Title: Laboratory exams in the diagnosis of CNS infections
1Laboratory exams in the diagnosis of CNS
infections
- Dr Paul Matthew Pasco
- June 7, 2008
2Lab exams for bacterial meningitis
- CSF GS/CS
- CSF cytology
- () of bacterial antigens in CSF
- Neuroimaging
- Molecular techniques (PCR)
3CSF 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
4CSF cytology GS (Reyes 1986)
5CSF cytology GS (Reyes 1986)
SENS 81
SPEC 34
SENS 85
SPEC 51
6How 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
7CSF cytology GS (Reyes 1986)
PPV 44
NPV 73
PPV 63
NPV 77
8Likelihood 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
9Likelihood 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
-
-
10A likelihood ratio nomogram
11How do we estimate our patients 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
12Etiology 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
13Local experience in bacterial meningitis
(Handumon 2000)
- Typical clinical picture
- Drowsy, 50
- Meningismus, 85
- Seizure, 26
- Focal neurological deficit, 18
- Fever headache sensorial change, 85
14Bacterial antigens in CSF (Garcia 1988)
- Phadebact, with culture as gold standard
- Sensitivity 83
- Specificity 93
- PPV 83
- NPV 93
15Bacterial antigens in CSF (Coovadia 1985)
CSF culture as gold standard
16Other 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)
17Neuroimaging
- 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
18Other tests
- GS/CS from throat and petechiae (esp. for
meningococcal disease) and blood - Serum CRP (Sutinen 1998) elevated CRP (gt10
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?
19How 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.
20Viral 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
22Clinical decision rules to distinguish between
bacterial and viral meningitis (Dubos 2006)
23Decision rule by Nigrovic (2002)
BMS gt 2 predicts bacterial meningitis with 100
sensitivity
24Lab 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
25CSF 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
26ELISA 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
27The Polymerase Chain Reaction (PCR) Technique
28PCR 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
29CT 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
30Clinical decision rules in TBM
- Kumar (1994) 110 Indian children with TBM and
94 with non-TBM predictive of TBM - Symptoms gt 6 days
- Optic atrophy
- Focal neurological deficit
- Abnormal movements
- Neutrophils lt 50 of CSF WBC count
- Thwaites (2002) 143 Vietnamese adults with TBM
108 with non-TBM predictive of TBM - Age gt 36
- Blood WBC lt 15,000
- Symptoms gt 6 days
- CSF WBC lt 750
- CSF neutrophils lt 90
- Pasco (200?) 300 Filipino adults with TBM
- focal deficit
- () PTB on CXR
- CSF WBC gt 50, lymphocytes predominant
- CSF lt 50 serum RBS
- Increased CSF protein
31Cryptococcal meningitis
- India Ink Sabourauds culture
- CALAS titers
- Lokin (2000) 8 cases of cryptococcal
meningitis 8 () by India Ink and mucicarmine
after 24h, still () by mucicarmine
32Summary
- 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 clinicians skills
and perceptions - They should only be applied after a complete
validation process.