Task Force Klein

Report of the Task Force on Diagnosis and Management of Meningitis
Jerome O. Klein, Ralph D. Feigin and George H. McCracken, Jr

Pediatrics 1986;78;959
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Diagnosis and Management of Meningitis
Children still die or suffer permanent neurologic meningitis, meningitis in the absence of evidence
sequelae as a result of bacterial meningitis. Prompt of a bacterial pathogen detectable in CSF by usual
diagnosis and aggressive management are the goals, laboratory techniques;* (4) encephalitis, inflam-
but early signs of meningitis are often subtle and mation of the brain; (5) meningoencephalitis, in-
nonspecific and, therefore, may be recognized only flammation of the brain accompanied by meningi-
in retrospect. The physician must identify among tis; (6) sepsis or septicemia, a clinical syndrome
the many febrile children seen every day in office suggesting invasion of the bloodstream by micro-
practice-most of whom have spontaneously re- organisms; (7) bacteremia, the presence of a bac-
solving illnesses usually caused by viruses-the few terial pathogen in blood; (8) colonization, the pres-
children who have serious bacterial infection re- ence of a microorganism without an immune re-
quiring early intervention. No single test or battery sponse and without clinical signs or symptoms; (9)
of tests replaces the clinical acumen of the physi- infection, the presence of a microorganism with an
cian in identifying the child with early signs of immune response but without clinical signs or
bacterial meningitis. Because of controversies symptoms; and (10) disease, the presence of a mi-
about diagnosis and treatment of meningitis voiced croorganism with an immune response and with
in various forums, including the courtroom, the clinical signs or symptoms.
Task Force on Diagnosis and Management of Men- The pathogenesis, microbiology, diagnosis, and
ingitis has been asked by the Executive Board of management of meningitis vary in the different
the American Academy of Pediatrics to prepare a periods of childhood. For the purposes of this re-
report on the causes, diagnosis, management, and port, data will be provided for the following age
groups: newborn infant (0 to 28 days); infant (29
outcome of meningitis in infants and children.
days through 2 years); toddler and preschool child
This task force selected for discussion issues of
(>2 years through 5 years); school-aged child (>5
current relevance and controversy in the diagnosis
years through 12 years); and adolescent (>12 years
and treatment of bacterial and nonbacterial men-
through 18 years).
ingitis. Many other aspects of meningitis are dis-
cussed elsewhere. Commentaries on the prevention
of disease by chemoprophylaxis (antimicrobial AGE-SPECIFIC ATTACK RATES
agents) or immunoprophylaxis (vaccines) have The most useful data on the bacteria currently
been prepared by the Committee on Infectious Dis- responsible for meningitis in the United States are
eases of the American Academy of Pediatrics. In provided by the Centers for Disease Control (Table
addition the Morbidity and Mortality Weekly Report 1).1 Because many cases are not reported, the pat-
(Centers for Disease Control, Atlanta) publishes terns of disease caused by the bacterial pathogens
recommendations on vaccine usage and chemopro- are of more interest than the specific numbers.
phylaxis formulated by the Advisory Committee on
Immunization Practices. These resources are of
* Aseptic meningitis was initially described as a syndrome of
value to the practitioner who cares for children and
acute onset with signs of meningitis, WBCs in CSF, an absence
needs information on optimal measures for the
of bacteria in cultures of CSF, and a relatively short and benign
treatment and prevention of meningitis.
course. This syndrome was most likely due to one or several
enteroviruses. Today, the definition of aseptic meningitis covers
DEFINITIONS a wide array of infectious and noninfectious etiologies (Table 3).
Many infections are likely to have a viral etiology, particularly
For the purposes of this article, we use the follow- when the disease occurs in epidemics (as does enteroviral disease
ing definitions: (1) meningitis, inflammation of the in the summer and fall). Children with aseptic meningitis who
meninges that is identified by an abnormal number experience a prolonged or complicated course or who are subject
to risk factors for one or more of the infectious or noninfectious
of white blood cells (WBCs) in cerebrospinal fluid
etiologies of aseptic meningitis (eg, tuberculous exposure) should
(CSF); (2) bacterial meningitis, meningitis and evi- be aggressively managed with regard to both diagnosis and
dence of a bacterial pathogen in CSF; (3) aseptic therapy.
SUPPLEMENT 959
TABLE 1. Annual Age-Specific Incidence of Meningitis, United States 1978 to 1981*
Age Neisseria Haemophilus Streptococcus Group B Listeria Total
meningitidis influenzae pneumoniae Streptococcus monocytogenes Meningitis
<1 mo 2.0 6.7 3.5 44.6 7.6 99.5
1-2 mo 9.1 18.6 5.7 10.0 1.3 56.7
3-5 mo 11.5 52.0 11.6 1.4 0.1 83.3
6-8 mo 10.6 65.1 8.0 0.3 0 88.4
9-11 mo 7.9 48.1 4.7 0 0.1 63.3
1-2 yr 3.8 19.0 1.5 25.3
3-4 yr 1.8 3.9 0.5 6.8
5-9 yr 0.7 0.7 0.3 2.0
10-19 yr 0.6 0.1 0.1 1.0
* Results are reported as numbers of children with meningitis per 100,000 population. Data were provided by C. V.
Broome, Centers for Disease Control, Atlanta, and by Schlech et al.1
Newborn Infants PATHOGENESIS OF BACTERIAL MENINGITIS
Sepsis and meningitis of early or late onset (ie, Most cases of bacterial meningitis progress
with signs appearing before or after seven days of through four steps: first, infection of the upper
life) are in most cases the result of organisms ac- respiratory tract; second, invasion of the blood from
quired at delivery and to a lesser extent to orga- the respiratory focus; third, seeding of the meninges
nisms acquired in the nursery or in the household. by the blood-borne organism; and fourth, inflam-
Group B streptococcus and Escherichia coli are the mation of the meninges and brain. The vast major-
major pathogens. Other streptococci (enterococci), ity of normal infants and children at some time
other Gram-negative enteric bacilli (Klebsiella, En- have upper respiratory tract colonization on infec-
terobacter, Serratia species), and Listeria monocy- tion with the bacteria responsible for meningitis.
togenes are also important. The organisms respon- In most children with a minimal upper respiratory
sible for bacterial meningitis in infants and older tract illness due to these organisms, only minor
children-Haemophilus influenzae type b, Neisseria disease develops, on the children are asymptomatic.
meningitidis, and Streptococcus pneumoniae-are A few children experience invasion of the blood-
of lesser importance but should be considered in stream by these organisms. In some of these bac-
therapy for infants who may have acquired infec- teremic children, the organisms are cleared from
tion in the household. Nontypable H influenzae is the bloodstream by natural defense mechanisms; in
also important as a pathogen in the newborn pe- others, infection is cured at this stage by a regimen
nod.2 of oral antimicrobial agents. However, in a few
children-treated on untreated-infection pro-
gresses to seeding ofthe CNS and meningitis.3 Why
Infants
this uncommon sequela of a common event devel-
The highest age-specific attack rates for bacterial ops in an individual child is unknown.
meningitis (other than in the newborn period) occur
between 3 and 8 months of age. The incidence Newborn Infants
remains high up to 2 years of age. H influenzae type
Meningitis in the newborn most commonly fol-
b, N meningitidis, and S pneumoniae are nesponsi- lows or is associated with septicemia. The intra-
ble for the vast majority of meningitides in previ-
uterine environment normally is sterile. Once the
ously well children.
amniotic membranes are ruptured, the infant is
exposed to microorganisms, some of which may be
Toddlers pathogens from the maternal genital tract. Al-
though all newborn infants are colonized by some
The incidence of acute meningitis decreases after
ofthe organisms with which they come into contact,
2 years of age; the responsible organisms in toddiers
it is rare for sepsis or meningitis to develop in an
are the same as those in infants.
infant. (The incidence of sepsis in the United States
varies from less than one to eight per 1,000 live
Schoolchildren and Adolescents
births; the incidence of bacterial meningitis is ap-
The incidence of meningitis is sharply reduced in proximately one for every four cases of sepsis.) The
older children; however, concern about S pneumo- blood is invaded from a colonized site-usually the
niae, N meningitidis, and H influenzae infections respiratory tract or umbilical cord. Bacteremia pre-
persists (Table 1). cedes meningitis; meningitis almost always is a
960 MENINGITIS
result of hematogenous seeding of the meninges by and nonpregnant women who are between 16 and
bacteria found in the blood. 31 years of age (45% to 50%).12 Approximately 70%
of infants born to culture-positive mothers acquire
Group B Streptococcus E coli Ki strains during the first 48 hours of life.
Between 10% and 15% of infants colonized with E
Septicemia and meningitis caused by group B
streptococci may involve any of the group B sub- coli Ki strains are born to Ki-negative mothers. In
this group of infants, E coli is acquired at three to
types (Ia, Ib, II, or III), and the specific serotype
four days of age, presumably via horizontal trans-
causing disease generally can be recovered from the
mission from nursery staff members or other in-
maternal vaginal tract.4’5 Most cases of group B
fants. Vertical acquisition of Ki organisms has been
streptococcal meningitis are caused by subtype III
documented in approximately 75% of newborn in-
organisms.5 Studies have shown that approximately
fants with E coli Ki meningitis. Colonization with
20% to 35% of women are colonized vaginally and!
E co/i Ki in an otherwise healthy infant is not an
or rectally with group B streptococci.6 Vertical
indication for therapy.
transmission from mother to infant occurs in 40%
to 70% of women who are colonized by this orga-
L monocytogenes
nism.79 Colonization with group B streptococci in
an otherwise healthy infant is not an indication for In many areas, listeriosis is an important neo-
therapy. natal disease.13 Pregnant women may be colonized
Although mother-to-infant transfer is the initial in the genital tract and transmit the infection to
mode of acquisition of group B streptococci by their infants, an event resulting in abortion or
newborns, it is not the only way in which a baby neonatal sepsis. In the United States, few women
can become colonized. Spread of organisms from are colonized with L monocytogenes during preg-
the hands of nursery personnel to the infant is nancy, and the organism is cultured infrequently
common and has been implicated as a cause of the from healthy premature and full-term infants.14’15
observed increase in rates of colonization with Nevertheless, L monocytogenes is the third most
group B streptococci over time in newborn nurser- important cause of meningitis in the neonate (Table
ies. 2). A recent outbreak of listeriosis due to contami-
Group B streptococcal meningitis of late onset nated cheese in southern California caused disease
(ie, at seven days to 8 months of age) presumably in mother-infant pairs and resulted in stillbirths
is a result of hematogenous dissemination of an and neonatal deaths.16
organism with which the baby has been colonized
for varying periods. Infants and Children Beyond the Newborn Period
The pathogenesis of meningitis in children be-

E co/i
yond the newborn period usually follows the steps
Strains of E co/i possessing the Ki antigen cause discussed in the beginning of this section.
approximately 75% of cases of E coli neonatal men- Uncommonly, infection may spread to the men-
ingitis.10”1 Moreover, disease caused by Ki strains inges via the hematogenous route in children with
is more severe than that associated with non-Ki infective endocarditis, pneumonia, or thrombophle-
strains.12 The reasons for the association between bitis or by direct extension in children with sinu-
Ki strains of E coli and neonatal meningitis are sitis, otitis media and mastoiditis, or osteomyelitis
unknown. of the skull.
The highest prevalence rates for rectal coloniza- Head trauma may precede bacterial meningitis;
tion with E coli Ki strains are found in pregnant cases of meningitis due to S pneumoniae and H
TABLE 2. Cerebrospinal Fluid Findings in Infants With Meningitis*

Age No. of WBC Polymorph onucle ar Leukocyte
Patients . .
