Vinnytsуa National Pirogov Memorial Medical University
Department of Children Infectious Diseases
“Approved”
at sub-faculty meeting
28.08.2012, protocol №_1_
Head of Department
prof. _______I.I. Nezgoda
Study guide for practical work of students
Topic: “Central nervous system infections in children. Differential diagnosis”.
Course VI
English-speaking Students’
Medical Faculty
Duration of the class-150min
Composed by assoc. prof. L.M. Stanislavchuk
Vinnytsa
2012
Chapter 1. Meningococcal disease
I. The theme urgency.
The gram-negative diplococcus Neisseria meningitides is a major infectious cause of childhood death
in developed countries. The mortality rate remains around 10%. Isolated meningococcal meningitis (5%
mortality rate) has a better prognosis than meningococcal septicemia (10-40% mortality rate). Infection
with N meningitides is highest in children aged 6 months to 2 years; these children have lost the maternal
antibodies and have not yet developed mature humoral immunity.
II. Primary aims of the study.
To teach students major methods of meningococcal disease diagnosis and treatment.
A student should know:
1) Etiology of meningococcal disease.
2) Epidemiology of meningococcal disease.
3) Pathogenesis of meningococcal disease.
3) Classification and clinical manifestations of meningococcal disease.
4) Laboratory studies of meningococcal disease.
5) Complications of meningococcal disease.
6) Treatment of meningococcal disease.
7) Prevention.
A student should be able to:
1) Find out history
2) Interpret data of physical examination
3) Interpret data of laboratory studies
4) Formulate clinical diagnosis
5) Make differential diagnosis
6) Administer prehospital and in-patient treatment in meningococcal disease.
7) Prevention
III. Educative aims of the study.
To facilitate:
1) The formation of deontology concepts and practical skills related to patients with meningococcal disease.
2) To acquire the skills of psychological contact establishment and creation of trusting relations between
the doctor and the patient and his parents.
3) The development of responsibility sense for timeliness and completeness of patient’s investigation.
IV. The contents of the theme.
Meningococcal disease, first described by Vieusseaux in 1805 as epidemic cerebrospinal fever, remains a significant health problem, particularly in the developing world. Although nasopharyngeal colonization rarely leads to disseminated disease, the fulminant, rapidly fatal course of meningococcemia is not
soon forgotten.
ETIOLOGY.
Neisseria meningitidis is a gram-negative diplococcus that is often described as biscuit shaped. It is
a common commensal organism of the human nasopharynx and has not been isolated from animal or environmental sources. The meningococcus is fastidious, and growth is facilitated in a moist environment at
35-37°C in an atmosphere of 5-10% carbon dioxide. It grows well on several enriched media, including
supplemented chocolate agar. Mueller-Hinton agar, blood agar base, and trypticase soy agar. On solid media, colonies are transparent, nonpigmented, and nonhemolytic. N. meningitidis is identified by its ability
to ferment glucose and maltose to acid and its inability to ferment sucrose or lactose. Indole and hydrogen
sulfide are not formed. The cell wall contains cytochrome oxidase, which results in a positive oxidase test
result.
The meningococci have been divided into serogroups based on antigenic differences in their capsular polysaccharides. Although 13 serogroups are currently recognized, groups A, B, C, W135, and Y account for most meningococcal disease. The other serogroups often colonize the nasopharynx but rarely dis-
seminate. Lipooligosaccharides (e.g., endotoxin) and proteins found in the outer membrane complex are
also used to serotype meningococcal strains.
EPIDEMIOLOGY.
Meningococcal dissemination occurs as endemic disease punctuated by outbreaks of cases that are
often clustered geographically. True epidemics have become rare in developed countries but remain a significant problem in much of the developing world. Endemic disease appears to be caused by a heterogeneous group of meningococcal serotypes, and epidemics are caused by a single serotype. Analysis with multilocus enzyme genetic methods has confirmed that a meningococcal epidemic is caused by strains derived
from a single clonotype.
The Centers for Disease Control (CDC) reported the results of a laboratory-based surveillance for
meningococcal disease in a large United States population for the years 1989-1991. The average annual
rate of invasive disease was 1.1/100,000 population, with an estimated 2,600 cases of meningococcal disease annually in the United States. The highest attack rates were during the winter and early spring months.
Males accounted for 55% of the total cases, and 29% of the cases occurred in children younger than 1 yr,
with the peak incidence of disease being 26/100,000 infants younger than 4 mo. Forty-six per cent of the
cases occurred in children 2 yr of age or younger, and an additional 25% of the cases occurred in persons
30 yr of age or older. Serogroup B and serogroup C meningococci accounted for nearly equal proportions
of disease (46% and 45%, respectively), but 69% of group C disease occurred in persons older than 2 yr.
Fifty-eight per cent of the patients were reported to have meningitis. N. meningitidis was isolated from
blood in 66% of cases, cerebrospinal fluid (CSF) in 51%, and joint fluid in 1%.
Subsequent data indicate that the proportion of cases caused by serogroup Y is increasing. The
United States has also experienced an increased incidence of outbreaks of serogroup C disease. Eight outbreaks occurred during 1992-1993, and most of these outbreaks had attack rates exceeding 10 cases per
100,000 population.
Meningococcal disease, particularly group A, remains a major health problem in much of the developing world. Many areas, such as China and Africa, have an endemic rate of disease of 10-25/100,000
persons and major periodic epidemics (100-500/100,000). Epidemic disease typically involves individuals
who are older than those with endemic disease.
PATHOGENESIS.
N. meningitidis is thought to be acquired by a respiratory route. Colonization of the nasopharynx
with meningococci usually leads to asymptomatic carriage, and only rarely does dissemination occur. Colonization can persist for weeks to months. Carriage rates vary from 2-30% in a normal population during
nonepidemic periods but are higher among children in daycare centers and in conditions of crowding. The
carriage rate can approach 100% in a closed population during an epidemic.
Meningococcal nasopharyngeal colonization is facilitated by the secretion of proteases that cleave
the proline-rich hinge region of secretory IgA and render it nonfunctional. Meningococci and gonococci
produce this enzyme, but nonpathogenic Neisseria organisms do not. Meningococci then adhere selectively
to nonciliated epithelial cells. Pili appear to be of major importance in the attachment of meningococci to
the human nasopharynx. The bacteria enter nonciliated epithelial cells by endocytosis and are carried
across the cell in membrane-bound vacuoles.
Meningococci disseminate from the upper respiratory tract through the bloodstream. Serum antibody leading to complement-mediated bacterial lysis has been shown to block this dissemination, and a
deficiency of antimeningococcal antibody is associated with the development of meningococcemia. Bactericidal antibody is directed against the capsular polysaccharide, subcapsular protein, and lipooligosaccharide antigens. Newborn infants have protective antibody that is primarily IgG of maternal origin. As this
antibody wanes, infants 3-24 mo of age experience the highest incidence of meningococcal disease. By
adulthood, most individuals have developed natural immunity against N. meningitidis from nasopharyngeal
colonization with N. meningitidis and colonization of the gastrointestinal tract with enteric bacteria that
express cross-reactive antigens. Infants have a high carriage rate of an unencapsulated, nonpathogenic neisserial strain, N. lactamica, that leads to the development of bactericidal antibody against the meningococcus.
The importance of the complement system in host defense against N. meningitidis is underscored
by the fact that individuals with primary or acquired complement deficiency have an increased risk of developing meningococcal disease, and 50-60% of individuals with properdin, factor D, or terminalcomponent deficiencies develop bacterial infections that are caused almost solely by N. meningitidis. Recurrent infection is common with terminal component deficiencies but is uncommon with properdin defi-
ciency. Acquired complement deficiency also carries an increased risk and can be seen with systemic diseases that deplete serum complement. Examples are systemic lupus erythematosus, nephrotic syndrome,
multiple myeloma, and hepatic failure.
The group B capsule is a homopolymer of sialic acid, which is known to inhibit alternative complement pathway activation. Antibody that activates the classic pathway can overcome this inhibition. The
lack of specific antibody coupled with inhibition of the alternative pathway may explain the prevalence of
serogroup B meningococcal disease in young children.
PATHOLOGY.
Disseminated meningococcal disease is associated with an acute inflammatory response. Hemorrhage and necrosis may be seen in any organ system and appear to be mediated by intravascular coagulation with deposition of fibrin in small vessels. The major organ systems involved in fatal cases of meningococcemia are the heart, central nervous system, skin, mucous and serous membranes, and adrenals. Myocarditis is found in more than 50% of patients who die of meningococcal disease. Cutaneous hemorrhages,
ranging from petechiae to purpura, occur in most fatal infections and are associated with acute vasculitis
with fibrin deposition in arterioles and capillaries. Diffuse adrenal hemorrhage may occur in patients with
fulminant meningococcemia (i.e., Waterhouse-Friderichsen syndrome). Meningitis is characterized by
acute inflammatory cells in the leptomeninges and perivascular spaces. Focal cerebral involvement is uncommon.
The interaction of endotoxin released by N. meningitidis and the complement system probably is
key in the pathogenesis of the clinical manifestations of meningococcal disease. Complement activation
correlates with the concentration of meningococcal lipooligosaccharide in the plasma. The concentration of
circulating endotoxin is directly correlated with activation of the fibrinolytic system, development of disseminated intravascular coagulopathy (DIC), multiple organ system failure, septic shock, and death. The
level of endotoxemia correlates with the concentration of circulating cytokines, which are released from
endotoxin-stimulated monocytes and macrophages. The concentrations of tumor necrosis factor-alpha and
interleukins have been directly associated with fatal meningococcal disease.
CLINICAL MANIFESTATIONS.
The spectrum of meningococcal disease can vary widely, from fever and occult bacteremia to sepsis, shock, and death. Recognized patterns of disease are bacteremia without sepsis, meningococcemic sepsis without meningitis, meningitis with or without meningococcemia, meningoencephalitis, and infection of
specific organs.
A well-recognized entity is occult bacteremia in a febrile child. Upper respiratory or gastrointestinal
symptoms or a maculopapular rash can be evident. The child often is sent home on no antibiotics or oral
antibiotics for a minor infection. Spontaneous recovery without antibiotics has been reported, but some
children have developed meningitis.
Acute meningococcemia initially can mimic a virus-like illness with pharyngitis, fever, myalgias,
weakness, and headache. With widespread hematogenous dissemination, the disease rapidly progresses to
septic shock characterized by hypotension, DIC, acidosis, adrenal hemorrhage, renal failure, myocardial
failure, and coma. Meningitis may or may not develop. Concomitant pneumonia, myocarditis, purulent pericarditis, and septic arthritis have been described. More often, meningococcal disease is manifested as
acute meningitis that responds to appropriate antibiotics and supportive therapy. Seizures and focal neurologic signs occur less frequently than in patients with meningitis caused by pneumococcus or Haemophilus
influenzae type b. Rarely, meningoencephalitis can occur with diffuse brain involvement.
