A 40-year old male with Human Immunodeficiency Virus (HIV) infection on anti-retroviral therapy presents with a two-week history of severe headache followed by fever, malaise, vomiting and confusion. A CT scan of his brain is reported as normal.
His blood CD4 count is reported as 77 cells/µL* (normal range: > 500). Cerebrospinal fluid examination shows the following:

Parameter

Patient Value

Adult Normal Range

Opening Pressure

35 cmH2O*

12 – 25

Total protein

0.90 g/L*

0.15 – 0.45

Glucose

2.1 mmol/L*

3.3 – 4.4

White Cell Count

48 cells/µL*

< 5

Mononuclear cells

42 cells/µL*

< 3

Polymorphonuclear cells

6 cells/µL*

0

Gram-stain

No organisms

a) What is the most likely diagnosis? (15% marks)

b) What is the most appropriate anti-microbial therapy for this condition? (10%)

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College answer

1.    Cryptococcus Neoformans (cryptococcal) meningitis*
2.    IV Amphotericin plus Flucytosine
* Although other causes infective meningitis with mononuclear preponderance (e.g. TB) are possible; headache on presentation, CD4 count < 100, CSF white cell count <50 makes cryptococcal meningitis the most likely diagnosis.
 

Discussion

This subacute onset of meningoencephalitis-sounding symptoms could be a whole range of things in a HIV patient whose CD4 count is in the "advanced disease" range (<200). Of the possible culprits, there are several equally likely possibilities:

  • Cryptococcus neoformans
  • Toxoplasmosis
  • Tuberculosis meningitis

The normal CT makes toxoplasmosis unlikely. The non-Gram-staining CSF does not discriminate between the others two, but the lack of visible organisms (and the relatively low CSF WCC) does not favour the more routine range of community-acquired pathogens. In TB meningitis among HIV patients, the CSF sample would be expected to have a normal cell count (≤5 cells/µL), a polymorphonuclear cell predominance, and normal glucose levels (Marais et al, 2011). Moreover, cryptococcal meningitis classically presents with a very high opening pressure (Spec & Powderly, 2020). So, that's probably what this is. 

Empirical management for cryptococcal meningitis is usually liposomal amphotericin and flucytosine. Super high dose fluconazole (1200mg daily) is a less effective alternative, if you prefer to sacrifice the liver instead of the kidneys.

References

Marais, Suzaan, et al. "Presentation and outcome of tuberculous meningitis in a high HIV prevalence setting." PloS one 6.5 (2011).

Spec, Andrej, and William G. Powderly. "Cryptococcal meningitis in AIDS." Handbook of clinical neurology. Vol. 152. Elsevier, 2018. 139-150.