No./zLt Percentile %t Percentile
25 50 75 25 50 75
<6 wk 64 3.73 ± 3.40 0.50 2.57 5.16 1.87 ± 2.98 0 0 2.42
6 wk-3 mo 67 2.92 ± 2.87 0.34 1.86 3.75 0.92 ± 1.77 0 0 0.66
3-6 mo 84 1.88 ± 2.01 0 1.11 2.31 0.59 ± 1.15 0 0 0.40
6-12 mo 75 2.63 ± 2.45 0.41 1.47 3.25 0.71 ± 1.36 0 0 0.52
7-12 mo 81 1.94 ± 2.72 0 0.68 1.82 0.51 ± 1.41 0 0 0
* Data were adapted from tables 1 and 2 of Portnoy and Olson52 and used with permission.
t Values are means ± 1 SD.
SUPPLEMENT 961
influenzae have been noted following fracture increased prevalence of meningitis, particularly
through the cribriform plate and paranasal sinuses that due to H influenzae type b, in selected popu-
and may be recurrent. Direct bacterial invasion of lation groups. In one study, the incidence of H
the CNS also may occur in individuals with dermoid influenzae meningitis was 3.5-fold greater in black
sinus tracts or meningomyeloceles, where a direct than in white persons, but this distribution of cases
communication between the skin and the meninges appeared to be related more closely to poverty than
is present. In this setting, infection most commonly to race.21 Among white individuals, there was no
is produced by organisms found on the skin. increase in incidence in overcrowded households,
Meningitis also may follow either neurosurgical but the incidence was greater in rural than in urban
procedures (particularly those designed for diver- areas. Fraser and associates21 suggested that the
sion of CSF in children with hydrocephalus) or higher incidence in rural white and black persons
osteomyelitis of the skull or vertebral column. was related to lack of access to early medical care.
Population-based studies performed in South Car-
Factors Influencing Susceptibility to Meningitis olina, New Mexico, Minnesota, and Vermont sug-
gest but do not prove that specific genetic factors
Host Factors predispose certain population groups to infection
Susceptibility to bacterial meningitis is affected with encapsulated microorganisms.224
by age and by congenital or acquired deficiencies in The incidence of H influenzae meningitis in the
host defense mechanisms. Boys are affected more United States in children younger than 5 years of
frequently than girls. An increased incidence and age varies from 32 to 71/100,000 per year. Among
severity of bacterial meningitis are observed in the Navajo Indians and Alaskan Eskimos, the incidence
very young.17 The precise age at which each of the is as high as 173 and 409/100,000 per year, respec-
various cellular and humoral immunologic factors tively, in the same age group. This increased mci-
that are functionally immature in the newborn dence apparently relates to genetic factors as yet
infant reaches the concentration and level of func- undefined.
tional activity noted in older children and adults is The predilection of some normal children for the
unclear and undoubtedly varies somewhat from in- development of bacteremia and meningitis may be
dividual to individual. An increased incidence of determined genetically. Tejani and associates25
overwhelming infection, including meningitis, has studied 50 white children less than 7 years of age
been reported following splenectomy, but the like- with H influenzae disease. Half of the patients had
lihood of such infection depends upon the age of invasive disease (positive blood or CSF cultures).
the child at the time of splenectomy, the number The other half had fever, nasopharyngitis, and
of years elapsing since splenectomy, and the mdi- throat cultures positive for H influenzae type b.
cations for splenectomy.’8 Congenital asplenia or Significant differences between the genetic markers
splenosis also has been associated with an increased of the two groups were seen. Histocompatibility
incidence of septicemia and meningitis due to S leukocyte antigen B12 (HLA-B12) was found in
pneumoniae,18 H influenzae type b, and Gram-neg- 52% of children with invasive disease but in only
ative enteric microorganisms. Children with sickle 16% of children in the other group (P < .01). HLA-
cell anemia and other hemoglobinopathies experi- Bw40 was present in 24% of children without in-
ence meningitis due to S pneumoniae and H influ- vasive disease but was absent in children with bac-
enzae more frequently than do other children.19 teremia or meningitis caused by H influenzae type
Meningococcal infections also occur with increased b(P<.01).
frequency in patients who have a deficiency of the Granoff and associates26 administered a prepa-
terminal components (C5 through C8) of the com- ration containing the type b polysaccharide capsule
plement system.2#{176} Individuals with a complement- (polyribosyl ribitol phosphate) and pertussis vac-
depleting underlying illness also are at particular cine to 26 healthy siblings of children who had
risk for invasive disease. An increased incidence of invasive disease due to H influenzae and 25 control
Salmonella meningitis has been noted in these children; the goal was to determine whether siblings
groups of children. Children with malignancies, es- of patients with Haemophilus meningitis had an
pecially those involving the reticuloendothelial sys- impaired antibody response to polyribosyl ribitol
tem, appear to be prone to meningitis caused by phosphate. Following two intramuscular injections
organisms of low virulence that pose a minimal given 1 month apart, siblings produced significantly
threat to healthy children. less IgG antibody to polyribosyl ribitol phosphate
than did control children, but the two groups pro-
Genetics duced similar amounts of 1gM. These data support
A number of previous studies have indicated an the concept that increased susceptibility to H influ-
962 MENINGITIS
enzae type b infection in some families is deter- is one of the most important signs of meningitis.
mined genetically. This deficiency in response may Such a subtle change may be recognized by the
be specific for polyribosyl ribitol phosphate or may observant parent and by the astute physician.
reflect a deficiency of a specific subclass of IgG Stiff neck (Kernig and Brudzinski signst), sei-
associated with polysaccharide antibodies.27 zures, bulging fontanel, and coma occur less com-
monly (especially in infants) and usually later in
C/osed Communities, Inc/uding Househo/ds and the illness but are sufficiently characteristic of
Group Day-Care Centers meningitis to prompt physicians to consider per-
forming a diagnostic lumbar puncture.
A cluster of cases of meningitis or of other inva-
It is often difficult for a physician to recognize
sive diseases caused by N meningitidis and H influ-
the one patient with meningitis among the many
enzae type b occasionally occurs in closed commu-
infants and children with febrile illnesses seen in a
nities. Most important, secondary cases occur with
busy practice. The ability to distinguish the men-
increased frequency in households, but other com-
ingitis case from the others results from accumu-
munities such as group day-care centers, class-
lated experience with managing pediatric patients
rooms, college and military dormitories, and insti-
and from rapport and communication that the phy-
tutions also can be involved. Children in group day
sician has developed with the patient and the fam-
care have more infectious exposures than children
ily. There is no substitute for clinical acumen in
in home care and may be at increased risk of
recognizing and promptly diagnosing meningitis in
acquiring invasive bacterial disease, including men-
infants and children.
ingitis caused by H influenzae type b.28’29 In con-
trast, meningitis due to S pneumoniae is rarely
Modes of Presentation of Meningitis
epidemic in small groups.
There are two patterns by which meningitis is
CLINICAL DIAGNOSIS OF MENINGITIS heralded in infants and children.35’36 The first pat-
tern is insidious and develops progressively over
Because the repertoire of clinical signs and symp-
one or several days; it may be preceded by a non-
toms of meningitis in infants and young children is
specific febrile illness. In this setting, it is usually
broad and is often similar for infectious and non-
difficult, if not impossible, to pinpoint the exact
infectious conditions, the index of suspicion of men-
onset of meningitis, especially when disease is
ingitis should be high in all physicians who manage
caused by H influenzae. The second pattern is acute
pediatric patients. No one clinical sign is pathog-
and fulminant, and the manifestations of sepsis
nomonic of meningitis.
and meningitis develop rapidly over a few hours.
Symptoms and signs of bacterial meningitis are
This rapidly progressive form is frequently associ-
variable and depend, in part, on the age of the
ated with severe brain edema that can provoke
patient, the duration of illness before examination,
transtentorial herniation, resulting in brainstem
and the child’s response to infection. As a rule, the
compression in some children. Although illness in
findings in neonates and young infants are minimal
the latter patients can be caused by any of the
and often subtle, making an early diagnosis difficult
common meningeal pathogens, it is associated most
to establish clinically.3034 Fever, which occurs in
frequently with N meningitidis. With this form of
approximately one halfof infected infants, lethargy,
meningitis, the case fatality rate is high.
respiratory distress, jaundice, disinterest in feeding,
Signs or Conditions That Can Be Associated
and/or vomiting and diarrhea are the frequent,
nonspecific manifestations of invasive bacterial in-
With Meningitis
fection in neonates.31 Approximately one third of
infants are increasingly irritable, often with an Cutaneous Manifestations
alteration in consciousness and poor muscle tone.
A variety of skin lesions, many of which are
Convulsions occur in 40% of newborn infants with
diagnostically important, can be observed in chil-
meningitis, whereas a bulging or full fontanel occurs
dren with sepsis and meningitis. Purpura and pe-
in approximately one third of such infants.
techiae can be the result of both infectious and
In children, fever, headache, photophobia, nausea
and vomiting, mental confusion and lethargy, and/
or excessive irritability are the usual initial com- t Kernig sign is elicited in the supine patient. With the knee
plaints.32’33 These manifestations are nonspecific flexed, the leg is flexed at the hip. In this position, the knee is
extended; if meningeal irritation is present, this movement elic-
and often indistinguishable from those of nonmen-
its pain. Brudzinski sign consists of spontaneous flexion of the
ingeal viral infections or of other febrile illnesses. lower extremities after passive flexion of the neck when menin-
A change in the child’s affect or state of alertness geal irritation is present.
SUPPLEMENT 963
noninfectious causes; when the etiology is infec- A/tered State of Consciousness
tious, these conditions are seen most commonly
The level of consciousness of a child with men-
with meningococcal disease but can be observed in
ingitis at the time of hospital admission has prog-
patients with meningitis caused by any of the bac-
nostic significance. If the child is obtunded, semi-
terial pathogens. The lesions can be generalized but
comatose, or comatose on admission, an adverse
are often pronounced on the extremities and can be
outcome is significantly more likely than ifthe child
preceded by an erythematous maculopapular erup-
is lethargic or somnolent.35
tion. A diffuse maculopapular eruption with or
without petechiae is frequently seen with viral ill-
Ataxia and Hearing Deficit
nesses (eg, those caused by the enteroviruses or
adenoviruses) but can also be an early manifesta- Ataxia is occasionally the presenting sign of bac-
tion of bacterial infection, especially meningococ- terial meningitis. In all children with meningitis,
cemia. Clinical acumen and repeated evaluation are including those with ataxia, evaluation of hearing
often necessary to distinguish the cutaneous signs by brainstem-evoked response audiometry tech-
of viral illnesses from those caused by N meningi- niques, if available, should be undertaken soon after
tidis or other bacterial pathogens. Purpura accom- the completion of therapy, when the child is seen
panied by hypothermia and shock is usually asso- for an initial follow-up examination, because audi-
ciated with disseminated intravascular coagulation tory and vestibular disturbances occur concomi-
and signifies a poor prognosis.35 tantly, presumably as a result of labyrinthitis.34
Tache cerebrale is sometimes seen in children
with CNS infection but is nonspecific for that con- Systemic Conditions
dition. The response is elicited by stroking of the Focal diseases such as cellulitis, septic arthritis,
skin with a blunt instrument. In 30 to 60 seconds, and pneumonia due to H influenzae type b are often
this stimulus produces an erythematous, raised re- associated with bacteremia and meningitis. Men-
action that lasts several minutes.36 ingitis is found in approximately 8% of patients
with buccal cellulitis37 or preseptal orbital cellulitis
Seizures and in approximately 20% of those with suppura-
Seizures occur before admission to the hospital tive arthritis.38’39 Meningitis occurs rarely in chil-
or within the first two days of hospitalization in dren with epiglottitis caused by H influenzae. In
20% to 30% of patients with meningitis.34 The patients who have a disease outside the CNS that
infants involved are usually febrile. Generalized is frequently accompanied by bacteremia, a lumbar
seizures usually do not portend a poor prognosis. puncture may be considered at the time of diagno-
In contrast, children with focal seizures are more sis.
likely to have neurologic sequelae of meningitis. In
addition, seizures that develop later in the course LUMBAR PUNCTURE
of management may signify the presence of map-
propriate production of antidiuretic hormone, with Criteria for Performance of Lumbar Puncture
resultant hyponatremia; other causes of late sei-
Lumbar puncture is performed to identify the
zures include cerebritis, subdural effusion, vascular
presence or status of infection of the CNS. It should
thrombosis, and abscess formation. Appropriate
be performed whenever the diagnosis of meningitis
studies need to be performed to rule out the latter
is known or suspected on the basis of clinical signs.
possibilities.
