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AUTHOR AND EDITOR INFORMATION

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Author: Niranjan N Singh, MD, DNB, Fellow in Neurophysiology, Department of Neurology, St Louis University School of Medicine

Niranjan N Singh is a member of the following medical societies: American Academy of Neurology

Coauthor(s): Florian P Thomas, MD, MA, PhD, Drmed, Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Associate Program Director, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University; Vitor Pacheco, MD, Staff Physician, Department of Neurology, St Louis University Hospital

Editors: Michael J Schneck, MD, Associate Professor, Department of Neurology and Neurosurgery, Loyola University Chicago, Stritch School of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Richard J Caselli, MD, Professor, Department of Neurology, Mayo Medical School, Rochester, MN; Chair, Department of Neurology, Mayo Clinic of Scottsdale; Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital; Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants

Author and Editor Disclosure

Synonyms and related keywords: acquired immunodeficiency syndrome, fungal infection of the nervous system, space-occupying lesion, meningitis, meningoencephalitis, HIV infection, AIDS-defining illness, Cryptococcus neoformans, C neoformans, cryptococcal CNS disease, cryptococcal disease, cryptococcal meningitis, highly active antiretroviral therapy, HAART, immune reconstitution inflammatory syndrome, CNS cryptococcosis, HIV-1 associated opportunistic infections

INTRODUCTION

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Background

Cryptococcosis is the most common fungal infection of the central nervous system and may present as a space-occupying lesion, meningitis, or meningoencephalitis. In addition, cryptococcosis is the most common fungal disease in HIV-infected persons, and it is the AIDS-defining illness for 60-70% of HIV-infected patients.

Pathophysiology

Cryptococcus neoformans spreads hematogenously to the CNS from pulmonary foci, which may be subclinical: No pneumonitis is found in more than 85% of patients with cryptococcal CNS disease. In addition to lung and CNS, cryptococci also invade skin, bone, and genitourinary tract, but meninges appear to be the preferred site. The reasons are not clear, but several suggestions have been made, including the following:

The cryptococcal capsule antigens may have limited ability in the cerebrospinal fluid (CSF) to induce an inflammatory response. Furthermore, the alternate pathway of complement is absent in the CSF. By contrast, 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 absent cryptococcus-toxic proteins.

Cryptococcal disease usually develops only when CD4 helper lymphocyte counts fall below 100 cells/mm3. At this stage, macrophage function also is impaired.

Frequency

United States

The annual incidence of cryptococcosis is 2-7 cases per 1000 HIV-infected patients, up to 89% occurring as a CNS manifestation. It is the fourth most common cause of opportunistic infections after Pneumocystis carinii, cytomegalovirus (CMV), and mycobacteria, and CNS manifestations (66-89%) are by far more common than those in other organs. Its incidence has declined recently because of widespread use of antifungal and antiretroviral agents.

Mortality/Morbidity

CNS cryptococcosis is fatal unless treated. Several studies report acute mortality rates of 6-14%. A minority of patients die within the first 6 weeks after diagnosis, despite treatment. Those who survive usually live for longer than 18 months. In addition, the rate of relapse after treatment is high (30-50%).

Race

African Americans with AIDS are more likely to develop cryptococcal meningitis than whites. However, a case-controlled study did not find an association between cryptococcal infection and race, suggesting that race may just be a surrogate for the presence of other conditions or exposures.

Age

CNS cryptococcosis is rare in children with AIDS.


CLINICAL

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History

Disease onset is usually insidious. This may be why the delay between symptom onset and diagnosis is on average 30 days or more. The delay also may be due to the waxing/waning course and the nonspecificity of symptoms. The initial fever and malaise could be the prodrome to a host of other conditions.

Rarely is the onset fulminant. Lung involvement is found in fewer than one third of patients with CNS cryptococcosis. Occasionally, evidence of unsuspected CNS cryptococcosis is detected on CSF analysis done for other reasons. In almost half of patients, cryptococcosis in the CNS or elsewhere is the AIDS-defining illness.

