Seminars Volume 12, Number 3
Management of Bacterial Meningitis in Children and Adults Karen L. K o o ~ M.D. ,
T h e clinical presentation and neurologic complications of bacterial meningitis are well known to the neurologist. 1)uring the last few years, significant advances in understanding the pathophysiology of bacterial meningitis have contributed to the management of these types of infections. Experimental models of meningitis have demonstrated that it is the presence of an inflammatory exudate in the subarachnoid space (SAS) that leads to the pathophysiologic changes, including altered cerebrospinal fluid (CSF) dynamics, alterations in bloodbrain barrier permeability, increased intracranial pressure, and loss of cerebral autoregulation. These produce life-threatening neurologic complications and permanent neurologic sequclae.' T h e degree of meningeal inflammation has been shown to be inversely related to outcome in experimental bacterial meningitis.' T h e pathophysiology of bacterial meningitis, clinical presentation, etiologic organisms, and CSF abnormalities will be reviewed, and then therapeutic recommendations made based on our present understanding of the pathophysiology.
PATHOPHYSIOLOGY COLONIZATION
'I'he initial step in the development of bacterial meningitis is colonization of the nasopharynx by the organism. Many bacteria have specialized surface structures and specific organelles that enable the organism to bind to receptors on the host nasopharyngeal mucosal cells.' For exarnple, Neisseria meningitidis strains adhere to the nasopharyngeal epithelial cells by surface appcndages called fimbriae."hese specialized structures allow the organisms to colonize the nasopharynx and ini~ i a t einfection. INTRAVASCULAR DISSEMINATION
Once the meningeal pathogen has adhered to and crossed the mucosal barrier, it gains access to the bloodstream. T h e cornrnon meningeal pathogens, Haemophilus influenzac type b (Hib), N. meningitidis, Streptococcus pneumoniae, and Escherichia coli, all have a
Associate Professor of Neurology, Indiana University School of Medicine, Indiariapolis, Indiana
Reprint requcsts: Dr. Roos, Associate Professor of Neurology, Deparirnent of' Neurology, Indiana Uriiveraity Medical Center, Regenstrief Health Centcr, 1050 Walnut Street, Indianapolis, I N 46202 C:opyright O 1992 by Thieme Medical Puhlishcrs, Inc., 381 Park Avenue South, New York, N Y 100 16. All rights reserved.
Downloaded by: National University of Singapore. Copyrighted material.
September 1992
invasion of SAS by meningeal pathogens
I Multlpllcatlon of organisms In CSF and iysls of omanisms by amlbiotlc therapy
I Generation of banerlal cell wall components
I
7 in concentrations of Inflammatory cytokines In SAS I
I i n c o n n n s of W
p t l n and l a t e in F
7
Altered CSF dynamics
,,
con~t,,
of CSF PGE2
I
Aneralions In biood-braln banier
I
I f In CSF outflow resistance
vaiogenic edema
I
I 7' In ICP
Tin ICP
I in cerebral pelhrslon pressure (In addlllon to loss of cerebral autoregulalon)
I Cerebral lschemla and Infarction
Figure 1. Steps in pathogenesis of the neurologic complications of bacterial meningitis. SAS: subarachnoid space. (Adapted from Odio et al.')
polysaccharide capsule. T h e bacterial capsule allows the organism to escape phagocytosis by neutrophils and classic complement pathway activation. The host, however, does have the means to counteract the antiphagocytic properties of the bacterial capsule. T h e host can produce antibodies to the bacterial antigen. T h e antigenantibody complex can activate the classic complement pathway. T h e alternative complement pathway is directly activated by the polysaccharide capsule and cell walls of S. pneumoniae and by the capsule of Hib. Activation of the alternate complement pathway ultimately results in leukocyte chemotaxis, bacterial phagocytosis, and intravascular clearance of the pathogen. For this reason, however, individuals with complement deficiencies are at particular risk for invasive and chronic infections with encapsulated meningeal pathogen^.^ INVASION OF THE SUBARACHNOID SPACE
156
V O L U M E 12, NUMBER 3
SEPTEMBER I992
therefore the opsonization process is inefficient arid encapsulated orginisms that are able to avoid phagocytosis can multiply to achieve high concentrations in the CSF. In addition, white blood cell (WBC) proteases degrade complement components in a process that contributes to the deficiency of complement." Complement-mediated opsonic activity has been measured, however, in CSF samples from patients with bacterial meningitis who had a favorable outcome, suggesting that complement concentrations and opsoriic activity can increase in CSF during bacterial meningitis.!' Purulent CSF is chemotactic for neutrophils, allowirig them to enter the SAS. T h e neutrophilic pleocytosis in the CSF is both beneficial and detrimental to the host. In experimental models of bacterial meningitis and in patients with bacterial meningitis, low concentrations of leukocytes in CSF in the presence of high CSF bacterial concentrations have been associated with a poor prognosis. However, large numbers of leukoyctes in the SAS are also detrimerltal to the host. Leukocytes contribute to the purulent exudate in the SAS. In addition, the adherence of leukocytes to cerebral capillary erldothelial cells increases the permeability of blood vessels, resulting in leakage o f plasrna proteins. Elevated protein concentrations in the CSF add to the mass of inflammatory exudate in the SAS." T h e neurologic complications of bacterial meningitis are pathophysiologic consequences of an inflammatory mass in the SAS (Fig. 1). Recent investigation has focused on the inflanlmatory mediators, such as bacterial cell wall components and the cytokines interleukin1 (IL-I) and tumor necrosis fBctor (TNF), that initiate and contribute to the inflammatory exudate in the SAS. Recent therapeutic interventions with dexamethasone and norlsteroidal anti-inflammatory drugs (NSAIDs) have been beneficial in reducing the degree of' meningeal inflammation and improving neurologic outcome by affecting the production of these mediators of inflammation. T h e contribution of bacterial cell wall components, inflammatory cytokines, and metabolites of arachidonic acid (AA) to meningeal inflamnlation will be discussed in order to demonstiate how these mediators trigger the pathophysiologic complications of bacterial meningitis.
