Laboratory exams in the diagnosis of CNS infections

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Laboratory exams in the diagnosis of CNS
infections

• Dr Paul Matthew Pasco
• June 7, 2008

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Lab exams for bacterial meningitis

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

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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

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CSF cytology GS (Reyes 1986)
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CSF cytology GS (Reyes 1986)
SENS 81
SPEC 34
SENS 85
SPEC 51
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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

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CSF cytology GS (Reyes 1986)
PPV 44
NPV 73
PPV 63
NPV 77
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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

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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

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A likelihood ratio nomogram
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How 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

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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

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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

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Bacterial antigens in CSF (Garcia 1988)

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

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

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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

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Other 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?

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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.
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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?

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• 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

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Clinical decision rules to distinguish between
bacterial and viral meningitis (Dubos 2006)
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Decision rule by Nigrovic (2002)
BMS gt 2 predicts bacterial meningitis with 100
sensitivity
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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

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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

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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

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The Polymerase Chain Reaction (PCR) Technique
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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

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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

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Clinical 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

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Cryptococcal 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

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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 clinicians skills
  and perceptions
• They should only be applied after a complete
  validation process.