++
Meningitis, an infection of the subarachnoid space and leptomeninges
caused by a variety of pathogenic organisms, continues to be an
important source of mortality and morbidity. Despite the introduction
of new vaccines that prevent the most severe causes, bacterial, or purulent,
meningitis remains the most important form in the United
States in terms of incidence, sequelae, and ultimate loss of productive life. Aseptic
meningitis, usually caused by viruses, especially enteroviruses
(see Chapter 306) is more common; however,
significant sequelae are uncommon and the disease is usually self-limited. Granulomatous
meningitis, caused either by M tuberculosis or
fungi, is a major cause of neurologic injury and death in the developing
world (See Chapter 269).
++
The first month after birth represents the period of highest
attack rate for meningitis, with likely pathogens including group
B streptococci (Streptococcus agalactiae), Escherichia coli, other
gram-negative enteric organisms, and less commonly, Listeria
monocytogenes (Table 231-1). Beyond
the neonatal period, the most important pathogens are Streptococcus
pneumoniae and Neisseria meningitidis. Formerly, Haemophilus
influenzae type b (Hib) was the most common
pathogen causing meningitis in infants and children, but the incidence
has been reduced substantially by immunization with conjugate vaccines
in developed countries.1,2 Recent studies of conjugate
pneumococcal vaccine, introduced in the United States in 2000, demonstrate
that it is effective in preventing pneumococcal meningitis.3 Similarly,
the meningococcal polysaccharide vaccine introduced in the early 1970s
has been effective in reducing meningococcal meningitis. Thus, the
incidence of infection and prevailing predominant causative organisms
varies depending upon the immunization status of the population.
++
++
Bacterial meningitis is reported with increased frequency among
African Americans, Native Americans, and individuals in rural areas.
It is unclear whether environmental or genetic factors are responsible
for enhanced susceptibility. Seasonal patterns of disease have been
noted to occur, with meningitis caused by N meningitidis and S
pneumoniae peaking in the winter months, Hib showing
a biphasic distribution with peaks in the early winter and spring,
and L monocytogenes occurring most frequently in
the summer months. In the “meningitis belt” of
sub-Saharan Africa, the shift from the wet to the dry season is
associated with an increase in meningitis. These patterns are likely
due to the modes for acquiring the organisms, with N meningitidis, S
pneumoniae, and Hib spread by the respiratory
route, in months with increased incidence of common respiratory
diseases, and L monocytogenes acquired from contaminated
food or contact with farm animals.
++
Host factors that predispose to increased susceptibility to encapsulated
organisms such as S pneumoniae increase the risk
of meningitis. Neisseria infections including N meningitidis occur
with increased frequency in persons with deficiencies of the terminal
components of complement. Polymorphisms in toll-like receptors,
integral parts of the innate immune response, have also been associated
with increased risk for N meningitidis invasive
disease.
++
The emergence of bacteria resistant to commonly prescribed antibiotics
has changed empiric treatment of presumed bacterial meningitis.
In the past decade, S pneumoniae with reduced susceptibility
to penicillins and cephalosporins have been identified in virtually
all parts of the world and, in some areas, may compromise the utility
of those drugs for empiric therapy. The 7-valent pneumococcal conjugate vaccine
currently available in the United States is directed at several
strains associated with increased antibiotic resistance. Since its
introduction, the number of strains causing invasive disease that
are resistant to penicillin has declined. According to the Centers
for Disease Control and Prevention, in 2002 34% of invasive
infections due to S pneumoniae were caused by pneumococci
nonsusceptible to at least one drug, and 17% were due to
a strain nonsusceptible to 3 or more drugs. Of children who received
the pneumococcal conjugate, 18.4% of those with invasive
pneumococcal disease had strains intermediately susceptible to penicillin,
and 19.1% had strains with high-level resistance to penicillin.
More recently, a nonvaccine serotype (19A) resistant to multiple
antibiotics has emerged as a cause of invasive disease.3,4 Increased
antibiotic resistance has also been seen with gram-negative enteric organisms
such as E coli. However, S agalactiae and N
meningitidis have generally remained susceptible to penicillin
and the third-generation cephalosporins. The clinician must be aware
of emerging patterns of resistance within the community and in the
hospital setting for patients who develop symptoms suspicious for invasive
bacterial disease, including meningitis.