A review of 100 children with invasive meningococcal disease revealed that 71% presented with
fever, 4% with hypothermia, and 42% with shock. Skin lesions occurred in 71% of the cases with petechiae
and/or purpura and in 49% with both. Purpura fulminans developed in 16%. Other rashes described were
maculopapular, pustular, and bullous lesions. Additional presenting symptoms and signs were irritability in
21%, lethargy in 30%, and emesis in 34%. Diarrhea, cough, rhinorrhea, seizure, and arthritis occurred
much less frequently (6-10%). Leukopenia and low platelet counts affected 21% and 14%, respectively,
and the white blood cell counts ranged from 900-46,000/mm3 . N. meningitidis was isolated in blood culture from 48% of the children, and meningitis was diagnosed in 55%. Six children had meningococci isolated from CSF in the absence of CSF pleocytosis, hypoglycorrhachia, or organisms detected by Gram
stain. Five of eight children who presented with arthritis had N. meningitidis isolated from joint aspiration
fluid. Eight per cent of the children had radiographic evidence of pneumonia on presentation.
Uncommon manifestations of meningococcal disease include endocarditis, purulent pericarditis,
pneumonia, septic arthritis, endophthalmitis, mesenteric lymphodenitis, and osteomyelitis. Primary puru-
lent conjunctivitis can lead to invasive disease. Sinusitis, otitis media, and periorbital cellulitis also can be
caused by the meningococcus. Primary meningococcal pneumonia is associated with pleural effusions or
empyema in 15% of cases. N. meningitidis is a rare isolate of the genitourinary tract in asymptomatic or
symptomatic individuals and has been the causal organism in urethritis, cervicitis, vaginitis, and proctitis.
Chronic meningococcemia is a rare manifestation of meningococcal disease that can occur in children and adults. It is characterized by fever, nontoxic appearance, arthralgias, headache, and rash. The rash
resembles that of disseminated gonococcal infection. Symptoms are intermittent, with the rash often appearing with fever. The mean duration of illness is 6-8 wk. Blood cultures may initially be sterile. Without
specific therapy, complications such as meningitis can result.
DIAGNOSIS.
Definitive diagnosis of meningococcal disease is made by isolation of the organism from a usually
sterile body fluid such as blood, CSF, or synovial fluid. Isolation of meningococci from the nasopharynx is
not diagnostic for disseminated disease. Blood and CSF are the usual sources of organism isolation. The
blood culture yields N. meningitidis in about half of the cases of disseminated disease, and culture or Gram
stain usually reveals the organism in those with meningitis. Culture or Gram stain of petechial or papular
lesions has been variably successful in identifying meningococci. Bacteria can occasionally be seen on
Gram stain of the buffy coat layer of a spun blood sample.
In meningitis, the morphologic and clinical characteristics of CSF are those of acute bacterial meningitis. CSF cultures can be positive in patients with meningococcemia but without clinical evidence of
meningitis or CSF pleocytosis. CSF cultures may be negative if the patient has received previous antibiotic
treatment.
Particle agglutination using latex beads, which has replaced counterimmunoelectrophoresis, can detect meningococcal capsular polysaccharide in CSF, serum, joint fluid, or urine. This is especially useful
when results are positive in the setting of partially treated infections with negative cultures. The available
latex agglutination tests do not detect group B meningococcus, the most common cause of endemic meningococcal infections, and therefore have limited usefulness. Latex agglutination is not a substitute for proper
Gram stain and culture techniques.
Other laboratory findings may include elevated sedimentation rate and C-reactive protein, leukocytopenia or leukocytosis, thrombocytopenia, proteinuria, and hematuria. Patients with DIC coagulation
have decreased serum concentrations of prothrombin and fibrinogen.
Differential Diagnosis.
This includes acute bacterial or viral meningitis, Mycoplasma infection, leptospirosis, syphilis,
acute hemorrhagic encephalitis, encephalopathies, serum sickness, collagen vascular diseases, HenochSchonlein purpura, hemolytic-uremic syndrome, and ingestion of various poisons. The petechial or purpuric rash of meningococcemia is similar to that in any patient with a disease characterized by generalized
vasculitis. These diseases include septicemia due to many gram-negative organisms; overwhelming septicemia with gram-positive organisms; bacterial endocarditis; Rocky Mountain spotted fever; epidemic typhus; Ehrlichia canis infection; infections with echoviruses, particularly types 6, 9, and 16; coxsackievirus
infections, predominantly of types A2, A4, A9, and A16; rubella; rubeola and atypical rubeola; HenochSchonlein purpura; Kawasaki's disease; idiopathic thrombocytopenia; and erythema multiforme or erythema nodosum due to drugs or infectious or noninfectious disease processes. The morbilliform rash occasionally observed may be confused with any macular or maculopapular viral exanthem.
TREATMENT.
Aqueous penicillin G is the drug of choice and should be given in doses of 250,000-300,000
U/kg/24 hr, administered intravenously in six divided doses. Cefotaxime (200 mg/kg/24 hr) and ceftriaxone
(100 mg/kg/24 hr) are acceptable alternatives. Chloramphenicol sodium succinate (75-100 mg/kg/24 hr IV
in four divided doses) provides effective treatment for patients who are allergic to beta-lactam antibiotics.
Therapy is continued for 5-7 days.
Isolates of N. meningitidis have been reported from Spain, South Africa, and Canada as being relatively resistant to penicillin, defined as having a minimal inhibitory concentration of penicillin of 0.1-1.0
mu/mL. Moderate resistance is caused, at least in part, by altered penicillin-binding protein 2. High-level
resistance due to beta-lactamase production has been reported from South Africa. The CDC estimated that
about 4% of meningococcal disease in 1991 in the United States was caused by N. meningitidis strains that
were relatively resistant to penicillin. None of the strains isolated produced beta-lactamase. The clinical
significance of moderate penicillin resistance is unknown. The CDC decided that routine susceptibility test-
ing of clinical meningococcal isolates is probably not indicated in the United States at this time, but continued surveillance is necessary.
Patients with acute meningococcal infections should be monitored carefully.
COMPLICATIONS.
Acute complications are related to the inflammatory changes, vasculitis, DIC, and hypotension of
invasive meningococcal disease. These can include adrenal hemorrhage, arthritis, myocarditis, pneumonia,
lung abscess, peritonitis, and renal infarcts. The vasculitis can lead to skin loss with secondary infection,
tissue necrosis, and gangrene. Skin sloughing can necessitate the use of skin grafts. Bone involvement can
lead to growth disturbance and late skeletal deformities secondary to epiphyseal avascular necrosis and epiphyseal-metaphyseal defects. Limb amputation has been reported for patients with purpura fulminans.
Meningitis rarely is complicated by subdural effusion or empyema or by brain abscess. Deafness is
the most frequent neurologic sequela, but the reported incidence varies from 0-38%. Other rare sequelae
include ataxia, seizures, blindness, cranial nerve palsies, hemiparesis or quadriparesis, and obstructive hydrocephalus.
The late complications of meningococcal disease are thought to be immune complex mediated and
become apparent 4-9 days after the onset of illness. The usual manifestations are arthritis and cutaneous
vasculitis. The arthritis is usually monarticular or oligoarticular. Effusions are usually sterile and respond to
nonsteroidal anti-inflammatory agents. Permanent joint deformity is uncommon. Because most patients
with meningococcal meningitis are afebrile by the 7th hospital day, the persistence or recrudescence of fever after 5 days of antibiotics warrants an evaluation for immune complex-mediated complications.
PROGNOSIS.
Despite the use of appropriate antibiotics, the mortality rate for disseminated meningococcal disease remains at 8-13% in the United States. Poor prognostic factors include hypothermia, hypotension,
purpura fulminans, seizures or shock on presentation, leukopenia, thrombocytopenia, and high circulating
levels of endotoxin and tumor necrosis factor. The presence of petechiae for less than 12 hr before admission, hyperpyrexia, and the absence of meningitis reflect rapid progression and poorer prognosis.
Screening for complement deficiency after resolution of the acute infection is recommended for individuals with meningococcal disease. In one series of 20 patients with a first episode of meningococcal
meningitis, meningococcemia, or meningococcal pericarditis, three had a deficiency of a terminalpathway
component and three had deficiencies of multiple complement components associated with underlying systemic diseases.
PREVENTION.
Close contacts of patients with meningococcal disease are at increased risk of infection and should
be carefully monitored and brought to medical attention if fever develops. Prophylaxis is indicated as soon
as possible for household, daycare, and nursery school contacts. Prophylaxis is also recommended for persons who have had contact with patients' oral secretions. Prophylaxis is not routinely recommended for
medical personnel except those with intimate exposure, such as with mouth-to-mouth resuscitation, intubation, or suctioning before antibiotic therapy was begun. Rifampin is given (10 mg/kg; maximum dose, 600
mg) orally every 12 hr for 2 days (total of four doses). The dose is reduced to 5 mg/kg for infants younger
than 1 mo. Other effective antimicrobial agents are ciprofloxacin (500 mg orally as a single dose for adults)
and ceftriaxone as a single intramuscular dose (125 mg for children < 15 yr and 250 mg for adults). Penicillin does not eradicate nasopharyngeal carriage, and patients treated with penicillin should receive chemoprophylactic antibiotics before hospital discharge.
Vaccine.
A quadrivalent vaccine composed of capsular polysaccharide of meningococcal groups A, C, Y,
and W135 is licensed in the United States. The vaccine is immunogenic in adults but is unreliable in children younger than 2 yr. The group B polysaccharide is poorly immunogenic in children and adults, and no
vaccine is available against this serogroup. Routine immunization of the United States population is not
recommended at this time, but the vaccine is routinely given to all American military recruits.
Immunization is useful to control outbreaks of meningococcal disease of the
serogroups represented in the quadrivalent vaccine. It is also recommended for travelers to countries with a high incidence of meningococcal disease. Immunization of close contacts of individuals with
A, C, Y, or W135 disease should be considered, because it has been useful in the prevention of secondary
cases. Individuals with anatomic or functional asplenia and those with complement component deficiencies
should be immunized.
Polysaccharide-protein conjugate vaccines are being developed for the prevention of meningococcal disease, and subcapsular proteins and detoxified lipooligosaccharides are being investigated as possible
vaccines.
V. Sources of information.
Basic literature:
№
Author(s)
№
1. Mikhailova
1
A.M., Minkov
I.P., Savchuk
A.I.
2 E. Nikitin,
M. Andreychin
Name of the source
(textbook, manual, monograph, etc)
Infection diseases in children
Infectious diseases
City,
Publishing house
Year of
edition,
vol.,
issue
Number
of pages
Odessa
2003
124-131
Ukrmedkn
iga
2004
Additional literature:
№
Author(s)
№
Robert
1
M.
Kliegman, MD,
Richard E. Behrman, MD, Hal
B. Jenson, MD
and Bonita
Name of the source
(textbook, manual, monograph, etc)
Nelson Textbook of pediatrics
City,
Publishing
house
W.B.Saun
ders company
Year of
edition,
vol.,
issue.
2007,
18 th
edition
Number
of pages
826829
Chapter 2. Central nervous system infections in children: acute bacterial meningi-
tis, viral meningitis, encephalitis
The theme urgency.
Acute infection of the central nervous system (CNS) is the most common cause of fever associated with signs and symptoms of CNS disease in children. Infection may be caused by virtually any microbe,
the specific pathogen being influenced by the age and immune status of the host and the epidemiology of
the pathogen. In general, viral infections of the CNS are much more common than bacterial infections,
which in turn are more common than fungal and parasitic infections. Infections caused by rickettsiae (e.g.,
Rocky Mountain spotted fever and Ehrlichia) are relatively uncommon but assume important roles under
certain epidemiologic circumstances. Mycoplasma spp also can cause infections of the CNS, although their
precise contribution often is difficult to determine.
Regardless of etiology, most patients with acute CNS infection have similar clinical syndromes.