Once the bacterial pathogen has survived and mulCELL WALL COMPONENTS tiplied in the bloodstream, the next step is invasion of the SAS. T h e exact site of invasion is not known. Early Bacterial cell wall components, which are liberated studies in experimental animals suggested that Hib en- into the SAS by the multiplication of organisms and their ters the CSF from the bloodstream through the dural lysis by antibiotics, are potent mediators of inflammavenous sinus ~ y s t e m Subsequent .~ studies suggested that tion. T h e specific bacterial cell wall conlponents that the bacterium invades the central nervous system (CNS) elicit inflammatory changes in the CSF have been identhrough an area of focal inflammation above the cribri- tified. T h e cell walls of most gram-positive bacteria, such form plate.# Recent experimental studies suggest that as S. pneumoniae, contain teichoic acid. This component the choroid plexus is the area where bacteria first enter of the cell wall is a strong inducer of meningeal inflamthe CSF, and that cells in the choroid plexus and cerebral mation. Tuomanen and coworkers1° tested whole pneucapillaries have receptors that allow for their a d h e r e n ~ e . ~mococcal cell wall and individual components of the cell Once the bacterial pathogen has crossed the blood- wall for specific activity in eliciting an inflammatory rebrain barrier and entered the CSF, host defense mech- sponse when injected intracisternally into the SAS of anisms are inadequate to control the infection. T h e pro- rabbits. Teichoic acid had the highest specific activity of cess of phagocytosis, whereby bacteria are ingested and the cell wall fractions, the greatest amount of inflamkilled by neutrophils and macrophages, is greatly en- mation occurring 5 hours after instillation.1° hanced by a prior process of opsonization, which coats Gram-negative bacteria have lipopolysaccharide encapsulated bacteria with antibody, complement frag- (LPS) molecules attached to their outer membranes. A ments, or both. In the CSF, there are only minimal complex toxic lipid, called lipid A, is a constituent of the concentrations of complement and immunoglobulins; outer membrane of LPS molecules. Lipid A is linked to
Downloaded by: National University of Singapore. Copyrighted material.
SEMINARS I N NEUKOLOGY
MANAGEMENT OF BACTERIAL MENINGITIS-Roos
~~~~~~~~~~~~~~~of
TUMOR NECROSIS FACTOR TNF-(Yis a hormone that is primarily produced by. macrophages and monocytes, but also by brain astrocytes and microglial cells, in response to multiple stimuli, but most importantly bacterial endotoxin. TNF-a is both beneficial and harmful to the host. In physiologic concentrations, it appears to activate the immune system and to be important in tissue healing. In high concentrations, it plays a criticalrole in fatal endotoxemia." T h e infusion of recombinant human T N F into laboratory animals produces physiologic changes, such as severe hypotension, lactic acidosis, and lethal shock, like that observed in animals with gram-negative septicemia.".14 Mustafa and coworker^^.^ detected T N F activity in the CSF of rabbits 45 minutes after the intracisternal inoculation of Hib LOS; this was followed in approximately 75 minutes by a CSF pleocytosis and 3 hours later by changes in CSF protein, glucose, and lactate concentrations. These meningeal inflammatory changes were markedly decreased by simultaneous administration of anti-TNF-a antibody with Hib LOS.I5 High serum T N F concentrations have been detected in patients in septic shock.'%Ievated serum T N F concentrations may be related to severity of illness, as has been observed in patients with meningococcal disease; the patients with the highest serum 'I'NF concentrations (more than 0.1 nglml) died." ZNTERLE UKZN-I IL-1 is also an inflammatory cytokine that is primarily released from monocytes and macrophages in response to microorganisms and their products, such as endotoxins and teichoic acid. IL-1 is also produced by
vascular endothelial cells, neutrophils, astrocytes, and ~~iicroglial cells." Like TNF-a, IL-1 appears to be both beneficial and detrimental to the host. 11,-1 is a potent chemoattractant for neutrophils, monocytes, B cells, and T cells and has a role in B-cell proliferation and antibody production as well as T-cell a~tivation.".~~ IL-1 appears to have a prorrlinerlt role in eliciting inflammatory changes in CSF and, in that way, contributing to an adverse outcome. There is a high correlation between neurologic sequelae and IL-1 concentrations more than 500 pglml in CSF from neonates, infants, and children obtained at the time of diagnosis of bacterial meningitis." ARACHIDONZC ACID METABOLITES TNF-(Yand IL-1 stimulate the production of metabolites of' AA, most notably prostaglandin E, (PGE,) and PGI, (prostacyclin) and leukotriene B,, all of which are potent mediators of inflammation.14 T h e intracisternal inoculation in rabbits of live pneumococcus or its purified cell wall causes increased CSF PGE, concentrations, which are followed by an increase in vascular permeability with leakage of plasma proteins."." Mustafa and coworkers1"demonstrated a direct correlation between concentrations of PGE,, TNF, and IL-1 in the initial sample of CSF of infants and children with bacterial rneriingitis and elevated IL-1, leukocyte, protein, and lactate concentrations in CSF. Experimental studies suggest that PGE, has a role in inhibiting T N F production by monocytes"' and in decreasing the influx of leukocytes into CSF.; In this way, PGE, may also be beneficial in decreasing the concentration of inflammatory medialors, and therefore have an anti-inflammatory role in meningitis.