On occasion, other sites may be used to obtain CSF,
Foca/ Neuro/ogic Findings including ventricles and shunts used to divert CSF.
For simplicity, we will use the term “lumbar punc-
Focal neurologic signs, such as hemiparesis,
ture” to cover all procedures used to obtain CSF.
quadriparesis, facial palsy, endophthalmitis, and
visual field defects, occur early or late in about 15%
Need for High Index of Suspicion of Meningitis
of patients with meningitis and denote the possible
presence of cortical venous or arterial thrombosis If meningitis is to be identified as early as possi-
secondary to edema and inflammation.31’34 Focal ble, many more lumbar punctures than ultimately
neurologic findings may indicate an adverse out- reveal infection will have to be done. For example,
come.35 Papilledema is uncommon early in the of 709 children who underwent lumbar puncture
course of acute meningitis and, when present, because of suspicion of meningitis in 1970 at Down-
should prompt immediate evaluation for venous state Medical Center in Brooklyn, NY, 16% were
sinus thrombosis, subdural collection of fluid, or found to have abnormal CSF.45 A similar survey of
brain abscess. lumbar punctures performed in the walk-in clinic
964 MENINGITIS
at Boston City Hospital (B. Dashefsky, MD, writ- Cultures of CSF may be positive for pathogenic
ten communication, February 1984) revealed that bacteria in the presence of normal cytologic and
one in ten procedures served to identify meningitis chemistry findings. Presumably, the lumbar punc-
(bacterial or aseptic). Although these data are rep- ture in such a case was performed during an early
resentative of care provided by housestaff in teach- stage of meningitis, ie, after bacterial invasion but
ing hospitals, we believe the ratio is appropriate for prior to the inflammatory response.42
physicians in all facilities that manage acute ill-
nesses in children. After Positive Resu/ts in an Initia/ Lumbar Puncture
For a discussion of the criteria for repeat lumbar

Lumbar Puncture for Neonates puncture after initially positive CSF findings, see p
In neonates, approximately one case of meningi- 974.
tis occurs for every four cases of sepsis. Because

meningitis frequently accompanies sepsis in the Prior Antimicrobial Agents and Criteria for
neonate, lumbar puncture should be considered for Lumbar Puncture
neonates who are to be treated for sepsis. If cultures Previously administered antimicrobial agents
of blood and urine alone are obtained and lumbar may modify clinical signs, but criteria for lumbar
puncture is not done, some cases of bacterial men- puncture should be the same irrespective of the use
ingitis will be missed. Approximately 15% of neo- of antimicrobial drugs.
nates with bacterial meningitis have a negative
blood culture.4#{176}Lumbar puncture may need to be Lumbar Puncture for Children With Febrile
postponed for some infants with significant cardio-
Seizures
pulmonary instability (see p 966).
Approximately 3% of all children at some point
Lumbar Puncture for Children With a Positive have a seizure associated with fever.43 Febrile sei-
Blood Culture zures represent about one third of all seizure dis-
orders in children. The vast majority of seizures
Because meningitis may follow bacteremia, it is
with fever are termed “simple febrile convulsions”;
possible that a child who has had a positive blood
these seizures occur in children with fever who are
culture may have meningitis or meningitis may
6 months to 6 years of age, are brief (usually less
develop. The infant or child with a positive blood
than 20 minutes’ duration) and generalized, and are
culture should be reassessed by the physician and
associated with no other neurologic signs. Pro-
a lumbar puncture considered if the febrile illness
longed or recurrent seizures with or without focal
persists or any suggestion of meningeal reaction is
neurologic signs suggest an underlying neurologic
present. disease that may be due to an acute illness, such as
meningitis; alternatively, such seizures may repre-
Criteria for Repeat Lumbar Puncture sent a convulsive disorder. A seizure associated with
the onset of meningitis may not be distinguishable
After Negative Resu/ts in an Initia/ Lumbar Puncture
from a simple febrile convulsion.
Because meningitis may be rapidly progressive, The vast majority of children who have seizures
previously normal findings in CSF should not deter with fever do not have meningitis. The results of a
the physician from repeating the lumbar puncture 1-year survey of 709 children who underwent lum-
hours or days later. Lumbar puncture does not bar punctures because of suspicion of meningitis at
necessitate hospitalization if the results of CSF Kings County Hospital in Brooklyn indicated that
examination are normal and admission is not war- febrile seizures were a common reason for lumbar
ranted by other criteria. Close observation at home puncture (225 children); only 5% of children who
is necessary, however, until the illness resolves. underwent lumbar puncture because of seizures had
Specific time sequences are difficult to identify meningitis, and most of these had other signs of
in evolving meningitis, but data are available to meningitis.45
suggest that bacteremia can progress to meningitis Some experts believe that lumbar puncture
in a matter of hours.41 This rapid progression has should not be considered a routine procedure after
been documented by the performance of simulta- an initial febrile seizure. They think that clinical
neous blood and CSF cultures at first and second acumen enables the skilled physician to identify,
clinic visits. Children with positive blood culture from the group of children with febrile seizures,
and negative CSF cultures at the first visit may be those who have meningitis.46’47 We believe that
found to have positive CSF cultures at a second caution must be used in managing the child with
visit only eight to 72 hours later.41 fever who has had a seizure. Unless the physician
SUPPLEMENT 965
is confident that the child is alert and well and has mated needle during lumbar puncture. In contrast,
no suggestion of signs of meningitis, lumbar punc- chemical or infectious meningitis may follow the
ture should be considered. introduction of foreign material into the CSF dur-
For the child who is known to have had a seizure ing the course of spinal anesthesia, myelography,
with fever, and at a later time has a new episode of or pneumoencephalography.
febrile seizure, the decision regarding lumbar punc- Lumbar puncture need not be withheld in cases
ture is based on an assessment of affect and other of thrombocytopenia if the administration of plate-
signs of meningitis. lets provides safety from bleeding. Because some
patients with thrombocytopenia have a malignancy
Adverse Reactions to Lumbar Puncture or another disease that suppresses immunity, cul-
ture of CSF is especially important in that a wide
Lumbar puncture is a safe procedure for most
variety of organisms may cause the meningitis.
children. Minor discomfort may occur, but serious
consequences are rare. Pain occurs with insertion
Management of the Patient With Suspected
of the needle, and headache may follow. On occa-
Meningitis in Whom Lumbar Puncture Is
sion, there is difficulty in inserting the needle into
Postponed
the spinal foramen, and several needle sticks may
be necessary. Bleeding into the tissues around the If lumbar puncture is delayed, the causes of the
spinal column or into the CSF may occur. In neither delay should be managed as expeditiously as pos-
case is significant injury a likely event. Herniation sible. For the patients involved, cultures of blood
of the brainstem and cerebellar tonsils into the and urine may suffice for microbiologic diagnosis
foramen magnum is rare in children but may occur before the initiation of therapy. Culture of blood
upon removal of CSF from the lumbar space when reveals the bacterial pathogen in more than 80% of
an excessive increase in intracranial pressure is previously untreated cases of meningitis (see p 969).
present. Antimicrobial agents should be administered in a
dosage schedule sufficient to treat meningitis. Lum-
bar puncture may be performed later when the
Reasons to Withhold Lumbar Puncture
patient can tolerate the procedure. Although cul-
Only three reasons may be considered justifica- tures may be sterile after onset of antimicrobial
tion for withholding or delaying lumbar puncture: therapy, the examination of cells, the study of
(1) clinically important cardiorespiratory compro- Gram-stained smears of CSF, and the performance
mise in a neonate, (2) signs of increased intracranial of tests for bacterial antigens and chemistries may
pressure, and (3) infection in the area that the provide evidence for or against a diagnosis of men-
needle will traverse to obtain CSF. ingitis.
Some infants may have a sufficient degree of
cardiac or respiratory compromise to make per-
Meningitis Following Lumbar Puncture in
formance of a lumbar puncture dangerous. Exces-
Children With Bacteremia
sive flexion of the neck and trunk during holding
for the procedure may produce hypoxemia.47 If an Clinical investigators have suggested a signifi-
infant has serious cardiac or respiratory disease, cant association between the performance of lum-
cardiopulmonary monitoring may be performed bar puncture during bacteremia and the later de-
during lumbar puncture or the procedure should be velopment of meningitis.48’49 This association was
postponed. evident in a survey ofbacterial meningitis at Boston
Lumbar puncture should be delayed if signs of City Hospital, but only in children younger than 1
increased intracranial pressure (eg, retinal changes, year of age.41 The explanation for the association
altered pupillary responses, increase in BP with is uncertain. No children had large numbers of
slow pulse rate, abnormal computed tomographic RBCs in the CSF; therefore, the introduction of
[CT] scan) are present. A neurologist or neurosur- blood was not an appropriate explanation.5#{176} It is
geon may be consulted and a plan made for further possible, in theory, that lumbar puncture during
diagnostic procedures (ie, cranial CT). Treatment the course of bacteremia produces a site for seeding
for bacterial meningitis should be considered, even of the CSF; it is more likely, however, that the
when CSF has not been obtained for examination. perceptive physician selects for a lumbar puncture
Infection in the skin, soft tissues, and epidural the child in whom clinical signs suggest developing
area may be transmitted to the CSF by a needle meningitis before CSF findings are diagnostic. Be-
passing first through the infected areas. To our cause the Boston survey identified later develop-
knowledge, there are no adequately documented ment of meningitis only in children younger than 1
cases of bacterial meningitis induced by a contam- year of age who underwent lumbar puncture during
966 MENINGITIS
bacteremia, the second explanation appears more 4% of newborn infants with E coli meningitis at the
plausible. These data should not deter the physician same institution had normal WBC counts in CSF
from performing a lumbar puncture in a child with when first evaluated. The ratio of CSF glucose to
any evidence of meningitis. The data suggest a need serum glucose was normal in 45% and 15% of
for close observation and, if appropriate, hospitali- newborn infants with group B streptococcal and E
zation and presumptive antimicrobjal therapy for coli meningitis, respectively. When a complete mi-
infants younger than 1 year of age who have risk tial CSF evaluation (including Gram stain) was
factors for bacteremia (high temperature, high made, however, fewer than 1% of infants with bac-
WBC count) and who undergo lumbar puncture. teriologically proven meningitis had completely
normal CSF findings (excluding culture).