Common symptoms include headache, nausea, vomiting, anorexia, restlessness, and irritability. Unfortunately, most of these symptoms are quite nonspecific. Common signs of CNS infection, in addition to fever, include photophobia, neck pain and rigidity, obtundation, stupor, coma, seizures, and focal neurologic
deficits. The severity and constellation of signs are determined by the specific pathogen, the host, and the
anatomic distribution of the infection. The anatomic distribution of infection may be diffuse or focal. Meningitis and encephalitis are examples of diffuse infection. Meningitis implies primary involvement of the
meninges, whereas encephalitis indicates brain parenchymal involvement. Because these anatomic boundaries are often not distinct, many patients have evidence of both meningeal and parenchymal involvement
and should be considered to have meningoencephalitis. Brain abscess is the best example of a focal infection of the CNS. The neurologic expression of this infection is determined by the site and extent of the abscess(es).
The diagnosis of diffuse CNS infections depends on careful examination of cerebrospinal fluid (CSF)
obtained by lumbar puncture (LP).
I. Primary aims of the study.
A student should know:
1) Etiology of meningitis and encephalitis
2) Pathogenesis of meningitis and encephalitis
3) Classification and clinical manifestations of meningitis and encephalitis
4) Complications of meningitis and encephalitis
5) Treatment of meningitis and encephalitis
6) Prevention.
A student should be able to:
1) Find out history
2) Interpret data of physical examination
3) Interpret data of laboratory studies
4) Formulate clinical diagnosis
5) Make differential diagnosis: purulent meningitis (meningococcal, pneumococcal, Hib), tuberculous meningitis, viral meningitis
6) Administer prehospital and in-patient treatment
7) Prevention
II. Educative aims of the study.
To facilitate:
1) The formation of deontology concepts and practical skills related to patients with meningitis and encephalitis
2) To acquire the skills of psychological contact establishment and creation of trusting relations between
the doctor and the patient and his parents.
3) The development of responsibility sense for timeliness and completeness of patient’s investigation.
III. The contents of the theme.
Bacterial meningitis is one of the most potentially serious infections in infants and older children. This infection is associated with a high rate of acute complications and risk of chronic morbidity. The
pattern of bacterial meningitis and its treatment during the neonatal period (0-28 days) are generally distinct from those in older infants and children (Chapters 105 and 106) . Nonetheless, the clinical patterns of
meningitis in the neonatal and postneonatal periods may overlap, especially in 1- to 2-mo-old patients, in
whom group B Streptococcus, Streptococcus pneumoniae (pneumococcus), Neisseria meningitidis (meningococcus), and Haemophilus influenzae type b all may cause meningitis.
The incidence of bacterial meningitis is sufficiently high that it should be included in the differential diagnosis of altered mental status such as lethargy or irritability, or evidence of other neurologic dysfunction, in febrile infants.
ETIOLOGY.
During the first 2 mo of life, the bacteria that cause meningitis in normal infants reflect the maternal
flora or the environment of the infant (i.e., group B Streptococcus, gram-negative enteric bacilli, and Listeria monocytogenes). In addition, meningitis in this age group may occasionally be due to H. influenzae
(both type b and nontypable strains) and the other pathogens usually found in older patients.
Bacterial meningitis in children 2 mo-12 yr of age is usually due to S. pneumoniae, N. meningitidis,
or H. influenzae type b. Before the widespread use of H. influenzae type b vaccines, approximately 70% of
cases of bacterial meningitis among children younger than 5 yr were due to H. influenzae type b. Subsequent to the implementation of universal immunization against these bacteria, beginning at about 2 mo of
age, the incidence of H. influenzae type b meningitis dropped precipitously. The median age of bacterial
meningitis in the United States increased from age 15 mo in 1986 to 25 yr in 1995; meningitis now is usually due to S. pneumoniae or N. meningitidis.
Alterations of host defense due to anatomic defects or immune deficits increase the risk of meningitis from less common pathogens such as Pseudomonas aeruginosa, Staphylococcus aureus, coagulasenegative staphylococci, Salmonella spp, and L. monocytogenes.
EPIDEMIOLOGY.
A major risk factor for meningitis is the lack of immunity to specific pathogens associated with
young age. Additional risks include recent colonization with pathogenic bacteria, close contact (e.g.,
household, daycare centers, schools, military barracks) with individuals having invasive disease, crowding,
poverty, black race, male sex, and possibly absence of breast-feeding for infants 2-5 mo of age. The mode
of transmission is probably person to person contact through respiratory tract secretions or droplets. The
risk of meningitis is increased among infants and young children with occult bacteremia (Chapter 172) ; the
odds ratio is greater for meningococcus (85 times) and H. influenzae type b (12 times) relative to that for
pneumococcus. Specific host defense defects due to altered immunoglobulin production in response to encapsulated pathogens may be responsible for the increased risk of bacterial meningitis in Native Americans
and Eskimos, whereas defects of the complement system (C5-C8) have been associated with recurrent meningococcal infection, and defects of the properdin system have been associated with a significant risk of
lethal meningococcal disease. Splenic dysfunction (sickle cell anemia) or asplenia (due to trauma, congenital defect, staging of Hodgkin disease) is associated with an increased risk of pneumococcal, H. influenzae
type b (to some extent), and, rarely, meningococcal sepsis and meningitis. T-lymphocyte defects (congenital or acquired by chemotherapy, AIDS, or malignancy) are associated with an increased risk of L. monocytogenes infections of the CNS. Congenital or acquired CSF leak across a mucocutaneous barrier, such as
cranial or midline facial defects (cribriform plate) and middle ear (stapedial foot plate) or inner ear fistulas
(oval window, internal auditory canal, cochlear aqueduct), or CSF leakage through a rupture of the meninges due to a basal skull fracture into the cribriform plate or paranasal sinus, is associated with an increased
risk of pneumococcal meningitis. Lumbosacral dermal sinus and meningomyelocele are associated with
staphylococcal and gram-negative enteric bacterial meningitis. Penetrating cranial trauma and CSF shunt
infections increase the risk of meningitis due to staphylococci (especially coagulase-negative species) and
other cutaneous bacteria.
Streptococcus pneumoniae.
The risk of sepsis and meningitis due to pneumococcus depends, at least in part, on the infecting
serotype. Throat or nasopharyngeal carriage of S. pneumoniae is acquired from family contacts after birth,
is transient (2-4 mo), is often associated with homotype antibody production, and, if recent (<1 mo), is a
risk factor for serious infection. The incidence of pneumococcal meningitis is 1-3/100,000 persons; infection may occur throughout life. The midwinter months are the peak season. The risk of meningitis is 5- to
36-fold greater among blacks than whites, especially among blacks with sickle cell anemia, who have a
more than 300-fold increased incidence compared with white children. Approximately 4% of children with
sickle cell anemia develop pneumococcal meningitis before the age of 5 yr if they are not given prophylac-
tic antibiotics. Additional risk factors for contracting pneumococcal meningitis include otitis media, sinusitis, pneumonia, CSF otorrhea or rhinorrhea, splenectomy, HIV infection, and chronic graft versus host disease following bone marrow transplantation.
Neisseria meningitidis.
Meningococcal meningitis may be sporadic or may occur in epidemics. In the absence of an epidemic, most infections are due to group B. Epidemics usually are caused by groups A and C. Cases occur
throughout the year but may be more common in the winter and spring. Nasopharyngeal carriage of N.
meningitidis occurs in 1-15% of adults. Colonization may last weeks to months; recent colonization places
nonimmune younger children at greatest risk for meningitis. The incidence of simultaneous disease occurring in association with an index case in the family is 1%, a rate that is 1,000-fold the risk in the general
population. The risk of secondary cases occurring in contacts at daycare centers is about 1/1,000. Most infections of children are acquired from a contact in a daycare facility, a colonized adult family member, or
an ill patient with meningococcal disease.
Haemophilus influenzae type b.
Before universal H. influenzae type b vaccination in the United States, invasive infections occurred
primarily in infants 2 mo-2 yr of age; peak incidence was at 6-9 mo of age, and 50% of cases occurred in
the 1st yr of life. The risk to children was markedly increased among family or daycare center contacts of
patients with H. influenzae type b disease. Unvaccinated individuals and those with blunted immunologic
responses to vaccine (e.g., children with HIV infection) remain at risk for H. influenzae type b meningitis.
PATHOLOGY.
A meningeal exudate of varying thickness may be distributed around the cerebral veins, venous sinuses, convexity of the brain, and cerebellum and in the sulci, sylvian fissures, basal cisterns, and spinal
cord. Ventriculitis with bacteria and inflammatory cells in ventricular fluid may be present, as may subdural effusions and, rarely, empyema. Perivascular inflammatory infiltrates may also be present, and the ependymal membrane may be disrupted. Vascular and parenchymal cerebral changes characterized by polymorphonuclear infiltrates extending to the subintimal region of the small arteries and veins, vasculitis,
thrombosis of small cortical veins, occlusion of major venous sinuses, necrotizing arteritis producing subarachnoid hemorrhage, and, rarely, cerebral cortical necrosis in the absence of identifiable thrombosis have
been described at autopsy. Cerebral infarction is a frequent sequela of vascular occlusion from inflammation, vasospasm, and thrombosis. Infarct size ranges from microscopic to involvement of an entire hemisphere.
Inflammation of spinal nerves and roots produces meningeal signs, and inflammation of the cranial
nerves produces cranial neuropathies of optic, oculomotor, facial, and auditory nerves. Increased intracranial pressure (ICP) also produces oculomotor nerve palsy due to the presence of temporal lobe compression
of the nerve during tentorial herniation. Abducens nerve palsy may be a nonlocalizing sign of raised ICP.
Increased ICP is due to cell death (cytotoxic cerebral edema), cytokine-induced increased capillary
vascular permeability (vasogenic cerebral edema), and, possibly, increased hydrostatic pressure (interstitial
cerebral edema) after obstructed reabsorption of CSF in the arachnoid villus or obstruction of the flow of
fluid from the ventricles. ICP often exceeds 300 mm H2 O; cerebral perfusion may be further compromised
if the cerebral perfusion pressure (mean arterial pressure minus ICP) is less than 50 cm H2 O owing to reduced cerebral blood flow. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) may produce excessive water retention, increasing the risk of raised ICP. Hypotonicity of brain extracellular spaces
may cause cytotoxic edema after cell swelling and lysis. Tentorial, falx, or cerebellar herniation does not
usually occur because the increased ICP is transmitted to the entire subarachnoid space and there is little
structural displacement. Furthermore, if the fontanels are still patent, increased ICP is readily dissipated.
Hydrocephalus is an uncommon acute complication of meningitis occurring after the neonatal period. It most often takes the form of a communicating hydrocephalus due to adhesive thickening of the
arachnoid villi around the cisterns at the base of the brain. Thus, there is interference with the normal resorption of CSF. Less often, obstructive hydrocephalus develops after fibrosis and gliosis of the aqueduct
of Sylvius or the foramina of Magendie and Luschka.
Raised CSF protein levels are due in part to increased vascular permeability of the blood-brain barrier and the loss of albumin-rich fluid from the capillaries and veins traversing the subdural space. Continued transudation may result in subdural effusions, usually found in the later phase of acute bacterial meningitis. Hypoglycorrhachia (reduced CSF glucose levels) is due to decreased glucose transport by the cerebral tissue.
