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CNS infections

  • Meningitis – infection of the meninges
    • Encephalitis – infection of the brain parenchyma
    • Myelitis – infection of the spinal cord tissue
  • Routes of invasion
    • Blood borne – most common
      • A pathogen gets into the blood
    • Peripheral nerves – less common 􏰀 Common route for viruses
    • Local invasion – rare
      • Infected ears or sinuses
    • Local injury or congenital defect – rare
      • Eg: congenital deformity of the cribriform plate

Viral meningitis

  • Common
  • Types
    • Enteroviruses (echo, Coxsackie A and B, polio)
      • Common viruses which may uncommonly cause meningitis
    • Paramyxovirus (mumps)
      • Meningitis is a fairly common complication of mumps
    • Herpes simplex virus (HSV)
      • Genital infection with HSV2 may cause meningitis
    • HIV (retrovirus)
      • Meningitis may occur early after infection
    • Other
      • Varicella-zoster, adenoviruses, arboviruses
  • Milder disease than bacterial meningitis
  • Symptoms:
    • Headache
    • Fever
    • Photophobia
    • Neck stiffness (less common than bacterial meningitis)
  • HOWEVER: Differentiation between bacterial and viral cannot be made on presentation, thus empirical antibiotic therapy should always be given - or else they'll die.
    • Meningitis should be treated as bacterial until proved otherwise (e.g. by PCR etc - below; once proved otherwise you can withdraw treatment)
  • Diagnosis
    • Virus isolation from CSF (<50% cases)
    • PCR
  • After diagnosis
    • Antibiotic therapy is withdrawn
    • Symptomatic treatment
      • Viral meningitis usually follows a benign course with a complete recovery



Fungal meningitis

  • Not very common, usually opportunistic
  • Types
    • Coccoides immitis
      • Follows a lung infection
      • Common in SW USA, Mexico and S America
    • Cryptococcus neoformans and Cryptococcus gattii (slower onset, days-weeks)
      • Opportunistic – targets patients with AIDS, lymphoma, immunosuppressed
      • Invade from a primary infection, eg: lungs
  • Diagnosis
    • India ink stain
    • Fluorescent antibody stain
      • India ink and fluorescent antibody stain look for capsules
    • Antigen detection – sera is added to CSF to see if there is an antigen reaction
  • Capsules
    • Protect the organisms from phagocytosis in the blood stream
  • Cryptococcal meningitis (neoformans and gattii)
    • Treatment
      • Amphotericin B IV + Flucytosine IV (or oral)
      • Maintenance therapy: Fluconazole for at least 10 weeks after a clear screen
  • HIV patients can have recurrent cryptococcal meningitis, thus constant low dose

Bacterial meningitis

  • Life threatening and requires urgent specific treatment
  • Less common but more severe than viral
  • Types
    • Neisseria meningitidis (Meningococcus) (40%)
      • Gram –ve diplococcus
      • Particularly affects children and adolescents – have no antibodies and no maternal protection
        • Carried in the nasopharynx in 20% of people
    • May not cause disease here, but can if spreads to the blood
    • Streptococcus pneumoniae (Pneumococcus) (15%)
      • Gram +ve cocci
      • Particularly affects infants and elderly (weak immune systems)
        • Carried in the throat of many healthy people
    • Haemophilus influenzae type B (30%)
      • Gram –ve rods
      • Particularly affects non-vaccinated children <5
      • decrease in cases due to vaccination
      • Infection is caused by capsulated strains
        • Unencapsulated strains are common in the throat
      • Mass vaccination began in 1993, had a massive effect in reducing the number of infections
    • Other
      • Listeria monocytogenes – gram +ve coccal bacillus (short rod) (5%)
        • Particularly affects immuno-compromised adults (neoplasms, diabetes, immune supp.)
      • Mycobacterium tuberculosis (other: 10%)
        • Meningitis following a lung infection
        • Particularly affects immuno-compromised and children in high incidence areas

