Lecture 1
Central Nervous System Infection
Dr. Hala Al Daghistani
Most CNS infections appear to result from blood-borne spread; for example, bacteremia or
viremia resulting from infection of tissue. CNS may result in penetration of the blood–brain
barrier. Examples of infectious agents that commonly infect the CNS by this route are
Haemophilus influenzae
Neisseria meningitides
Streptococcus pneumonia
Mycobacterium tuberculosis
Viruses such as Enteroviruses and Mumps.
Type’s of meningitis
Purulent meningitis refers to infections of the meninges associated with a marked, acute
inflammatory exudate and is usually caused by a bacterial infection.
Such infections frequently involve the underlying CNS tissue to a variable degree
Most cases of purulent meningitis are acute in onset and progression
Characterized by fever, stiff neck, irritability, and varying degrees of neurologic dysfunction.
Large numbers of PMN leukocytes are present in the CSF of established cases.
Chronic meningitis has a more insidious onset, with progression of signs and symptoms over a
period of weeks.
This is usually caused by mycobacteria or fungi that produce granulomatous inflammatory
changes, but occasionally protozoal agents are responsible.
The cellular response in the CSF reflects the chronic inflammatory nature of the disease.
Aseptic meningitis is a term used to describe a syndrome of meningeal inflammation
associated mostly with an increase of cells (pleocytosis), primarily lymphocytes and other
mononuclear cells in the CSF, and absence of readily cultivable bacteria or fungi.
It is associated most commonly with viral infections and is often self-limiting.
The syndrome can also occur in syphilis and some other spirochetal diseases, from tumors or
bleeding involving the meninges or subarachnoid space.
Such patients may have fever, headache, a stiff neck or back, nausea, and vomiting
Common Causes of Purulent Central Nervous System Infections
AGE GROUP AGENT Newborns (1 mo old) Group B streptococci (most common)
Escherichia coli, Listeria Monocytogenes, Klebsiella species, other enteric Gram-negative bacteria
Infants and children Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae Adults S. pneumoniae, Neisseria meningitidis
Laboratory diagnosis
Normal Cerebrospinal Fluid Characteristics
Clear, colorless, and sterile fluid
90 to 150 ml in adult
15 to 45 mg/dL protein
40 to 80 mg/dL glucose
0 to 7 leukocytes/microliter
60% - 80% lymphocytes, 10% - 40% monocytes, and 0%- 15% neutrophils
Newborns have higher CSF concentrations
Causative agents of meningitis
Neisseria meningitides
Meningococci produce medium-sized smooth colonies on blood agar plates after
overnight incubation.
Twelve serogroups have been defined on the basis of the antigenic specificity of a
polysaccharide capsule. The most important disease-producing serogroups are A, B, C,
W-135, and Y.
In addition to the group polysaccharides, individual N. meningitidis strains may contain
two distinct classes of pili and multiple classes of OMPs. Some OMPs, Porins, and
adherence proteins have structural and functional similarities to those found in
gonococci
Meningococcal diseases
Meningococci are usually members of the nasopharyngeal flora but may produce
fulminant infection of the blood stream and/or CNS.
The major disease is an acute, purulent meningitis with fever, headache, seizures, and
mental signs secondary to inflammation and increased intracranial pressure. Even when
the CNS is not involved, N. meningitides infections have a marked tendency to be
accompanied by rash, purpura, thrombocytopenia, and other manifestations associated
with endotoxemia.
Epidemiology
Meningococci are found in the nasopharyngeal flora of approximately 10% of healthy
individuals.
Transmission occurs by inhalation of aerosolized respiratory droplets
Factors that foster transmission are contact with a virulent strain and susceptibility (lack
of protective antibody).
B, C, and Y are the most common serogroups involved. For unknown reasons, group A
meningococci have the capability to cause widespread epidemics sweeping through
communities, even countries.
Pathogenesis
For most individuals, the carrier state is associated with acquisition of protective
antibodies, but for some, spread from the nasopharynx to produce bacteremia, endotoxemia,
and meningitis takes place too quickly for immunity to develop.
Meningococci use pili for initial attachment to the microvilli of the nasopharyngeal
epithelium as a prelude to invasion.
Once inside, meningococci quickly pass through the cytoplasm, exiting into the
submucosa on the other side. They damage the ciliated cells, possibly by direct release of
endotoxin.
An important and critical nutrient, iron, is supplied by N. meningitidis proteins, which
are able to acquire it from the human transferrin.
As with other encapsulated bacteria, the polysaccharide capsule enables meningococci to
resist complement-mediated bactericidal activity and subsequent neutrophil phagocytosis.
Meningococcal LOS (Lipooligosaccharide) also has features that facilitate evasion of
host immune responses. Its chemical structure mimics sphingolipids found in the
human brain enough for them to be recognized as self by the immune system.