Downloaded by: National University of Singapore. Copyrighted material.
a polysaccharide and is released when bacterial cells are lysecl. T h e LPS of Hib organisms has a shorter saccharide chain than does the LPS of enteric bacteria and is therefore referred to as a lipooligosaccharide (LOS)." Syrogiannopoulos and coworkersl:'investigated the ability of Hib 1,OS to induce meningeal inflammation in rabbits. T h e intracisternal inoculation of purified Hib LOS ~ r o d u c e da dose- and time-dewendent increase in the number of leukocytes and the protein concentration in the CSF. T h e inflammatory response produced by Hib LOS was blocked by preincubation of LOS with polyrnyxin B, a catiorric antibiotic that neutralizes LOS by binding to the lipid A region of the molecule, and by acyloxyacyl hydrolase, a neutrophil enzyme that cleaves nonhydroxylated fatty acids from the lipid A region of LOS. Experimental evidence suggests that it is the lipid A region of Hib LOS that is responsible for eliciting the inflammatory response." I ' T h e capsular polysaccharide of Hib and S. pneumoniae contributes significantly to the invasiveness of these organisms by allowing them to resist phagocytosis; however, in experimental studies, the isolated capsular either organism did not induce meningeal inflammation."' Recent experimental evidence suggests that bacterial cell wall components elicit an inflammatory response in the SAS by siimulating the relcase of inflammatory CNS cytokines, such as TNF-(Y,1L-I, and prostaglandins 11.1'5
EXCITATORY AMINO ACIDS T h e role of calcium and the excitatory amino acids glutamate and aspartate in the pathogenesis of cytotoxic brain edema has been the focus of recent research. These excitatory amino acids have a role in the opening of the receptor-operated calcium channels. T h e subsequent intracellular accumulation of calcium disturbs the metabolic processes of the cell and results in cytotoxic edema and neuronal cell death."
COMPLICATIONS OF MENINGEAL INFLAMMATION OBSTRUCTION OF CSF RESORPTION T h e accumulation of leukocytes and purulent exudate in the SAS eventually alters CSF dynamics (Fig. 1). T h e exudate is most abundant in the cisterns at the base of the brain and over the convexities of the hemispheres in the rolandic and sylvian sulci.*' As the exudate accumulates in the basal cisterns, the flow of CSF may become obstructed, with resultant noncommunicating or obstructive hydrocephalus. T h e SAS exudate also interferes with the absorption of CSF by the arachnoid villi. This obstruction to CSF resorption leads to communicating hydrocephalus. As the exudate persists in the SAS, the arachnoid villi become fibrotic and pockets of exudate become walled off by adhesions in the SAS.21
157
SEMINARS IN NEUKOLOGY
INCREASED INTRACRANZAL PRESSURE Increased intracranial pressure (ICP), a common complication of bacterial meningitis, is caused by interstitial, cytotoxic, and vasogenic edema. As has been discussed, interstitial edema results from altered CSF dynamics caused by obstruction of CSF flow by a purulent exudate in the SAS. T h e inflammatory cytokines IL-I and TNF, AA metabolites, arid leukocytes alter bloodbrain barrier permeability at the level of the cerebral capillary endothelial cell; the end result is vasogenic edema." Cytotoxic brain edema is caused by toxic factors from neutrophils and bacteria that affect cell metabolism, with subsequent swelling of neurons. Cytotoxic cerebral edema results from the intracellular accumulation of water and sodium caused by secretion of antidiuretic hormone, which produces hypotonicity of extracellular fluid.".'"
CEREBRAL PERFUSION PRESSURE Increased ICP adversely affects cerebral perfusion pressure (CPP), defined as the difference betwcen the systemic mean arterial pressure (MAP) and the ICP (CPP = M A P - ICP).5." If ICP increases o r systemic arterial pressure decreases sufficiently, cerebral ischemia and infarction may result. Cerebral blood flow is normally constant within a range of MAP from 50 to 150 mmHg. There is experimental evidence that autoregulation of cerebral blood flow is lost in bacterial meningitis; under those circumstances, cerebral blood flow becomes dependent on systemic arterial pressure."," Systemic hypotension results in decreased cerebral blood flow and cerebral tissue ischemia.""