Damage to the cerebral cortex may be due to the focal or diffuse effects of vascular occlusion (infarction, necrosis, lactic acidosis), hypoxia, bacterial invasion (cerebritis), toxic encephalopathy (bacterial
toxins), raised ICP, ventriculitis, and transudation (subdural effusions). These pathologic factors result in
the clinical manifestations of impaired consciousness, seizures, hydrocephalus, cranial nerve deficits, motor and sensory deficits, and later psychomotor retardation.
PATHOGENESIS.
Bacterial meningitis most commonly results from hematogenous dissemination of microorganisms
from a distant site of infection; bacteremia usually precedes meningitis or occurs concomitantly. Bacterial
colonization of the nasopharynx with a potentially pathogenic microorganism is the usual source of the
bacteremia. There may be prolonged carriage of the colonizing organisms without disease or, more likely,
rapid invasion after recent colonization. Prior or concurrent viral upper respiratory tract infection may enhance the pathogenicity of bacteria producing meningitis.
N. meningitidis and H. influenzae type b attach to mucosal epithelial cell receptors by pili. After attachment to epithelial cells, bacteria breach the mucosa and enter the circulation. N. meningitidis may be
transported across the mucosal surface within a phagocytic vacuole after ingestion by the epithelial cell.
Bacterial survival in the bloodstream is enhanced by large bacterial capsules that interfere with opsonic
phagocytosis and are associated with increased virulence. Host-related developmental defects in bacterial
opsonic phagocytosis also contribute to the bacteremia. In young, nonimmune hosts, the defect may be due
to an absence of preformed IgM or IgG anticapsular antibodies, whereas in immunodeficient patients, various deficiencies of components of the complement or properdin system may interfere with effective opsonic phagocytosis. Direct activation of the antibody-independent properdin system is one mechanism that
counteracts the effects of antibody deficiency and the antiphagocytic properties of the bacterial capsule.
Splenic dysfunction also may reduce opsonic phagocytosis by the reticuloendothelial system.
Bacteria gain entry to the CSF through the choroid plexus of the lateral ventricles and the meninges
and then circulate to the extracerebral CSF and subarachnoid space. Bacteria rapidly multiply because the
CSF concentrations of complement and antibody are inadequate to contain bacterial proliferation. Chemotactic factors then incite a local inflammatory response characterized by polymorphonuclear cell infiltration. The presence of bacterial cell wall lipopolysaccharide (endotoxin) of gram-negative bacteria ( H. influenzae type b, N. meningitidis) and of pneumococcal cell wall components (teichoic acid, peptidoglycan)
stimulates a marked inflammatory response, with local production of tumor necrosis factor, interleukin-1,
prostaglandin E, and other cytokine inflammatory mediators. The subsequent inflammatory response, directly related to the presence of these inflammatory mediators, is characterized by neutrophilic infiltration,
increased vascular permeability, alterations of the blood-brain barrier, and vascular thrombosis. Excessive
cytokine-induced inflammation continues after the CSF has been sterilized and is thought to be partly responsible for the chronic inflammatory sequelae of pyogenic meningitis.
Meningitis may rarely follow bacterial invasion from a contiguous focus of infection such as paranasal sinusitis, otitis media, mastoiditis, orbital cellulitis, or cranial or vertebral osteomyelitis or may occur
after introduction of bacteria via penetrating cranial trauma, dermal sinus tracts, or meningomyeloceles.
Meningitis may occur during endocarditis, pneumonia, or thrombophlebitis. It also may be associated with
severe burns, indwelling catheters, or contaminated infusion equipment.
CLINICAL MANIFESTATIONS.
The onset of acute meningitis has two predominant patterns. The more dramatic and, fortunately,
less common presentation is sudden onset with rapidly progressive manifestations of shock, purpura, disseminated intravascular coagulation (DIC) and reduced levels of consciousness frequently resulting in
death within 24 hr. More often, meningitis is preceded by several days of upper respiratory tract or gastrointestinal symptoms, followed by nonspecific signs of CNS infection such as increasing lethargy and irritability.
The signs and symptoms of meningitis are related to the nonspecific findings associated with a systemic infection and to manifestations of meningeal irritation. Nonspecific findings include fever (present in
90-95%), anorexia and poor feeding, symptoms of upper respiratory tract infection, myalgias, arthralgias,
tachycardia, hypotension, and various cutaneous signs, such as petechiae, purpura, or an erythematous
macular rash. Meningeal irritation is manifested as nuchal rigidity, back pain, Kernig sign (flexion of the
hip 90 degrees with subsequent pain with extension of the leg), and Brudzinski sign (involuntary flexion of
the knees and hips after passive flexion of the neck while supine). In some children, particularly in those
younger than 12-18 mo, Kernig and Brudzinski signs may not be evident with meningitis. Increased ICP is
suggested by headache, emesis, bulging fontanel or diastasis (widening) of the sutures, oculomotor or ab-
ducens nerve paralysis, hypertension with bradycardia, apnea or hyperventilation, decorticate or decerebrate posturing, stupor, coma, or signs of herniation. Papilledema is uncommon in uncomplicated meningitis and should suggest a more chronic process, such as the presence of an intracranial abscess, subdural
empyema, or occlusion of a dural venous sinus. Focal neurologic signs usually are due to vascular occlusion. Cranial neuropathies of the ocular, oculomotor, abducens, facial, and auditory nerves also may be due
to focal inflammation. Overall, about 10-20% of children with bacterial meningitis have focal neurologic
signs. This frequency increases to more than 30% with pneumococcal meningitis, because this organism
tends to stimulate the most vigorous inflammatory response.
Seizures (focal or generalized) due to cerebritis, infarction, or electrolyte disturbances occur in 2030% of patients with meningitis. Seizures that occur on presentation or within the first 4 days of onset are
usually of no prognostic significance. Seizures that persist after the 4th day of illness and those that are difficult to treat are associated with a poor prognosis.
Alterations of mental status and a reduced level of consciousness are common among patients with
meningitis and may be due to increased ICP, cerebritis, or hypotension; manifestations include irritability,
lethargy, stupor, obtundation, and coma. Comatose patients have a poor prognosis. Additional manifestations of meningitis include photophobia and tache cerebrale, which is elicited by stroking the skin with a
blunt object and observing a raised red streak within 30-60 sec.
DIAGNOSIS.
The diagnosis of acute pyogenic meningitis is confirmed by analysis of the CSF, which reveals microorganisms on Gram stain and culture, a neutrophilic pleocytosis, elevated protein, and reduced glucose
concentrations (Table 174-1) . LP should be performed when bacterial meningitis is suspected. Contraindications for an immediate LP include (1) evidence of increased ICP (other than a bulging fontanel), such as
3rd or 6th cranial nerve palsy with a depressed level of consciousness, or hypertension and bradycardia
with respiratory abnormalities; (2) severe cardiopulmonary compromise requiring prompt resuscitative
measures for shock or in patients in whom positioning for the LP would further compromise cardiopulmonary function; and (3) infection of the skin overlying the site of the LP. Thrombocytopenia is a relative
contraindication for immediate LP. If an LP is delayed, immediate empirical therapy should be initiated.
CT scanning for evidence of a brain abscess or increased ICP also should not delay therapy. LP may be
performed after increased ICP has been treated or a brain abscess has been excluded.
A number of bacterial antigen detection systems have been developed, the most popular and widely
used being based on latex particle agglutination. In the presence of bacterial meningitis, antigen is most
consistently detected in the CSF. Antigenuria also is quite common. Serum is not a useful specimen for antigen detection because false-positive reactions are common. Tests for antigen are best reserved for patients
who were receiving antibiotics when their cultures were obtained, because antigen may remain detectable
for several days after the initiation of antibiotics, whereas cultures may be negative. Recent immunization
with the H. influenzae type b polysaccharide vaccine may produce a false-positive result of the antigen test
in serum and urine but not in CSF.
Blood cultures should be performed in all patients with suspected meningitis. Blood cultures may
reveal the responsible bacteria in 80-90% of cases of childhood meningitis.
Lumbar Puncture.
LP is usually performed with a patient in the flexed lateral decubitus position; the styletted needle is
passed into the L3-L4 or L4-L5 intervertebral space. After entry into the subarachnoid space, the patient's
position is changed to a more extended one to measure the opening CSF pressure, although an accurate
reading may not be able to be determined in a crying child. When the pressure is high, only a small volume
of CSF should be removed to avoid a precipitous decline in ICP.
The CSF leukocyte count in bacterial meningitis is usually elevated to greater than 1,000/mm3 and
reveals a neutrophilic predominance (75-95%). Turbid CSF is present when the CSF leukocyte count exceeds 200-400/mm3 . Normal healthy neonates may have as many as 30 leukocytes/mm3 , and older children without viral or bacterial meningitis may have 5 leukocytes/mm3 in the CSF; in both age groups there
is a predominance of lymphocytes or monocytes.
A CSF leukocyte count less than 250/mm3 may be present in as many as 20% of patients with acute
bacterial meningitis; pleocytosis may be absent in patients with severe overwhelming sepsis and meningitis
and is a poor prognostic sign. Pleocytosis with a lymphocyte predominance may be present during the early
stage of acute bacterial meningitis; conversely, neutrophilic pleocytosis may be present in patients during
the early stages of acute viral meningitis. The shift to lymphocytic-monocytic predominance in viral men-
ingitis invariably occurs within 12-24 hr of the initial LP. The Gram stain is positive in most (70-90%) patients with bacterial meningitis.
Traumatic LP complicates the diagnosis of meningitis. Repeat LP at another interspace may produce less hemorrhagic fluid, but this fluid usually also contains red blood cells. Interpretation of CSF leukocytes and protein concentration are affected by LPs that are traumatic, although the gram stain, culture,
and glucose level may not be influenced. Although methods for correcting for the presence of red blood
cells have been proposed, it is prudent to rely on the bacteriologic results rather than to attempt to interpret
the CSF leukocyte and protein results of a traumatic LP.
Differential Diagnosis.
In addition to S. pneumoniae, N. meningitidis, and H. influenzae type b, many other microorganisms can cause generalized infection of the CNS with similar clinical manifestations. These organisms include less typical bacteria, such as Mycobacterium tuberculosis, Nocardia, Treponema pallidum (syphilis),
and Borrelia burgdorferi (Lyme disease); fungi, such as those endemic to specific geographic areas ( Coccidioides, Histoplasma, and Blastomyces) and those responsible for infections in compromised hosts (
Candida, Cryptococcus, and Aspergillus); parasites, such as Toxoplasma gondii and those that cause cysticercosis, resulting from infection with the larval stages ( Cysticercus cellulosae) of the pork tapeworm
Taenia solium; and, most frequently, viruses. Focal infections of the CNS including brain abscess and parameningeal abscess (subdural empyema, cranial and spinal epidural abscess) also may be confused with
meningitis. Noninfectious illnesses also can cause generalized inflammation of the CNS. These disorders
are uncommon relative to infections and include malignancy, collagen vascular syndromes, and exposure
to toxins.
Determining the specific cause is facilitated by careful examination of the CSF with specific stains
(Kinyoun carbol fuchsin for mycobacteria, India ink for fungi), cytology, antigen detection (bacteria, Cryptococcus), serology (syphilis), and viral culture (enterovirus). Other potentially valuable diagnostic tests
include CT or MRI of the brain, blood cultures, serologic tests, and possibly brain biopsy. Acute viral meningoencephalitis is the most likely infection to be confused with bacterial meningitis. Although, in general, children with viral meningoencephalitis appear less ill than those with bacterial meningitis, both types
of infection have a spectrum of severity. Some children with bacterial meningitis may have relatively mild
signs and symptoms, whereas some with viral meningoencephalitis may be critically ill. The classic CSF
profiles associated with bacterial versus viral infection tend to be distinct (Table 174-1) , but as with clinical manifestations, specific test results may have considerable overlap.