  • Symptoms at onset may be nonspecific and include 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%), and cranial neuropathies (6%).
  • Occasionally, patients may experience focal neurological symptoms or seizures.

Physical

Seizures, focal neurological deficits, change in mental status (20-30%), papilledema (10%), nuchal rigidity (22-44%), retroorbital pain, and rarely various cranial neuropathies, including nystagmus and amblyopia, are among the presenting signs.

  • Focal signs may indicate that the infectious meningeal process has reached superficial layers of the cortex and cerebellum, or they may point to cryptococcomas (ie, cryptococcal abscesses), most commonly in the basal ganglia and cerebellum (see Image 1-2).
  • Mental status changes include confusion, psychomotor retardation, irritability, agitation, personality changes, and psychosis.
  • Nuchal rigidity may be absent because of minimal inflammation.
  • Hydrocephalus must be suspected with new-onset impaired consciousness, motor signs, nausea, vomiting, or visual impairment. This usually occurs late in the course of cryptococcosis.
  • Bilateral visual loss also can result from arachnoiditis at the level of the optic nerves or cryptococcal invasion of the optic nerve.
  • Occasionally, symptoms and signs of a radiculomyelopathy predominate because of spinal cord involvement. Patients may have radicular pain, stiffness or spasticity, limb weakness, sphincter disturbances, loss of sensation, and weakness.

Causes

C neoformans is a round or oval yeast (4-6 micrometer in diameter) surrounded by a 30-micrometer–thick capsule. Based on the polysaccharide wall serology, use of nutrients and DNA sequence, it is subclassified into C neoformans neoformans and C neoformans gatii. Patients with AIDS typically are affected by C neoformans neoformans serotype A. Toxoplasmosis and lymphoma are differential diagnoses in cases of cryptococcal mass lesion (ie, cryptococcoma).


DIFFERENTIALS

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Aphasia
Brainstem Gliomas
Cavernous Sinus Syndromes
Complex Partial Seizures
EEG in Dementia and Encephalopathy
Frontal Lobe Syndromes
HIV-1 Encephalopathy and AIDS Dementia Complex
Intracranial Epidural Abscess
Intracranial Hemorrhage
Low-Grade Astrocytoma
Meningococcal Meningitis
Primary CNS Lymphoma
Tuberculous Meningitis

Other Problems to be Considered

Brainstem syndromes


WORKUP

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Lab Studies

  • CSF may yield normal (ie, reference) results in one fourth of patients, and be minimally abnormal in as many as one half; thus identifying the organism via India ink and serology is crucial.
    • Opening pressure is elevated to >200 mm H2O in approximately two thirds of patients, so this is an important test.
    • Appearance can be clear or turbid.
    • Protein levels exceed 45 mg/dL in one third to two thirds. They range from normal to 300 mg/100 dL.
    • Glucose is usually normal and is less than 60% of serum level in only 17-65%.
    • Mononuclear pleocytosis (>20 cells/mm3) occurs in 13-31%. Numbers vary between reports, but in one study 55% had less than 10 mononuclear cells/mm3.
    • Close to 100% of CSF culture results are positive for C neoformans, while 66-80% of blood culture results are positive.
    • India ink stain is positive in 74-88% of infected patients.
    • Test results for serum and CSF cryptococcal antigen may be positive. The initial diagnostic sensitivity of cryptococcal CSF antigen is 94.1%, followed by the serum antigen at 93.6%; this should not be used for discontinuing treatment.
    • A positive titer is sufficient to initiate therapy, while cultures are pending, in the appropriate clinical setting.

