Laboratory exams in the diagnosis of CNS infections - PowerPoint PPT Presentation

Laboratory exams in the diagnosis of CNS infections

Dr Paul Matthew Pasco

June 7, 2008

• CSF GS/CS
• CSF cytology
• (+) of bacterial antigens in CSF
• Neuroimaging
• Molecular techniques (PCR)

• 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%

SENS = 81%

SPEC = 34%

SENS = 85%

SPEC = 51%

• 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

PPV = 44%

NPV = 73%

PPV = 63%

NPV = 77%

• 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

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

• Clinical experience
• Local prevalence statistics
• Information from databases
• Original studies to assess diagnostic tests
• Studies devoted specifically to determining pre-test probabilities

• 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%

• Typical clinical picture:
• Drowsy, 50%
• Meningismus, 85%
• Seizure, 26%
• Focal neurological deficit, 18%
• Fever + headache + sensorial change, 85%

• Phadebact, with culture as gold standard:
• Sensitivity = 83%
• Specificity = 93%
• PPV = 83%
• NPV = 93%

*CSF culture as gold standard

• 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)

• 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%

• 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?

*Lab results should help us

cross a threshold;

*We may have to perform

several tests to cross a

threshold.

• 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?

• Solution: propose clinical decision rules which combine clinical and simple laboratory features

*BMS > 2 predicts bacterial meningitis with 100% sensitivity

• 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

• 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

• 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

• 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%

• 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

• 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

• 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

• 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.