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Laboratory exams in the diagnosis of CNS infections. Dr Paul Matthew Pasco June 7, 2008. Lab exams for bacterial meningitis. CSF GS/CS CSF cytology (+) of bacterial antigens in CSF Neuroimaging Molecular techniques (PCR). CSF culture & sensitivity. Gonzaga (1967): (+) in 57/85 patients

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lab exams for bacterial meningitis
Lab exams for bacterial meningitis
  • CSF GS/CS
  • CSF cytology
  • (+) of bacterial antigens in CSF
  • Neuroimaging
  • Molecular techniques (PCR)
csf culture sensitivity
CSF culture & sensitivity
  • Gonzaga (1967): (+) in 57/85 patients
    • Pneumococcus in 26%; G(-) bacilli in 33%
  • Punsalan (1988) = (+) in 9/12
  • Handumon (2000) = (+) in 11/50 adults
  • Reyes (1979): 82 children
    • Most common: G(-) bacilli in 53.7%
    • Others: S. pneumoniae, N. meningitidis
  • Kho (1992): 50 culture-proven cases; G(+) in 62% (S. pneumoniae), G(-) in 38%
csf cytology gs reyes 19865
CSF cytology & GS (Reyes 1986)

SENS = 81%

SPEC = 34%

SENS = 85%

SPEC = 51%

how do we use sensitivity specificity
How do we use sensitivity & specificity?
  • SnNout = for a test with high sensitivity, a negative result rules out the diagnosis
  • SpPin = for a test with high specificity, a positive result rules in the diagnosis
  • A perfect test is both a SpPin & SnNout
  • A useless test: SENS + SPEC – 100 = 0
csf cytology gs reyes 19867
CSF cytology & GS (Reyes 1986)

PPV = 44%

NPV = 73%

PPV = 63%

NPV = 77%

likelihood ratios
Likelihood ratios
  • LR(+) = probability of (+) test for a person with the disease

probability of (+) test for a person

without the disease

  • LR(-) = probability of (-) test for a person

with the disease

probability of (-) test for a person

without the disease

likelihood ratios9
Likelihood ratios

Not very good!

  • For cytology:
    • LR(+) = 22/27 = 1.23

27/41

    • LR(-) = 5/27 = 0.54

14/41

  • For gram stain:
    • LR(+) = 23/27 = 1.77

13/27

    • LR(-) = 4/27 = 0.29

14/27

how do we estimate our patient s pre test probability of having the disease
How do we estimate our patient’s pre-test probability of having the disease?
  • Clinical experience
  • Local prevalence statistics
  • Information from databases
  • Original studies to assess diagnostic tests
  • Studies devoted specifically to determining pre-test probabilities
etiology of cns infections in 7 hospitals punsalan 1999 892 cases
Etiology of CNS infections in 7 hospitals (Punsalan 1999) (892 cases)
  • Bacterial meningitis – 29.9%
  • TB meningitis – 28.9%
  • Meningitis unspecified – 12.2%
  • Viral meningitis – 10.5%
  • Brain abscess – 8.1%
  • Cryptococcal meningitis – 2.0%
  • Tuberculoma – 1.6%
  • Others – 3.3%
local experience in bacterial meningitis handumon 2000
Local experience in bacterial meningitis (Handumon 2000)
  • Typical clinical picture:
    • Drowsy, 50%
    • Meningismus, 85%
    • Seizure, 26%
    • Focal neurological deficit, 18%
    • Fever + headache + sensorial change, 85%
bacterial antigens in csf garcia 1988
Bacterial antigens in CSF (Garcia 1988)
  • Phadebact, with culture as gold standard:
    • Sensitivity = 83%
    • Specificity = 93%
    • PPV = 83%
    • NPV = 93%
bacterial antigens in csf coovadia 1985
Bacterial antigens in CSF (Coovadia 1985)

*CSF culture as gold standard

other tests on csf
Other tests on CSF
  • CSF CRP: sensitivity of 61%, specificity of 100%, PPV of 100%, NPV of 80% (Changco 1987)
  • CSF leukocyte esterase: sensitivity of 100%, specificity of 93%; CSF nitrite: specificity and NPV of 85%(Tan 1997)
  • CSF pH: decreased in 10/11 cases of purulent meningitis (Espiritu 1986)
neuroimaging
Neuroimaging
  • CT scan of head:
    • Not routinely done
    • Only to rule out other causes of CNS infection
  • Cranial ultrasound (Lee 2001): 95 culture-proven cases
    • Wide and highly echogenic sulci = 87%
    • Convexity leptomeningeal thickening = 86%
    • Hydrocephalus = 62%
    • Extra-axial fluid collection = 8-48%
other tests
Other tests
  • GS/CS from throat and petechiae (esp. for meningococcal disease) and blood
  • Serum CRP (Sutinen 1998): elevated CRP (>10 mg/ml) has 100% sensitivity in 19 cases of bacterial meningitis (but may be low in early stages of infection)
  • Molecular techniques – not available locally
    • PCR for N. meningitidis & S. pneumoniae
    • Quantitative PCR to determine bacterial load?
how should lab results help us in management of cns infections
How should lab results help us in management of CNS infections?