EXAMINATION OF CSF The CSF of every infant with possible meningitis
must be evaluated completely: total WBC and dif-
Newborn Infants ferential counts, protein concentration, and glucose
concentration interpreted in relation to a concom-
Norma/ Va/ues itant serum glucose value. Gram stain and appro-
priate cultures should be performed. In some pa-
WBCs. During the first week of life, the normal
CSF contains an average WBC count of 84tL but
tients whose diagnoses remain uncertain, repeat
lumbar puncture performed four to six hours after
as many as 32/L have been observed in healthy,
the initial tap will help to establish a diagnosis
uninfected babies.51 Approximately 60% of the cells
whether or not treatment has been administered in
observed may be polymorphonuclear leukocytes.
the interim. Gram-stained smears from as many as
The cell count diminishes slowly in full-term in-
20% of newborn infants with proven bacterial men-
fants and increases in premature infants during the
ingitis may reveal no bacteria. CSF should, how-
first week of life. By 1 month of age, counts in the
ever, be scrutinized routinely by Gram stain; grossly
range of 0 to 10/FL are noted.
clear fluid with few WBCs may contain many bac-
Protein. The mean CSF protein concentration in
teria.
full-term infants is 90 mg/dL (range, 20 to 170 mg/
dL) and in preterm infants is 115 mg/dL (range, 65
Infants and Children Beyond the Newborn Period
to 150 mg/dL). Normal CSF values are based on
data obtained from newborn infants who were sus-
Pressure
pected to be at risk for CNS disease or who were
apparently healthy but were not followed to rule Opening and closing pressures are often not mea-
out disease. If protein levels in CSF are elevated in sured in infants and young children because the
the absence of pleocytosis, the physician should patient is crying, difficult to hold, or critically ill.
consider other diagnostic possibilities (eg, para- Nevertheless, such measurements are an important
meningeal infections, intracranial hemorrhage, component of each CSF examination and should be
congenital infections). considered whenever possible. When the pressure
Glucose. The serum glucose concentration in is very high, just enough fluid should be removed
newborn infants, and particularly in premature to permit a careful examination. Compression of
neonates, may be low (30 to 50 mg/dL). The per- the jugular vein should be avoided unless compres-
centage ratio of CSF glucose to blood glucose av- sion of the spinal cord is suspected.
erages 70:80 and frequently is greater than 100% in
Co/or
full-term and preterm infants. Blood should be
obtained for the measurement of glucose concentra- Normal CSF is crystal clear. Xanthochromic CSF
tions prior to lumbar puncture because the perform- derives its color primarily from bilirubin pigment.
ance of a lumbar puncture may result in increased Xanthochromia may be associated with hemor-
glucose levels in the blood. rhage, bilirubin staining (in icteric patients who
have meningitis, eg, infants with leptospirosis), or
Va/ues in Patients With Meningitis simply an elevated protein concentration in CSF.
The cellular and chemical characteristics found
RBCs and WBCs
in an initial evaluation of CSF from newborn in-
fants with proven bacterial meningitis may overlap CSF should be examined as soon as possible after
considerably with the corresponding values for nor- it has been obtained. After about 90 minutes, the
mal newborns. Approximately 30% of infants with WBCs in CSF begin to disintegrate. The total num-
group B streptococcal meningitis at one institution ber of WBCs should be counted in a counting
had normal WBC counts in CSF (<324tL). Only chamber, and, following centrifugation, a differen-
SUPPLEMENT 967
tial cell count should be performed on a Wright- about 66%) is the rule. For every 1,000 RBCs in
stained smear of the sediment. CSF, 1 mg of protein per decileter can be sub-
The morphologic and chemical characteristics of tracted.53’54
CSF from normal infants and children between 1
week and 12 months of age vary within rather Stained Smears of CSF
narrowly defined limits.52 One group of investiga-
When indicated, smears should be Gram-stained
tors evaluated variability of CSF findings in a group
for bacteria and stained for mycobacteria. The
of children whose condition was deemed to warrant
probability of visualizing bacteria on a Gram-
CSF examination but who were found to have dis-
stained CSF preparation is dependent upon the
ease unrelated to infection of the CNS.52 Specific
number of organisms present: 25% of smears are
attention was given to the characteristics of CSF
positive with si0 colony-forming units (CFU)/
from children who presented with seizures but who
mL, 60% with iO to iO CFU/mL, and 97% with
did not have meningitis. The normal WBC and
polymorphonuclear leukocyte values and the per-
>io CFU/mL.55 Possible causes of false-positive
results of Gram stains include contamination of
centiles of WBCs and polymorphonuclear leuko-
tubes from lumbar puncture trays, of glass slides,
cytes in CSF are shown in Table 2.
and of Gram reagents.56 The contamination of re-
These data suggest that the normal CSF of mdi-
viduals 12 months of age and younger contains agents can be eliminated by Millipore filtration of
fewer WBCs than 6/L. It should be emphasized staining solutions.
that 95% of the normal population has no poly- Another possible cause of a false-positive Gram
morphonuclear leukocytes in the CSF; thus, the stain finding is the use of an unoccluded needle for
presence of a polymorphonuclear leukocyte in the lumbar puncture.57 An unoccluded needle may cut
CSF may be regarded as abnormal. When lumbar free a small core of epidermal tissue. Despite ap-
puncture has been performed in a febrile child and propriately cleansing of skin prior to lumbar punc-
a single polymorphonuclear leukocyte has been ture, organisms may be visible in association with
noted, close clinical observation is imperative and epidermal cells that have been carried into the CSF.
treatment may be considered until results of cul- Quellung and agglutination reactions can be used
tures of CSF are available. It should be noted, for the immediate identification of various orga-
however, that a single polymorphonuclear leuko- nisms if the appropriate type of specific antiserum
cyte may be found in the CSF of 5% of normal is available.
children.
If a lumbar puncture has been traumatic, a total CSF Cu/tures
cell count can be performed in a counting chamber.
The CSF should be cultured on a blood agar plate,
The RBCs then can be lysed by acetic acid and a
on a chocolate agar plate (or on Fildes or Leventhal
repeat cell count performed. If the total number of
medium), and in broth. CSF specimens should al-
WBCs compared with the number of RBCs exceeds
ways be cultured, even when the fluid appears to be
the value for whole blood, the presence of CSF
crystal clear and is without WBCs.
pleocytosis can be assumed. If the peripheral RBC
and WBC counts are normal, then one WBC per
Analysis of CSF in the Child Who Has Received
700 RBCs can be subtracted from the total WBC
Therapy
count in CSF (prior to the use of acetic acid for
lysis of RBCs). Antibiotic treatment of a child with bacterial
meningitis prior to initial lumbar puncture usually
Protein and G/ucose does not markedly alter either the morphologic and
Proteins in CSF should be measured; values are Gram stain characteristics of bacteria or the chem-
usually elevated in bacterial meningitis. In addition, ical results for the CSF obtained via this procedure.
the CSF glucose level should be compared with the Even when children receive appropriate antibiotic
blood glucose concentration determined shortly be- drugs intravenously for 44 to 68 hours, the bacterial
fore lumbar puncture. character of the chemical and morphologic findings
The normal level of protein in CSF from individ- can be discerned in most cases.58 When children
uals beyond the second month of life is less than with H influenzae meningitis were pretreated with
40 mg/dL. The glucose level in CSF should be oral antibiotic agents on an outpatient basis, CSF
greater than two thirds of the glucose concentration cultures generally grew H influenzae. There was a
in blood obtained concomitantly. In patients with tendency for pretreatment with effective drugs to
bacterial meningitis, the depression of CSF glucose render sterile the CSF of children with pneumococ-
and of the CSF to blood glucose ratio (normally cal or meningococcal disease.58
968 MENINGITIS
Rapid Diagnostic Tests ing of urine for H influenzae type b may yield
positive results for up to ten days after children
Although not essential, the various rapid diag-
have received H influenzae polysaccharide vaccine.
nostic tests-including countercurrent immuno-
In various studies, latex particle agglutination was
electrophoresis, latex particle agglutination, and
capable of detecting polyribose phosphate antigen
the enzyme-linked immunosorbent assays-may be
in the CSF of 95% to 100% of patients; this antigen
helpful in establishing an etiologic diagnosis rap-
was detected by countercurrent immunoelectropho-
idly. CSF, blood, and urine from newborn infants
resis in only 80% to 85% of the same patients.626
can be examined by countercurrent immunoelectro-
Recently, a commercial latex particle agglutination
phoresis for group B streptococci; Ki strains of E.
kit containing antibody-coated latex particles for H
coli; H influenzae type b; N meningitidis groups A,
influenzae type b, S pneumoniae, and N meningiti-
B, C, Y, and W135; and S pneumoniae. Latex
dis groups A and C has become available.
particle agglutination testing for group B menin-
A commercially available system for the detec-
gococci can be performed with commercially avail-
tion of group B streptococcal antigen (Phadebact)
able monoclonal latex test reagents. Antigens from
by protein A coagglutination has been evaluated by
L monocytogenes, Klebsiella pneumoniae, and Pseu-
Webb and co-workers.67 This system has acceptable
domonas aeruginosa also can be detected by coun-
sensitivity and specificity and may prove to be a
tercurrent immunoelectrophoresis.12’59’#{176} Quantita-
valuable adjunct for the detection of group B strep-
tion of antigen may be helpful in predicting the
tococcal antigen in CSF.
prognosis for infants with E coli Ki meningitis;
patients with the highest concentration of antigen OTHER TESTS OR PROCEDURES HELPFUL IN
are most likely to experience sequelae of their dis-
DIAGNOSING MENINGITIS
ease.12
Countercurrent immunoelectrophoresis also has
Cultures of Materials Other Than CSF
been shown to be useful for the rapid diagnosis
(within one hour) and management of bacterial Nose, Throat, and Other Mucosa and Surface
meningitis due to H influenzae type b, S pneumo- Cu/tures
niae, or N meningitidis groups A, B, C, Y, and
W135. The methodology used is sensitive and can Cultures of body surfaces and orifices such as the
detect nonviable bacteria, thus permitting the de- nose and throat may yield the meningitis-causing
tection of bacterial antigen even in patients whose pathogen, but such cultures are neither sensitive
infections have been pretreated with appropriate (the organism causing the meningitis may not be
antibiotic regimens. Countercurrent immunoelec- present) nor specific (other organisms may be pres-
trophoresis is most effective when CSF, serum, and ent). Cultures of the nose and throat are not helpful
urine are screened concomitantly. Evaluation of in identifying the etiology of meningitis.
urine by countercurrent immunoelectrophoresis is
enhanced by the concentration of urine with either B/ood
a B15 filter system or an ethanol precipitant tech- Most children with bacterial meningitis are mi-
nique. A negative countercurrent immunoelectro- tially bacteremic. Blood cultures are of value in
phoresis result does not exclude the diagnosis of patients with possible bacterial meningitis. In one
bacterial meningitis. study in which blood was obtained from every pa-
Latex particle agglutination kits are commer- tient (none of whom had been previously treated
cially available for detecting the polysaccharide an- with antibiotics), the cultures were positive in 90%
tigens of H influenzae type b, S pneumoniae, N of cases of H influenzae meningitis, in 80% of cases
meningitidis, and group B streptococci. Latex par- of pneumococcal meningitis, and in 90% of cases of
tide agglutination testing is more sensitive for this meningococcal meningitis.68 Uncommonly, culture
purpose than countercurrent immunoelectropho- of the blood reveals a bacterial pathogen, and pleo-
resis and has been used to establish a diagnosis of cytosis identifies meningitis, but the CSF culture is
group B streptococcal infection within 15 minutes negative.