++
The most common progression of infection in children with bacterial
meningitis is hematogenous spread from the nasopharynx and bacterial
entry into the subarachnoid space where bacterial growth occurs
freely because the CSF contains few fixed or circulating scavenger
cells to remove bacteria and has poor opsonic and bactericidal capability
so there is not a rapid, cellular or humoral immune response.5 It
may also occur as a direct extension from a contiguous focus or
as a result of congenital, traumatic, or surgical disruption of
normal anatomic barriers. Examples of such disruption include basilar
skull fractures, placement of cerebrospinal fluid (CSF) shunts,
and congenital dermal sinuses along the craniospinal axis.5
++
In the case of hematogenous spread, the portal of entry across
the blood-brain barrier to the subarachnoid space appears to be
the choroid plexus where bacterial growth occurs freely, usually
to the level of 106 to 107 organisms
per milliliter of spinal fluid. This is because the CSF contains
few fixed or circulating scavenger cells to remove bacteria and
has poor opsonic and bactericidal capability so there is not a rapid,
cellular or humoral immune response.5
++
Many of the neurologic sequelae of bacterial meningitis are a
consequence of altered physiology due to the host’s inflammatory
response to the infecting organism (eFig. 231.1).6 In
the subarachnoid space, components of the surface of the multiplying
bacteria (lipopolysaccharide, lipo-oligosaccharide, teichoic acid)
stimulate generation of proinflammatory cytokines (tumor necrosis factor [TNF]-α,
interleukin [IL]-1β, IL-6, platelet
activating factor [PAF], and others). These, in
turn, increase adhesion of leukocytes to cerebral vascular endothelium,
promoting increased blood-brain barrier permeability and migration
of leukocytes into the subarachnoid space. White blood cell and
endothelium-derived reactive oxygen species, and perhaps nitric
oxide, then participate in altering cerebrovascular reactivity. Cerebral
edema associated with meningitis represents a combination of vasogenic,
cytotoxic, and intersititial edema. Cerebral perfusion is reduced
in meningitis in approximately 30% of children in whom
brain blood-flow studies have been performed. Cerebral edema not only
contributes to reduced cerebral perfusion pressure but may also
cause cerebral herniation due to increased intracranial pressure.5,6
++
++
Direct cytotoxic neuronal injury, frequently found in postmortem
studies, is likely caused by reactive oxygen and nitrogen species
(oxygen radical, nitric oxide, peroxynitrite, hydroxyl radical),
excitatory amino acids, caspases, and matrix metalloproteinases
(MMPs). Experimental animal studies demonstrate improved neuronal
survival when specific inhibitors of these compounds are used.7
++
Abnormalities of brain metabolism include hypoglycorrhachia and
CSF lactic acidosis. Low CSF glucose levels occur by impaired glucose
transport across the blood-brain barrier and possibly by increased
cerebral glucose utilization. CSF lactic acidosis indicates anaerobic
glucose utilization within the central nervous system.
++
Pathologic changes in meningitis reflect the inflammatory mass
in the subarachnoid space, cerebral vasculitis, cerebral edema,
and cellular injury. The inflammatory mass usually begins in the
basilar cisterns, spreads around the cerebellum, and then spreads
over the cerebral convexities. Those cranial nerves that traverse the
subarachnoid space are particularly prone to injury in meningitis,
perhaps due to the surrounding inflammation. Vasculitis of both
arteries and veins occurs, particularly in meningitis caused by S
pneumoniae, resulting in tissue ischemia and arterial and
venous infarcts. Direct cellular injury, as a result of bacterial
toxins, host factors, or ischemia, is frequently noted in postmortem
studies.
+++
Clinical Manifestations
++
The classic triad of symptoms in meningitis includes fever, headache,
and stiff neck. However, in children under 2 years of age, and especially
in young infants, stiff neck or other signs of meningeal irritation
may be absent. Alteration of level of consciousness is usual, occurring
in up to 90% of patients. The majority present with irritability,
lethargy, or confusion, and 10% to 15% present
in coma, a very poor prognostic sign. Physical examination of older
children may reveal typical signs of meningeal irritation—stiff
neck and positive Kernig and Brudzinski signs. Infants often have
a bulging fontanel. Cranial nerve abnormalities, particularly of
the sixth cranial nerve, may be the consequence of increased intracranial
pressure or of inflammation in the subarachnoid space. Focal neurologic abnormalities
are uncommon early in the disease, but when present may be indicators
of cerebral infarct.1
++
Systemic signs may also be present in children with meningitis.