Another diagnostic conundrum in the evaluation of children with suspected bacterial meningitis is
the analysis of CSF obtained from children already receiving antibiotic therapy. This is an important issue,
because 25-50% of children being evaluated for bacterial meningitis are receiving oral antibiotics when
their CSF is obtained. Such partial treatment of a patient with acute bacterial meningitis usually does not
substantially alter the typical bacterial CSF profile. Although the frequency of positive CSF Gram stain results and ability to grow the bacteria may be reduced, the concentration of CSF glucose and protein and the
neutrophil profile are not substantially altered by pretreatment.
TREATMENT.
The therapeutic approach to patients with presumed bacterial meningitis depends on the nature of
the initial manifestations of the illness. A child with rapidly progressing disease of less than 24 hr duration,
in the absence of increased ICP, should receive antibiotics immediately after an LP is performed. If there
are signs of increased ICP or focal neurologic findings, antibiotics should be given without performing an
LP and before obtaining a CT scan. Increased ICP should be treated simultaneously. Immediate treatment
of associated multiple organ system failure, such as shock and adult respiratory distress syndrome, is also
indicated.
Patients who have a more protracted subacute course and become ill over a 1- to 7-day period
should also be evaluated for signs of increased ICP and focal neurologic deficits. Unilateral headache,
papilledema, and other signs of increased ICP suggest a focal lesion such as a brain or epidural abscess, or
subdural empyema. Under these circumstances, antibiotic therapy should be initiated before LP and CT
scanning. If no signs of increased ICP are evident, an LP should be performed.
Initial Antibiotic Therapy.
The initial (empiric) choice of therapy for meningitis in immunocompetent infants and children
should be based on the antibiotic susceptibilities of S. pneumoniae, N. meningitidis, and H. influenzae type
b. Selected antibiotic(s) should achieve bactericidal levels in the CSF. Although there are substantial geographic differences in the frequency of resistance of S. pneumoniae to antibiotics, rates are increasing
throughout the world. In the United States, 25-50% of strains of S. pneumoniae are currently resistant to
penicillin; relative resistance (MIC, 0.1-1.0 mug/mL) is more common than high-level resistance (MIC >
2.0 mug/mL). Resistance to cefotaxime and ceftriaxone also is evident in 5-10% of isolates. Most strains of
N. meningitidis are sensitive to penicillin and cephalosporins, although rare resistant isolates have been reported. Approximately 30-40% of isolates of H. influenzae type b produce beta-lactamases and therefore
are resistant to ampicillin. These beta-lactamase-producing strains remain sensitive to the extendedspectrum cephalosporins.
The increasing frequency of S. pneumoniae resistance to beta-lactam drugs has necessitated a
change in empirical therapy in most regions of the United States. Currently, either of the third-generation
cephalosporins, cefotaxime (200 mg/kg/24 hr, given every 6 hr) or ceftriaxone (100 mg/kg/24 hr administered once per day or 50 mg/kg/dose, given every 12 hr), combined with vancomycin (60 mg/kg/24 hr, given every 6 hr) is recommended. Patients allergic to beta-lactam antibiotics should be treated with chloramphenicol, 100 mg/kg/24 hr, given every 6 hr.
If L. monocytogenes infection is suspected, as in infants 1-2 mo old or patients with a Tlymphocyte deficiency, ampicillin (200 mg/kg/24 hr, given every 6 hr) should be given with ceftriaxone or
cefotaxime because all cephalosporins are inactive against L. monocytogenes. Intravenous trimethoprimsulfamethoxazole is an alternate treatment for L. monocytogenes.
If a patient is immunocompromised and gram-negative bacterial meningitis is suspected, initial
therapy might include ceftazidime and an aminoglycoside.
Duration of Antibiotic Therapy.
Therapy for uncomplicated penicillin-sensitive S. pneumoniae meningitis should be completed with
a third-generation cephalosporin or intravenous penicillin (300,000 U/kg/24 hr, given every 4-6 hr) for 1014 days. If the isolate is resistant to penicillin and the third-generation cephalosporin, therapy should be
completed with vancomycin. Intravenous penicillin (300,000 U/kg/24 hr) for 5-7 days is the treatment of
choice for uncomplicated N. meningitidis meningitis. Uncomplicated H. influenzae type b meningitis
should be treated for a total of 7-10 days. Ampicillin should be used to complete the course of therapy if
the isolate is found to be sensitive.
Patients who receive intravenous or oral antibiotics before LP and who do not have an identifiable
pathogen (on Gram stain, culture, or antigen detection) but do have evidence of an acute bacterial infection
on the basis of their CSF profile should continue to receive therapy with ceftriaxone or cefotaxime for 7-10
days. If focal signs are present or the child does not respond to treatment, a parameningeal focus may be
present and a CT or MRI scan should be performed.
A routine repeat LP is not indicated in patients with uncomplicated meningitis due to antibioticsensitive S. pneumoniae, N. meningitidis, or H. influenzae type b. Repeat examination of CSF is indicated
in some neonates, in patients with gram-negative bacillary meningitis, or in infection caused by a betalactam-resistant S. pneumoniae. Improvement in the CSF profile is indicated by an increase in CSF glucose
concentration and the appearance of lymphocyte-monocyte cells. The CSF should be sterile within 24-48
hr of initiation of appropriate antibiotic therapy.
Meningitis due to E. coli or P. aeruginosa requires therapy with a third-generation cephalosporin active against the isolate in vitro. Most isolates of E. coli are sensitive to cefotaxime or ceftriaxone, whereas
most isolates of P. aeruginosa are sensitive to ceftazidime. Gram-negative bacillary meningitis should be
treated for 3 wk or for at least 2 wk after CSF sterilization, which may occur after 2-10 days of treatment.
Side effects of antibiotic therapy of meningitis include phlebitis, drug fever, rash, emesis, oral candidiasis, and diarrhea. Ceftriaxone may cause reversible gallbladder pseudolithiasis, detectable by abdominal ultrasonography. This is usually asymptomatic but may produce emesis and right upper quadrant
pain.
Corticosteroids.
Rapid killing of bacteria in the CSF effectively sterilizes the meningeal infection but releases toxic
cell products after cell lysis (cell wall endotoxin) that precipitates the cytokine-mediated inflammatory response. The resultant edema formation and neutrophilic infiltration may produce additional neurologic injury with worsening of CNS signs and symptoms. Therefore, agents that limit production of inflammatory
mediators may be of benefit to patients with bacterial meningitis.
Data support the use of intravenous dexamethasone, 0.15 mg/kg/dose given every 6 hr for 2 days, in
the treatment of children older than 6 wk with acute bacterial meningitis, especially for H. influenzae type
b. A regimen of 0.4 mg/kg/dose given every 12 hr for 2 days is also appropriate. Corticosteroid recipients
have less fever, lower CSF protein and lactate levels, and a reduction in permanent auditory nerve damage,
as manifested by sensorineural hearing loss, than do placebo recipients. Most experience with dexamethasone treatment has been with H. influenzae type b infection, and extrapolation to other bacterial pathogens should be done with caution, balancing potential benefits against risks. Corticosteroids appear to have
maximum benefit if given just before antibiotics and should be administered with 1-2 hr of antibiotics.
Complications of the 2-day regimen are uncommon but may include gastrointestinal bleeding, hypertension, hyperglycemia, leukocytosis, and rebound fever after the last dose. No evidence shows that dexamethasone for longer than 2 days offers additional benefit, and it appears to be associated with an increased
incidence of gastrointestinal bleeding.
Supportive Care.
Repeated medical and neurologic assessments of patients with bacterial meningitis are essential to
identify early signs of cardiovascular, CNS, and metabolic complications. Pulse rate, blood pressure, and
respiratory rate should be monitored frequently. Neurologic assessment, including pupillary reflexes, level
of consciousness, motor strength, cranial nerve signs, and evaluation for seizures, should be made frequently during the first 72 hr, when the risk of neurologic complications is greatest. Thereafter, neurologic assessment should be performed once a day. Important laboratory studies include an assessment of blood
urea nitrogen; serum sodium, chloride, potassium, and bicarbonate levels; urine output and specific gravity;
complete blood and platelet counts; and coagulation factors (fibrinogen, prothrombin, and partial thromboplastin times) in the presence of petechiae, purpura, or abnormal bleeding.
Patients should initially receive nothing by mouth. If a patient is judged to be normovolemic, with
normal blood pressure, intravenous fluid administration should be restricted to one half to two thirds of
maintenance, or 800-1,000 mL/m2 /24 hr, until it can be established that increased ICP or SIADH is not
present. Fluid administration may be returned to normal (1,500-1,700 mL/m2 /24 hr) when serum sodium
levels are normal. Fluid restriction is not appropriate in the presence of systemic hypotension because reduced blood pressure may result in a cerebral perfusion pressure of less than 50 cm H2 O, with subsequent
CNS ischemia. Therefore, shock must be treated aggressively to prevent brain and other organ dysfunction
(acute tubular necrosis, adult respiratory distress syndrome). Patients with shock, a markedly raised ICP,
coma, and refractory seizures require intensive monitoring with central arterial and venous access and frequent vital signs, necessitating admission to a pediatric intensive care unit. Patients with septic shock require fluid resuscitation and therapy with vasoactive agents such as dopamine, epinephrine, and sodium
nitroprusside (Chapter 173) . The goal of such therapy in patients with meningitis is to avoid excessive increases in ICP without compromising blood flow and oxygen delivery to vital organs (brain, heart, lung,
kidney).
Neurologic complications include increased ICP with subsequent herniation, seizures, and an enlarging head circumference due to a subdural effusion or hydrocephalus. Signs of increased ICP (other than
a bulging fontanel or isolated coma) should be treated emergently with endotracheal intubation and hyperventilation (to maintain the P CO2 at approximately 25 mm Hg). In addition, intravenous furosemide
(Lasix, 1 mg/kg) and mannitol (0.5-1 g/kg) osmotherapy may reduce ICP (Chapter 64 .7). Furosemide may
reduce brain swelling by venodilation and diuresis without increasing intracranial blood volume, whereas
mannitol produces an osmolar gradient between the brain and plasma, thus shifting fluid from the CNS to
the plasma with subsequent excretion during an osmotic diuresis.
Seizures are common during the course of bacterial meningitis. Immediate therapy for seizures includes intravenous diazepam (0.1-0.2 mg/kg/dose) or lorazepam (0.05 mg/kg/dose), paying careful attention to the risk of respiratory suppression. Serum glucose, calcium, and sodium levels should be monitored
to determine if hypoglycemia, hypocalcemia, or hyponatremia is precipitating seizures. After immediate
management of seizures, patients should receive phenytoin (15-20 mg/kg loading dose, 5 mg/kg/24 hr
maintenance) to reduce the likelihood of recurrence. Phenytoin is preferred to phenobarbital because it
produces less CNS depression and permits assessment of a patient's level of consciousness. Serum phenytoin levels should be monitored to maintain them in the therapeutic range (10-20 mug/mL).
COMPLICATIONS.