*Very important pathogenic mechanism for these bacteria is the capsule - protects them from phagocytosis etc

Neonatal meningitis

  • Bacterial causes:
    • Eschericia coli (fecal flora)
    • Group B streptococci (Strptococcus agalactiae)
    • Listeria monocytogenes
    • Source - genital tract of the mother (from the birth canal or through colonisation of the amniotic fluid)
    • Difficult to diagnose
    • Symptoms are non-specific, not typical of meningitis
      • Eg: trouble breathing, fever, unsettled, not eating
    • Often leads to permanent neurological consequences
    • Fatal in 35% (first few days, 60% mortality, next few weeks, 20%)
    • Presdisposing factors
      • Immature immune system
      • Preterm delivery
      • Premature rupture of membranes (invasion of amniotic fluid)
      • Prolonged labour (invasion of amniotic fluid)
      • Heavily colonised mother (group B strep)
  • At 35-57 weeks, there is screening for GBS
    • If found, prophylactic antibiotics given (mother may get it later than this, however)

Clinical diagnosis

  • Bacterial meningitis signs and symptoms:
    • Fever (>90%)
    • Headache (80-90%)
    • Stiff neck (>80%) – can’t bend head forward
    • Brudzinski’s sign (50%)
      • If the head is flexed onto the chest, the lower limbs are drawn up
    • Kernig’s sign (50%)
      • Hip flexion to 90 degrees, attempt to straighten leg results in pain and hamstring spasm
    • Myalgia (muscle pains) (30-60%)
    • Nausea, vomiting (>80%)
    • Altered sensorium(>80%)

Meningococcal meningitis (due to Neisseria meningitidis)

  • Acute onset
  • Neurological signs in 6-24 hours
  • May be preceded by URTI
  • Important sign: haemorrhagic rash that does not blanch when a glass is pressed into the skin
    • Known as the petechial rash
  • Caused by the multiplication of organisms in the blood stream o Commonly affects children and adolescents
  • Transmitted by respiratory droplets
  • Fulminating (sudden, severe onset) meningococcal infection
    • 35% of cases
      • septicaemia is overwhelming
    • no time for signs of meningitis to show
    • symptoms:
      • high fever
      • shock
      • extensive purpura
      • often associated with disseminated intravascular coagulation (DIC)
    • organism releasing cytokine to stimulate immune response, we get lots of coagulation resulting in a loss of coagulative factors in blood. Then you get haemorrhaging in the suprarenal glands, known as:
      • Waterhouse Friedrichsen syndrome – haemorrhaging into the suprarenal glands
        • sepsis, organ failure and death



Pneumoncoccal meningitis

  • Acute onset with patient comatose in a few hours (no rash)
  • Occurs in all ages, but especially elderly and children
    • May follow pneumonia septicaemia, otitis media or head injuries

Haemophilus influenzae type B

  • Onset is less acute (1-2 days) (no rash)
  • Especially suspect in children <5 (unvaccinated) and the elderly

Management

  • Before hospital
    • If fulminating meningococcal (meningococcaemia) is suspected clinically (rash + fever)
      • IV or IM Benzyl penicillin
        • Or Ceftriaxon IV (a III cephalosporin) if penicillin allergy
      • Can be fatal quickly
  • Immediate and early hospital
    • If no penicillin treatment, CT scan + specimen collection
      • Cerebrospinal fluid, blood, throat swab
    • If no antibiotic treatment and these tests can’t be done in 20 minutes, need to give dexamethasone and empirical broad spectrum antibiotics
      • Dexamethasone – reduces inflammation in the brain and thus reduces consequences and improves outcomes
        • Early treatment is important starting before or with the first antibiotic dose
        • Improves outcomes in adults with acute bacterial meningitis
  • Empirical therapy
    • If CSF Gram stain, Ag testing or PCR don’t give results use:
      • IV Cefotaxime/Ceftriaxone (Cephalosporins III) - can cross the BBB
      • IV Benzyl penicillin (covers Listeria monocytogenes)
      • IV Ampicillin/Amoxycillin (modified penicillins, covering Listeria)
    • If Gram +ve diplococcis are seen, need to use vancomycin
      • Especially if streptococcus pneumonia – which is becoming resistance to penicillin