of receipt of a specimen by a laboratory.61 Latex
particle agglutination is superior to countercurrent
Urine
immunoelectrophoresis in detecting polyribose
phosphate antigen of H influenzae type b in CSF, Infections of the urinary tract are infrequently
serum, and urine. However, nonspecific agglutina- the primary source of the meningitis-causing path-
tion of latex particles in serum, urine, and other ogen in neonates and young infants. In older chil-
body fluids may result in an indeterminate test dren without underlying malignancy, the associa-
result. In addition, latex particle agglutination test- tion of urinary tract infection and meningitis is
SUPPLEMENT 969
unusual. Efforts should be made to obtain urine for TABLE 3. Infectious and Noninfectious Causes Of
culture before therapy in the child younger than 1 Aseptic Meningitis*
year of age, but therapy should not be withheld if Infectious Agents and Diseases
an adequate specimen cannot be promptly obtained. Bacteria: Partially treated meningitis, Mycobacterium
tuberculosis, parameningeal focus (brain abscess,
epidural abscess), acute or subacute bacterial endo-
Skin Lesions carditis
Viruses: Enteroviruses, mumps, lymphocytic chorio-
Petechiae may represent microemboli, with bac-
meningitis, Epstein-Barr, arboviruses (Eastern
teria present in the lesion. Gram-stained smears equine, Western equine, St Louis), cytomegalovirus,
made from petechiae may provide immediate clues varicella-zoster, herpes simplex, human immunode-
to the identity of the invading organism. ficiency virus
Rickettsiae: Rocky Mountain spotted fever
Spirochetes: Syphilis, leptospirosis, Lyme disease
Midd/e Ear Effusion Mycoplasma: Mpneumoniae, M hominis (neonates)
Fungi: Candida albicans, Coccidioides immitis, Crypto-
Although some children with otitis media have
coccus neoformans
concomitant meningitis due to the same organism, Protozoa: Toxoplasma gondii, malaria, amoebas, vis-
a direct route to the meninges is unlikely in most ceral larval migrans (Taenia catis or Taenia canis)
cases. More likely is the occurrence of a respiratory Nematode: Rat lung worm larvae (eosinophilic men-
infection that results in meningitis through simul- ingitis)
Cestodes: Cysticercosis
taneous invasion of the bloodstream and seeding of
Noninfectious Diseases
the meninges as well as direct invasion of the mid- Malignancy: Primary medulloblastoma, metastatic
dle ear via the eustachian tube. Needle aspiration leukemia, Hodgkin disease
of the middle ear fluid and preparation of a Gram- Collagen-vascular disease: Lupus erythematosus
stained smear may permit immediate identification Trauma: Subarachnoid bleed, traumatic lumbar
puncture, neurosurgery
of the likely organism and may be of value if the
Granulomatous disease: Sarcoidosis
smear findings of CSF are equivocal. Direct toxin: Intrathecal injections of contrast media,
spinal anesthesia
Tests of Inflammatory Response Poison: Lead, mercury
Autoimmune disease: Guillain-Barr#{233} syndrome
Tests of inflammatory response, such as periph- Unknown: Multiple sclerosis, Mollaret’s meningitis,
eral blood WBC count and differential, ESR, and Behcet syndrome, Vogt-Koyanagi syndrome, Har-
ada syndrome, Kawasaki disease
C-reactive protein, may assist in identifying the
* Aseptic meningitis is defined as meningitis in the ab-
child who is likely to be septic. The test results are
too variable and nonspecific to be useful in making sence of evidence of a bacterial pathogen detectable in
or excluding a diagnosis of bacterial meningitis. CSF by usual laboratory techniques.
The mean WBC count is elevated in patients
TREATMENT OF MENINGITIS
with bacterial meningitis, but the standard devia-
tion around the mean is large. There may be differ- After a diagnostic lumbar puncture, treatment
ences among the bacterial pathogens: Valmari69 for meningitis is started promptly; for most pa-
noted mean WBC counts of 14,605/zL for 44 cases tients, this point is reached before results of the
of meningitis due to H influenzae; 19,391/1uL for 11 CSF examination become available. Prior treat-
cases due to N meningitidis; and 23,833/tL for six ment can alter the results of the CSF examination
cases due to S pneumoniae. Low WBC counts but rarely to the extent that bacterial meningitis is
(3,000/zL) suggest severe disease and poor out- not suspected or diagnosed on the bases ofthe WBC
come. count and differential and (later) the results of
cultures.70’71
Tests for Diagnosis of Aseptic Meningitis
Selection of Initial Antimicrobial Therapy
If a patient has meningitis but no bacteria are
cultured from the CSF or other body fluids by Antimicrobial therapy for bacterial meningitis
routine laboratory methods, the physician must entails the selection of appropriate antibiotics that
consider the various causes of aseptic meningitis are effective against the likely etiologic agents and
(Table 3). Many children will have a viral infection, the use of proper drug doses and administration
but some will have either another type of infection schedules that will result in adequate bactericidal
or a noninfectious disease. Children should have a activity in CSF (Table 4).
skin test for tuberculosis if they are in a high-risk The initial regimen chosen for treatment should
group. Other tests and procedures should be consid- be broad enough to affect all the likely pathogens
ered as applicable to the individual child. for the age group involved. Although Gram-stained
970 MENINGITIS
TABLE 4. Antimicrobial Agents for Treatment of Meningitis
Regimen Daily Dose*
Neonates Infants and
Children
0-7 D of Age 8-28 D of Age
Conventional
Penicillin G 100,000-150,000 U/kg” 150,000-200,000 U/kgC 250,000 U/kgcd
Ampicillin 100-150 mg/kg” 150-200 mg/kg” 200-300 mg/kg’
Kanamycin 15-20 mg” 20-30 mgb
Gentamicint 5 mg/kg” 7.5 mg/kg”
Tobramycint 4 mg/kg” 6 mg/kg”
Amikacint 15-20 mg/kg” 20-30 mg/kg”
Chloramphenicolt 25 mg/kg 50 mg/kg” 75-100 mg/kgc
Alternative
Cefotaxime 100 mg/kg” 150-200 mg/kgc 200 mg/kgc
Moxalactam 100 mg/kg” 150-200 mg/kg” 200 mg/kg’
Ticarcillin 150-225 mg/kg”' 225-300 mg/kg
Methicillin 100-150 mg/kg”' 150-200 mg/kgc
Oxacillin 100-150 mg/kgb 150-200 mg/kg””
Nafcillin 100-150 mg/kg”1’ 150-200 mg/kg”
Vancomycin 20 mga 30 mg/kg” 40-60 mg/kgc
Ceftriaxone 100 mg/kg”
Ceftazidime 60 mg/kg” 90 mg/kg” 125-150 mg/kg”
* Dosage divided and given every: “ 12 hours, b 8 hours, C 6 hours, d 4 hours.
t Serum concentrations should be monitored and dosages adjusted accordingly.
smears or results of latex agglutination tests may Meningitis caused by Gram-negative enteric ba-
indicate a specific pathogen, it is prudent to initiate cilli can pose special management problems. Erad-
broad-spectrum therapy until results of cultures ication of the pathogen is often delayed, and brain
and susceptibility tests are available. The preferred abscess or other complications may occur.72 Ampi-
initial antimicrobial regimen varies with the age of cillin and an aminoglycoside have been used for 20
the patient and with the expected pathogens and years with satisfactory results, although bacteri-
their susceptibilities. A number of new 3-lactam cidal activity in CSF is often low. Despite superior
antibiotics have been evaluated for the treatment in vitro and CSF bactericidal activity of the third-
of meningitis in infants and children, but none has generation cephalosporins, the outcome of neonatal
been proved superior to standard regimens that meningitis caused by enteric Gram-negative bacilli
have been used for many years. was shown to be similar when the combination of
moxalactam and ampicillin was compared with that
Newborn /nfants of ampicillin and amikacin in 63 infants.73 Cefotax-
A penicillin, usually ampicillin, and an aminogly- ime is preferred to other third-generation cephalo-
coside such as gentamicin are recommended for sporins for use in neonates both because it has been
initial empiric treatment of neonatal meningitis. used more extensively74’75 and because it is not
An alternative regimen might include ampicillin excreted in the bile (excretion could have an inhib-
and cefotaxime, but considerably less experience itory effect on the bacterial flora of the intestinal
has been gained with this drug combination than tract).76 Thus, either cefotaxime or the conven-
with the former regimen. Once results of cultures tional regimen of ampicillin and an aminoglycoside
and susceptibility testing are available, the initial is satisfactory for treatment of enteric Gram-neg-
antimicrobial regimen can be changed. As a rule, ative bacillary meningitis. If facilities are not avail-
ampicillin or penicillin G is preferred for infection able for determining aminoglycoside concentra-
caused by group B streptococci. Some physicians tions, or if the patient has abnormal renal function,
prefer to continue the combination of ampicillin cefotaxime is preferred.
and gentamicin for the full course of treatment.72 If meningitis develops in a low birth weight infant
Ampicillin is the preferred agent for L monocyto- who has been in the nursery for several weeks or
genes or enterococcal meningitis, although, again, longer or in any neonate who has received one or
the aminoglycoside can be continued with ampicil- several previous courses of antimicrobial therapy
lin until repeat cultures of CSF are sterile or for for presumed sepsis, an alternative initial antimi-
the entire course, depending on the preference of crobial regimen should be considered. Because en-
the physician; to date, no hard data support one of terococci and gentamicin-resistant Gram-negative
these choices over the others. enteric bacilli are potential pathogens in these set-
SUPPLEMENT 971
tings, as are the usual organisms of neonatal sepsis, col is effective against most of the relatively peni-
a combination of ampicillin and an aminoglycoside cillin-resistant pneumococcal strains and against 13-
(preferably amikacin) or ampicillin and cefotaxime lactamase-positive strains of Haemophilus. On rare
could be used. In those patients with long-term occasions, a strain of H influenzae resistant to
vascular lines, an antistaphylococcal agent (a pen- ampicillin and chloramphenicol has caused men-
icillinase-resistant penicillin or vancomycin) ingitis in the United States, and it is predicted that
should be added to the regimen or substituted for the prevalence of these strains will increase in the
ampicillin because septicemia caused by Staphylo- next several years.77 Cefotaxime, moxalactam, or
coccus aureus or Staphylococcus epidermidis is pos- ceftriaxone are likely to be effective against these
sible. For P aeruginosa meningitis, ceftazidime plus multiply resistant organisms.78
an aminoglycoside could be considered for therapy
because of the excellent in vitro activity of ceftazi- Factors Affecting Se/ection of Drugs
dime against these strains.
