in newborns, most importantly group B streptococcal (GBS) and With Haemophilus on the decline, Neisseria menin- E. coli, are also well equipped with adhesive pro- gitides has become the leading meningitis patho- teins allowing them to invade the CNS [Maisey gen in developing countries, but it continues to et al. 2007; Prasadarao et al. 1997]. Detailed pose a major health problem in the US and knowledge of how bacteria activate and invade Europe. In addition to classical meningitis, cells may allow to block these interactions and meningococci frequently cause systemic disease therefore to prevent disease progression. including fulminant gram-negative sepsis and disseminated intravascular coagulopathy. WHO Inflammatory response estimates at least 500 000 newly symptomatic Inflammatory activation of endothelial cells infections per year worldwide, leading to seems to be a prerequisite for bacterial invasion at least 50 000 deaths [Stephens et al. 2007]. but also results in the regulation of adhesion 402 http://tan.sagepub.com  O Hoffman and JR Weber molecules as ICAM-1 [Freyer et al. 1999]. compartments [Rennels et al. 1985] that could Subsequently, these molecules promote the mul- deliver soluble bacterial and inflammatory toxic tistep process of leukocyte invasion. Leukocytes, mediators. in particular the presence of granulocytes in the CSF, are the diagnostic hallmark of meningitis. Neuronal damage in meningitis is clearly multi- Early inflammatory response and bacterial inva- factorial, involving bacterial toxins, cytotoxic sion seem to progress in parallel and products of products of immune competent cells, and indi- activated leukocytes such as MMPs [Kieseier rect pathology secondary to intracranial compli- et al. 1999] and NO [Koedel et al. 1995] cations (Figure 1). In the case of S. pneumoniae, and others contribute to early damage of the the pathogen associated with the highest fre- blood—brain and blood—CSF barrier. Once bac- quency of neuronal damage, two major toxins teria have entered the subarachnoidal space, they have been identified, H2O2 and pneumolysin, replicate, undergo autolysis and cause further a pore-forming cytolysin. In experimental menin- inflammation. gitis induced by toxin-deficient pneumococcal mutants, neuronal damage was reduced by 50% Several cell types seem to be involved and as compared to wild-type bacteria [Braun et al. mentioned endothelial cells, perivascular macro- 2002]. The proof of direct bacterial toxicity phages and mast cells may play a crucial role underlines the critical importance of rapid anti- [Polfliet et al. 2001; Weber et al. 1997]. Heat biotic elimination of living bacteria and their killed bacteria and pathogen-associated molecu- metabolism. In insufficiently treated patients or lar patterns (PAMP) of meningitis pathogens as resistant bacteria toxic activity may be signifi- lipoprotein (LP), lipoteichoic acid (LTA), pepti- cantly prolonged and harm neuronal functions. doglycan (PG), and lipopolysaccarid (LPS) cause Mechanistically, these toxins seem to cause meningitis indistinguishable from living bacteria programmed death of neurons and microglia [Hoffmann et al. 2007a; Ivey et al. 2005; by inducing rapid mitochondrial damage. Tuomanen et al. 1985]. Immune pattern recog- nition molecules as CD14 and LBP function as sensors in identifying PAMPs [Beutler, 2003]. Pneumococcal PG and LP are recognized by TLR2 [Weber et al. 2003; Aliprantis et al. 1999] whereas LPS, and interestingly the pneu- mococcal toxin pneumolysin, signal through TLR4 [Malley et al. 2003]. TLR signals are con- veyed by the intracellular adapter protein MyD88 downstream to a multitude of inflammatory sig- naling cascades including NFkB and MAP kinases leading to a rapid inflammatory response in meningitis [Lehnardt et al. 2006]. Neuronal damage Up to 50% of survivors of bacterial meningitis suffer from disabling neuropsychological deficits [van de Beek et al. 2002; Merkelbach et al. 2000]. Clinically as well as experimentally, the hippo- campus seems to be the most vulnerable area of the brain [Nau et al. 1999a; van Wees et al. 1990]. Neuronal loss translates into hippocampal atro- phy and has been reported on MRI scans in sur- vivors of bacterial meningitis [Free et al. 1996]. Figure 1. Two major routes involving bacterial toxins The predisposition of the hippocampus for neu- and cytotoxic products of the inflammatory response ronal damage remains unclear. The extracellular lead to intracranial complications and brain damage. fluid around brain cells is contiguous with the Peptidoglycan (PG), bacterial lipopeptide (LP), lipopo- CSF and the proximity to the ventricular lysaccharide (LPS), apoptosis inducing factor (AIF), system allows diffusion between these intracranial pressure (ICP). http://tan.sagepub.com 403 Therapeutic Advances in Neurological Disorders 2 (6) In particular, pneumolysin was shown to translo- Taken together, bacterial components activate cate to mitochondria and induce pore formation microglia in a TLR-dependent fashion and in mitochondrial membranes [Braun et al. 2007; microglia releases cell death signals such as NO Bermpohl et al. 2005; Braun et al. 2001]. Release to neighboring neurons. Bacterial and host- of apoptosis inducing factor (AIF) from damaged derived reactive oxygen and nitrogen