CLINICAL PRESENTATION 'l'he classic presentation of bacterial meningitis includes a combination of syniptoms of infection (fever, headache, photophobia, vomiting, lethargy, or an altered level of consciousness) accompanied by signs of meningeal irritation, such as nuchal rigidity and Kernig's o r Brudzinski's signs. T h e presentation of this type of infection in children and in younger and older adults is similar; however, each age group has a particular combination of symptoms and signs that deserves emphasis.
CHILDREN Children with bacterial meningitis typically are febrile, irritable, o r lethargic; they may vomit and, if old enough, complain of headache, nuchal rigidity, and photophobia. In a review of 110 cases of culture-proven bacterial meningitis in children, fever (38.5"C or greater) was present in 94% of patients. Vomiting and nuchal rigidity were present in 80%' of the children who were 1 year of age o r older.?-he presentation of meningitis in children is either that of a subacute illness, which has been progressive over 24 to 72 hours, o r of a fulminant illness that develops over several hours and is associated with signs and symptoms of meningeal irritation and raised ICP on initial pre~entation."",'~ Bacterial meningitis in childrcn is complicated by the development of seizures, subdural effusions, hyporiatrernia, and neurologic deficits. Seizures occur in 30 to 40% of children with bacterial meningitis within the first 3 days of illne~s.~" Focal rieurologic signs, such as cranial nerve abnormalities, hemiparesis, and ataxia, occur during the course of bacterial meningitis in approximately 15% of ~ h i l d r e n . ~At . ~least ' 50% of children with H, intluenzae meningitis will develop hyporlatremia due to inappropriate sccrction of antidiuretic hormone; therefore the serum sodium should be monitored frequently in children with Hib meningitis, and fluid administration restricted unless hypotension o r septic ,. shock develops."~"'
INFECTIOUS VASCULZTZS Cerebral perfusion is also affected by inflammatory changes in blood vessels. Within the first 48 to 72 hours of infection. there is evidence of inflammation in the walls of the small and medium-sized subarachnoid arteries. T h e adventitia is infiltrated by neutrophils, and endothelial cells swell and multiply, narrowing the lumen of the blood vessel.",21T h e result is ischemia and infarction of brain parenchyma and, subsequently, focal neurologic deficits. Similarly, the inflammatory process involves the walls and lumen of the major cortical veins and dural sinuses, resulting in thrombosis and hemorrhagic cortical infarction." T h e latter is, at least in part, the pathologic basis for seizure disorders.
ADDITIONAL COMPLICATIONS
158
T h e purulent exudate in the SAS extends into the arachnoidal sheaths of the cranial nerves, producing cranial nerve deficits. Subdural effusions are due to an increase in the permeability of the thin-walled capillaries and veins in the inner layer of the dura, with leakage of fluid into the subdural spaceus
ADULTS 'l'he typical presentation of bacterial meningitis in adults is very similar to that of children, except that adults more frequently have altered mental status on admission, which may rapidly progress to stupor o r coma. I'he level of consciousness on admission was recorded in a review of 191 cases of bacterial meningitis in adults.'l Nine patients (5%) were alert, 48 (29%) were lethargic, 44 (22%) were confused, and the remainder were obtunded o r comatose."' I'he increased frequency of' altered mental status in adults with bacterial meningitis n ~ a ybe explained by the increased incidence of pneutnococcal meningitis in adults. Individuals with pneumococcal meningitis are more likely to have an altered mental status on admission and to develop recurrent seizure activity than are individuals with rneningococcal o r H. influcnzac meningitis." Pneumonia is evident on chest x-ray at thc time of admission in 25 to 50% of adults with prieumococcal meningitis.:" Acute or chronic otitis media and posttrauniatic dural sinus fistula are also conditions that often predispose to pneumococcal meningitis.
Downloaded by: National University of Singapore. Copyrighted material.
CSF can no longer be resorbed by the arachnoid villi and there is transependymal movement of CSF from the ventricles into the brain parenchyma with the development of interstitial edema.
