What if the cerebrospinal fluid (CSF) Cartridge-Based Nucleic Acid Amplification Test (CBNAAT) is negative?

Management of Negative CSF CBNAAT in Suspected Tuberculous Meningitis

A negative cerebrospinal fluid (CSF) CBNAAT (Cartridge-Based Nucleic Acid Amplification Test) does not rule out tuberculous meningitis (TBM), and empirical anti-tuberculosis therapy should be continued if clinical suspicion remains high.

Understanding CSF CBNAAT Limitations

• CBNAAT (GeneXpert) has a sensitivity of only 62% for detecting TB in cerebrospinal fluid, meaning false-negative results occur in approximately 38% of cases 1
• The specificity of NAAT is high at 98% for cerebrospinal fluid, indicating that positive results are reliable, but negative results cannot exclude TBM 1
• TBM is a paucibacillary disease, which often evades definitive diagnosis through molecular testing 2

Diagnostic Approach After Negative CBNAAT

• Continue diagnostic workup with additional CSF studies:

  • Repeat lumbar puncture and CSF examination after 24-48 hours to increase diagnostic yield 1, 3
  • Submit larger volumes of CSF for mycobacterial culture to improve detection rates 3
  • Consider additional testing such as CSF adenosine deaminase (ADA) levels and TB-specific antibody testing 4

• Look for TB elsewhere in the body:

  • Attempt diagnostic sampling from extra-neural sites of disease (lung, gastric fluid, lymph nodes, liver, bone marrow) 3
  • Chest imaging to identify miliary or pulmonary TB patterns that support the diagnosis 5

Treatment Recommendations

• Do not discontinue anti-tuberculosis therapy based solely on a negative CBNAAT result if clinical suspicion for TBM remains high 5, 3
• Continue empirical treatment with standard four-drug regimen (isoniazid, rifampicin, pyrazinamide, ethambutol) for suspected TBM 3
• Treatment delay is strongly associated with mortality in TBM, making early empirical therapy crucial 3, 2
• Consider adjunctive corticosteroids (dexamethasone or prednisolone) for all patients with suspected TBM to reduce mortality 3

Clinical Decision Points

• Maintain high suspicion for TBM if:
  • CSF shows lymphocytic predominance, elevated protein, and low glucose ratio (<50%) despite negative CBNAAT 3, 4
  • Patient has risk factors for TB (origin from endemic area, immunocompromised status) 5
  • Neuroimaging shows characteristic findings (basal meningeal enhancement, tuberculomas, hydrocephalus) 2
  • Patient has an atypical CSF profile (such as neutrophilic predominance) but clinical picture is consistent with TBM 6

Monitoring and Follow-up

• Monitor clinical response to empirical therapy:
  • Improvement in symptoms and neurological status supports the diagnosis 4
  • Lack of improvement may indicate drug resistance or alternative diagnosis 2
• Consider drug susceptibility testing if available from any positive culture 2
• Minimum treatment duration of 9-12 months is recommended for TBM 3, 2

Common Pitfalls to Avoid

• Waiting for microbiological confirmation before starting treatment can lead to poor outcomes 5, 3
• Stopping treatment prematurely based on a single negative CBNAAT result 5
• Failing to consider drug-resistant TB in patients not responding to first-line therapy 2
• Not recognizing atypical CSF profiles that can occur in up to 32.4% of TBM cases 6