Al- Balqa Applied University Faculty of Medicine

Neurosciences- Lecture 1Central 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 AGENTNewborns (1 mo old) Group B streptococci (most common)

Escherichia coli, Listeria Monocytogenes, Klebsiella species, other entericGram-negative bacteria

Infants and children Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae

Adults S. pneumoniae, Neisseria meningitidis

Laboratory diagnosis

Normal Cerebrospinal Fluid CharacteristicsClear, 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 meningitisNeisseria 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 (LOS activates the Hageman factor (clotting factor XII), which causes DIC that appears as a rash on the affected individual).

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 Lipooligosaccharide (LOS) 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.

IMMUNITYProtective 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.

DiagnosisDirect 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 populationsQuadrivalent 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.

EpidemiologyGBS 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).

PathogenesisGBS 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 infectionRespiratory 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 casesThe 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

PreventionIn 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 influenzaePathogenesis

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 infectionsBacteriologically, 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.

- It is catalase-positive and has a tumbling end-over-end motility at 22–28°C but not at 37°C

EpidemiologyMembers 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 of the intestinal tract, the blood–brain barrier, and the placenta, promoting phagocytosis.

- 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 FindingsThere 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 preventionIntense 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.