VOI,UME 12, NUMREK 3 SEPTEMBER I992
T h e rash of meningococcemia may initially be a diffuse erythematous maculopapular rash, with purpuric and petechial lesions on the trunk and lower extremities appearing subsequently; or it may start as a purpuric or petechial rash. Petechiae may develop in the skin, mucous membranes, or conjunctivae, but the nail beds are spared in patients with meningococcemia. Petechiae usually fade in 3 or 4 days,',3'
OLDER ADULTS T h e most common symptoms of bacterial meningitis in the older adult are fever and confusion. Gorse et a]:':' compared the .initial presentation of bacterial meningitis in individuals aged 50 years or older to that of individuals aged 15 to 4 9 years: confusion was present in 92% of the older individuals with pneumococcal meningitis (12 of 13) and in 78% of the older individuals with gram-negative meningitis (7 of 9); the incidence of more severe mental status abnormalities in the older age group was significantly greater than in the younger age group ( p
Management of Bacterial Meningitis in Children and Adults Karen L. K o o ~ M.D. ,
T h e clinical presentation and neurologic complications of bacterial meningitis are well known to the neurologist. 1)uring the last few years, significant advances in understanding the pathophysiology of bacterial meningitis have contributed to the management of these types of infections. Experimental models of meningitis have demonstrated that it is the presence of an inflammatory exudate in the subarachnoid space (SAS) that leads to the pathophysiologic changes, including altered cerebrospinal fluid (CSF) dynamics, alterations in bloodbrain barrier permeability, increased intracranial pressure, and loss of cerebral autoregulation. These produce life-threatening neurologic complications and permanent neurologic sequclae.' T h e degree of meningeal inflammation has been shown to be inversely related to outcome in experimental bacterial meningitis.' T h e pathophysiology of bacterial meningitis, clinical presentation, etiologic organisms, and CSF abnormalities will be reviewed, and then therapeutic recommendations made based on our present understanding of the pathophysiology.
PATHOPHYSIOLOGY COLONIZATION
'I'he initial step in the development of bacterial meningitis is colonization of the nasopharynx by the organism. Many bacteria have specialized surface structures and specific organelles that enable the organism to bind to receptors on the host nasopharyngeal mucosal cells.' For exarnple, Neisseria meningitidis strains adhere to the nasopharyngeal epithelial cells by surface appcndages called fimbriae."hese specialized structures allow the organisms to colonize the nasopharynx and ini~ i a t einfection. INTRAVASCULAR DISSEMINATION
Once the meningeal pathogen has adhered to and crossed the mucosal barrier, it gains access to the bloodstream. T h e cornrnon meningeal pathogens, Haemophilus influenzac type b (Hib), N. meningitidis, Streptococcus pneumoniae, and Escherichia coli, all have a
Associate Professor of Neurology, Indiana University School of Medicine, Indiariapolis, Indiana
Reprint requcsts: Dr. Roos, Associate Professor of Neurology, Deparirnent of' Neurology, Indiana Uriiveraity Medical Center, Regenstrief Health Centcr, 1050 Walnut Street, Indianapolis, I N 46202 C:opyright O 1992 by Thieme Medical Puhlishcrs, Inc., 381 Park Avenue South, New York, N Y 100 16. All rights reserved.
Downloaded by: National University of Singapore. Copyrighted material.
September 1992
invasion of SAS by meningeal pathogens
I Multlpllcatlon of organisms In CSF and iysls of omanisms by amlbiotlc therapy
I Generation of banerlal cell wall components
I
7 in concentrations of Inflammatory cytokines In SAS I
I i n c o n n n s of W
p t l n and l a t e in F
7
Altered CSF dynamics
,,
con~t,,
of CSF PGE2
I
Aneralions In biood-braln banier
I
I f In CSF outflow resistance
vaiogenic edema
I
I 7' In ICP
Tin ICP
I in cerebral pelhrslon pressure (In addlllon to loss of cerebral autoregulalon)
I Cerebral lschemla and Infarction
Figure 1. Steps in pathogenesis of the neurologic complications of bacterial meningitis. SAS: subarachnoid space. (Adapted from Odio et al.')
polysaccharide capsule. T h e bacterial capsule allows the organism to escape phagocytosis by neutrophils and classic complement pathway activation. The host, however, does have the means to counteract the antiphagocytic properties of the bacterial capsule. T h e host can produce antibodies to the bacterial antigen. T h e antigenantibody complex can activate the classic complement pathway. T h e alternative complement pathway is directly activated by the polysaccharide capsule and cell walls of S. pneumoniae and by the capsule of Hib. Activation of the alternate complement pathway ultimately results in leukocyte chemotaxis, bacterial phagocytosis, and intravascular clearance of the pathogen. For this reason, however, individuals with complement deficiencies are at particular risk for invasive and chronic infections with encapsulated meningeal pathogen^.^ INVASION OF THE SUBARACHNOID SPACE
156
V O L U M E 12, NUMBER 3
SEPTEMBER I992
therefore the opsonization process is inefficient arid encapsulated orginisms that are able to avoid phagocytosis can multiply to achieve high concentrations in the CSF. In addition, white blood cell (WBC) proteases degrade complement components in a process that contributes to the deficiency of complement." Complement-mediated opsonic activity has been measured, however, in CSF samples from patients with bacterial meningitis who had a favorable outcome, suggesting that complement concentrations and opsoriic activity can increase in CSF during bacterial meningitis.!' Purulent CSF is chemotactic for neutrophils, allowirig them to enter the SAS. T h e neutrophilic pleocytosis in the CSF is both beneficial and detrimental to the host. In experimental models of bacterial meningitis and in patients with bacterial meningitis, low concentrations of leukocytes in CSF in the presence of high CSF bacterial concentrations have been associated with a poor prognosis. However, large numbers of leukoyctes in the SAS are also detrimerltal to the host. Leukocytes contribute to the purulent exudate in the SAS. In addition, the adherence of leukocytes to cerebral capillary erldothelial cells increases the permeability of blood vessels, resulting in leakage o f plasrna proteins. Elevated protein concentrations in the CSF add to the mass of inflammatory exudate in the SAS." T h e neurologic complications of bacterial meningitis are pathophysiologic consequences of an inflammatory mass in the SAS (Fig. 1). Recent investigation has focused on the inflanlmatory mediators, such as bacterial cell wall components and the cytokines interleukin1 (IL-I) and tumor necrosis fBctor (TNF), that initiate and contribute to the inflammatory exudate in the SAS. Recent therapeutic interventions with dexamethasone and norlsteroidal anti-inflammatory drugs (NSAIDs) have been beneficial in reducing the degree of' meningeal inflammation and improving neurologic outcome by affecting the production of these mediators of inflammation. T h e contribution of bacterial cell wall components, inflammatory cytokines, and metabolites of arachidonic acid (AA) to meningeal inflamnlation will be discussed in order to demonstiate how these mediators trigger the pathophysiologic complications of bacterial meningitis.