Imaging Studies

  • CT scan is acceptable as a screening study, but MRI, with and without contrast, is the preferred diagnostic imaging modality.
    • CT scan findings may be nonspecific or normal.
    • Twenty to thirty percent of patients show meningeal enhancement, parenchymal solid mass lesion without hemorrhage (granuloma), atrophy, cerebral edema, or hydrocephalus (see Image 3).
    • Commonly, in patients with increased intracranial pressure, the ventricles are actually small.
    • Cryptococcal pseudocysts may appear as nonenhancing, hypodense lesions on CT scan.
  • With MRI, T1 images may show low-intensity lesions in the basal ganglia, which are hyperintense on T2 and may enhance with gadolinium.

Procedures

  • At times, intracranial hypertension, secondary to obstruction of the basal meninges or impaired absorptive mechanisms, and in the absence of mass lesions and or other risk of herniation, can be managed by CSF removal through repeated lumbar puncture; some favor ventriculoperitoneal shunt in such situations. For many patients, this results in almost immediate relief of headache, nausea, and vomiting.

Histologic Findings

The meninges are opaque, and a capsular material may fill the subarachnoid space. Mixed meningeal infiltrates consisting of lymphocytes, eosinophils, plasma cells, multinucleated giant cells (containing phagocytized organisms), and neutrophils may surround clusters of organisms and sometimes form granulomas, but often the inflammatory response is scant. Cryptococci extend along Virchow-Robin spaces into the brain. Parenchymal tubercles consisting of pseudocysts filled with organisms without significant inflammatory response, capsule formation, or gliosis are observed most often in the basal ganglia and cortical gray matter, but may be found elsewhere.


TREATMENT

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Medical Care

Untreated cryptococcal CNS infections are fatal. Treatment with amphotericin B, flucytosine, fluconazole, and other antifungal agents greatly improves the prognosis, but a mortality rate of 6%, despite aggressive therapy, has been reported.

Primary prophylaxis is not routinely recommended.

  • Current consensus for initial therapy
    • Induction: Amphotericin B 0.7-1 mg/kg/d with 5-flucytosine 100 mg/kg/d in 4 divided doses for 2 weeks, followed by fluconazole 400 mg/d for a minimum of 10 weeks.
    • Alternative: Amphotericin B 0.7-1 mg/kg/d plus flucytosine 100 mg/kg/d for 6-10 weeks. Liposomal amphotericin B may lead to quicker improvement with less renal toxicity. The usual dose is 3-6 mg/kg/d for 6-10 weeks. (This is not approved by the FDA for use in cryptococcal meningitis.)
    • Maintenance therapy should be continued with fluconazole 200 mg/d, with amphotericin B 1 mg/kg/wk as an alternative for patients who experience relapse on fluconazole or for those who cannot tolerate it.
    • For selected patients who have responded well to highly active antiretroviral therapy (HAART), consideration might be given to discontinue secondary antifungal prophylaxis after 12-18 months of successful suppression of HIV viral replication. This remains controversial.
  • Recent experimental data suggest that recombinant interferon-gamma 1b induces more rapid early sterilization of CSF among patients with HIV-associated Cryptococcus meningitis.

Surgical Care

Increased intracranial pressure (>200 mm H2O) occurs in over half of all patients with AIDS who have cryptococcal CNS infection, probably because of decreased CSF absorption. Since increased intracranial pressure is a prognostic factor whose correction leads to symptomatic improvement, this must be managed aggressively.

  • In the absence of obstructive hydrocephalus or risk of herniation, increased pressure (>250 mm H2O) can be relieved by serial spinal taps or a lumbar-peritoneal shunt; in the presence of either of these, however, ventriculoperitoneal shunt is indicated. Decreasing intracranial pressure can rapidly improve headache, nausea, and vomiting.
  • On a case-by-case basis, the presence of a cryptococcoma may lead to consideration of surgical intervention.
  • Rare visual loss due to local arachnoiditis or cryptococcal invasion of the nerves can be approached by nerve sheath decompression.

Consultations

Consultation with an infectious disease specialist should be considered for diagnosis and treatment.


MEDICATION

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The goals of pharmacotherapy are to eradicate the infection, to reduce morbidity, and to prevent complications.

Drug Category: Antifungal agents

Their mechanism of action may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.