During the treatment of meningitis, complications due to CNS or systemic effects of infection are
common. Neurologic complications include seizures, increased ICP, cranial nerve palsies, stroke, cerebral
or cerebellar herniation, transverse myelitis, ataxia, thrombosis of dural venous sinuses, and subdural effusions.
Collections of fluid in the subdural space develop in 10-30% of patients with meningitis and are
asymptomatic in 85-90% of patients. Subdural effusions are especially common in infants. Symptomatic
subdural effusions may result in a bulging fontanel, diastasis of sutures, enlarging head circumference, em-
esis, seizures, fever, and abnormal results of cranial transillumination. However, many of these manifestations are also present in patients with meningitis without subdural effusion. CT or MRI scanning confirms
the presence of a subdural effusion. In the presence of increased ICP or a depressed level of consciousness,
symptomatic subdural effusion should be treated by aspiration through the open fontanel. Fever alone is not
an indication for aspiration.
SIADH occurs in the majority of patients with meningitis, resulting in hyponatremia and reduced
serum osmolality in 30-50%. This may exacerbate cerebral edema or independently produce hyponatremic
seizures. Later in the course of therapy, central diabetes insipidus may develop as a result of hypothalamic
or pituitary dysfunction.
Fever associated with bacterial meningitis usually resolves within 5-7 days of the onset of therapy.
Prolonged fever (>10 days) is noted in about 10% of patients. Prolonged fever usually is due to intercurrent
viral infection, nosocomial or secondary bacterial infection, thrombophlebitis, or drug reaction. Pericarditis
or arthritis may occur in patients being treated for meningitis. Involvement of these sites may result either
from bacterial dissemination or from immune complex deposition. In general, infectious pericarditis or arthritis occurs earlier in the course of treatment than does immune-mediated disease. Secondary fever refers
to the recrudescence of elevated temperature after an afebrile interval. Nosocomial infections are especially
important to consider in the evaluation of these patients.
Thrombocytosis, eosinophilia, and anemia may develop during therapy for meningitis. Anemia may
be due to hemolysis or bone marrow suppression. DIC is most often associated with the rapidly progressive
pattern of presentation and is noted most commonly in patients with shock and purpura (purpura fulminans). The combination of endotoxemia and severe hypotension initiates the coagulation cascade; the coexistence of ongoing thrombosis may produce symmetric peripheral gangrene.
PROGNOSIS.
Appropriate recognition, prompt antibiotic therapy, and supportive care have reduced the mortality
of bacterial meningitis after the neonatal period to 1-8%. The highest mortality rates are observed with
pneumococcal meningitis. Severe neurodevelopmental sequelae may occur in 10-20% of patients recovering from bacterial meningitis, and as many as 50% have some, albeit subtle, neurobehavioral morbidity.
The prognosis is poorest among infants younger than 6 mo and in those with more than 106 colonyforming units of bacteria/mL in their CSF. Those with seizures occurring more than 4 days into therapy or
with coma or focal neurologic signs on presentation also tend to have more long-term sequelae. There does
not appear to be a correlation between duration of symptoms before diagnosis of meningitis and outcome.
The most common neurologic sequelae include hearing loss, mental retardation, seizures, delay in
acquisition of language, visual impairment, and behavioral problems. Sensorineural hearing loss is the most
common sequela of bacterial meningitis. It is due to labyrinthitis following cochlear infection and occurs in
as many as 30% of patients with pneumococcal meningitis, 10% with meningococcal, and 5-20% of those
with H. influenzae type b meningitis. Hearing loss may also be due to direct inflammation of the auditory
nerve. Adjunctive therapy with dexamethasone appears to reduce the incidence of severe hearing loss, at
least for meningitis caused by H. influenzae type b. Regardless of the bacterial agent, type of antibiotic
therapy, or use of dexamethasone, all patients with bacterial meningitis should undergo careful audiologic
assessment before or soon after discharge from the hospital. Frequent reassessment on an outpatient basis is
indicated for all patients who have a hearing deficit.
Repeated episodes of meningitis are rare but have three distinct patterns. Recrudescence is the reappearance of infection during therapy with appropriate antibiotics. CSF culture reveals the growth of bacteria that have developed antibiotic resistance. Relapse occurs between 3 days and 3 wk after therapy and
represents persistent bacterial infection in the CNS (subdural empyema, ventriculitis, cerebral abscess) or
other site (mastoid, cranial osteomyelitis, orbital infection). Relapse is often associated with an inadequate
choice, dose, or duration of antibiotic therapy. Recurrence is a new episode of meningitis due to reinfection
with the same bacterial species or another pyogenic pathogen. Recurrent meningitis suggests the presence
of an acquired or congenital anatomic communication between the CSF and a mucocutaneous site. Defects
in immune host defense also predispose to recurrent meningitis.
PREVENTION.
Vaccination and antibiotic prophylaxis of susceptible at-risk contacts represent the two available
means of reducing the likelihood of bacterial meningitis. The availability and application of each of these
approaches are different for each of the three major causes of bacterial meningitis in children.
Neisseria meningitidis.
Chemoprophylaxis is recommended for all close contacts of patients with meningococcal meningitis regardless of age or immunization status. Close contacts should be treated with rifampin 10 mg/kg/dose
every 12 hr (maximum dose of 600 mg) for 2 days as soon as possible after identification of a case of suspected meningococcal meningitis or sepsis. Close contacts include household, daycare center, and nursery
school contacts and health care workers who have direct exposure to oral secretions (e.g., mouth-to-mouth
resuscitation, suctioning, intubation). Exposed contacts should be treated immediately on suspicion of infection in the index patient; bacteriologic confirmation of infection should not be awaited. In addition, all
contacts should be educated about the early signs of meningococcal disease and the need to seek prompt
medical attention if these signs develop.
Meningococcal quadrivalent vaccine against serogroups A, C, Y, and W135 is recommended for
high-risk children older than 2 yr. High-risk patients include those with anatomic or functional asplenia or
deficiencies of terminal complement proteins. The vaccine may also be used as an adjunct with chemoprophylaxis for exposed contacts and during epidemics of meningococcal disease. Unfortunately, most cases
of endemic meningococcal meningitis are due to group B, for which there currently is no effective vaccine.
Haemophilus influenzae type b.
Rifampin prophylaxis should be given to all household contacts, including adults, if any close family member younger than 48 mo has not been fully immunized or if an immunocompromised child resides
in the household. A household contact is one who lives in the residence of the index case or who has spent
a minimum of 4 hr with the index case for at least 5 of 7 days preceding the patient's hospitalization. Family members should receive rifampin prophylaxis immediately after the diagnosis is suspected in the index
case because more than 50% of secondary family cases occur in the 1st wk after the index patient has been
hospitalized.
The risk of secondary cases of H. influenzae type b infection in daycare center contacts is less than
that for household contacts and probably greater than that for the general population. The risk is exceedingly low for daycare center children who are not classroom contacts and those older than 2 yr. The efficacy of
chemoprophylaxis in daycare centers is uncertain, and there are difficulties in ensuring that all at-risk daycare center attendees receive the drug. Chemoprophylaxis for children and adults in daycare centers that
resemble households (e.g., >25 hr/wk of close contact) should be provided to all adults and children if two
or more cases of H. influenzae type b infection occur within 60 days and some of the children are younger
than 2 yr and not fully immunized.
The dose of rifampin is 20 mg/kg/24 hr (maximum dose of 600 mg) given once each day for 4 days.
Rifampin discolors the urine and sweat red-orange, stains contact lenses, and reduces the serum concentrations of some drugs, including oral contraceptives. Rifampin is contraindicated during pregnancy. In addition to receiving prophylaxis, daycare center workers and parents should be educated about the signs of
serious H. influenzae infection and the importance of seeking prompt medical attention for fever or other
potential manifestations of H. influenzae disease.
H. influenzae type b nasopharyngeal colonization may not be eradicated in the index case despite
10 days of appropriate parenteral antibiotic therapy. Therefore, before discharge from the hospital, patients
should receive rifampin (20 mg/kg/dose every day for 4 days) to prevent introduction or reintroduction of
the organism into the household or daycare center.
The most exciting advance in the prevention of childhood bacterial meningitis is the development
and licensure of vaccines against H. influenzae type b. Four conjugate vaccines are licensed in the United
States. Although each vaccine elicits different profiles of antibody response in infants immunized at 2-6 mo
of age, all three result in protective levels of antibody with efficacy rates ranging from 70-100%. Efficacy
is not as consistent in Native American populations, a group recognized as having an extremely high incidence of disease. As a result, all children should be immunized with H. influenzae type b conjugate vaccine
beginning at 2 mo of age.
Streptococcus pneumoniae.
No chemoprophylaxis or vaccination is required for normal hosts who may be contacts of patients
with pneumococcal meningitis, because secondary cases rarely have occurred. High-risk patients age 2 yr
or older should receive the 23-valent pneumococcal vaccine, and patients with sickle cell anemia should
also receive chemoprophylaxis with daily oral penicillin, amoxicillin, or trimethoprim-sulfamethoxazole.
Viral Meningoencephalitis
Viral meningoencephalitis is an acute inflammatory process involving the meninges and, to a variable degree, brain tissue. These infections are relatively common and may be caused by a number of different agents. The CSF is characterized by pleocytosis and the absence of microorganisms on Gram stain and
routine bacterial culture. In most instances, the infections are self-limited; in some cases, however, substantial morbidity and mortality may be observed.
ETIOLOGY.
Although the specific etiologic agent is not identified in most cases, clinical and research experience indicate that viruses are usually the responsible pathogens, accounting for the seasonal pattern of disease. Enteroviruses cause more than 80% of all cases. Other frequent causes of infection include arboviruses and herpesviruses. Mumps is a common pathogen in regions where mumps vaccine is not widely used.
Enteroviruses are small RNA-containing viruses; almost 70 specific serotypes have been identified.
The severity of disease ranges from mild, self-limited illness with primarily meningeal involvement to severe encephalitis with death or significant sequelae. Epidemics, some devastating, have occurred among
newborns.
Arboviruses are zoonoses in which humans, not being essential in the viral life cycle, are infected
accidentally by an arthropod vector. Most commonly, mosquitoes or ticks acquire arboviruses by biting
infected birds or small mammals, which often have prolonged viremia without illness. The insect vectors
transmit the virus to other vertebrates, including humans and horses. Encephalitis in horses ("blind staggers") may be the first indication of an incipient epidemic. Although rural exposure is most common, urban
and suburban outbreaks are also frequent. The most common arboviruses responsible for CNS infection in
the United States are St. Louis and California encephalitis viruses (Chapter 258) .
Herpes simplex virus type 1 (HSV-1) is an important cause of severe, sporadic encephalitis in children and adults. Brain involvement usually is focal; progression to coma and death occurs in 70% of cases
without antiviral therapy. Severe encephalitis with diffuse brain involvement is caused by herpes simplex
virus type 2 (HSV-2) in neonates who usually contract the virus from their mothers at delivery. A mild
transient form of meningoencephalitis may accompany genital herpes infection in sexually active adolescents; most of these infections are caused by HSV-2. Varicella-zoster virus (VZV) may cause CNS infection in close temporal relationship with chickenpox. The most common manifestation of CNS involvement
is cerebellar ataxia, and the most severe is an acute encephalitis. After primary infection, VZV becomes
latent in spinal and cranial nerve roots and ganglia, expressing itself later as herpes zoster, often with accompanying mild meningoencephalitis. Cytomegalovirus (CMV) infection of the CNS may be part of congenital infection or disseminated disease in immunocompromised hosts, but it does not cause meningoencephalitis in normal infants and children. Epstein-Barr virus (EBV) has been associated with myriad CNS
syndromes (Chapter 247) .