The most common occur in the setting of meningococcal disease. The
rash in meningococcal sepsis evolves from a transient erythematous,
macular eruption to the presence of petechiae, ecchymoses, and purpura.
Approximately 50% of these patients will have concurrent
meningitis. Meningitis due to N meningitidis and
gram-negative rod organisms frequently results in hypotension due
to the systemic effects of endotoxin. Most other causes of meningitis,
including those due to S pneumoniae, Hib, and L
monocytogenes, are usually not accompanied by endotoxic
shock. Hypotension in the setting of disease caused by these other
organisms is most commonly the result of volume depletion or purpura
fulminans. Purpura fulminans is a condition associated
with overwhelming infections and includes rapidly evolving disseminated
intravascular coagulation (DIC), fever, chills, and ecchymotic skin
lesions that may ulcerate and progress to peripheral gangrene, shock,
and death.1
++
Once the diagnosis of meningitis is suspected, immediate examination
of the CSF is indicated. A specific reason to delay lumbar puncture is
if there is a strong suspicion of an intracranial mass lesion. Worrisome
findings include papilledema or a history of an indolent process with
focal neurologic findings. In those instances, lumbar puncture can
be delayed until a mass can be excluded by cranial computerized
tomography (CT) or magnetic resonance (MR) scanning. CSF abnormalities
include elevated numbers of white blood cells, elevated protein
concentration, hypoglycorrhachia, elevated opening pressure, and
organisms observed on Gram stain. Pleocytosis is typical in bacterial
meningitis, with CSF white blood cell (WBC) concentrations in the
range of 100 to 10,000 cells/μL, although
occasionally early in the disease, the WBC concentration may be normal
or slightly elevated. Polymorphonuclear cells predominate and usually
account for more than 90% of the total. Very high WBC concentrations
(greater than 50,000/μL) raise the possibility
of an intracranial abscess that has ruptured into the ventricles.1
++
Hypoglycorrhachia is commonly found in bacterial meningitis,
with CSF glucose usually less than 50% of simultaneous
serum glucose. Other causes of hypoglycorrhachia include tuberculous
and fungal meningitis, subarachnoid hemorrhage, and carcinomatous
meningitis. Cerebrospinal fluid protein concentration is usually
elevated, in the range of 100 to 500 mg/dL, but as elevated
protein reflects an alteration in the blood-brain barrier, it is
not, by itself, diagnostic of bacterial infection.
++
In contrast to bacterial meningitis, CSF from patients with aseptic
(including viral) meningitis is typically characterized by lower
WBC counts and a glucose concentration near or within the normal
range. Although the percentage of neutrophils may be variable, it
is usually much lower in aseptic meningitis where a lymphocyte predominance
is more common. CSF protein concentration may be normal or elevated
in patients with meningitis caused by enterovirus or M tuberculosis.
++
The Gram stain is positive in more than 90%, and the
CSF culture is positive in 70% to 90% of patients
with untreated hematogenous bacterial meningitis.1 The
Gram stain must be interpreted by an experienced microbiologist, as
errors in interpretation are common. Pneumococci, when overdecolorized,
may resemble meningococci, Hib may be thought to
be gram-negative enteric organisms or vice versa, and debris may
resemble gram-positive cocci. L monocytogenes are
frequently difficult to identify on direct smear.
++
Prior treatment with oral antibiotics substantially reduces the
yield of CSF bacterial cultures. In this setting, the use of antigen-detection
methods such as latex particle agglutination may help in etiologic
identification. More recently, molecular diagnostic methods, including
polymerase chain reaction (PCR) of a portion of the bacterial gene
encoding the 16S ribosome, have been successful in the early diagnosis
and speciation of bacterial meningitis (see Future Directions).
One of these methods, when performed in the first 48 to 72 hours
after oral antibiotics are given, will identify the pathogen in
approximately 90% of patients.8,9
++
In addition to culture and Gram stain of the CSF, blood culture
may be useful in specific etiologic diagnosis. Blood cultures are
positive in 40% to 75% of cases of bacterial meningitis,
depending on the pathogen, and should be performed routinely.
