25 Central nervous system infections Flashcards
CNS infection occurs usually via blood vessel (polio/ neisseria) or nerves (HSV/ VZV/ rabies) of CNS
What are innate barriers to CNS infection?
Blood-brain barrier - tightly joined endothelial cells with thick basement membrane, surrounded by glial processes
Blood- CSF barrier - endothelial cells with fenestrations, tightly joined to choroid plexus epithelial cells
How do infections traverse barriers of CNS?
Infecting cells that compromise the barrier, so they can cross
Passively transported in intracellular vacuoles
Passively transported across by infected white blood cells
What is clinical presentation of:
Meningitis - meninges/ membrane surrounds brain
Encephalitis - brain itself
Meningitis - fever, headache, neck stiffness, photophobia, nausea/ vomiting. Strictly speaking it is a pathological diagnosis, but we use other tests as surrogate markers.
Meningism - triad headache/ neck stiffness/ photophobia. May be due to infection. Can also be SAH/ migraine
Encephalitis - fever, confusion, seizure, focal neurological feature e.g weakness, visual disturbance, dysphasia. Usually viral cause
Meningoencephalitis - mixture of both, inflammation of meninges and adjoining brain parenchyma
Myelitis - inflammation spinal cord
Name some examples of viruses which cause encephalitis
Arbovirus - Yellow Fever West nile Tick borne encephalitis Japanese encephalitis Equine encephalitides St Louis encephalitis Zika
Enterovirus -
Coxsackievirus
Echovirus
Poliomyelitis
Myxovirus infections Measles - subacute scleorsing panencephalitis Mumps Rubella Influenza Hendra Nipah Rabies
Herpesvirus infections HSV VZV CMV HHV6
Polymoavirus
JC virus
There are many other causes of encephalitis, including bacteria, rickettsia, fungi, parasites (malaria) and AI
Travel history dictates further investigations e.g malaria
What is life cycle of polio?
Similar life cycle to mumps, haemophilus, pneumococci, meningococci
Infection by ingestion - taken up by GALT to local lymph nodes
Lymph nodes then spreads via blood to liver and throughout bloodstream, causing viraemia/ fever
Invades meninges after infecting vascular endothelial cells at blood-CSF barrier
Invades neurones by infecting vascular endothelial cells at blood-brain-barrier
How do HSV/ VSV and rabies spread to CNS?
HSV/ VZV in skin/ mucosal lesions travel up axons using normal retrograde transport mechanisms at rate 200mm/day to reach dorsal root ganglion (similar to tetanus toxin)
Rabies infects muscle fibes after bite, and binds to nicotinic acetylcholine receptors. Travels in retrograde fashion until reaches CNS glial cells and neurones
What are glial cells?
The glial cells surround neurons and provide support for and insulation between them. Glial cells are the most abundant cell types in the central nervous system.
CNS - astrocytes oligodendrocytes ependymal cells microglia
PNS -
Schwann cells
satellite cells
What is role of these glial cells in CNS?
astrocytes
oligodendrocytes
astrocytes - involved in physical structure of brain. Formation of synapses, formation of BBB
oligodendrocytes - involved in physical structure of brain. Support and insulate neurones - myelinating cells of CNS
What is role of these glial cells in CNS?
ependymal cells
microglia
ependymal cells - line ventricles of brain, and central canal of spinal cord. Assist production and monitoring of CSF
microglia - macrophage like cells remove microbes, cell debris
What is role of these glial cells in PNS?
Schwann cells
satellite cells
Schwann cells - myelin sheath
satellite cells - surround neurone cell bodies in ganglia. Provide structure and protection as cushions. Can express receptors to interact with neurotransmitters
What is definition of aseptic meningitis?
Meningitis but CSF is sterile on regular bacteriological culture/ molecural diagnostics
Means another cause e.g viruses, TB, leptospira, fungi, brain abscess, partially treated bacterial meningitis
In septic meningitis what changes would you expect in CSF?
Cell count
Protein
Glucose
Causes by bacteria, TB, leptospira, amoebae, fungi, brain abscess
Normal cell count <5
Normal protein 150-450
Cell count 200- 20 000 mostly neutrophils
Protein >1000
Glucose <4.5
In aseptic meningitis what changes would you expect in CSF?
Normal cell count <5
Normal protein 150-450
Cell count 100-1000 mostly lymphocytes
Protein 500-1000
Glucose normal
What are ways in which viruses can damage CNS?
