Dr Rajesh Deshwal MD, FHM, FIACM, FACPConsultant in Internal Medicine and HIV MedicineApex Immunodeficiency Center, Base Hospital, Delhi Cantonment, India

CNS CRYPTOCOCCOSIS

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

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

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

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

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%)

• 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

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%)

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

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

• 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

TOXICITIES RELATED TO DRUGS

Flucytosine

• Bone marrow suppression

Fluconazole

• GI and hepatotoxicity

Amphotericin B

• Renal toxicity and electrolyte abnormalities

• 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

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

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)

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

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