Drug NameAmphotericin B conventional (Fungizone, Amphocin)
DescriptionProduced from a strain of Streptomyces nodosus. Antifungal activity of amphotericin B results from its ability to insert itself into fungal cytoplasmic membrane at sites containing ergosterol or other sterols. Aggregates of amphotericin B accumulate at sterol sites, resulting in an increase in cytoplasmic membrane permeability to monovalent ions (eg, potassium, sodium). At low concentrations, the main effect is increased intracellular loss of potassium, resulting in reversible fungistatic activity; however, at higher concentrations, pores of 40-105 nm in cytoplasmic membrane are produced, leading to large losses of ions and other molecules. A second effect of amphotericin B is its ability to cause auto-oxidation of the cytoplasmic membrane and release of lethal free radicals. Main fungicidal activity of amphotericin B may reside in ability to cause auto-oxidation of cell membranes.
If therapy is supplemented by oral flucytosine, therapy can be used until patient is afebrile and alert and spinal fluid cultures are negative for 6 wk; then, patient can be placed on fluconazole.
Adult Dose0.7-1 mg/kg/d IV with flucytosine 100 mg/kg/d PO qid for minimum of 2 wk
Pediatric Dose0.7-1 mg/kg/d IV
ContraindicationsDocumented hypersensitivity
InteractionsAntineoplastic agents may enhance potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; risk of renal toxicity is increased with cyclosporine
PregnancyC - Safety for use during pregnancy has not been established.
PrecautionsMonitor renal function, serum electrolytes such as magnesium and potassium, liver function, CBC, and hemoglobin concentrations; resume therapy at lowest level (eg, 0.25 mg/kg) when therapy is interrupted for more than 7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in patients with neutropenia who receive leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion); fever and chills are not uncommon after first few administrations of drug; rare acute reactions may include hypotension, bronchospasm, arrhythmias, and shock

Drug NameFlucytosine (Ancobon)
DescriptionAlthough the exact mode of action is unknown, flucytosine is proposed to act directly on fungal organisms by competitive inhibition of purine and pyrimidine uptake and indirectly by intracellular metabolism where it is converted to 5-fluorouracil after penetrating fungal cells. Inhibits RNA and protein synthesis. Active against Candida and Cryptococcus species and generally used in combination with amphotericin B.
Use in combination with another agent because acquired resistance develops frequently when flucytosine is administered alone.
Well absorbed orally but should be administered IV to patients who are critically ill.
Adult Dose100 mg/kg/d PO qid as supplement to amphotericin B therapy for minimum of 2 wk
Pediatric Dose50-100 mg/kg/d PO divided qid
ContraindicationsDocumented hypersensitivity
InteractionsAmphotericin B may increase toxicity of flucytosine; cytosine may inactivate flucytosine
PregnancyC - Safety for use during pregnancy has not been established.
PrecautionsCaution in bone marrow suppression; adjust dose in renal impairment

Drug NameFluconazole (Diflucan)
DescriptionSynthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes. Has little affinity for mammalian cytochromes, which is believed to explain its low toxicity. Available as tab for oral administration, as a powder for oral susp, and as a sterile solution for IV use. Has fewer adverse effects and better tissue distribution than older systemic imidazoles. DOC for long-term prophylaxis.
Adult Dose400 mg PO qd for 10 wk; then 200 mg PO qd for life
Pediatric Dose2-3 mg/kg PO qd
ContraindicationsDocumented hypersensitivity
InteractionsLevels may increase with hydrochlorothiazides; fluconazole levels may decrease with long-term coadministration of rifampin; may increase concentrations of theophylline, phenytoin, tolbutamide, cyclosporine, glyburide, and glipizide; effects of anticoagulants may increase with fluconazole coadministration
PregnancyC - Safety for use during pregnancy has not been established.
PrecautionsAdjust dose for renal insufficiency; closely monitor if rashes develop, and discontinue drug if lesions progress; may cause clinical hepatitis, cholestasis, and fulminant hepatic failure (including death) when taken with underlying medical conditions (eg, AIDS, malignancy) or while taking multiple concomitant medications; not recommended for breastfeeding mothers
Convenience and efficacy of single-dose regimen for treatment of vaginal yeast infections should be weighed against difficulties resulting from higher incidence of adverse reactions reported with oral fluconazole versus intravaginal agents