The exact mechanism of CNS invasion is unclear but is probably related to the level of
the bacteremia. After CNS invasion, an intense subarachnoid space inflammatory
response is generated, induced by the release of cell wall peptidoglycan fragments, LOS,
and possibly other virulence factors causing the release of inflammatory cytokines.
IMMUNITY
Protective antibody is stimulated by infection and through the carrier state, which
produces immunity within a few weeks.
Purified capsular polysaccharides are immunogenic, generating T cell–independent
immune responses (as with other polysaccharide immunogens, these responses are not
strong).
Manifestations A prominent feature of meningococcal meningitis is the appearance of scattered skin
petechiae. These cutaneous manifestations are signs of the disseminated intravascular
coagulation (DIC) syndrome that is part of the endotoxic shock brought on by meningococcal
bacteremia (meningococcemia).
However, the disease is not always fulminant, and some patients have only low-grade
fever, arthritis, and skin lesions that develop slowly over a period of days to weeks.
DIAGNOSIS Direct Gram smears of cerebrospinal fluid (CSF) in meningitis usually demonstrate the
typical bean-shaped, Gram-negative diplococci.
Definitive diagnosis is by culture of CSF, blood, or skin lesions. Growth is good on blood
or chocolate agar after 18 hours of incubation.
Speciation is based on carbohydrate degradation patterns or immunologic tests.
Purified polysaccharide meningococcal vaccines have been shown to prevent group A
and C disease in military and civilian populations
Quadrivalent vaccine containing A, C,Y, and W-135 polysaccharides is now licensed for
use in the United States.
Group B Streptococci
Group B streptococci (GBS) produce short chains and diplococcal pairs of spherical or
ovoid Gram-positive cells.
β-hemolysis is less distinct than with group A streptococci and may even be absent.
In addition to the Lancefield B antigen, GBS produce polysaccharide capsules of nine
antigenic types (Ia, Ib, II through VIII) all of which contain sialic acid in the form of
terminal side chain residues.
Epidemiology GBS are the leading cause of sepsis and meningitis in the first few days of life. The
organism is resident in the gastrointestinal tract, and vagina.
GBS can be found in the vaginal flora of 10 to 30% of women, and during pregnancy
and delivery, these organisms may again access to the amniotic fluid or colonize the newborn
as it passes through the birth canal.
The risk is much higher when factors are present that decrease the infant’s innate
resistance (prematurity) or increase the chances of transmission (ruptured amniotic
membranes).
Pathogenesis GBS capsule is the major organism factor. The sialic acid moiety of the capsule has
been shown to bind serum factor H, which in turn accelerates degradation of C3b
before it can be effectively deposited on the surface of the organism. This makes alternate
pathway–mediated mechanisms of opsonophagocytosis relatively ineffective.
GBS have also been shown to produce a peptidase that inactivates C5a, the major
chemoattractant of PMNs.
Clinical manifestation of GBS infection Respiratory distress, fever, lethargy, irritability, and hypotension are common. Fever is
sometimes absent, and infants may even be hypothermic.
Pneumonia is common, and meningitis is present in 5 to 10% of cases
The onset is typically in the first few days of life, and signs of infection are present at
birth in almost 50% of cases.
The late-onset (1 to 3 month) cases have similar findings but are more likely to have
meningitis and focal infections in the bones
DIAGNOSIS
The laboratory diagnosis of GBS infection is by culture of blood, cerebrospinal fluid, or
other appropriate specimen.
Definitive identification involves serologic determination of the Lancefield group ,
CAMP test
Prevention In colonized women, attempts to eradicate the carrier state have not been successful,
but antimicrobial prophylaxis with penicillin or ampicillin has been shown to reduce
transmission and disease in high-risk populations. The incidence of early-onset neonatal
GBS disease dropped 65% over a 5-year period when these strategies were being
implemented.
Streptococcus pneumoniae
The most common form of infection with S. pneumoniae is pneumonia, which begins
with fever and a shaking chill followed by signs that localize the disease to the lung. The
bacteria may spread to the bloodstream and thus other organs. The most important is the
CNS, where seeding with pneumococci leads to acute purulent meningitis.
Epidemiology S. pneumoniae is a leading cause of pneumonia, Acute purulent meningitis,
bacteremia, and other invasive infections.
S. pneumoniae is also the most frequent cause of otitis media , a virtually universal
disease of childhood. Pneumococcal infections occur throughout life but are most
common in the very young (2 years) and in the old (60 years).
Alcoholism, diabetes mellitus, chronic renal disease, asplenia, and some malignancies are
all associated with more frequent and serious pneumococcal infection.
Infections are derived from colonization of the nasopharynx, where pneumococci
can be found in 5 to 40% of healthy persons depending on age, season, and other
factors.
About 23 of the 90 pneumococcal serotypes produce disease more often than the others.
Pathogenesis Pneumococcal adherence to nasopharyngeal cells involves multiple factors. The primary
is the bridging effect of the choline binding protein’s (CBP) attachment to cell wall
cholines When organisms reach the alveolus, the involvement of pneumococcal virulence factors
appears to operate in two stages.
