Meningitis Flashcards
Meninges
- the membranes that envelop the CNS (brain and spinal cord)
- includes pia mater, arachnoid mater, and dura mater
- CSF is between the arachnoid and pia maters
What is meningitis?
- viral or bacterial infection of the meninges
Is viral or bacterial meningitis more sever?
- viral is less severe and usually resolves without specific treatment
- bacterial meningitis can be rapid and life-threatening
What is the Blood Brain Barrier?
- a protective cellular structure that restricts passage of chemicals, toxins, and microorganisms from the blood to the CNS
- also protects your CNS from the peripheral immune system
What creates the BBB?
endothelial cells stitched together by structures called “tight junctions” to prevent things from diffusing across
What is the role of astrocytes and pericytes in the BBB?
- provide support for other cells of the CNS, including the BBB
What is the role of microglia cells in the BBB?
- they are the tissue macrophages of the CNS but not really designed to fight microorganisms - more fore eating up cellular debris
are WBCs present in the CNS?
- no they are normally not present in the CNS, therefore there are no b cells or antibodies.
- inflammation is not very good here
Bacterial Meningitis Process (10 steps)
- nasopharyngeal colonization
- invasion into blood
- multiplication in blood
- crossing of the blood brain barrier (BBB)
- invasion of the meninges
- production of proinflammatory cytokines/chemokines
- recruitment of leukocytes into CNS
- Edema, increased cranial pressure
- inflammation
- neuronal damage
How do microorganisms transverse the BBB?
- method is not well understood
- three ways: transcellular, paracellular, trojan-horse
Transcellular Transversal
- Invade into endothelial cells and go out through other side
- Essentially eating through the cell
- Most meningitis pathogens probably use this pathway
Paracellular Transversal
- Bacteria drive themselves through tight junctions
- e.g. Lyme disease
Trojan-horse Mechanism
- Bacteria gain access to macrophage that is living within a phagocyte and phagocyte crosses through
- Tuberculosis
The Disease: Bacterial Meningitis
- a rare but very dangerous disease – can kill in days
- early signs may be non-specific
- in an outbreak, the first people to develop disease are most at risk (because they delay treatment)
- mortality rate has remained high (10-25%)
- survivors may have irreversible damage
brain damage, blindness, hearing loss, learning disabilities
Clinical symptoms of Meningitis in children and adults
- high fever
- severe headache
- stiff neck
- confusion
- vomiting or nausea
- seizures
- sleepiness or difficulty waking up
- photophobia - sensitivity to light
- skin rash in cases of meningococcal meningitis
Clinical symptoms of Meningitis in infants
can be subtle, variable and non-specific:
- fever
- constant crying
- excessive sleepiness or irritability
- poor feeding
- inability to maintain eye contact
- a bulge in the soft spot on top of a baby’s head (fontanel)
- stiffness in the baby’s body and neck
- skin rash in cases of meningococcal meningitis
Risk factors for bacterial meningitis
- lack of vaccination
young age (infants) - living in a community setting (university students living in dormitories, military personnel, boarding schools, child care facilities, prisons)
- immunocompromised individuals due to disease or chemotherapy
- cranial surgery
Bacterial Meningitis Diagnosis
- history and symptoms
- blood tests for inflammatory markers, culture
- CT imaging
Lumbar puncture (spinal tap): spinal needle inserted between 3rd and 4th lumbar vertebrae
- cloudy CSF
- Gram stain and culture
- presence of white cells (neutrophils)
- low glucose
Physical Signs of Bacterial Meningitis
Nucal Rigidity, Brudzinksi’s sign, Kernig’s sign
- if there were no signs, it is inconclusive (you may or may not have the disease) BUT if the signs are present, you have meningitis
Nucal rigidity
inability to flex the head forward
Brudzinski’s sign
severe neck stiffness causes a patient’s knees to flex when the neck is flexed
Kernig’s sign
severe stiffness of the hamstrings causes and inability to straighten the leg when the hip is flexed to 90 degrees
Treatment of bacterial meningitis
- must be sought immediately
- intravenous antibiotics (prior to culture analysis)
- corticosteroids (dexamethasone) to reduce swelling in the meninges
- supportive therapies (monitoring, oxygen, fluids etc)
What are the major causes of meningitis?
Almost all known bacterial pathogens have the potential to cause meningitis, but relatively few account for most cases. Major causes of bacterial meningitis:
- Neisseria meningitidis
- Streptococcus pneumoniae
- (Haemophilus influenzae)
- Listeria monocytogenes
In infants:
- streptococcus agalactiae (Group b streptococcus)
Which virulence factor is mainly produced by meningitis causing bacteria?
capsules (except by listeria)
What is a capsule?
- a loose, relatively unstructured network of polymers that cover the surface of some bacteria
- most are composed of polysaccharides
What is a capsule’s main role in meningitis?
- to protect bacteria from the complement system
- complement: innate immune system serum proteins (e.g. C3b)
- encapsulated bacteria are less likely to be opsonized by through the complement system
Capsules as vaccines
- an effective host response against capsules is the generation of antibodies from B cells that can recognize the capsule
- antibodies that recognize the capsule promote opsonization and phagocytosis
- capsules can therefore be used as vaccines
What is a problem associated with using capsules as vaccines?