++
Studies other than those aimed at making an etiologic diagnosis
are indicated as well. Peripheral-blood WBC and differential are
useful in assessing the likelihood of a serious bacterial infection,
and leukopenia may be a poor prognostic sign, indicating failure
of the inflammatory response, particularly in the settings of meningococcal
and pneumococcal disease. Similarly, prolonged blood coagulation
studies in conjunction with thrombocytopenia may indicate DIC, which
is often present with serious gram-negative infection. Serum and
urine electrolytes and osmolality should be measured routinely to
look for the syndrome of inappropriate antidiuretic hormone (SIADH)
secretion, marked by hyponatremia in association with increased
urine osmolality and increased urine concentration of sodium. Additional studies,
such as roentgenographic examinations, are rarely needed in the
diagnosis of meningitis; however, they may be useful in identifying
coexisting complicating factors. Cranial CT may indicate cerebral
edema early in the infection, and later may show subdural effusion
or subdural empyema.1
++
Effective treatment of meningitis depends on early aggressive
supportive therapy and selection of empiric antimicrobials appropriate
for the likely pathogens. The principles of antimicrobial therapy
of meningitis include selection of an antibiotic that is bactericidal
against the suspected pathogen and that achieves a concentration
in CSF at least 10 times the minimal bactericidal concentration
for the organism, as this is the concentration that has been shown
in animal studies to correlate with most effective sterilization
of CSF.10 Suggested choices for empiric therapy
are listed in Table 231-2 and should be based
on the likely pathogens for age group, known exposures, and any
unusual risk factors for the patient. Definitive antibiotic therapy
depends on the antibiotic susceptibility of the organism. N
meningitidis is susceptible to penicillin but cefotaxime
or ceftriaxone can be used. For patients who must avoid all beta-lactam
antibiotics, chloramphenicol would be an appropriate choice. Hib are
uniformly susceptible to ceftotaxime or ceftriaxone, but the majority
of isolates are susceptible to ampicillin, which is the drug of choice
if the isolate is susceptible. Doses of antibiotics used to treat
the more common causes of bacterial meningitis in children are shown in eTable 231.1.
++
++
++
The numbers of pneumococcal clinical isolates with high-level
resistance to third-generation cephalosporins have been increasing,
so empiric therapy with vancomycin is warranted when pneumococcal
meningitis is suspected. An exception may be in a country or region where
monitoring for pneumococcal resistance has shown it to be absent. Duration
of antibiotic therapy is 14 to 21 days for neonatal meningitis caused
by group B streptococci, and a minimum of 21 days for gram-negative
enteric organisms. For meningitis in older infants or children,
treatment should be 7 days for N meningitidis, 7
to 10 days for Hib, and 10 to 14 days for S
pneumoniae.11
++
Regarding the possible benefits of adjunctive early corticosteroid
treatment, despite numerous studies, there have been inconsistent
results in children with bacterial meningitis (not caused by Hib).
Dexamethasone, 0.15 mg/kg per dose, administered prior
to or concurrently with the start of antibiotic treatment and continued
every 6 hours for 2 to 4 days is the regimen used in published studies.
Some data suggest steroid administration improves mortality in adults
with pneumococcal meningitis, but there is insufficient literature
to support this as a blanket recommendation for children.12-14
++
There are supportive measures that address the consequences of
serious intracranial pathology. Patients who are comatose or who
have impaired gag reflex should have their stomach contents emptied,
and intubation should be considered to protect the airway. Hypoxia
should be treated with supplemental oxygen. Hypoventilation is particularly
worrisome in these patients because elevated PACO2 may
cause cerebral vasodilatation and potentiate increased intracranial
pressure. Hypercarbia should be considered as another indication
for intubation and assisted ventilation.
++
Fluid management is critically important in patients with meningitis.
SIADH occurs in approximately 30% of patients with bacterial meningitis,
and warrants fluid restriction after restoration of normal blood
volume. However, a clinical study has documented the importance
of maintaining an adequate cerebral perfusion pressure in this disease.
Inappropriate fluid restriction may result in volume depletion,
leading to inadequate circulating volume if carried to extremes.
