Etiology, evaluation, management

1. Dr Rajesh Deshwal MD, FHM, FIACM, FACP
Consultant in Internal Medicine and HIV Medicine
Apex Immunodeficiency Center, Base Hospital, Delhi Cantonment,
India
CNS CRYPTOCOCCOSIS

2. OVERVIEW
• Most common fungal infection of the central nervous system
• Space-occupying lesion, meningitis, or meningoencephalitis
• Cryptococcosis is the most common fungal disease in HIV -
infected persons
• AIDS-defining illness for 60-70% of HIV-infected patients

3. PATHOPHYSIOLOGY
• Spreads hematogenously to the CNS from pulmonary foci
• Cryptococci also invade the skin, bone, and genitourinary tract, but
meninges appear to be the preferred site
• Cryptococcal capsule antigens may have limited ability to induce
an inflammatory response in the cerebrospinal fluid
• Alternative pathway of complement is absent in the CSF
• CSF is a good growth medium for the organism in culture,
possibly because of trophic properties of dopamine and other
neurotransmitters in the CSF and the absence of cryptococcus-
toxic proteins
• When CD4+ lymphocyte counts fall below 100 cells/mL

4. ETIOLOGY
• Cryptococcus neoformans is a round or oval yeast, 4-6 mm in
diameter, surrounded by a 30-mm-thick capsule
• Subclassified into C neoformans neoformans and C neoformans
gatii
• Sero type A

6. PROGNOSIS
• Fatal unless treated
• Rate of relapse after treatment is high (30-50%)
Predictors of poor prognosis
• High CSF cryptococcal antigen titer (>1:1024)
• Minimal CSF pleocytosis
• Altered mental status at presentation
• Positive India Ink preparation
• Hyponatremia
• Positive cultures from extrameningeal sites

7. CLINICAL PRESENTATION
• Onset is usually insidious
• Lung involvement is found in fewer than one third of patients with
CNS cryptococcosis
• Headache (73-81%)
• Fever (62-88%)
• Malaise (38-76%)
• Nausea and vomiting (8-42%)
• Stiff neck (22-44%)
• Visual disturbances (30%)
• Altered mental status with somnolence (18-28%)
• Photophobia (19%)
• Papilledema (10%)
• Cranial neuropathies, including nystagmus and amblyopia (6%)

8. • Occasionally, patients may experience focal neurologic symptoms
or seizures
• Mental status changes include confusion, psychomotor
retardation, irritability, agitation, personality changes, and
psychosis
• Nuchal rigidity may be absent because of minimal inflammation.
• Bilateral visual loss also can result from arachnoiditis at the level
of the optic nerves or cryptococcal invasion of the optic nerve
• Patients may have radicular pain, stiffness or spasticity, limb
weakness, sphincter disturbances, loss of sensation, and
weakness

9. CSF ANALYSIS
• Opening pressure is elevated to greater than 200 mm H2 O in
approximately two thirds of patients
• CSF fluid appearance can be clear or turbid
• Protein levels exceed 45 mg/dL in one third to two thirds of cases,
ranging from normal to 300 mg/100 dL
• The glucose level is usually normal and is less than 60% of the
serum level in only 17-65%.
• Mononuclear pleocytosis (>20 cells/mL) occurs in 13-31% of cases
• Close to 100% of CSF culture results are positive for Cryptococcus
neoformans
• India ink stain is positive in 74-88% of infected patients.
• CSF cryptococcal antigen(CRAG) may be positive(94.1%)

10. CT AND MRI
• CT scan is acceptable as a screening study
• MRI, with and without contrast, is the preferred diagnostic imaging
modality
• CT scan findings may be nonspecific or normal
• Cryptococcal pseudocysts may appear as nonenhancing,
hypodense lesions on CT scan
• With MRI, T1-weighted images may show low-intensity lesions in
the basal ganglia, which are hyperintense on T2-weighted images
and may enhance with gadolinium

