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Cryptococcus Meningoencephalitis - Ronak Shah PGY-3

posted Dec 16, 2014, 8:45 AM by Kevin Hauck

Last week, we had another interesting case for COS with Dr. Nosanchuk. This was a 54-year-old gentleman with 2 weeks of cough and fever, recently treated unsuccessfully with Augmentin in the outpatient setting. On presentation, the patient had severe sepsis with concomitant hypoxia, found to have multiple b/l pulmonary emboli, required to be intubated, and needed a brief stay in the ICU. Post ICU, the patient’s blood cultures came back positive, surprisingly, growing Cryptococcus neoformans.

I encourage all of you to read the beautifully written, thorough Monte Minute article by Dr. Rohit Das back from Feb. 2013 regarding cryptococcus infections. Here, I will focus more on the CNS complications, particularly meningoencephalitis of cryptococcus.

Cryptococcus meningnoencephalitis:

What is it?

This entity is an invasive fungal infection of the CNS caused by the encapsulated yeast, Crytococcus neoformans mostly in immunocompromised patients [particularly HIV]. Fortunately, here in the US, we do not see many cases of this disease. But worldwide, it remains a significant burden as there are up to a million cases annually, with mortality reaching >50% in some areas of sub-Saharan Africa.


  • the presentation of the CNS disease is usually a slow, progressive onset: 1-2 weeks.
  • non-specific symptoms of fever, malaise and a headache.
  • stiff neck, photophobia and vomiting seen in only ¼ of the patients.
  • but disseminated cryptococcemia, like our patient, is more likely to present with cough, dyspnea or even cutaneous lesions. The sepsis and pneumonia studies indicate that cryptococcus is usually an unexpected, incidental finding.
  • physical exam: signs of CNS disease are usually lacking, but meningismus, papilledema and CN palsies [particularly CN VI] indicate advanced disease and a much poorer prognosis.
  • labs: non-specific; look for immunosuppressive hints [leukopenia, protein gap]


Cryptococcal infection is inhaled by aerolized particles. Most people convert serologically during childhood [especially in the Bronx!]. Given the fact that the infection is common and the disease is rare, our body likely has defense mechanisms in immunologic intact hosts. There is some evidence that certain cryptococcal infections lead to state of latency, with viable organisms harbored in possible granulomas. The mechanism of how the fungus disseminates into the extrapulmonary system and into the CNS is not clear. But once in the CNS, the infection proliferates in the subarachnoid space, clogging the arachnoid villi, eventually leading to increased intracranial pressure.


  • prior to LP, obtain imaging! especially in patients suspecting increase ICP and/or HIV.
  • made by LP / analyzing the CSF:
    • elevated opening pressure: >20 cm H20 in 50-60% patients in the US.
    • classically have low WBC count, mild elevation of protein and low glucose.
    • CSF should be sent for cryptococcal culture.
    • perform an India Ink stain [80-85% sensitive in HIV patients]
    • check for cryptococcal antigen: strongly supports the diagnosis and enough to initiate treatment. very sensitive and specific, both >93%.
  • serum cryptococcal antigen: useful diagnostic test in patients that cannot undergo a LP. titers generally correlate to organism burden.
  • routine blood cx: cryptococcus positive in ⅔ patients of meningoencephalitis; but should check fungal blood cx to improve sensitivity.
  • bottom line: diagnosis is conclusive by isolating the organism with culture, but now the antigen testing [given how accurate it is] has surpassed the culture in guiding initial therapy.


  • Abnormal mental status, CSF titers >1:1024 and CSF WBC <20 are all signs of poor prognosis.


  • The IDSA divides the treatment for cryptococcal meningoencephalitis into three phases:
    • two week induction - preferred regimen: amphotericin B [0.7 - 1.0 mg / kg per d] and flucytosine [100 mg / kg per d]. at the end of the induction phase, repeat LP to ensure clearance of the infection.
    • followed by eight week consolidation - fluconazole 400-800 mg per d
    • extended maintenance phase - for secondary prophylaxis - fluconazole 200 mg per d
  • general principles: there are fungicidal [amphotericin B and flucytosine] and fungistatic drugs [fluconazole]. The fungicidal regimen in the induction phase yields better clinical outcomes.
  • toxicities: amphotericin B - watch for IV related phlebitis, need to administer IVF [1-2 L saline / d], watch for electrolyte abnormalities. lipid formulations are better tolerated.
  • regardless of the antifungal medications, the elevated opening pressure needs to be managed aggressively! Need serial LPs, even on a daily basis until the OP <20 cm. May need therapeutic drains if persistent elevated OP. If symptomatic elevated pressures, then can consider removing up to 30 mL.
  • When to restart ARV? There is not great evidence to support the exact time point for ARV. There is a concern for IRIS if starting too soon, particularly in the induction phase. But on the other side, waiting too long increases the risks for other complications from immunosuppression. Typically ok to restart ARV after 10 weeks.

Back to the patient:

The patient was found to have disseminated cryptococcemia. He received an LP, which showed WBC of 15, glucose 47, total protein 63. +fungal csf cx of cryptococus neoformans. Initial csf cryptococcal antigen titer of 1:2048! He finished a course of induction tx, now only on fluconazole. Patient has started ARV. Unfortunately, currently still in the hospital with headaches and changes in his mental status. Unclear the exact relation of his b/l pulmonary emboli with current disease. But suspect possible hypercoagulable process with HIV. Awaiting to undergo other age appropriate cancer screening.

Attaching some of the review articles:

Prognosis and management of cryptococcal meningitis in patients with HIV. Neurobehavioral HIV Medicine. 2012.

HIV-associated cryptococcal meningitis. AIDS 2007.

IDSA 2010 Cryptococcus Guidelines

Other sources:  Harrison’sUTD