- polysaccharide vaccines do not provide long-term memory because they are T cell-independent
- T cells provide “help” to B cells
- long-term memory
BUT, T cells respond to proteins/peptides, not sugars
Conjugate Vaccines
- polysaccharide conjugated to protein carrier
- this vaccine will be T cell-dependent
- you are essentially tricking the immune system
Neisseria Meningitidis
- “meningococcus”
- Gram-negative, diplococcus
- a human specific pathogen
- colonizes the nose and throat – asymptomatic carriage is common
- produces a polysaccharide capsule
- antigenic variants (i.e. serotypes)
- A, B, C, W135 and Y
- a leading cause of bacterial meningitis and also meningococcemia - termed invasive meningococcal disease
- this infection is highly contagious and may cause local epidemics in college dormitories, boarding schools and on military bases
How are Neisseria meningitidis antigenically different?
- all strains of not make the same capsule (antigenically different)
Meningococcal disease
- meningitis occurs after bacteria enter the bloodstream and cross the BBB
- endotoxin (LPS) can lead to septic shock
- disseminated intravascular coagulation
- widespread blood clotting
- ischemia
- purpuric rash
What is a purpuric rash?
- basically a rsh underneath the skin
- clotting factors are used up which leads to small skin bleeds
How do you test if rash is a purpuric rash?
rash does not fade under pressure (“glass test”)
Vaccines for Neisseria meningitidis
- Menactra (Sanofi Pasteur)/Menveo (GSK) – quadrivalent conjugate capsule vaccine from 4 serotypes of meningococcus (serogroup A, C, Y, W-135)
- Serogroup B most common for invasive disease in Canada but the capsule is poorly immunogenic
- Bexsero (GSK) – contains 4 recombinant protein antigens – now licensed (as of 2014) for use in Canada –> now used to go after serogroup B strains
The African Meningitis Belt
- the highest burden of the disease in the world
- up to ~500/100,000
- mostly caused by serogroup A
The pathogen: Streptococcus pneumoniae
- “pneumococcus”
- Gram-positive cocci, grows in chains
commonly resides asymptomatically in the nasopharynx
What symptoms does streptococcus pneumoniae cause?
- causes pneumonia, ear infections, sinusitis and many other diseases
- the leading cause of bacterial meningitis in children > 2 years and adults
How many people die by Streptococcus pneumoniae globally per year?
> 700 000
How Streptococcus pneumoniae work?
produces a polysaccharide capsule (may different serotypes exist)
Vaccine for Streptococcus pneumoniae
- A pneumococcal vaccine has been licensed for use in Canada
- Previously a 7 serotype vaccine (PCV7)
- now Prevnar 13 (PCV13)
- use of the vaccine is associated with decreasing rates of invasive pneumococcal disease in Canada and elsewhere
- 23-valent polysaccharide vaccine for high-risk adults, but poorly immunogenic in children (T cell-independent)
What is prevnar 13 (PCV13)
- a conjugate capsule vaccine from the 13 most prevalent serotypes of pneumococcus
What is a trend seen with the vaccines for Streptococcus pneumoniae?
- people are vaccinated for only the most prevalent serotypes
- as those strains are vaccinated against, others that were less common (and not present in the vaccine), are becoming more prevalent
Haemophilus influenzae type B
- “Hib”
- Gram negative, coccobacillus, produces a polysaccharide capsule
primarily causes meningitis in children under 5 - when it occurs, it tends to follow an upper respiratory infection, ear infection or sinusitis
Hib Vaccine Effectiveness
- Hib conjugate vaccine available as part of the routine childhood immunization schedules has reduced 99% of invasive Hib disease to low levels (<1 per 100,000)
- Before the 1990s, H. influenzae type b was the leading cause of bacterial meningitis
Listeria monocytogenes
- Gram-positive rod
- not your ‘typical’ meningitis pathogen
a food-borne pathogen - “listeriosis” can range from gastroenteritis –> bacteremia –> meningitis
- high rates of mortality in immunocompromised individuals including neonates and the fetus
- can grow at 4°C (a psychrotroph) – important for a food-borne pathogen (soft cheeses often implicated)
- Listeria causes <5% of meningitis cases
How does listeria escape your immune system?
- Escapes into cytoplasm (intracellular bacteria)
- There is a protein on its surface that polymerizes actin that drives the bacteria along (NOT FLAGELLA)
- Can push itself into an adjacent cell
- Listeria invades intestinal epithelial cells and replicates within the cytosol (actin-based motility and cell-to-cell spread)
Streptococcus agalactiae
- Group B Streptococcus” (GBS)
- Gram positive cocci, grows in chains
- produces a capsule
many women carry S. agalactiae in the urogenital tract as a commensal - GBS can be passed from the mother to infant during labour
- women are usually tested for GBS at ~36 weeks
- women who are positive may be treated with antibiotics during labour to prevent infection of the newborn