Mumps meningoencephalitis is mild, but deafness due to damage of the 8th cranial nerve is not uncommon. Meningoencephalitis is caused occasionally by respiratory viruses, rubeola, rubella, or rabies.
EPIDEMIOLOGY.
The epidemiologic pattern of viral meningoencephalitis reflects the prevalence of the enteroviruses,
the primary etiology. Infection with enteroviruses is spread directly from person to person, with a usual incubation period of 4-6 days. Most cases in temperate climates occur in the summer and fall. Epidemiologic
considerations in aseptic meningitis due to agents other than enteroviruses also include season, geography,
climatic conditions, animal exposures, and factors related to the specific pathogen.
PATHOGENESIS.
The sequence of events varies with the infecting agent and host. In general, viruses enter the lymphatic system, either through ingestion of enteroviruses; by inoculation of mucous membranes by measles,
rubella, VZV, or HSV; or by hematogenous spread from a mosquito or other insect bite. There, multiplication begins, and seeding of the bloodstream leads to infection of several organs. At this stage (the extraneural phase), a systemic febrile illness is present, but if further viral multiplication takes place in the seeded
organs, a secondary propagation of large amounts of virus may occur. Invasion of the CNS is followed by
clinical evidence of neurologic disease. HSV-1 probably reaches the brain by direct spread along neuronal
axons.
Neurologic damage is caused by direct invasion and destruction of neural tissues by actively multiplying viruses or by a host reaction to viral antigens. Most neuronal destruction is probably due directly to
viral invasion, whereas the host's vigorous tissue response induces demyelination and vascular and perivascular destruction.
Tissue sections of the brain generally are characterized by meningeal congestion and mononuclear
infiltration, perivascular cuffs of lymphocytes and plasma cells, some perivascular tissue necrosis with myelin breakdown, and neuronal disruption in various stages, including ultimately neuronophagia and endothelial proliferation or necrosis. A marked degree of demyelination with preservation of neurons and their
axons is considered predominantly to represent "postinfectious" or "allergic" encephalitis. The cerebral cortex, especially the temporal lobe, is often severely affected by HSV; the arboviruses tend to affect the entire brain; rabies has a predilection for the basal structures. Involvement of the spinal cord, nerve roots, and
peripheral nerves is variable.
CLINICAL MANIFESTATIONS.
The progression and ultimate severity of the clinical course are very much determined by the relative degree of meningeal and parenchymal involvement, which in turn is determined, at least in part, by the
specific infectious agents. However, the clinical manifestations have as wide range of severity, even with
the same etiologic agent. Some children may appear to be mildly affected initially, only to lapse into coma
and die suddenly. In others, the illness may be ushered in by high fever, violent convulsions interspersed
with bizarre movements, and hallucinations alternating with brief periods of clarity, but then complete recovery.
The onset of illness is generally acute, although CNS signs and symptoms often are preceded by a
nonspecific acute febrile illness of a few days duration. The presenting manifestations in older children are
headache and hyperesthesia, and in infants, irritability and lethargy. Headache is most often frontal or generalized; adolescents frequently note retrobulbar pain. Fever, nausea and vomiting, photophobia, and pain
in the neck, back, and legs are common. As body temperature rises, there may be mental dullness, eventuating in stupor in combination with bizarre movements and convulsions. Focal neurologic signs may be
stationary, progressive, or fluctuating. Loss of bowel and bladder control and unprovoked emotional bursts
may occur.
Exanthems often precede or accompany the CNS signs, especially with echoviruses, coxsackieviruses, VZV, measles, and rubella. Examination often reveals nuchal rigidity without significant
localizing neurologic changes, at least at the onset.
Specific forms or complicating manifestations of CNS viral infection include Guillain-Barre syndrome, acute transverse myelitis, acute hemiplegia, and acute cerebellar ataxia.
DIAGNOSIS.
The diagnosis of viral encephalitis is usually made on the clinical presentation of nonspecific prodrome followed by progressive CNS symptoms. The diagnosis is supported by examination of the CSF,
which usually shows a mild mononuclear predominance (Table 174-1) . Other tests of potential value in the
evaluation of patients with suspected viral meningoencephalitis include an electroencephalogram (EEG)
and neuroimaging studies. The EEG typically shows diffuse slow-wave activity, usually without focal
changes. Neuroimaging studies (CT or MRI) may show swelling of the brain parenchyma. Focal seizures
or focal findings on EEG or CT or MRI, especially involving the temporal lobes, suggest HSV encephalitis.
Differential Diagnosis.
A number of clinical conditions that cause CNS inflammation mimic viral meningoencephalitis.
The most important group of alternate infectious agents to consider is bacteria. Most children with bacterial
infections of the CNS have a more acute onset and appear more critically ill, but this is not always the case.
Bacterial meningitis caused by S. pneumoniae, N. meningitidis, and H. influenzae type b may be insidious
in onset. CNS infection caused by other bacteria, such as tuberculosis, T. pallidum (syphilis), Borrelia
burgdorferi (Lyme disease), and Bartonella henselae, the bacillus associated with cat-scratch disease, also
may have very indolent courses. Analysis of CSF and appropriate serologic tests is necessary to differentiate these various pathogens. Parameningeal bacterial infections, such as brain abscess or subdural or epidural empyema, may have features similar to viral CNS infections. CNS imaging procedures are critical for
the diagnosis of these processes.
Nonbacterial infectious agents also need to be considered in the differential diagnosis of CNS infections. These agents include fungi, rickettsiae, Mycoplasma, protozoa, and other parasites. Consideration of
these agents usually arises as a result of accompanying symptoms, geographic locality of infection, or host
immune factors.
Various noninfectious disorders also may be associated with CNS inflammation and have manifestations overlapping with those associated with viral meningoencephalitis. Some of these disorders include
malignancy, collagen vascular diseases, intracranial hemorrhage, and exposure to certain drugs or toxins.
Attention to history and other organ involvement usually allows early elimination of these diagnostic possibilities. Recent exposure to possibly infected persons, animals, mosquitoes, or ticks and any recent travel
should be noted. Inquiry should also be made about recent injections of biologic substances and about the
possibilities of exposure to heavy metals, pesticides, or noxious substances.
LABORATORY FINDINGS.
The CSF contains from a few to several thousand cells per cubic millimeter. Early in the disease,
the cells are often polymorphonuclear; later, mononuclear cells predominate. This change in cellular type is
often demonstrated in CSF samples obtained as little as 8-12 hr apart. The protein concentration in CSF
tends to be normal or slightly elevated, but concentrations may be very high if brain destruction is extensive, as illustrated by HSV encephalitis. The glucose level is usually normal, although with certain viruses,
for example, mumps, a substantial depression of CSF glucose concentrations is often observed.
Cerebrospinal Fluid(CSF) Findings in Central Nervous System Disorders
Condition: normal
CSF is the color of water
Pressure (mm H2 O) averages 100mm (in the recumbent and relaxed position)
Leukocytes (mm3 ) <5, >75% lymphocytes
Protein (g/L) 0,15-0,33
Glucose (millimole/L) 2,2-3,3 (or 50-75% serum glucose)
Chloride (millimole/L) 120-140
Comments: CSF is sterile
Condition: viral meningitis
CSF is the color of water
Pressure (mm H2 O) normal or slightly elevated (100-150)
Leukocytes (mm3 ) rarely >1,000 cells. Eastern equine encephalitis and lymphocytic choriomeningitis (LCM) may have cell
counts of several thousand. PMNs early but mononuclear cells predominate through most of the course
Protein (g/L) usually slightly elevated
Glucose (millimole/L) generally normal; may be decreased in some viral diseases, particularly mumps (15-20% of cases)
Comments: HSV encephalitis is suggested by focal seizures or by focal findings on CT or MRI scans or EEG. Enteroviruses
and HSV infrequently recovered from CSF. HSV and enteroviruses may be detected by PCR of CSF
Condition: purulent meningitis(e. g. meningococcal meningitis) :
CSF is turbid
Increased opening pressure
Pleocytosis: 100-10,000 or more; usually 300-2,000, predominantly neutrophils
Increased protein concentration: usually 1,0-5,0 g/L
Decreased glucose concentration
Chloride concentration is normal
Comments: organisms usually seen on Gram stain(Gram-negative diplococcus is Neisseria meningitidis) and recovered by culture. Latex agglutination of CSF usually positive
Condition; tuberculous meningitis
- Spinal fluid is xanthochromic
- Increased opening pressure
- Pleocytosis, predominantly lymphocytes
- Increased protein concentration
- Decreased glucose concentration
- Decreased chloride concentration
The CSF should be cultured for viruses, bacteria, fungi, and mycobacteria; in some instances, special examinations are indicated for protozoa, Mycoplasma, and other pathogens. The success of isolating
viruses from the CSF of children with viral meningoencephalitis is determined by the time in the clinical
course that the specimen is obtained, the specific etiologic agent, whether the infection is a meningitic as
opposed to a localized encephalitic process, and the skill of the diagnostic laboratory. Isolating a virus is
more likely early in the illness, and the enteroviruses tend to be the easiest to isolate, although recovery of
these agents from the CSF rarely exceeds 70%. To increase the likelihood of identifying the putative viral
pathogen, specimens for culture also should be obtained from nasopharyngeal swabs, feces, and urine. Although isolating a virus from one or more of these sites does not prove causality, it is highly suggestive.
A serum specimen should be obtained early in the course of illness and, if viral cultures are not diagnostic, again 2-3 wk later for serologic studies. Serologic methods are not practical for diagnosing CNS
infections caused by the enteroviruses because there are too many serotypes. However, this approach may
be useful to confirm that a case is caused by a known circulating viral type. Serologic tests also may be of
value in determining the etiology of nonenteroviral CNS infection. Newer diagnostic techniques for suspected viral meningoencephalitis that use polymerase chain reaction to detect viral DNA or RNA in CSF
are promising.
TREATMENT.
Until a bacterial cause is excluded by culture of blood and CSF, parenteral antibiotic therapy should
be administered. With the exception of the use of acyclovir for HSV encephalitis, treatment of viral meningoencephalitis is nonspecific. Treatment of mild disease may require only symptomatic relief. Headache
and hyperesthesia are treated with rest, non-aspirin-containing analgesics, and a reduction in room light,
noise, and visitors. Acetaminophen is recommended for fever. Codeine, morphine, and the phenothiazine
derivatives may be necessary for pain and vomiting, but if possible, their use in children should be minimized because they may induce misleading signs and symptoms. Intravenous fluids are occasionally necessary because of poor oral intake. More severe disease may require hospitalization and intensive care.
It is important to anticipate and be prepared for convulsions, cerebral edema, hyperpyrexia, inadequate respiratory exchange, disturbed fluid and electrolyte balance, aspiration and asphyxia, and cardiac or
respiratory arrest of central origin. Therefore, all patients with severe encephalitis should be monitored
closely. In patients with evidence of increased ICP, placement of a pressure transducer in the epidural
space may be indicated for monitoring ICP. The risks of cardiac and respiratory failure or arrest are high
with severe disease. All fluids, electrolytes, and medications are initially given parenterally. In prolonged
states of coma, parenteral alimentation is indicated.