Identification of causative organisms

  • Gram stains of CSF
    • Often difficult to interpret due to amount of inflammatory cells
    • Can enable immediate diagnosis
  • Latex agglutination (if antibiotics already given)
    • Rapid antigen detection in CSF
    • H. influenzae (sens >80%, spec >95%)
    • S. Pneumoniae (sens 50-70%, spec >95%)
    • N. meningitidis (sens >80%, spec >95%)
  • PCR
  • CSF compositions
    • Fungal/viral meningitis
      • Leukocytes increased (100-500ul)
      • Protein increased (50-100mg/dl)
      • Appearance may be slightly opalescent else clear
    • Bacterial meningitis
      • Leukocytes increased (>1000ul)
      • Neutrophils increased (>50%)
      • Glucose decreased (<30mg/dl) – because bacteria uses it up
      • Protein increased (>100mg/dl)
      • Appearance is turbid
      • RBC level not significantly raised



Culture of causative agents

  • Used for isolation and identification
    • Neisseria meningitidis
      • CBA, gram –ve diplococci with polysaccharide capsule
      • Usually inside PMN
      • Oxidase positive
    • Haemophilus influenzae type B
      • CBA, gram –ve rods with polysaccharide capsule
      • Requires X and V factors for growth (NAD and Haem)
    • Streptococcus pneumoniae
      • Gram +ve cocci that occur in pairs
        • Alpha haemolytic
        • Sensitive to optochin
      • Encapsulated (more than 85 capsular types)
  • Can get disease more than once, immunity to only one capsular type
  • Pneumococcal meningitis is often preceded by URTI (80%), ear infection or LRTI
  • Sensitivity testing - necessary for directed therapy
    • Conducted in parallel with culture

Time

  • Gram stain, Agglutination detection, PCR – 2-6 hours
  • Isolation and identification – 6-48 hours
  • Sensitivity testing – 48-72 hours

Directed treatment

  • Haemophilus influenzae meningitis
    • Cephalosporin III: Cefotaxime or Ceftriaxone IV
      • If susceptible: Benzyl penicillin or Amoxy/ampicillin IV
    • If penicillin or cephalosporin hypersensitivity (allergy) use Chloramphenicol or Ciprofloxacin
    • Prophylaxis for those in close contact: Rifampicin or Ceftriaxone
  • Pneumococcal meningitis
    • Resistance to penicillin is increasing thus use Vancomycin IV and Cephalosporin III (cefotaxime or ceftriaxone)
    • If susceptible to penicillin (minimal inhibitory concentration < 0.125mg/L) use Benzyl penicillin
  • Meningococal meningitis
    • Benzylpenicillin IV
      • If penicillin or cephalosporin hypersensitivity (allergy) use Ciprofloxacin
    • Prophylaxis for contacts
      • Ceftriaxone IM or Ciprofloxacin or Rifampicin
  • Listeria monocytogenes
    • Benzyl penicillin or ampi/amoxicillin IV
      • Addition of Trimethoprim and sulfamethoxazole IV may be helpful
    • Penicillin allergy, just use trimethoprim and sulfamethoxazole
  • Neonatal meningitis (with unknown organism)
    • Provisional therapy using Cefotaxime or ceftriaxone and penicillin or ampicillin (to cover Listeria)

Mortality and sequelae

  • Untreated has 100% mortality
  • Treated:
    • S. pneumoniae – 20-30% mortality, 15-20% sequelae
    • N. meningitidis – 7-10% mortality, <1% sequelae
    • H. influenzae – 5% mortality, 9% sequelae
  • Sequelae
    • S. pneumoniae – severe neurological deficit
    • N. meningitidis – hearing loss
    • H. influenzae – hearing loss, delayed language development, mental retardation, seizures