The first stage is early in infection, when the surface capsule of intact organisms acts to
block phagocytosis by complement inhibition. This allows the organisms to multiply and
spread despite an acute inflammatory response.
The second stage occurs when organisms begin to disintegrate and release a number of
factors either synthesized by the pneumococcus or part of its structure, thus causing
injury. These include Pneumolysin, Autolysin, and components of the cell wall.
Pneumolysin Pneumolysin also has direct effects on phagocytes and suppresses host inflammatory and
immune functions. Because pneumolysin is not actively secreted outside the bacterial cell, the
action of the autolysins is required to release it.
Other Virulence Determinants
Pneumococcal surface protein A (PspA), is found in virtually all pneumococci and has
been shown to
- interfere with complement deposition
- has a role in attachment. Peptidoglycan and teichoic acid components of the cell wall have been shown to
stimulate inflammation and cerebral edema
Diagnosis Gram smears of material from sputum and other sites of pneumococcal infection typically
show Gram-positive, lancet-shaped diplococci.
S. pneumoniae grows well overnight on blood agar medium and is usually distinguished from
Viridans streptococci by susceptibility to Optochin or by a Bile solubility
Hemophilus influenza
Pathogenesis H. influenzae can be found in the normal nasopharyngeal flora of 20 to 80% of
healthy persons, depending on age, season, and other factors.
Most of these are nonencapsulated, but capsulated strains, including Hib, are not rare
(the capsule is polyribosylribitol phosphate-PRP).
Meningitis is the most common form and most often attacks those under 2 years of age.
Of the major acute Hib infections, meningitis accounts for just over 50% of cases. The
remaining are distributed among Pneumonia, epiglottitis, septicemia, cellulitis, and
septic arthritis.
Diagnosis
The combination of clinical findings and a typical Gram smear is usually sufficient to
make a presumptive diagnosis of Haemophilus infection.
The diagnosis must be confirmed by isolation of the organism from the CSF. Blood
cultures are particularly useful in systemic H. influenzae infections
Bacteriologically, small coccobacillary Gram-negative rods that grow on chocolate
agar (required X and V factors) but not blood agar .
Prevention Purified PRP vaccines became available. PRP-protein conjugate vaccines were developed
using proteins derived from Corynebacterium diphtheriae (toxoid, CRM 197) or N. meningitidis
(outer membrane protein).
Listeria monocytogenesis
Listeria monocytogenes is a Gram-positive rod with some bacteriologic features that
resemble those of both corynebacteria and streptococci.
- L. monocytogenes are able to grow slowly in the cold even at temperatures as low as 1°C
under conditions of low pH and high salt conditions. Therefore, it is able to overcome
food preservation and safety barriers making it an important food-borne pathogen.
- L. monocytogenes is a short, gram-positive rod.
- It is catalase-positive and has a tumbling end-over-end motility at 22–28°C but not at
37°C
EPIDEMIOLOGY Members of Listeria are widespread among animals in nature, including those associated
with our food supply (e.g, fowl)
Most of the cases were among mother–infant pairs. Dairy product outbreaks have been
traced to post-pasteurization contamination
L. monocytogenes may also be transmitted transplacentally to the fetus, presumably
following hematogenous dissemination in the mother. It may also be transmitted to
newborns in the birth canal in a manner similar to group B streptococci.
Most cases occur at the extremes of life (eg, in infants less than 1 month of age or adults
over 60 years of age).
Pathogenesis & Immunity
- L. monocytogenes enters the body through the gastrointestinal tract after ingestion of
contaminated foods such as cheese or vegetables.
- The organism has a cell wall surface protein called internalin A that interacts with E-
cadherin, a receptor on epithelial cells, promoting phagocytosis into the epithelial cells.
- After phagocytosis, the bacterium is enclosed in a phagolysosome, where the low pH
activates the bacterium to produce listeriolysin O.
- This enzyme lyses the membrane of the phagolysosome and allows the listeriae to escape
into the cytoplasm of the epithelial cell.
- The organisms proliferate and a listerial surface protein, induces host cell actin
polymerization, which propels them to the cell membrane. Pushing against the host cell
membrane, they cause formation of elongated protrusions called filopods.
- These filopods are ingested by adjacent epithelial cells, macrophages, and hepatocytes,
the listeriae are released, and the cycle begins again.
Clinical Findings There are two forms of perinatal human listeriosis.
Granulomatosis infantiseptica is the result of infection in utero and is a
disseminated form of the disease characterized by neonatal sepsis, death may occur
before or after delivery.
Adults can develop Listeria meningoencephalitis, bacteremia, and (rarely)
focal infections.
L. monocytogenes has a tropism for the CNS, including the brain parenchyma
(encephalitis) and brainstem
Treatment and prevention Intense surveillance to prevent the sale of Listeria-contaminated ready-to-eat meat products has
led to a marked decrease in the incidence of new infections. There is no vaccine.