SIADH is quite common in acute CNS disorders; thus, constant evaluation is required for its early detection. Normal blood levels of glucose, magnesium, and calcium must be maintained to minimize the threat
of convulsions. If cerebral edema or seizures become evident, vigorous treatment should be instituted.
PROGNOSIS.
Supportive and rehabilitative efforts are very important after patients recover. Motor incoordination, convulsive disorders, total or partial deafness, and behavioral disturbances may appear only after an
interval of time. Visual disturbances due to chorioretinopathy and perceptual amblyopia may also have a
delayed appearance. Special facilities and, at times, institutional placement may become necessary. Some
sequelae of infection may be very subtle. Therefore, neurodevelopmental and audiologic evaluations
should be part of the routine follow-up of children who have recovered from viral meningoencephalitis.
Most children completely recover from viral infections of the CNS, although the prognosis depends
on the severity of the clinical illness, the specific cause, and the age of the child. If the clinical illness is
severe and substantial parenchymal involvement is evident, the prognosis is poor, with potential deficits
being intellectual, motor, psychiatric, epileptic, visual, or auditory in nature. Severe sequelae also should be
anticipated in those with infection caused by HSV. Although some literature suggests that infants who contract viral meningoencephalitis have a poorer long-term outcome than older children, other data refute this
observation. Although about 10% of children younger than 2 yr with enteroviral CNS infections suffer an
acute complication such as seizures, increased ICP, or coma, almost all have favorable long-term neurologic outcomes.
PREVENTION.
Widespread use of effective attenuated viral vaccines for polio, measles, mumps, rubella, and varicella has almost eliminated CNS complications from these diseases in the United States. The availability of
domestic animal vaccine programs against rabies has reduced the frequency of rabies encephalitis. Control
of encephalitis due to arboviruses has been less successful because specific vaccines for the arboviral diseases that occur in North America are not available. However, control of insect vectors by suitable spraying
methods and eradication of insect breeding sites reduce the incidence of these infections.
Eosinophilic Meningitis
Eosinophilic meningitis is defined as 10 or more eosinophils/mm3 of CSF. The most common
cause worldwide of eosinophilic pleocytosis is CNS infection with helminthic parasites. However, in countries such as the United States, where helminthic infestation is uncommon, the differential diagnosis of
CSF eosinophilic pleocytosis is broad.
ETIOLOGY.
Although any tissue-migrating helminth may cause eosinophilic meningitis, the most common
cause is human infection with the rat lungworm Angiostrongylus cantonensis (Chapter 289) . Other parasites that can cause eosinophilic meningitis include Gnathostoma spinigerum (dog and cat roundworm)
(Chapter 293) , Baylisascaris procyonis (raccoon roundworm), Ascaris lumbricoides (human roundworm),
Trichinella spiralis, Toxocara canis, Toxoplasma gondii, Paragonimus westermani, Echinococcus granulosus, Schistosoma japonicum, Onchocerca volvulus, and T. solium. Eosinophilic meningitis also may occur as an unusual manifestation of more common viral, bacterial, or fungal infections of the CNS. Noninfectious causes of eosinophilic meningitis include multiple sclerosis, malignancy, hypereosinophilic syndrome, or a reaction to medications or a ventriculoperitoneal shunt.
EPIDEMIOLOGY.
A. cantonensis is found in Southeast Asia, the South Pacific, Japan, Taiwan, Egypt, Ivory Coast,
and Cuba. Infection is acquired by eating raw or undercooked freshwater snails, slugs, prawns, or crabs
containing infectious third-stage larvae. Gnathostoma infections are found in Japan, China, India, Bangladesh, and Southeast Asia. Gnathostomiasis is acquired by eating undercooked or raw fish, frog, bird, or
snake meat.
CLINICAL MANIFESTATIONS.
When eosinophilic meningitis results from helminthic infestation, patients become ill 1-3 wk after
exposure, as the parasites migrate from the gastrointestinal tract to the CNS. Common concomitant findings include fever, peripheral eosinophilia, vomiting, abdominal pain, creeping skin eruptions, or pleurisy.
Neurologic symptoms may include headache, meningismus, ataxia, cranial nerve palsies, and paresthesias.
Paraparesis or incontinence can result from radiculitis or myelitis.
DIAGNOSIS.
The presumptive diagnosis of helminth-induced eosinophilic meningitis is made by travel and exposure history in the presence of typical clinical and laboratory findings.
TREATMENT.
Treatment is supportive, because infection is self-limited and anthelmintic drugs do not appear to
influence the outcome of infection. Analgesics should be given for headache and radiculitis, and CSF removal or shunting should be performed to relieve hydrocephalus, if present.
PROGNOSIS.
The prognosis is good; 70% of patients improve sufficiently to leave the hospital in 1-2 wk. Mortality associated with eosinophilic meningitis is less than 1%.
IV. Sources of information.
Basic literature:
№
Author(s)
№
2. Mikhailova
1
A.M., Minkov
I.P., Savchuk
A.I.
2 E. Nikitin,
M. Andreychin
Name of the source
(textbook, manual, monograph, etc)
Infection diseases in children
Infectious diseases
City,
Publishing house
Year of
edition,
vol.,
issue
Odessa
2003
Ukrmedkn
iga
2004
Number
of pages
Additional literature:
№
Author(s)
№
Richard
1
E.Behrman,
Robert
M.Kliegman,
Hal B. Jenson
Name of the source
(textbook, manual, monograph, etc)
Nelson. Textbook of pediatrics
City,
Publishing
house
W.B.Saun
ders company
Year of
edition,
vol.,
issue.
2000,
16 th
edition
Number
of pages
751760,82
6829,94
8,952,9
55,969,
971,97
4,985,
Tests / Tasks / Laboratory tests
Test1.
Meningitis is:
A. Inflammation of the leptomeninges
B. Inflammation of the brain itself
C. Inflammation of the spinal cord
D. All answers are correct
Test 2.
Encephalitis is:
A. Inflammation of the leptomeninges
B. Inflammation of the brain itself
C. Inflammation of the spinal cord
D. All answers are correct
Test 3.
Altered consciousness, seizure and focal neurological signs are typically for:
A. Meningitis
B. Encephalitis
C. Myelitis
Test 4.
Typical cerebrospinal fluid abnormalities in meningococcal meningitis include the following:
A. Increased opening pressure; pleocytosis, lymphocytes predominate
B.CSF is turbid; increased opening pressure; pleocytosis, predominantly neutrophils; decreased
glucose concentration
C.CSF is xanthochromic; increased opening pressure; pleocytosis, lymphocytes predominate; increased protein concentration; decreased glucose concentration
Test 5.
Typical cerebrospinal fluid abnormalities in enteroviral meningitis include the following:
A. CSF is the color of water; increased opening pressure; pleocytosis, lymphocytes predominate;
protein concentration is normal; glucose concentration is normal
B.CSF is turbid; increased opening pressure; pleocytosis, predominantly neutrophils; decreased
glucose concentration
C.CSF is xanthochromic; increased opening pressure; pleocytosis, lymphocytes predominate; increased protein concentration; decreased glucose concentration
Test 6.
Typical cerebrospinal fluid abnormalities in tuberculous meningitis include the following:
A. CSF is the color of water; increased opening pressure; pleocytosis, lymphocytes predominate;
protein concentration is normal; glucose concentration is normal
B.CSF is turbid; increased opening pressure; pleocytosis, predominantly neutrophils; decreased
glucose concentration
C.CSF is xanthochromic; increased opening pressure; pleocytosis, lymphocytes predominate; increased protein concentration; decreased glucose concentration
Task1.
A 4 year old child fell acutely ill, body temperature rose up to 39,5oC, there appeared anxiety, recurrent
vomiting, headache. Examination revealed positive signs of meningeal irritation (typical patient’s posture,
stiff neck, Brudzinski signs, Kernig sign), after this lumbal puncture was performed . Spinal fluid is turbid,
opening pressure is 200 mm water, protein concentration is 2,4 g/l; Pandy reaction is +++, glucose concentration is 1,8 millimole/l (serum glucose concentration is 4,8 millimole/l), chloride concentration - 120 millimole/l, pleocytosis is 6,350 cells/ mm3 (86% of neutrophils, 14% of lymphocytes). Gram stain of CSF
identified a gram-negative diplococcus.
1.What is the diagnosis?
2.What clinical manifestations of this infection do you know?
3.Make the plan of treatment.
4.What methods of specific prophylaxis against this infection do you know?
Task 2.
A 7 year old child fell acutely ill, body temperature rose up to 39,3oC, there appeared recurrent vomiting, headache (a child is vaccinated according with the schedule of immunization). Examination: skin was
without changes; there were hyperemia of pharynx and small, 1-2mm vesicles and ulcers on the anterior
tonsillar pillars, soft palate, uvula, tonsils; positive signs of meningeal irritation (stiff neck, Brudzinski
signs, Kernig sign). After this lumbal puncture was performed. Cerebrospinal fluid is the color of water,
opening pressure is 150 mm water, pleocytosis is 200 cells/ mm3 (20% of neutrophils, 80% of lymphocytes),
protein concentration is 0,24g/l, glucose concentration is 2,2 millimole/l, chloride concentration is 123
millimole/l.
1.What is the most probable diagnosis?
2.What clinical manifestations of this infection do you know?
3.What laboratory examinations should be administered for the definition of etiology?
4.Make the plan of treatment.
Laboratory test 1.
A 7- year- old child fell acutely ill, body temperature rose up to 39,3oC, there appeared recurrent vomiting, headache. Examination revealed positive signs of meningeal irritation (stiff neck, Brudzinski signs,
Kernig sign). After this lumbal puncture was performed. CSF laboratory findings: cerebrospinal fluid is the
color of water, opening pressure is 150 mm water, pleocytosis is 200 cells/ mm3 (80% of lymphocytes,
20% of neutrophils), protein concentration is 0,24g/l, glucose concentration is 2,2 millimole/l, chloride
concentration is 123 millimole/l.
Questions:
1. What is the most probable diagnosis?
2. Estimate the data of the laboratory examination.
Laboratory test 2.
A 4- year -old child fell acutely ill, body temperature rose up to 39,5oC, there appeared anxiety, recurrent
vomiting, headache. Examination revealed positive signs of meningeal irritation (typical patient’s posture,
stiff neck, Brudzinski signs, Kernig sign), after this lumbal puncture was performed . Spinal fluid is turbid,
opening pressure is 200 mm water, pleocytosis is 6,350 cells/ mm3 (86% of neutrophils, 14% of lymphocytes), protein concentration is 2,4 g/l; Pandy reaction is +++, glucose concentration is 1,8 millimole/l (se-
rum glucose concentration is 4,8 millimole/l), chloride concentration is 120 millimole/l. Gram stain of
CSF identified a gram-negative diplococcus.
Questions:
1. What is the diagnosis?
2. Estimate the data of the laboratory examination.
Laboratory test 3.
A 3- year -old unimmunized child had gradual onset of headache and decreased consciousness. Examination revealed positive signs of meningeal irritation. After this lumbal puncture was performed. Spinal
fluid is xanthochromic, opening pressure is 250 mm water, pleocytosis is 500 cells/ mm3 (28% of neutrophils, 72% of lymphocytes), protein concentration is 3 g/l; Pandy reaction is ++++, glucose concentration is 0,9 millimole/l (serum glucose concentration is 4,8 millimole/l), chloride concentration is 100 millimole/l.
Questions:
1. What is the diagnosis?
2. Estimate the data of the laboratory examination.