Once the bacterial pathogen has survived and mulCELL WALL COMPONENTS tiplied in the bloodstream, the next step is invasion of the SAS. T h e exact site of invasion is not known. Early Bacterial cell wall components, which are liberated studies in experimental animals suggested that Hib en- into the SAS by the multiplication of organisms and their ters the CSF from the bloodstream through the dural lysis by antibiotics, are potent mediators of inflammavenous sinus ~ y s t e m Subsequent .~ studies suggested that tion. T h e specific bacterial cell wall conlponents that the bacterium invades the central nervous system (CNS) elicit inflammatory changes in the CSF have been identhrough an area of focal inflammation above the cribri- tified. T h e cell walls of most gram-positive bacteria, such form plate.# Recent experimental studies suggest that as S. pneumoniae, contain teichoic acid. This component the choroid plexus is the area where bacteria first enter of the cell wall is a strong inducer of meningeal inflamthe CSF, and that cells in the choroid plexus and cerebral mation. Tuomanen and coworkers1° tested whole pneucapillaries have receptors that allow for their a d h e r e n ~ e . ~mococcal cell wall and individual components of the cell Once the bacterial pathogen has crossed the blood- wall for specific activity in eliciting an inflammatory rebrain barrier and entered the CSF, host defense mech- sponse when injected intracisternally into the SAS of anisms are inadequate to control the infection. T h e pro- rabbits. Teichoic acid had the highest specific activity of cess of phagocytosis, whereby bacteria are ingested and the cell wall fractions, the greatest amount of inflamkilled by neutrophils and macrophages, is greatly en- mation occurring 5 hours after instillation.1° hanced by a prior process of opsonization, which coats Gram-negative bacteria have lipopolysaccharide encapsulated bacteria with antibody, complement frag- (LPS) molecules attached to their outer membranes. A ments, or both. In the CSF, there are only minimal complex toxic lipid, called lipid A, is a constituent of the concentrations of complement and immunoglobulins; outer membrane of LPS molecules. Lipid A is linked to
Downloaded by: National University of Singapore. Copyrighted material.
SEMINARS I N NEUKOLOGY
MANAGEMENT OF BACTERIAL MENINGITIS-Roos
~~~~~~~~~~~~~~~of
TUMOR NECROSIS FACTOR TNF-(Yis a hormone that is primarily produced by. macrophages and monocytes, but also by brain astrocytes and microglial cells, in response to multiple stimuli, but most importantly bacterial endotoxin. TNF-a is both beneficial and harmful to the host. In physiologic concentrations, it appears to activate the immune system and to be important in tissue healing. In high concentrations, it plays a criticalrole in fatal endotoxemia." T h e infusion of recombinant human T N F into laboratory animals produces physiologic changes, such as severe hypotension, lactic acidosis, and lethal shock, like that observed in animals with gram-negative septicemia.".14 Mustafa and coworker^^.^ detected T N F activity in the CSF of rabbits 45 minutes after the intracisternal inoculation of Hib LOS; this was followed in approximately 75 minutes by a CSF pleocytosis and 3 hours later by changes in CSF protein, glucose, and lactate concentrations. These meningeal inflammatory changes were markedly decreased by simultaneous administration of anti-TNF-a antibody with Hib LOS.I5 High serum T N F concentrations have been detected in patients in septic shock.'%Ievated serum T N F concentrations may be related to severity of illness, as has been observed in patients with meningococcal disease; the patients with the highest serum 'I'NF concentrations (more than 0.1 nglml) died." ZNTERLE UKZN-I IL-1 is also an inflammatory cytokine that is primarily released from monocytes and macrophages in response to microorganisms and their products, such as endotoxins and teichoic acid. IL-1 is also produced by
vascular endothelial cells, neutrophils, astrocytes, and ~~iicroglial cells." Like TNF-a, IL-1 appears to be both beneficial and detrimental to the host. 11,-1 is a potent chemoattractant for neutrophils, monocytes, B cells, and T cells and has a role in B-cell proliferation and antibody production as well as T-cell a~tivation.".~~ IL-1 appears to have a prorrlinerlt role in eliciting inflammatory changes in CSF and, in that way, contributing to an adverse outcome. There is a high correlation between neurologic sequelae and IL-1 concentrations more than 500 pglml in CSF from neonates, infants, and children obtained at the time of diagnosis of bacterial meningitis." ARACHIDONZC ACID METABOLITES TNF-(Yand IL-1 stimulate the production of metabolites of' AA, most notably prostaglandin E, (PGE,) and PGI, (prostacyclin) and leukotriene B,, all of which are potent mediators of inflammation.14 T h e intracisternal inoculation in rabbits of live pneumococcus or its purified cell wall causes increased CSF PGE, concentrations, which are followed by an increase in vascular permeability with leakage of plasma proteins."." Mustafa and coworkers1"demonstrated a direct correlation between concentrations of PGE,, TNF, and IL-1 in the initial sample of CSF of infants and children with bacterial rneriingitis and elevated IL-1, leukocyte, protein, and lactate concentrations in CSF. Experimental studies suggest that PGE, has a role in inhibiting T N F production by monocytes"' and in decreasing the influx of leukocytes into CSF.; In this way, PGE, may also be beneficial in decreasing the concentration of inflammatory medialors, and therefore have an anti-inflammatory role in meningitis.