A number of factors or conditions can influence
/nfants 1 to 3 Months of Age the selection of antimicrobial therapy for meningi-
Controversy exists about the most appropriate tis. These include the condition of the child on
antimicrobial regimen for initial treatment of men- admission to the hospital, abnormal renal or he-
ingitis in 1- to 3-month-old infants. Because the
patic function, coadministration of pharmacologi-
cally antagonistic drugs, availability of laboratory
potential pathogens in this age group include or-
facilities to determine concentrations of drugs in
ganisms commonly encountered in neonates as well
as those seen beyond the newborn period, antimi- body fluids, and prior treatment with antimicrobial
agents of the same class.
crobial agents commonly used in either period could
If the patient has persistent hypotension or shock
be appropriate for infants in this age group. The
develops, it is preferable to avoid, whenever possi-
initial choice among drugs can be guided by results
ble, chloramphenicol and the aminoglycosides be-
of stained smears of CSF and of tests for antigen
cause of diminished excretion via the hepatic and
in CSF, blood, and urine. The combination of am-
renal routes. In such patients and in those with
picillin and chloramphenicol would be appropriate
underlying abnormalities in hepatic or renal func-
in most infants unless Gram-negative enteric path-
tion, /3-lactam antibiotics are preferred for therapy
ogens are suspected, in which case ampicillin and
unless the concentrations of chloramphenicol or
cefotaxime should be administered. The combina-
aminoglycosides can be promptly determined. Be-
tion of ampicillin and cefotaxime is a satisfactory
cause of the unpredictable metabolism of chloram-
alternative regimen for initial empiric treatment of
phenicol in newborn and young infants and the
all infants in this age group. pharmacologic interactions of this agent when ad-
ministered concomitantly with phenobarbital,79
Infants and Children 0/der Than 3 Months of Age
phenytoin,79 and rifampin,tm serum levels of chlor-
Inc/uding Todd/ers, Schoo/-Aged Children, and
amphenicol should be determined and the dosage
Ado/escents
adjusted accordingly to avoid toxic or subtherapeu-
Ampicillin in combination with chloramphenicol tic concentrations. The effective and safe range of
. is the preferred drug regimen for initial empiric chloramphenicol concentrations in serum is 15 to
treatment of meningitis in infants and children, at 30 jzg/mL.
least during the first 10 years of life. This regimen Aminoglycoside concentrations in sera of new-
has been used for many years and has been proven born infants are unpredictable, especially in those
to be safe and effective. Alternative agents for weighing less than 1,500 g at birth.72 Dosages of
initial treatment of meningitis include ceftriaxone, these agents should be tailored to achieve concen-
cefotaxime, or ceftazidime. On the basis of limited trations in the range considered to be therapeutic
experience, these drugs appear to be safe and effec- and nontoxic. The actual concentrations that are
tive. Once the results of cultures and susceptibility toxic in newborn and young infants have not been
testing are available, the initial antibiotic regimen determined; rather, those that are believed to be so
can be altered. Generally, ampicillin or penicillin G in adults have been applied to neonates, infants,
is preferred for treatment of meningitis caused by and children. In general, the goal in neonates is to
N meningitidisor S pneumoniae and ampicillin for maintain peak concentrations of gentamicin, netil-
disease caused by f3-lactamase-negative strains of micin, and tobramycin between 5 and 10 zg/mL
H influenzae. Because some pneumococcal strains and of kanamycin and amikacin between 15 and 30
are relatively resistant to penicillin, all strains of S g/mL with trough concentrations of the former
pneumoniae isolated from CSF culture should be agents below 2 to 3 tg/mL and of the latter agents
tested for penicillin susceptability. Chlorampheni- below 8 to 10 sg/mL. If dosages are adjusted to
972 MENINGITIS
maintain proper serum concentrations, ototoxicity on the causitive agent, the clinical response, and
and nephrotoxicity occur uncommonly in neonates, the development of complications. In
general, a
infants, and children. minimum of ten days of therapy is required for
meningitis caused by H influenzae or Spneumoniae,
Partia//y Treated Meningitis
14 to 21 days for that caused by group B strepto-
In the patient who has received an antibiotic cocci or L monocytogenes, and 21 days for disease
prior to diagnosis, initial empiric therapy should be
caused by Gram-negative enteric bacilli. Patients
broad enough to affect the likely pathogens that
with meningococcal meningitis can usually be
occur in the age group involved. In the event that
treated for seven to ten days. The duration of
a bacterial pathogen cannot be identified as the
therapy may need to be extended as a result of
causitive agent, and the patient has improved din-
complications such as brain abscess or subdural
ically, therapy could be continued with the same
empyema, delayed sterilization of CSF cultures
drug or a drug similar to that started before diag-
(which occurs frequently with coliform meningitis),
nosis. Thus, if a child received ampicillin prior to
prolonged fever, persistence of meningeal signs, or
lumbar puncture, ampicillin and chloramphenicol
development of nosocomial bacterial infections. In
would be administered parenterally for initial ther-
such cases, the time of discontinuation of antimi-
apy. If cells present in the CSF defined meningitis
crobial therapy is individualized.
but cultures were sterile for bacteria at 72 hours,
the prior course of ampicillin may have been re-
Treatment of the Child Who Is Transported to a
sponsible for suppressing bacterial growth or steri-
Tertiary Facility
lizing the CSF. Continuing ampicillin alone to com-
plete the course of therapy would be appropriate For optimal management, many children are
because this drug was the agent responsible for the transported to a tertiary care facility after clinical
presumed “partially treated” meningitis. In many or laboratory diagnosis of meningitis in an office,
cases, it is likely that the patient had nonbacterial clinic, or community hospital. If lumbar puncture
meningitis for which ampicillin or another drug was has been performed and the examination of CSF
initially administered. identifies meningitis, an aliquot of the CSF should
be sent with the patient and the remainder kept at
Decision to Withho/d Therapy the primary hospital. The laboratory at the tertiary
In some patients, the results of initial examina- care facility may have additional resources to assist
tion of CSF do not distinguish between a bacterial in specific microbiologic diagnosis. Antimicrobial
and a viral process. In these cases, the WBC count therapy is initiated for presumptive bacterial men-
is <1,000/id, 60% to 70% of the cells being poly- ingitis as early as possible after the CSF has been
morphonuclear cells; the CSF glucose concentra- obtained.
tion is normal; and the Gram-stained smear and If the diagnosis of meningitis is based on clinical
latex agglutination reactions are negative. Some findings and a lumbar puncture is not or cannot be
investigators advocate withholding antibiotic ther- performed at the primary hospital, the decision to
apy in such cases and repeating the lumbar punc- initiate antibiotic therapy should be made in con-
ture after four to six hours of close observation in sultation with physicians at the tertiary care facil-
the hospital.8’ The repeat examination of CSF may ity. If the period preceding arrival at the tertiary
substantiate the impression of aseptic meningitis hospital is likely to be prolonged, presumptive an-
(a shift to a predominance of lymphocytes) or may timicrobial therapy may be initiated. When the
indicate more conclusively a bacterial process. This child arrives at the new facility, diagnosis of men-
course of action is not recommended if the patient ingitis can be made on the basis of cytologic and
has been pretreated with antibiotics, is younger chemistry findings. Specific microbiologic diagnosis
than 1 year, is clinically unstable, or deteriorates may still be possible by culture or antigen detection
clinically during the observation period. Other in- techniques despite prior therapy.
vestigators advocate presumptive therapy after cul- During transport to the tertiary care facility,
tures of CSF and blood have been obtained if the supportive care should be provided by experienced
results of examination of CSF are even suggestive attendants.
of bacterial meningitis. In this situation, antimicro-
bial therapy is stopped if the cultures are sterile Monitoring the Course of Illness During Treatment
after 72 hours and the clinical course indicates a
Laboratory Faci/ities
nonbacterial process.
The minimal requirement for the bacteriology
Duration of Antibiotic Therapy
laboratory diagnosing meningitis is to be able to
The duration of antimicrobial therapy is based identify all of the commonly encountered menin-
SUPPLEMENT 973
geal pathogens of infants and children and to de- status needs to be documented. If a hospital cannot
termine the susceptibility of those organisms to the provide this monitoring, which is considered a mm-
antimicrobial agents prescribed. Whenever possi- imal requirement for the management of patients
ble, the physician should be expeditiously informed with meningitis, consideration should be given to
about the susceptibility of Gram-negative enteric sending the child by ambulance to another hospital,
bacilli to the aminoglycosides and to selected third- preferably a tertiary care facility, that can do so.
generation cephalosporins, the production of 13-lac- Initially, all fluid is administered intravenously,
tamase by H influenzae and the susceptibility of and input and output of fluids are measured care-
this organism to ampicillin and chloramphenicol, fully. During the first days of therapy, the patient
and the susceptibility of S pneumoniae to penicillin is evaluated for inappropriate secretion of antidi-
by the standard oxacillin disk diffusion method or uretic hormone. This evaluation is best accom-
by a broth dilution technique. plished by the monitoring of body weight, serum
From 5% to 15% of pneumococcal strains in the electrolyte values, serum and urine osmolality, and
United States are relatively resistant to penicillin urine volume and specific gravity. The best indica-
(minimum inhibitory concentration, 0.1 to 1.0 g/ tions of inappropriate secretion of antidiuretic hor-
mL), which, if used for treatment of meningitis, mone are increased body weight, diminished serum
may be ineffective.82’ Although most of these rel- osmolality, and hyponatremia.TM The simplest and
atively penicillin-resistant strains are susceptible most effective means for reducing the effect of
to chloramphenicol, an occasional strain is resistant inappropriate antidiuretic hormone secretion is to
to the latter drug as well.82 Thus, susceptibility of restrict fluid intake to approximately 1,000 mL/m2
pneumococci to a 1-tg oxacillin disk on agar me- in 24 hours. Fluids should not be restricted in
dium should be determined in all cases; those patients with hypotension or hypovolemia.
strains with zone diameters of <20 mm should be
tested by a standard broth dilution technique to Repeat CSF Examination
determine the minimum inhibitory concentrations
If the child appears to respond appropriately to
of penicillin and chloramphenicol. Cefotaxime, cef-
therapy, no further examination of CSF is neces-
triaxone, or vancomycin is usually effective against
sary. Because delayed sterilization of CSF cultures
such strains.82M Stock strains with known suscep-
may imply inadequate therapy and can indicate a
tibilities should be tested simultaneously with the
test strain as a quality control for the laboratory.
poor prognosis,’ when clinical evidence of im-
provement is lacking after 24 to 72 hours of therapy,
Supportive Care another lumbar puncture should be performed. If
the organism is identified again by culture after two
The first three or four days of treatment are
to three days of therapy, the antimicrobial regimen
critical because complications of septicemia and
should be reevaluated.
meningitis occur most frequently at that time. It is
When the patient’s management and course of
advisable to manage infants and children with men-
illness are uncomplicated, CSF examination and
ingitis in a hospital that has specialized equipment
culture at the completion of therapy are unneces-
and staff with expertise in caring for infants and
sary.87m The information provided at that point is
children who are critically ill. The staff should
not useful in predicting which patients will have
include physicians who are capable of managing the
recurrent disease and complications, and arbitrary
complications of meningitis.
rules regarding approximate numbers of WBCs and
The following schedule may be used as a model
concentrations of sugar and protein in CSF often
for supportive care of children with suspected or
delay discharge from the hospital.
documented bacterial meningitis. All patients are
weighed on admission. Their vital signs are re-
Complications
corded at 15- to 30-minute intervals until stable
and then regularly during the first 24 to 48 hours It is advisable to evaluate patients with menin-
of treatment. Urine specific gravity, body weight, gitis daily by means of physical and neurologic
and concentrations of sodium, chloride, carbon examinations so that complications (which can de-
dioxide, and potassium in serum are measured every velop anytime during therapy) will be detected
12 to 24 hours for the first two days. Neurologic promptly. Head circumference should be measured
examination should be performed initiallyand daily and recorded daily. The head may be transillumi-
throughout hospitalization. To institute proper nated daily to detect subdural collections of fluid
treatment, a brief evaluation of neurologic function and possibly hydrocephalus or porencephaly.