Direct damage to neurones - polio/ rabies
Direct damage to oligodendrocytes - loss of myelin sheath JC virus
Perivascular infiltration with lymphocytes/ monocytes can cause damage
Oedema in “closed box” of skull, can rapidly be life threatening
Rabies can descend from CNS to salivary glands. It also affects limbic system, and changes behavior to make animal more aggressive and bite
Bacterial meningitis is more severe, but less common than viral meningitis.
What are common causes?
Neisseria meningitidis
Streptococcus pneumoniae
Haemophilus influenzae
E. Coli
Listeria
TB
Cryptococcus
Since Hib vaccine introduced, it has gone from most common, to third. After neisseria and strep
What is general treatment for bacterial meningitis?
Ceftriaxone 2g QDS
Cefotaxime 2g QDS
If suspect listeria (immunocompromised/pregnant/ age >60/ diabetes/ alcohol)
Add amoxicillin 2g 4hourly
Penicillin allergy -
Chloramphenicol 25mg/kg QDS
If suspect listeria (pregnant/ age >60)
Co-trimoxazole 20mg/kg QDS
If penicillin resistance expected (foreign travel) start -
vancomycin 20mg/kg BD
Rifampicin 600mg BD
dexamethasone 10mg QDS IV. Start initially. If strep pneumoniae, continue for 4 days. Otherwise can stop if other pathogen
TB - specific agents
Cryptococcus - amphotericin B + flucytosine
For these causes of bacteria meningitis, what treatment/ vaccine is available for prevention or following close-contact exposure?
Although 20% asymptomatic colonised with these bacteria anyway, risk of meningitis is 1000x higher after exposure compared to background population.
Neisseria meningitidis
Streptococcus pneumoniae
Haemophilus influenzae
Neisseria meningitidis - ciprofloxacin prophylaxis for close contacts, polysaccharide vaccine
Streptococcus pneumoniae - polyvalent (23 serotypes) polysaccharide vaccine. Treat any respiratory infections/ otitis media promptly
Haemophilus influenzae - polysaccharide vaccine against type B (Hib)
Occupational health organises it for staff - those at risk e.g intubation/ CPD
PHE organises prophylaxis for contacts
For these causes of bacteria meningitis, what treatment/ vaccine is available for prevention or following close-contact exposure?
E. Coli
Listeria
TB
Cryptococcus
E. Coli - no vaccine
Listeria - no vaccine
TB - BCG vaccine. Isoniazid prophylaxis for close contacts recommended in USA
Cryptococcus - no vaccine
Neisseria meningitidis is carried by approximately 20% of population asymptomatically. Attached by pili to epithelial cells of nasopharynx. Invasion of blood/ meningies poorly understood
What is mode of transmission?
Droplet spread - often facilitated by other respiratory infection, such as viral causes, which cause increased respiratory secretions.
Outbreaks seen in conditions of overcrowding such as prison, military barracks, university dormitories
Peaks occur early spring and late winter. Carrier rate may reach 60-80%
What are virulence factors for bacterial meningitis?
Capsule IgA protease Pili Endotoxin Outer membrane proteins
Neisseria meningitidis/ haemophilus have all of these
Strep pneumoniae just has capsule/ IgA protease
Which groups of people are at high risk of infection with neisseria meningitidis?
Outbreaks seen in conditions of overcrowding such as prison, military barracks, university dormitories
C5-C9 complement deficiencies
Children who have lost maternal antibodies, but not yet developed their own immune response
Which menigococcal serotypes predominate in resource-rich countries, and which pre-dominate in resource-poor countires?
resource-rich countries
B, W, Y, C in that order
resource-poor countries
A, W-135
What vaccines are available for meningococcal?
Important strains: A, B, C, Y, W-135
Polysaccharide A, C, Y, W quadrivalent vaccine
B vaccine
Quadrivalent vaccine introduced 1999 routine childhood immunisation, and recently for school-leavers. Men B vaccine introduced 2015 for infants
What vaccines are available against these causes of meningitis?
Haemophilus influenzae
Streotococcus pneumoniae
Group B Strep
E. Coli
Haemophilus influenzae - B is most important type. Polysaccharide Hib for <1 year olds
Streotococcus pneumoniae - many strains. Polysaccharide pneumovax works against 23 different types
Group B Strep - Ia, Ib, II, III - many types. Vaccine in development
E. Coli - KI type causes meningitis. No vaccine
What are different clinical features/ groups seen in these causes of bacterial meningitis?
