eMedicine Specialties > Neurology > Neurological Infections

HIV-1 Associated Opportunistic Infections - CNS Cryptococcosis

Author: Niranjan N Singh, MD, DNB, Assistant Professor of Neurology, University of Missouri Columbia
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; 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
Contributor Information and Disclosures

Updated: Mar 14, 2007

Introduction

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

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).

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