*Lab results should help us

cross a threshold;

*We may have to perform

several tests to cross a

threshold.

viral encephalitis
Viral encephalitis
  • Standard cell culture
  • Brain biopsy
  • Serologic diagnosis: detect a 3-fold or more increase in specific antibody production
  • CSF ELISA & PCR – how to determine sensitivity and specificity?
slide21
Problem: no single lab test or clinical feature can distinguish between different types of CNS infections
  • Solution: propose clinical decision rules which combine clinical and simple laboratory features
decision rule by nigrovic 2002
Decision rule by Nigrovic (2002)

*BMS > 2 predicts bacterial meningitis with 100% sensitivity

lab exams for tuberculous meningitis
Lab exams for tuberculous meningitis
  • CSF AFB smear and TB culture
  • CSF qualitative & quantitative exams
  • ELISA – to detect IgG antibodies to mycobacterial antigens in CSF
  • PCR – to detect mycobacterial DNA elements
  • Neuroimaging
csf tb culture
CSF TB culture
  • Montoya (1991) – (+) in 4/17 clinically presumptive cases of TBM
  • Pasco (2007) – (+) in 3/63 probable TBM
  • De Guzman (2005) – MGIT mycobacterial culture system: using a surrogate gold standard, 75% sensitive and 31% specific
elisa for tb meningitis
ELISA for TB meningitis
  • Montoya (1991) – 30 kDa native antigen: (+) in 3 of 4 definite TBM, (-) in all normal & non-TBM cases
  • Valenzuela (2000) – 38 kDa antigen: (+) in 1 of 1 definite TBM; specificity of 72%
  • Montoya (2000) – antigen A60: 3 definite cases; 100% sensitive and 94% specific
pcr for tb meningitis
PCR for TB Meningitis
  • Montoya (1997) – (+) in 7/8 culture-proven TB Meningitis; no data in non-TBM
  • Pasco (2007) – 63 probable TBM: 3/63 (+) by smear or culture, 14/63 (+) by PCR; 2/3 definite TBM also (+) by PCR
  • Udarbe-Agustin (2004) – 3/6 definite TBM (+) by PCR
  • Montoya (2001) – 9 definite TBM: 1 (+) by Amplicor, 2 (+) by nested PCR
  • Meta-analysis by Pai (2003) – sensitivity is 56%, specificity is 98%
ct scan in tb meningitis
CT scan in TB Meningitis
  • Malazo (1995) – 30 children with TBM: 28 had hydrocephalus, 14 had basal exudates, 2 were normal
  • Kumar (1996) – compared CT scans of 94 children with TBM and 52 with pyogenic meningitis: basal meningeal enhancement, tuberculoma, or both, were 89% sensitive and 100% specific for TBM
clinical decision rules in tbm
Clinical decision rules in TBM
  • Kumar (1994) – 110 Indian children with TBM and 94 with non-TBM; predictive of TBM:
    • Symptoms > 6 days
    • Optic atrophy
    • Focal neurological deficit
    • Abnormal movements
    • Neutrophils < 50% of CSF WBC count
  • Thwaites (2002) – 143 Vietnamese adults with TBM & 108 with non-TBM; predictive of TBM:
    • Age > 36
    • Blood WBC < 15,000
    • Symptoms > 6 days
    • CSF WBC < 750
    • CSF neutrophils < 90%
  • Pasco (200?) – 300+ Filipino adults with TBM
    • focal deficit
    • (+) PTB on CXR
    • CSF WBC > 50, lymphocytes predominant
    • CSF < 50% serum RBS
    • Increased CSF protein
cryptococcal meningitis
Cryptococcal meningitis
  • India Ink & Sabouraud’s culture
  • CALAS titers
  • Lokin (2000) – 8 cases of cryptococcal meningitis: 8 (+) by India Ink and mucicarmine; after 24h, still (+) by mucicarmine
summary
Summary
  • Lab results should help us move across a testing or treatment threshold
  • Use clinical decision rules that combine clinical and laboratory exam results
    • These should not replace the clinician’s skills and perceptions;
    • They should only be applied after a complete validation process.