Motivation: As one of my attendings put it after morning rounds filled with arcane diagnoses, "By the time you end up at MGH, you the definition of atypical." One of the atypical diagnoses we often consider is central nervous system tuberculosis - entering into the differential for both persistent meningitis and brain masses. Every time you mention CNS TB, some smirk while others edge towards a face mask. I am torn between the two largely because I do not know what the typical presentation is or even how to diagnose it prior to a culture that takes weeks to mature. So, how do you diagnose CNS TB?
As way of background, central nervous system tuberculosis is thought to occur from hematogenous spread of TB from a primary pulmonary focus. There is TB deposition and formation of subpial and subependymal foci - called Rich foci. If these foci rupture, TB meningitis results. Otherwise, growth of these foci results in tuberculomas.
Paper: Systematic review of diagnoses of CNS TB by British Infectious Society. "British Infectious Society guidelines for the diagnosis and treatement of tuberculosis of the central nervous system in adults and children" Journal of Infection (2009); 59: 167-187.
Methods: Systematic clinical evidence review of papers published in Medline and Pubmed between 1966 and 2008 dealing with CNS TB. The working group consisted of an interdisciplinary group of specialists.
Results:
Basic Clinical and Laboratory Features of CNS TB:
TB Meningitis: The top three clinical features were fever (60-95%), headache (50-80%), and anorexia/weight loss (60-80%). Top three clinical signs were neck stiffness (40-80%), focal cranial nerve palsy (30-50%), and coma (30-60%). On CSF examination, majority have clear appearance (80-90%) with 50% having opening pressure > 25 cm H2O. CSF glucose:blood glucose ratio was < 0.5 in 95% of patients with TB meningitis. The leucocyte count varies between 5-1000 cells with variable neutrophilic and lymphocytic predominance. Protein was also variable ranging from 45 to 300 mg/dL.
CNS Tuberculoma: Few large case series but most common presenting feature is seizure with complaints of headache, fever, and weight loss. CSF pleocytosis of 10-100 cells is present in only 50%.
Microbiology:
TB Meningitis: Sensitivity of AFB smear up to 80% provided that multiple large volume (>6 mL) taps are submitted for analysis. Culture media usually takes > 2 weeks to be positive and not helpful with decision making.
Tuberculoma: CSF AFB smear usually not positive and require stereotactic biopsy, which is diagnostic in about 94% of patients.
Nucleic Acid Amplification:
TB Meningitis: Currently available nuceic acid amplification tests about 56% sensitive (95% CI 46-66%) and 98% specific (95% CI 97-99%). After start of anti-TB treatment, PCR test may retain sensitivity even when AFB smear turns negative. PCR methods of CSF have not been well studies with tuberculomas.
PPD: Rates of positive PPD with CNS TB vary widely with reported ranges around 10-50%.
CSF adenosine deaminase activity: Unclear sensitivity (estimated around 57%) with CNS TB but lack of specificity with false positives from lymphoma, malaria, crytococcoal meningitis, and other etiologies.
Interferon-gamma release assay: Estimated sensitivity of about 50% since CSF lymphocytes may die more rapidly than peripheral lymphocytes.
Discussion: Analysis of the literature supports why TB occupies such a murky place in the differential for brain masses or meningitis. There are no very sensitive ways to prove TB meningitis. In some sense, the history of subacute onset of symptoms with a suggestive CSF profile is the best clue for TB meningitis. The rest of diagnostic tests are not sensitive enough to rule out TB meningitis over clinical suspicion alone. One point that I was especially surprised to learn is that although TB is acquired via pulmonary source and spread hematogenously, the PPD is positive in only 50%. Other assays like CSF adenosine deaminase or even interferon-gamma release assay are relatively insensitive. So, one has to be careful to over-rule clinical suspicion!
As way of background, central nervous system tuberculosis is thought to occur from hematogenous spread of TB from a primary pulmonary focus. There is TB deposition and formation of subpial and subependymal foci - called Rich foci. If these foci rupture, TB meningitis results. Otherwise, growth of these foci results in tuberculomas.
Paper: Systematic review of diagnoses of CNS TB by British Infectious Society. "British Infectious Society guidelines for the diagnosis and treatement of tuberculosis of the central nervous system in adults and children" Journal of Infection (2009); 59: 167-187.
Methods: Systematic clinical evidence review of papers published in Medline and Pubmed between 1966 and 2008 dealing with CNS TB. The working group consisted of an interdisciplinary group of specialists.
Results:
Basic Clinical and Laboratory Features of CNS TB:
TB Meningitis: The top three clinical features were fever (60-95%), headache (50-80%), and anorexia/weight loss (60-80%). Top three clinical signs were neck stiffness (40-80%), focal cranial nerve palsy (30-50%), and coma (30-60%). On CSF examination, majority have clear appearance (80-90%) with 50% having opening pressure > 25 cm H2O. CSF glucose:blood glucose ratio was < 0.5 in 95% of patients with TB meningitis. The leucocyte count varies between 5-1000 cells with variable neutrophilic and lymphocytic predominance. Protein was also variable ranging from 45 to 300 mg/dL.
CNS Tuberculoma: Few large case series but most common presenting feature is seizure with complaints of headache, fever, and weight loss. CSF pleocytosis of 10-100 cells is present in only 50%.
Microbiology:
TB Meningitis: Sensitivity of AFB smear up to 80% provided that multiple large volume (>6 mL) taps are submitted for analysis. Culture media usually takes > 2 weeks to be positive and not helpful with decision making.
Tuberculoma: CSF AFB smear usually not positive and require stereotactic biopsy, which is diagnostic in about 94% of patients.
Nucleic Acid Amplification:
TB Meningitis: Currently available nuceic acid amplification tests about 56% sensitive (95% CI 46-66%) and 98% specific (95% CI 97-99%). After start of anti-TB treatment, PCR test may retain sensitivity even when AFB smear turns negative. PCR methods of CSF have not been well studies with tuberculomas.
PPD: Rates of positive PPD with CNS TB vary widely with reported ranges around 10-50%.
CSF adenosine deaminase activity: Unclear sensitivity (estimated around 57%) with CNS TB but lack of specificity with false positives from lymphoma, malaria, crytococcoal meningitis, and other etiologies.
Interferon-gamma release assay: Estimated sensitivity of about 50% since CSF lymphocytes may die more rapidly than peripheral lymphocytes.
Discussion: Analysis of the literature supports why TB occupies such a murky place in the differential for brain masses or meningitis. There are no very sensitive ways to prove TB meningitis. In some sense, the history of subacute onset of symptoms with a suggestive CSF profile is the best clue for TB meningitis. The rest of diagnostic tests are not sensitive enough to rule out TB meningitis over clinical suspicion alone. One point that I was especially surprised to learn is that although TB is acquired via pulmonary source and spread hematogenously, the PPD is positive in only 50%. Other assays like CSF adenosine deaminase or even interferon-gamma release assay are relatively insensitive. So, one has to be careful to over-rule clinical suspicion!