is done more frequently, especially during the first Seizures. About 20% to 30% of patients have
24 hours of management, when changing neurologic seizures before admission to the hospital; these
974 MENINGITIS
events do not portend an adverse outcome.34 In fever. If no cause is found and the fever persists,
contrast, generalized seizures that occur after the the course of action is individualized. If the child is
third or fourth day of therapy or focal seizures irritable and the CSF examination reveals a protein
developing anytime during therapy may signify an concentration of>100 mg/dL or a substantial num-
abnormality within the CNS and are associated ber of polymorphonuclear cells, persisting infection
with abnormal neurologic examination on follow- in the CNS is possible and renewed efforts to erad-
up.34’35 Patients experiencing either of the latter icate such infection should be undertaken. If the
types of seizures require close observation, medi- child appears well despite continued fever and the
cation to control seizures, and evaluation of the CSF values are approaching normal values, anti-
cause of seizures, possibly including cranial CT microbial therapy can generally be discontinued at
scanning. the usual time, the assumption being that the pa-
Brain Abscess. Brain abscess can occur at any tient has a hospital-acquired viral infection or drug
age and can result from extension of infection of fever.
the sinuses, from trauma or neurosurgical proce- Because fever is an important sign with regard
dures, or from bloodstream infection associated to the clinical course, drugs for the control of fever
with congenital heart disease; brain abscess can should be used sparingly (and not for temperatures
also represent a complication of meningitis. In the <39#{176}C).
unusual case of neonatal meningitis caused by Ci-
trobacter diversus, brain abscess should be antici- CT Scanning
pated and a CT scan performed early in manage- CT scanning and cranial sonography provide
ment. Selection of antibiotic therapy is based on noninvasive means of accurately diagnosing some
identification of the pathogen and results of suscep- intracranial complications of meningitis. CT scans
tibility studies. It is best to avoid aminoglycoside are especially useful in detecting subdural collec-
therapy because of the conditions within the ab- tions of fluid, cerebral vascular thrombosis, brain
scess (eg, low pH, anaerobiasis) that preclude the abscess, and ventricular dilation. A CT scan should
optimal activity of these agents. Repeat CT scans be considered for patients with prolonged obtun-
are indicated to determine results of antimicrobial dation, irritability, or seizures, focal neurologic ab-
therapy, and drainage or excision may be necessary, normalities, enlarging head circumference, persist-
depending on the patient’s condition, the location ent elevation of CSF protein concentration, per-
of the abscess, and the response to therapy. sistent preponderance of polymorphonuclear cells
Subdural Collections of Fluid. Subdural effusions in CSF, or recurrence of disease.
are not generally associated with signs and symp- Radioisotope scanning may be helpful in selected
toms and usually resolve spontaneously. Indica- patients. The pattern of distribution of radioactiv-
tions for tapping of a subdural effusion include a ity recorded by fly-camera coincides with the accu-
clinical suspicion that the fluid is infected, a rapidly mulation of purulent material. An increased con-
enlarging head circumference in a child without centration of isotope may be related to the inflam-
hydrocephalus, focal neurologic findings, and/or matory response within the meninges or in the
evidence of increased intracranial pressure. Aspi- periventricular region or to an alteration in the
ration of subdural fluid collections is necessary only blood-brain barrierY#{176}
if signs or symptoms appear to be related to the
effusions. Subdural empyema is best managed by OUTCOME
drainage and antimicrobial therapy.
Both deaths and complications of meningitis in
Fever. Fever persists for as many as five days in
survivors occur despite early diagnosis and use of
a majority of children with meningitis and for five
appropriate antimicrobial agents. The pathologic
to nine days in 13% of patients. Fever is prolonged
findings and pathophysiologic events are generally
for ten days or longer in 13% of patients and occurs
similar regardless of bacterial etiology and are
secondarily (after a minimum of 24 hours of being
largely independent of age.
afebrile) in 16% of patients.89 The most common
conditions associated with persistent and prolonged
Pathophysiologic Basis for Clinical Course and
fevers are subdural effusion, disease at other foci
Outcome
(eg, arthritis or pneumonitis), nosocomial infec-
tions, thrombophlebitis (from intravenous admin- The precise moment at which a microorganism
istration of medications and fluids), sterile or in- invades the meninges never can be ascertained with
fected abscesses (from intramuscular injections), certainty. Once meningeal invasion has occurred,
and drug fever. Nosocomial infections and subdural pathologic changes ensue. The most detailed ac-
effusions are frequently associated with secondary count in the English language literature of the
SUPPLEMENT 975
Cerebral necrosis plus increased intracranial pres-
pathologic features of meningitis was that by Ad-
ams et al.91 Most of the cases described occurred sure may result in total dissolution of the cerebrum.
before effective antibiotic therapy became avail-
able. The pathologic findings reported by these Vascular and Parenchymatous Changes
authors differ little from those described by Smith Polymorphonuclear infiltrates extending to the
and Landing,92 Rorke and Pitts,93 and Dodge and subintimal region of small arteries and veins have
Swartz,94 whose patients died despite antibiotic in- been associated with the exudative meningeal proc-
tervention. The following pathologic aspects sum- ess. Thrombosis of small cortical veins associated
marize the information presented in these reports. with necrosis of the cerebral cortex may be noted.
A meningeal exudate varying in thickness may Occlusion of one of the major venous sinuses, sub-
be found. Purulent material is distributed widely arachnoid hemorrhage secondary to a necrotizing
but may accumulate about the veins and venous arteritis, and necrosis of the cerebral cortex in the
sinuses, over the convexity of the brain, in the absence of identifiable thrombosis of small vessels
depths of the sulci, in the sylvian fissures, within rarely may be observed. Reactive microglia and
the basal cisterns, and around the cerebellum. The astrocytes may be identified in the cerebral cortex,
spinal cord may be encased in pus. Ventriculitis particularly adjacent to and under areas of heavy
(purulent material within the ventricles) has been subarachnoid exudate. Because no bacteria are
noted repeatedly in children who have died of their found in the cerebral cortex, these pathologic
disease. Recent experience suggests that ventricu- changes should be viewed as a noninfectious en-
litis may also be a relatively common finding in cephalopathy. “Toxic or circulatory factors” have
children with bacterial meningitis who survive, par- been suggested as being of possible importance.9’
ticularly in the neonatal period. Invasion of the Dodge and Swartz94 suggested systemic hypoxia and
ventricular wall, with perivascular collections of fever as additional possible causes of the encepha-
purulent material, has been noted.94 Loss of epen- lopathy and also noted that an increase in intracra-
dymal lining and subependymal gliosis may be ob- nial pressure may interfere with cerebral circula-
served. In some studies, purulent exudate has tion.
tended to be thicker over the convexity of the brain Damage to the cerebral cortex, reflecting the
in pneumococcal meningitis than in other forms of effects of vascular occlusion, hypoxia, bacterial in-
meningitis.93’94 Subdural empyema (as opposed to vasion, toxic encephalopathy, or some combination
subdural effusion) occurs rarely.91’92’94 of these factors, provides an adequate explanation
Meningeal signs noted during the acute illness for impaired consciousness, deficits in motor and
are most probably related to inflammation of the sensory function, seizures, and retardation that
pain-sensitive spinal nerves and roots. Residual may be observed.
sensory or motor paralysis following recovery from
meningitis in some cases is best explained on the Subdural Effusions
basis of pressure on the peripheral nerves early in
The high incidence of subdural effusions, coupled
the illness.
with the fact that subdural fluid may be found early
in the course of bacterial meningitis, suggests that
Increased Intracrania/ Pressure
effusions could be considered a concomitant effect
Patients with meningitis have a CSF pressure rather than a complication of meningeal inflam-
that frequently exceeds 300 mm H20 and that may mation. The ratio of albumin to ‘y-globulin is higher
exceed 500 to 600 mm H20. Papilledema is rare, in the subdural fluid of children with meningitis
however, probably because of the relatively brief than in serum.95 Numerous veins normally traverse
duration of pressure elevation. the subdural space, and inflammation of these veins
Hydrocephalus is not a common complication of and of the dural capillaries could produce an in-
meningitis beyond the neonatal period. If hydro- crease in vascular permeability and loss of albumin-
cephalus occurs, it is usually communicating and is rich fluid into the subdural space.94 When the in-
the result of adhesive thickening of the arachnoid flammatory process subsides, fluid formation gen-
about the cisterns at the base of the brain. Less erally ceases, but fluid may persist owing to a
frequently, the aqueduct of Sylvius or the foramina continued transudation through newly formed ves-
of Magendie and Luschka are obstructed by fibrosis sels in the subdural membrane. Although rupture
and reactive gliosis. The ventricular dilation that of veins in the subdural space due to shifts in
ensues may be coupled with coexistent necrosis of intracranial contents has been suggested as a pos-
cerebral tissue due to the meningitis itself or due sible pathogenetic factor, it seems unlikely to ex-
to occlusion of cerebral veins and (rarely) arteries. plain subdural effusions in the majority of children.
976 MENINGITIS
Inappropriate Secretion of Antidiuretic Hormone and auditory nerves also are at risk as they pass
through the infected temporal bone. Their ability
Inappropriate secretion of antidiuretic hormone
to swell without compromising the vascular supply
induces water retention and places the patient at
is limited.
greater risk for the development of increased intra-
cranial pressure or seizuresY Cellular electrolyte
Mortality
disturbances may depolarize neuronal membranes,
predisposing the patient to seizures. Increased oxi- The mortality rate for bacterial meningitis in the
dation of glucose and increased production of lac- neonate remains high, varying between 15% and
tate, as well as depletion of high-energy compounds 20%. The mortality rate for bacterial meningitis in
such as adenosine 5’-triphosphate and phospho- children who are beyond the neonatal period has
creatine, are observed. The choroid plexuses, epen- been reduced by antibiotic therapy to <10%. Never-
dyma, and pia mater respond to inflammation in theless, as many as 50% of the survivors of men-
the subarachnoid space by becoming more perme- ingitis have some sequelae of their disease.94’9101
able to serum protein.
Morbidity
Glucose Metabolism and Oxygen Utilization
Prospective Studies
Hypoglycorrhachia (decreased concentration of
glucose in CSF) is a frequent occurrence in bacterial The frequency of complications of meningitis can
meningitis. However, this condition is also found be assessed more accurately by prospective evalua-
in meningitis that is due to bacterial disease in tion. Specific sequelae or complications of bacterial
which cultures are sterile by standard methods of meningitis that have been observed include cranial
isolation (tuberculosis, partially treated meningitis, nerve involvement, hemi- or quadriparesis, muscu-
infections with parameningeal foci and endocardi- lar hypertonia, ataxia, permanent seizure disorders,
tis); in meningitis due to infection with other mi- and the development of obstructive hydrocephalus.
croorganisms, including some viruses (herpes sim- Other CNS or systemic complications occasionally
plex, mumps, lymphocytic choriomeningitis), fungi, noted in patients with bacterial meningitis include
and parasites (Naegleria, Plasmodium); and in men- transient or persistent diabetes insipidus, trans-
ingitis due to some noninfectious conditions includ- verse myelitis in the absence of any evidence of
ing hemorrhage and malignancy. The decrease in spasm or occlusion of the arterial supply to the
sugar concentration in CSF results primarily from spinal cord, pericardial effusion, and polyarteritis.
decreased transport of glucose across the inflamed Subdural effusions (as noted) are so frequent in
choroid plexus and from increased utilization of young children that they can be considered a part
glucose by host tissues. Utilization of glucose by of the general disease process rather than a persist-
bacteria, other microorganisms, and polymorpho- ent or troublesome complication of the meningeal
nuclear leukocytes is of less importance with regard infection. Brain abscess following bacterial menin-
to the low concentration of glucose in CSF.94’97 gitis is exceedingly rare; when an abscess is found,
Meningitis also decreases cerebral blood flow and the possibility that it preceded the development of
utilization of oxygen. Loss of cerebral vascular au- meningeal infection must be entertained and a care-
toregulation occurs, possibly as a result of tissue ful search for infection at other sites (eg, endocar-
acidosis.97 In some cases, autoregulation is restored ditis) should be initiated.