species coa- mitochondria leads to large-scale fragmentation lesce to form highly reactive, tissue damaging of the DNA and apoptosis-like cell death. This intermediates [Hoffmann et al. 2006]. type of cell death is executed in a caspase- Moreover, dying parenchymal cells release TLR independent manner. As a consequence, cells ligands as endogenous ‘danger signals’, leading to exposed to live pneumococci or pneumolysin a vicious circle of inflammatory tissue damage in vitro cannot be rescued by caspase inhibitors [Lehnardt et al. 2008]. These mechanisms are [Bermpohl et al. 2005; Braun et al. 2001]. In vivo, important and clearly add to our understanding however, intrathecal application of the broad of how activated microglia can damage surround- spectrum caspase inhibitor, z-VAD-fmk, prevents ing neurons and expand the importance of the about 50% of neuronal damage in experimental findings beyond meningitis. meningitis [Braun et al. 1999]. Further studies in caspase-3 deficient mice revealed that late but Leukocyte influx as the hallmark of acute menin- not early neuronal damage is dependent on cas- gitis contributes to neuronal damage and may in pase activity [Mitchell et al. 2004]. The interpre- fact be more detrimental than beneficial to the tation of these findings is that early caspase- host [Tuomanen et al. 1989]. Neutrophils, independent cell death may be induced by bac- which form the first line of defense in bacterial terial toxins while delayed, caspase-mediated meningitis, are equipped with cytotoxic and proinflammatory activity, placing these cells apoptosis occurs as a consequence mostly of the both as direct effectors of tissue damage and as host immune response. The in vivo findings can orchestrators of further immune activation. be modeled in cell culture systems, and the coex- Granulocyte depletion is neuroprotective in istence of different forms and time courses of cell experimental meningitis, while persistence of damage has been confirmed in vitro [Bermpohl et granulocytes was associated with more pro- al. 2005; Colino and Snapper, 2003]. nounced neuronal damage [Hoffmann et al. 2007b]. Especially in the context of sufficient Antibiotic treatment results in an increase of bac- antibiotic therapy, it may therefore be desirable terial debris, including bacterial DNA and extre- to limit granulocyte activity and to speed up mely powerful stimuli of the immune response granulocyte clearance from the CSF. The cyto- such as PG and LPS [Fischer and Tomasz, kine TRAIL was recently identified as a factor 1984]. The concentration of PG in the CSF cor- that reduces the life span of activated granulo- relates with the clinical outcome of pneumococ- cytes [Renshaw et al. 2003]; TRAIL deficient cal meningitis [Schneider et al. 1999], just as LPS mice displayed prolonged CSF pleocytosis and concentrations in body compartments are linked increased neurotoxicity in experimental meningi- to the severity of meningococcal disease tis, while therapeutic application of recombinant [Brandtzaeg et al. 1992]. While they are extre- TRAIL reversed this effect and provided neuro- mely potent inflammatory stimuli [Hoffmann protection [Hoffmann et al. 2007b]. et al. 2007a], these bacterial cell wall components have no direct toxic effect on cultured neurons Clinical features and diagnosis [Lehnardt et al. 2006, 2003]. This resistance of neurons to TLR ligands can be explained by the Clinical features absence of TLR4 and TLR2 on these cells. Early clinical features of bacterial meningitis are Instead, PAMPs induce indirect neurotoxicity nonspecific and include fever, malaise and head- by activation of pattern recognition receptors ache; and later on, meningismus (neck stiffness), (PRRs) present on microglia, as has been photophobia, phonophobia and vomiting develop shown elegantly in coculture systems. Neuronal as signs of meningeal irritation [van de Beek et al. death is efficiently induced by TLR ligands in the 2004]. Headache and meningismus indicate presence of microglia, and it is strictly dependent inflammatory activation of the trigeminal sensory on the presence of the exact matching TLR and nerve fibers in the meninges and can be blocked an intact downstream MyD88 pathway in micro- experimentally by 5-HT1B/D/F receptor agonists glia [Lehnardt et al. 2006, 2003]. (triptans) [Hoffmann et al. 2002]. However the 404 http://tan.sagepub.com  O Hoffman and JR Weber role of triptans for headache control in patients pathogens, but imperfect sensitivity and specifi- with bacterial meningitis remains to be clarified city argue against routine clinical use at this time [Lampl et al. 2000]. [Hayden and Frenkel, 2000]. Meningismus may be absent very early in the The CSF in bacterial meningitis is characterized disease, in deeply comatose patients, in children by a strongly elevated white blood cell count and in immunocompromised patients such as in (>500 cells/ml) with predominant neutrophils liver cirrhosis [Cabellos et al. 2008]. It is impor- and a strongly elevated protein (>1 g/l), indicat- tant to consider that the classical triad of fever, ing severe blood—CSF barrier disruption. neck stiffness and altered mental state is present Increased lactate (>0.3 g/l) and decreased glu- in less than 50% of adults with proven bacterial cose CSF/blood ratio (