If SIADH is present, fluids should be limited to replacement of
insensible losses plus urine output (generally, approximately two
thirds of maintenance requirement) until ADH excess resolves. If SIADH
is not present, fluids should be administered in an amount appropriate
to maintenance requirements plus intercurrent losses, and electrolytes
should be carefully monitored.15
++
Therapy of increased intracranial pressure must be directed at
maintaining an adequate degree of cerebral perfusion pressure as
in other conditions complicated by intracranial hypertension (see Chapter 111). Available modalities may include hyperventilation, withdrawal
of CSF through an intraventricular catheter, or possibly the careful
use of osmotic diuretic agents.
++
Mortality rates in bacterial meningitis vary considerably depending
on the age of the patient and the pathogen. Individuals with meningococcal
meningitis without overwhelming meningococcemia have a fatality
rate of 12%, whereas newborns with gram-negative meningitis
succumb up to 70% of the time. Death rates from Hib and S
pneumoniae are approximately 3% and 6%,
respectively, at children’s hospitals in developed countries.
++
Morbid sequelae occur in approximately 30% of survivors,
but there is also an age and pathogen predilection, with the greatest
incidence of sequelae occurring among the very young and in those
infected with either gram-negative bacteria or S pneumoniae. Although many
patients with meningitis have good neurologic outcome with standard
supportive measures and antibiotics, patients with more profound
central nervous system disturbance require more intensive treatment
to reduce intracranial pressure in conjunction with supportive care
and antimicrobial therapy. In addition to depressed mental status
at the time of presentation, other poor prognostic factors include
the presence of comorbid conditions, leukopenia, and severe hypoglycorrhachia.
The most common neurologic sequelae include deafness in 3% to
25% of patients; cranial nerve palsies in 2% to
7%; and severe injury, such as hemiparesis or global brain
injury, in 1% to 2% of patients. More than 50% of
patients with neurologic sequelae at discharge from hospital will
improve with time, and recent advances in cochlear implant therapy
may provide hope for the child with hearing loss.1
++
Prevention of meningitis currently takes two forms: chemoprophylaxis
for susceptible individuals known to be exposed to an index patient
and active immunization. Chemoprophylaxis is currently indicated
for preventing secondary meningitis due to Hib and N
meningitidis (see and ).
Active immunization with conjugate vaccine against Hib has
resulted in a dramatic reduction in invasive disease, with a >95% reduction
in meningitis caused by that organism. The introduction of the conjugate
pneumococcal vaccine has also reduced rates of invasive pneumococcal
disease such as meningitis, including in high-risk communities, such
as Native American communities. A quadrivalent conjugate meningococcal
vaccine has become available against groups A, C, Y, and W-135 N
meningitidis. It is indicated for children over 2 years
of age who are considered to be at increased risk of meningococcal
infection and for all young adolescents.
++
Molecular techniques applied to the diagnosis of bacterial meningitis
include polymerase chain reaction (PCR) amplification of bacterial
DNA from CSF and in situ DNA hybridization. PCR amplifies a portion
of the 16sRNA gene from the bacteria which is then sequenced. The
DNA sequence is compared to a database of bacterial DNA sequences
to identify the organism. Advantages of PCR include the following:
(1) DNA amplification from killed organisms. This can be particularly helpful
after a patient has been treated with oral antibiotics prior to
collection of CSF for examination. (2) If done rapidly after a positive
Gram stain, species identification can be done earlier than standard
culture techniques. Because PCR is very sensitive, a potential disadvantage
is a false-positive result from contaminating bacteria. In situ
hybridization uses a DNA probe that can be visualized after hybridization
to the DNA of specific organisms. This test can be done fairly quickly
to get an identification of the organism. However, in situ hybridization
usually only tests for common organisms, so pathogens can be missed. Currently,
these molecular tests are expensive and only available at laboratories
with the proper equipment and expertise.8,9
++
There has been little change in morbidity associated with bacterial
meningitis over the last several decades. This is likely due to
the fact that the inflammatory response to the organism is as responsible
for much of the neurological damage and sequelae as the organism
itself. Although the data on the use of steroids in bacterial meningitis
for most organisms remain controversial, the development of anti-inflammatory
agents that target molecules important in the pathogenesis of meningitis
(TNF-α, matrix metalloproteases) have shown promise
in animal studies. This is an area of active research, and immunomodulatory
and anti-apoptotic drugs that prevent neuronal injury in animal
models are being developed that may reduce sequelae in the future.6,7