Neisseria meningitidis
Haemophilus influenzae
Streptococcus pneumoniae
Neisseria meningitidis - children/ adolescents. Skin rash. Acute onset <24 hours
Haemophilus influenzae - children <5. Onset 1-2 days
Streptococcus pneumoniae - children <2 and elderly. Onset follows pneumonia/ sepsis
Approximate mortality rates for these diseases, and sequelae (deafness, seizures, mental retardation)
Neisseria meningitidis
Haemophilus influenzae
Streptococcus pneumoniae
Neisseria meningitidis - 10% mortality, sequelae <1%
Haemophilus influenzae - 5% mortality, sequelae 10%
Streptococcus pneumoniae - 25% mortality, sequelae 20%
What are symptoms of neisseria menigitis?
Sore throat Headache Drowsiness Fever Neck stiffness Photophobia Rash - petechiae
Septicaemia causes DIC, endotoxaemia, shock and renal failure.
In severe cases, bleeding into brain/ adrenal glands can cause addisonian crisis termed Waterhouse-Friedrichsen syndrome
What are investigations for meningitis?
Bloods - CRP/ WCC/ coag/ platelets
CT/ MRI
LP
Serology not helpful as disease too acute for antibody response to occur
Haemophilus influenzae has six types (a-f), what is unique about type b which causes meningitis?
Why are children most at risk?
Capsulated type b can occasionally invade blood/ meninges
Uncapsulated other strains are common, and present in throat of most healthy people
Maternal antibodies protect infant until 4 months of age, but this weakens, and there is a window of susceptibility before child produces own antibodies.
What are risk factors for strep pneumoniae?
<2 years old Elderly Sickle cell Splenectomy patients Head trauma
Immunity is type specific, and there are over 85 capsular types of strep pneumoniae
Vaccine recommenced in childhood, and those high risk - sickle cell, splenectomy, HIV, immunodeficiency.
Which groups are at risk of listeria meningitis?
Why is treatment different for listeria than empirical treatment?
Children
Elderly
Immunocompromised
Use ceftriaxone and amoxicillin because listeria is less susceptible to penicillin, so combination therapy better
Why are neonates at increased risk of meningitis?
Higher risk if premature/ LBW
Immature innate and adaptive immune systems
Difficult diagnosis - may only have lethargy, poor feeding
Often leads to permanent neurological sequelae such as cerebral palsy, cranial nerve palsy, epilepsy, mental retardation, hydrocephalus
What is empirical treatment for neonatal meningitis?
Benzylpenicillin and gentamicin
Antibiotics given in pregnancy to eliminate carriage, but does not guarantee this
How does TB meningitis present?
25% have no history of previous TB
50% of cases present with acute miliary TB
Insidious onset over weeks
If high TB prevalence - presents in children aged 0-4
If low TB prevalence - presents in adults
How does pulmonary TB lead to TB meningitis?
Primary lesion in lung
Bacilli move to lymph nodes
Lymphatics drain into lymphatic duct/ SVC
Moves in bloodstream to CNS causing tubercles
Tubercle ruptures into subarachnoid space
Bacilli spread in CSF
What are fungal causes of meningitis?
Cryptococcus neoformans - immunocompromised
Coccidioides immitis
How does fungal meningitis present?
Slow, over days or weeks
How to diagnose cryptococcal infection
Treatment cryptococcal infection?
Cryptococcal antigen in blood/ CSF
India ink stain CSF
Amphotericin B + flucytosine
Which geographical areas at risk of coccidioides immitis meningitis?
CNS infection occurs <1% of those infected
What is treatment for coccidioides immitis?
North/ South america
Rarely visible in CSF, cultures positive <50% cases
Detect antibodies in serum
Amphotericin B or fluconazole
What are causes of protozoal meningitis?
Amobes:
- Naegleria fowleri
- Acanthomoeba
- Balamuthia madrillaris
Can infect healthy individuals
- plasmodium
- toxoplasmosis
Where does naegleria fowleri live?
How does it reach CNS?
Fresh warm water - lakes, swimming pools
Feeds on bacteria
North/ South America, Asia
Via olfactory tract and cribiform plate. Rapid onset
What is treatment for amoebic meningoencephalitis?
Amphotericin B, with miconazole and rifampicin.
Miltefosine addition has shown some benefit
Mortality approximately 95%
Diagnosis of amoebic meningoencephalitis?
CSF microscopy
Brain biopsy
PCR/ serology in specialist centres
Viral meningitis is more common than bacterial, and often has milder disease.
Which viruses are responsible?
Up to 85% of cases no causative agent is identified
Enetroviruses - echoviruses, coxsackie A/B, poliviru
HSV
VSV
CMV
Paramyxovirus - mumps, nipah (pig farms Malaysia)
Rabies
Flavivirus - JE, WNV
HIV
Influenza H5N1 has been shown to cause encephalitis