FOLLOW-UP

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Further Outpatient Care

  • Lifelong secondary prevention may be required. Fluconazole 200 mg/d was shown to be more effective than amphotericin B.
  • Itraconazole 400 mg/d can be an alternative to fluconazole, but it is less effective.
  • In case of recurrence despite compliance, amphotericin B 1 mg/kg/wk IV is an alternative.
  • Some reports suggest that oral prevention can be stopped if CD4+ counts rise higher than 100 with HAART and the HIV load becomes undetectable.

Complications

  • Relapses occur if secondary prevention is stopped or becomes ineffectual. Relapse rates without prevention range from 15-27%; this drops to 0-7% with prophylactic antibiotics.
  • Seizures should be treated with standard therapy. Drugs that are less likely to affect bioavailability of HAART agents or anticryptococcal therapy are preferred.
  • Cognitive impairment may improve with successful anticryptococcal therapy.
  • Immune reconstitution inflammatory syndrome occurs in some patients after treatment with HAART. This syndrome is a paradoxical deterioration in the clinical status despite satisfactory control of viral replication and improvement of CD4+ counts as a result of an exuberant inflammatory response toward previously diagnosed or latent opportunistic pathogens.

Prognosis

  • Relapse rate is high.
  • Predictors of poor prognosis are controversial, but have included the following:
    • 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


MISCELLANEOUS

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Medical/Legal Pitfalls

  • Delay in diagnosis and treatment may lead to permanent neurological disability or death.


MULTIMEDIA

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Media file 1:  Magnetic resonance imaging showing a cryptococcoma in the medulla.
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Media type:  MRI

Media file 2:  Coronal section of brain showing a cryptococcoma in the basal ganglia
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Media type:  Photo

Media file 3:  Magnetic resonance imaging shows meningeal enhancement in a patient with cryptococcal meningitis.
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Media type:  MRI


REFERENCES

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  • Hajjeh RA, Conn LA, Stephens DS, et al. Cryptococcosis: population-based multistate active surveillance and risk factors in human immunodeficiency virus-infected persons. Cryptococcal Active Surveillance Group. J Infect Dis. Feb 1999;179(2):449-54. [Medline].
  • Kaplan JE, Hanson D, Dworkin MS, et al. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis. Apr 2000;30 Suppl 1:S5-14. [Medline].
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  • Offiah CE, Turnbull IW. The imaging appearances of intracranial CNS infections in adult HIV and AIDS patients. Clin Radiol. May 2006;61(5):393-401. [Medline].
  • Pappas PG, Bustamante B, Ticona E, et al. Recombinant interferon- gamma 1b as adjunctive therapy for AIDS-related acute cryptococcal meningitis. J Infect Dis. Jun 15 2004;189(12):2185-91. [Medline].
  • Quality Standards Subcommittee of the AAN. Evaluation and management of intracranial mass lesions in AIDS. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. Jan 1998;50(1):21-6. [Medline].
  • Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis. Apr 2000;30(4):710-8. [Medline].
  • Said G, Saimont AG, Lacroix C. Neurological complications of HIV and AIDS. Philadelphia: WB Saunders;1998.
  • Schwartz P, Janbon G, Dromer F. Combination of amphotericin B with flucytosine is active in vitro against flucytosine-resistant isolates of Cryptococcus neoformans. Antimicrob. Agents Chemother. 2006;51:383-85. [Medline].
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HIV-1 Associated Opportunistic Infections: CNS Cryptococcosis excerpt

Article Last Updated: Mar 14, 2007