Downloaded by: National University of Singapore. Copyrighted material.
a polysaccharide and is released when bacterial cells are lysecl. T h e LPS of Hib organisms has a shorter saccharide chain than does the LPS of enteric bacteria and is therefore referred to as a lipooligosaccharide (LOS)." Syrogiannopoulos and coworkersl:'investigated the ability of Hib 1,OS to induce meningeal inflammation in rabbits. T h e intracisternal inoculation of purified Hib LOS ~ r o d u c e da dose- and time-dewendent increase in the number of leukocytes and the protein concentration in the CSF. T h e inflammatory response produced by Hib LOS was blocked by preincubation of LOS with polyrnyxin B, a catiorric antibiotic that neutralizes LOS by binding to the lipid A region of the molecule, and by acyloxyacyl hydrolase, a neutrophil enzyme that cleaves nonhydroxylated fatty acids from the lipid A region of LOS. Experimental evidence suggests that it is the lipid A region of Hib LOS that is responsible for eliciting the inflammatory response." I ' T h e capsular polysaccharide of Hib and S. pneumoniae contributes significantly to the invasiveness of these organisms by allowing them to resist phagocytosis; however, in experimental studies, the isolated capsular either organism did not induce meningeal inflammation."' Recent experimental evidence suggests that bacterial cell wall components elicit an inflammatory response in the SAS by siimulating the relcase of inflammatory CNS cytokines, such as TNF-(Y,1L-I, and prostaglandins 11.1'5
EXCITATORY AMINO ACIDS T h e role of calcium and the excitatory amino acids glutamate and aspartate in the pathogenesis of cytotoxic brain edema has been the focus of recent research. These excitatory amino acids have a role in the opening of the receptor-operated calcium channels. T h e subsequent intracellular accumulation of calcium disturbs the metabolic processes of the cell and results in cytotoxic edema and neuronal cell death."
COMPLICATIONS OF MENINGEAL INFLAMMATION OBSTRUCTION OF CSF RESORPTION T h e accumulation of leukocytes and purulent exudate in the SAS eventually alters CSF dynamics (Fig. 1). T h e exudate is most abundant in the cisterns at the base of the brain and over the convexities of the hemispheres in the rolandic and sylvian sulci.*' As the exudate accumulates in the basal cisterns, the flow of CSF may become obstructed, with resultant noncommunicating or obstructive hydrocephalus. T h e SAS exudate also interferes with the absorption of CSF by the arachnoid villi. This obstruction to CSF resorption leads to communicating hydrocephalus. As the exudate persists in the SAS, the arachnoid villi become fibrotic and pockets of exudate become walled off by adhesions in the SAS.21
157
SEMINARS IN NEUKOLOGY
INCREASED INTRACRANZAL PRESSURE Increased intracranial pressure (ICP), a common complication of bacterial meningitis, is caused by interstitial, cytotoxic, and vasogenic edema. As has been discussed, interstitial edema results from altered CSF dynamics caused by obstruction of CSF flow by a purulent exudate in the SAS. T h e inflammatory cytokines IL-I and TNF, AA metabolites, arid leukocytes alter bloodbrain barrier permeability at the level of the cerebral capillary endothelial cell; the end result is vasogenic edema." Cytotoxic brain edema is caused by toxic factors from neutrophils and bacteria that affect cell metabolism, with subsequent swelling of neurons. Cytotoxic cerebral edema results from the intracellular accumulation of water and sodium caused by secretion of antidiuretic hormone, which produces hypotonicity of extracellular fluid.".'"
CEREBRAL PERFUSION PRESSURE Increased ICP adversely affects cerebral perfusion pressure (CPP), defined as the difference betwcen the systemic mean arterial pressure (MAP) and the ICP (CPP = M A P - ICP).5." If ICP increases o r systemic arterial pressure decreases sufficiently, cerebral ischemia and infarction may result. Cerebral blood flow is normally constant within a range of MAP from 50 to 150 mmHg. There is experimental evidence that autoregulation of cerebral blood flow is lost in bacterial meningitis; under those circumstances, cerebral blood flow becomes dependent on systemic arterial pressure."," Systemic hypotension results in decreased cerebral blood flow and cerebral tissue ischemia.""
