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