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Laboratory exams in the diagnosis of CNS infections

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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Laboratory exams in the diagnosis of CNS infections

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  1. Laboratory exams in the diagnosis of CNS infections Dr Paul Matthew Pasco June 7, 2008

  2. Lab exams for bacterial meningitis • CSF GS/CS • CSF cytology • (+) of bacterial antigens in CSF • Neuroimaging • Molecular techniques (PCR)

  3. 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%

  4. CSF cytology & GS (Reyes 1986)

  5. CSF cytology & GS (Reyes 1986) SENS = 81% SPEC = 34% SENS = 85% SPEC = 51%

  6. 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

  7. CSF cytology & GS (Reyes 1986) PPV = 44% NPV = 73% PPV = 63% NPV = 77%

  8. 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

  9. 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

  10. A likelihood ratio nomogram

  11. 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

  12. 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%

  13. 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%

  14. Bacterial antigens in CSF (Garcia 1988) • Phadebact, with culture as gold standard: • Sensitivity = 83% • Specificity = 93% • PPV = 83% • NPV = 93%

  15. Bacterial antigens in CSF (Coovadia 1985) *CSF culture as gold standard

  16. 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)

  17. 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%

  18. 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?

  19. 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.

  20. 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?

  21. 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

  22. Clinical decision rules to distinguish between bacterial and viral meningitis (Dubos 2006)

  23. Decision rule by Nigrovic (2002) *BMS > 2 predicts bacterial meningitis with 100% sensitivity

  24. 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

  25. 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

  26. 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

  27. The Polymerase Chain Reaction (PCR) Technique

  28. 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%

  29. 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

  30. 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

  31. 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

  32. 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.

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