CLINICAL PRESENTATION 'l'he classic presentation of bacterial meningitis includes a combination of syniptoms of infection (fever, headache, photophobia, vomiting, lethargy, or an altered level of consciousness) accompanied by signs of meningeal irritation, such as nuchal rigidity and Kernig's o r Brudzinski's signs. T h e presentation of this type of infection in children and in younger and older adults is similar; however, each age group has a particular combination of symptoms and signs that deserves emphasis.
CHILDREN Children with bacterial meningitis typically are febrile, irritable, o r lethargic; they may vomit and, if old enough, complain of headache, nuchal rigidity, and photophobia. In a review of 110 cases of culture-proven bacterial meningitis in children, fever (38.5"C or greater) was present in 94% of patients. Vomiting and nuchal rigidity were present in 80%' of the children who were 1 year of age o r older.?-he presentation of meningitis in children is either that of a subacute illness, which has been progressive over 24 to 72 hours, o r of a fulminant illness that develops over several hours and is associated with signs and symptoms of meningeal irritation and raised ICP on initial pre~entation."",'~ Bacterial meningitis in childrcn is complicated by the development of seizures, subdural effusions, hyporiatrernia, and neurologic deficits. Seizures occur in 30 to 40% of children with bacterial meningitis within the first 3 days of illne~s.~" Focal rieurologic signs, such as cranial nerve abnormalities, hemiparesis, and ataxia, occur during the course of bacterial meningitis in approximately 15% of ~ h i l d r e n . ~At . ~least ' 50% of children with H, intluenzae meningitis will develop hyporlatremia due to inappropriate sccrction of antidiuretic hormone; therefore the serum sodium should be monitored frequently in children with Hib meningitis, and fluid administration restricted unless hypotension o r septic ,. shock develops."~"'
INFECTIOUS VASCULZTZS Cerebral perfusion is also affected by inflammatory changes in blood vessels. Within the first 48 to 72 hours of infection. there is evidence of inflammation in the walls of the small and medium-sized subarachnoid arteries. T h e adventitia is infiltrated by neutrophils, and endothelial cells swell and multiply, narrowing the lumen of the blood vessel.",21T h e result is ischemia and infarction of brain parenchyma and, subsequently, focal neurologic deficits. Similarly, the inflammatory process involves the walls and lumen of the major cortical veins and dural sinuses, resulting in thrombosis and hemorrhagic cortical infarction." T h e latter is, at least in part, the pathologic basis for seizure disorders.
ADDITIONAL COMPLICATIONS
158
T h e purulent exudate in the SAS extends into the arachnoidal sheaths of the cranial nerves, producing cranial nerve deficits. Subdural effusions are due to an increase in the permeability of the thin-walled capillaries and veins in the inner layer of the dura, with leakage of fluid into the subdural spaceus
ADULTS 'l'he typical presentation of bacterial meningitis in adults is very similar to that of children, except that adults more frequently have altered mental status on admission, which may rapidly progress to stupor o r coma. I'he level of consciousness on admission was recorded in a review of 191 cases of bacterial meningitis in adults.'l Nine patients (5%) were alert, 48 (29%) were lethargic, 44 (22%) were confused, and the remainder were obtunded o r comatose."' I'he increased frequency of' altered mental status in adults with bacterial meningitis n ~ a ybe explained by the increased incidence of pneutnococcal meningitis in adults. Individuals with pneumococcal meningitis are more likely to have an altered mental status on admission and to develop recurrent seizure activity than are individuals with rneningococcal o r H. influcnzac meningitis." Pneumonia is evident on chest x-ray at thc time of admission in 25 to 50% of adults with prieumococcal meningitis.:" Acute or chronic otitis media and posttrauniatic dural sinus fistula are also conditions that often predispose to pneumococcal meningitis.
Downloaded by: National University of Singapore. Copyrighted material.
CSF can no longer be resorbed by the arachnoid villi and there is transependymal movement of CSF from the ventricles into the brain parenchyma with the development of interstitial edema.
VOI,UME 12, NUMREK 3 SEPTEMBER I992
T h e rash of meningococcemia may initially be a diffuse erythematous maculopapular rash, with purpuric and petechial lesions on the trunk and lower extremities appearing subsequently; or it may start as a purpuric or petechial rash. Petechiae may develop in the skin, mucous membranes, or conjunctivae, but the nail beds are spared in patients with meningococcemia. Petechiae usually fade in 3 or 4 days,',3'
OLDER ADULTS T h e most common symptoms of bacterial meningitis in the older adult are fever and confusion. Gorse et a]:':' compared the .initial presentation of bacterial meningitis in individuals aged 50 years or older to that of individuals aged 15 to 4 9 years: confusion was present in 92% of the older individuals with pneumococcal meningitis (12 of 13) and in 78% of the older individuals with gram-negative meningitis (7 of 9); the incidence of more severe mental status abnormalities in the older age group was significantly greater than in the younger age group ( p