by hypocapnia. In 1975, Sell101 began a prospective study of 50
infants and children who recovered from H influ-
Nerve Inflammation
enzae meningitis. Of this group, 50% were entirely
Because the cranial and spinal nerves course normal, 9% were normal except for behavioral prob-
through the subarachnoid space, they often become lems, and 28% had significant handicaps. The ma-
irritated during meningitis. Deafness and vestibular jor handicaps noted included hearing loss (10% to
disturbances are well recognized; less frequently, 11%), language disorders or delayed development
visual loss from optic nerve involvement also may of language (15%), impaired vision (2% to 4%),
occur. In addition to a direct involvement of the mental retardation (10% to 11%), motor abnormal-
nerves as they pass through the infected subarach- ities (3% to 7%), and seizures (2% to 8%). Twenty-
noid spaces, other factors must be considered when one postmeningitic children were paired with a
extravascular and facial nerve functions are com- sibling and tested by means of the Wechsler Intel-
promised. For example, increased intracranial pres- ligence Scale for Children. The mean IQ of the
sure may result in transtentorial herniation and postmeningitic children was 86 and that of control
compression of the extravascular nerves. The facial children was 97 (P < .05). Comparison of results
SUPPLEMENT 977
for individual pairs revealed that 29% of postmen- niques, such as radionuclide scintigraphy107”#{176}8 and
ingitic children scored 1 SD below their siblings; no CT scanning,1#{176}’11#{176}
have not improved upon the
survivor of meningitis had a score 1 SD higher than sensitivity of transillumination for the detection of
his or her sibling. subdural effusion in younger patients. The newer
In a large prospective study, the mean IQ (± SD) techniques offer the advantage of visualization of
for the entire group of 235 patients following recov- parenchymal lesions as well as effusions in older
ery was 94 ± 23, with a range of 33 to 150 (R. D. patients when transillumination is technically un-
Feigin, MD, and P. R. Dodge, MD, unpublished satisfactory. In experienced hands, cranial ultraso-
data, 1974 to 1984). Twenty-nine children (17.3%) nography has been shown to be useful,’1’ particu-
had IQ scores of <70. A comparison of these pa- larly in infants, and the refinement of scanning
tients with their own siblings and with other control techniques has increased the sensitivity of this pro-
children revealed no significant difference in mean 12
IQ. A significantly greater proportion (P < .01) of Subdural effusions appear to be more frequent
children who recovered from meningitis than of and/or more readily detectable in infants. In a
children from control groups had IQ scores of <80. prospective study, subdural effusions were noted in
These results differ from those of Sell’#{176}’ that were 32.9% of children with H influenzae meningitis, in
noted previously. Tejani and associates102 also pro- 19% of children with pneumococcal meningitis, in
spectively evaluated children who had recovered 8% of children with meningococcal meningitis, and
from bacterial meningitis, using siblings as con- in 24% of children with meningitis due to other
trols. These authors reported no significant differ- organisms or to no detectable organism (R. D.
ences in verbal performance or full-scale IQ be- Feign, MD, and P. R. Dodge, MD, unpublished
tween meningitis patients and the sibling control data, 1974 to 1984). When appropriate corrections
population. were made for age, however, the incidence of sub-
There is a tendency for even major neurologic
dural effusion proved to be independent of the type
defects to resolve unpredictably with time. Another of organism producing disease.
large, prospective study of bacterial meningitis in
The frequency with which vomiting, seizures, a
children revealed that 32.8% of children had ab-
full fontanel, focal neurologic signs, and persistent
normalities detectable on neurologic examination
fever are noted in children with bacterial meningitis
at the time of hospital discharge; by 5 years after
who do not have subdural effusions is such that
discharge, however, specific deficits were noted in
their occurrence can only rarely be attributed to
only 11.1% of the total group (R. D. Feign, MD,
the subdural effusion per se. Most effusions resolve
and P. R. Dodge, MD, unpublished data, 1974 to
spontaneously; removal of subdural effusions ap-
1984). Soon after discharge, hemi- or quadriparesis
pears not to be beneficial in most cases. Indications
was noted in 30 patients (12.4% of the total group),
for diagnostic aspiration of subdural fluid are de-
but 1 year after discharge, paralysis was noted in
scribed in “Subdural Collections of Fluid,” p 975.
only five children. This important observation sug-
gests the need to be cautiously optimistic in dis-
Hearing Impairment
cussing long-term complications of meningitis with
parents. Evoked response audiometry has been used to
detect hearing deficits. In one prospective study,
Development of Subdura/ Effusions some deficit in auditory nerve function was docu-
The first reports of the occurrence of subdural
mented by this sensitive technique in 6% of chil-
effusion in children with bacterial meningitis were
dren with H influenzae meningitis, in 31% of chil-
published in the 1950s by McKay and co-work- dren with pneumococcal meningitis, and in 10.5%
ers.103”#{176}4The effusion was considered to be a com- of patients with meningococcal disease.121
plication of meningitis and to be responsible for The mechanisms responsible for hearing deficits
signs and symptoms that prompted aspiration of include the spread of infection along the auditory
the subdural space. In this population, the inci- canal and cochlear aqueduct, serous or purulent
dence of effusion was 31%. In the 1960s, when labyrinthitis, and (with time) replacement of the
transillumination became recognized widely as a membranous labyrinth with fibrous tissue and new
sensitive, noninvasive diagnostic technique,’#{176}5”#{176}6 it bone.113117 Deafness generally is noted early in the
became apparent that effusion commonly occurred course of bacterial meningitis and is independent
in patients in whom these signs and symptoms were of the therapy provided.’1122 Ataxia has been re-
lacking and in patients who experienced no other ported as a presenting sign of bacterial meningitis
sequelae of their disease. in the same children in whom hearing losses were
It is noteworthy that more sophisticated tech- noted to develop at a later date.’23’124 Presumably,
978 MENINGITIS
insults to the vestibular and auditory systems oc- Spinal cord infarction producing quadriplegia
curred concomitantly in these children. and respiratory arrest also may occur in children
Early diagnosis and treatment will not prevent with bacterial meningitis as an acute or delayed
deafness in many children in whom loss of hearing event. The rapidity with which the diagnosis is
develops as a consequence of bacterial meningitis. made and therapy is instituted appears to be unre-
Estimates of the frequency of hearing loss, deter- lated to the vascular events that lead to infarction
mined in retrospective studies, vary
from 2.4% to of the spinal cord.’28”29
29%h19,123 In prospective studies, 7% of children When pericardial or joint effusions appear early
have experienced marked to extensive (75 dB) in the course of illness, the bacteria causing men-
hearing losses.’18’119”2’ Occasionally, hearing loss ingitis frequently may be recovered by pericardial
noted early may become less severe over a period tap or by aspiration of joint fluid. Pericardial and
of weeks to months.”7 The early loss of hearing joint effusions that appear seven to ten days after
noted by several investigators suggests that hearing the initiation of effective therapy generally are ster-
loss is not specifically associated with the use of a ile. These late-occurring effusions may persist from
particular antimicrobial agent. several days to more than 1 month.
Prospectively, evaluations have shown no corre-
lation between loss of hearing and either the age of Relapse
the patient at the onset of meningitis or the dura-
Bacteriologic relapse following treatment of men-
tion of illness prior to hospitalization.”9’121 In con-
ingitis (particularly that which is due to H influ-
trast, there has been a significant correlation be-
enzae and is treated with ampicillin) has been high-
tween hearing loss and the occurrence of seizures
lighted in a number of reports.130’38 Relapse of H
prior to hospital admission, the duration of fever in
influenzae meningitis after chioramphenicol treat-
the hospital after initiation of therapy (an event
ment also has been reported.’39 To assess precisely
presumably reflecting more severe disease), and a
the frequency of relapse in children, one needs to
depressed ratio of CSF glucose concentration to
know that an appropriate antibiotic has been ad-
blood glucose concentration at the time of admis-
ministered, that the pathogen is sensitive to that
sion’19’12’
antibiotic, that an appropriate intravenous dose has
Because hearing deficits are so common in pa-
tients with bacterial meningitis, a hearing evalua- been used, and that therapy has continued for an
appropriately extended period. In one retrospective
tion by means of evoked response audiometry in
study in which these criteria were fulfilled, the
young, uncooperative children is recommended as
a routine practice at the time of or soon after relapse rate following treatment of H influenzae
discharge from the hospital.’25’126 Repeated audio- meningitis with ampicillin was 4%#{149}137 Currently,
metric evaluation is recommended after discharge the relapse rate is <1%.
if the results of the initial examination are abnor-
Factors Correlated With Prognosis
mal. Pure tone audiometry can be used for older,
more cooperative children. It is important to differ- Prospective studies have permitted an assess-
entiate hearing deficits that are due to conductive ment of factors that herald a poor prognosis and
disturbances from those that are related to damage that may be discernible at or near the time of
to the eighth cranial nerve. Some children who have admission to the hospital.
repeated episodes of otitis media may experience Evidence of inappropriate secretion of antidi-
conductive loss that is unrelated to meningitis. uretic hormone was correlated significantly (P <
.01) with abnormal neurologic findings 3 months
Brain or Spinal Cord Infarction and Pericardial or after discharge and with low IQ scores. The age of
Joint Effusions the child was correlated inversely with the devel-
CT scanning has revealed evidence of cerebral opment of subdural effusion (P < .05). Thus, the
infarction in children for whom a diagnosis of bac- significantly increased impact of the disease upon
terial meningitis is established within a day or two young children was documented. The presence of
after the onset of symptoms of a febrile illness.127 focal neurologic findings in patients who were not
In most of these cases, evidence of abnormalities in postictal at the time of admission to the hospital
cerebrovascular dynamics (arteritis, thrombosis, was correlated significantly (P < .001) with abnor-
thrombophlebitis), and/or ventricular dilation has mal neurologic findings as noted previously. Thus,
been observed. In some of these cases, infarction focal neurologic findings at the time of admission
has been associated with profound hypotension re- proved to be a most reliable predictor of permanent
lated to endotoxemia (S. L. Kaplan and R. D. sequelae of bacterial meningitis. Focal neurologic
Feigin, unpublished data, 1977 to 1986). signs were positively correlated with low IQ scores
SUPPLEMENT 979
(P < .001), even 2 and 3 years following discharge other American populations. Am J Epidemiol 1974;100:29-
34
from the hospital. The quantity of antigen in the 23. Fraser DW, Henke CE, Feldman RA: Changing patterns
initial CSF specimen and the number of organisms of bacterial meningitis in Olmstead County, Minnesota,
present were also correlated significantly (P < .01) 1935-1970. J Infect Dis 1973;128:300-307
24. Fraser DW, Mitchell JE, Silverman LP, et al: Undiagnosed
with sequelae of meningitis.98 bacterial meningitis in Vermont children. Am J Epidemiol
1975;102:394-399
25. Tejani A, Mahadevan R, Dobias B: Occurrence of HLA
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980 MENINGITIS
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982 MENINGITIS
Report of the Task Force on Diagnosis and Management of Meningitis
Jerome O. Klein, Ralph D. Feigin and George H. McCracken, Jr
Pediatrics 1986;78;959
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Report of the Task Force on Diagnosis and Management of Meningitis

Jerome O. Klein, Ralph D. Feigin and George H. McCracken, Jr

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Newborn Infants PATHOGENESIS OF BACTERIAL MENINGITIS

The pathogenesis of meningitis in children be-

TABLE 2. Cerebrospinal Fluid Findings in Infants With Meningitis*

For a discussion of the criteria for repeat lumbar

tis occurs for every four cases of sepsis. Because

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