11. TREATMENT
• Treatment with amphotericin B, flucytosine, fluconazole, and other
antifungal agents greatly improves the prognosis
• Mortality rate of 6%, despite aggressive therapy, has been
reported
• Amphotericin B deoxycholate (0.7-1.0 mg/kg/day IV)
plus flucytosine (100 mg/kg/day orally in 4 divided doses) for at
least 2 weeks
• Followed by fluconazole (400 mg [6 mg/kg] per day orally) for a
minimum of 8 weeks
• Lipid formulations of amphotericin B (eg, liposomal amphotericin
B [AmBisome], 6 mg/kg/day IV) can be substituted for
amphotericin B

12. • Results of a randomized trial suggest that a 2-week course of
high-dose fluconazole (1200 mg/day) combined with flucytosine
(100 mg/kg/day) is the optimal oral therapy for cryptococcal
meningitis
Nussbaum JC, Jackson A, Namarika D, Phulusa J, Kenala J, Kanyemba
C. Combination flucytosine and high-dose fluconazole compared
with fluconazole monotherapy for the treatment of cryptococcal
meningitis: a randomized trial in Malawi. Clin Infect Dis. 2010 Feb
1. 50(3):338-44

13. TOXICITIES RELATED TO DRUGS
Flucytosine
• Bone marrow suppression
Fluconazole
• GI and hepatotoxicity
Amphotericin B
• Renal toxicity and electrolyte abnormalities

14. • A double-blind, placebo-controlled phase II study suggested that
adjunctive recombinant interferon-gamma 1b (rIFN- gamma 1b)
may induce more rapid early sterilization of CSF in patients with
HIV-associated Cryptococcus meningitis
• 100 or 200 µg 3 times weekly for 10 weeks, plus standard
antifungal therapy
Pappas PG, Bustamante B, Ticona E, et al. Recombinant interferon-
gamma 1b as adjunctive therapy for AIDS-related acute
cryptococcal meningitis. J Infect Dis. 2004 Jun 15.
189(12):2185-91

15. MAINTAINENCE THERAPY
• Fluconazole 200 mg/day
• Amphotericin B (1 mg/kg/wk) is less effective than fluconazole
• Itraconazole 400 mg/day can be an alternative to fluconazole, but
it is less effective
• Lifelong secondary prevention may be required
• Relapses occur if secondary prevention is stopped or becomes
ineffectual
• Maintenance of a CD4+ cell count above 100 cells/µL and an
undetectable or very low HIV RNA level for 3 months or longer
(minimum of 12 months of antifungal therapy)
• The guidelines advise considering reinstitution of maintenance
therapy if the CD4+ cell count falls below 100 cells/µL

16. TREATMENT FAILURE
• Repeat lumbar puncture if no improvement or worsening of
symptoms
• Consider alternative diagnosis
• Fluconazole and amphotericin resistance (rare)
• Consider immune reconstitution syndrome (IRIS)

17. TREATMENT OF RAISED INTRACRANIAL
PRESSURE
• Increased intracranial pressure (>200 mm H2 O) occurs in over half
of all patients with AIDS who have cryptococcal CNS infection,
probably because of obstruction of the basal meninges or impaired
CSF absorption
• In the absence of obstructive hydrocephalus or risk of herniation,
increased pressure (>250 mm H2 O) can be relieved by serial
spinal taps or a lumbar-peritoneal shunt
• Ventriculoperitoneal shunt is indicated in case of hydrocephalus or
risk of herniation
• Mannitol has no proven benefit and is not routinely recommended

18. TAKE AWAYS…..
• Cryptococcus meningitis is fatal if untreated
• Elevated intracranial pressure is associated with a poor prognosis
and must be managed promptly
• Obtain brain image prior to lumbar puncture in patients with focal
neurological deficits, papilledema and/or obtundation
• Treatment is a three-phase process of induction, consolidation and
maintenance therapy
• Maintenance treatment with fluconazole may be discontinued
following immune reconstitution with HAART
• Otherwise fluconazole may be needed for lifetime
• Relapse is seen if secondary prevention is stopped