CNS Cryptococcosis

What Causes CNS Cryptococcosis?

A Cryptococcus neoformans infection begins when a person breathes the fungus into their lungs. The infection rarely causes symptoms in the lungs, but it often travels to the central nervous system, where it can have a severe impact.

Cryptococcus neoformans is extremely common, but most people with healthy immune systems do not acquire an infection even when they inhale the fungus. However, people with compromised immune systems are at risk of severe infections. 

People at increased risk include:

• People with HIV/AIDS
• People who have had an organ transplant
• People taking immune-suppressive medications to treat autoimmune disorders such as rheumatoid arthritis

Is CNS Cryptococcosis Hereditary?

External environmental sources cause CNS cryptococcosis, and family history plays no part in developing an infection.

How Is CNS Cryptococcosis Detected?

Early detection of CNS cryptococcosis is essential because long-term damage is more likely to occur if treatment is delayed until symptoms are advanced. Unfortunately, early diagnosis of the condition is difficult because the first symptoms are usually vague and may be caused by various problems other than an infection.

Although the infection does not always cause symptoms when it affects the lungs, respiratory symptoms sometimes occur. These symptoms may include:

• Shortness of breath
• Cough
• Chest pain
• Fever

If the infection is left untreated, more severe symptoms may develop, such as vomiting, stiff neck, seizures, and personality changes. Eventually, an untreated infection is likely to be fatal.

How Is CNS Cryptococcosis Diagnosed?

When your doctor suspects CNS cryptococcosis may be present, they may follow a diagnostic procedure that includes:

• Medical history questions. Your doctor will look for signs that you may be at increased risk for certain infections.
• Blood tests. These laboratory tests will look for signs of infection in your bloodstream.
• Lumbar puncture (spinal tap). This test will look for evidence of the fungus in the cerebral spinal fluid (CSF).
• Imaging tests. Magnetic resonance imaging (MRI) and computerized tomography (CT) scans can be used to produce an image of your brain. An infection is likely to show up on these scans.
• Biopsy of brain lesions. Doctors may remove a sample of the infected tissue using a fine needle. Tests of this sample can identify the source of the infection and allow for more effective treatment.

How Is CNS Cryptococcosis Treated?

Treatment of CNS cryptococcosis involves drugs to eliminate the infection source and prevent relapses.

• Anti-fungal medications such as amphotericin B, flucytosine, and fluconazole are typically used to treat the infection.
• Lumbar punctures or other procedures to relieve pressure in the brain may be required if the infection causes a buildup of cerebrospinal fluid.
• Anti-seizure medications may be used to treat or prevent seizures.
• Maintenance treatment with anti-fungal medications will continue for at least a year to prevent relapses. In some cases, doctors may recommend life-long preventive treatment.

How Does CNS Cryptococcosis Progress?

Treatment of CNS cryptococcosis is usually successful, but the condition is typically fatal when left untreated. Even with treatment, the infection has a mortality rate of 6%.

Treatment of CNS cryptococcosis in immune-compromised patients usually continues even after the infection is under control. This is because long-term treatment aims to prevent the reactivation of the infection while the immune system is still unable to fight it effectively. However, patients who don’t follow their long-term treatment plan are vulnerable to relapse. Relapse rates for people without preventive treatment are as high as 27%, while the rate for those who follow maintenance treatment plans is no higher than 7%.

How Is CNS Cryptococcosis Prevented?

Because Cryptococcus neoformans is so common in the environment, preventing infection is difficult. The infection can’t be passed from person to person or from animals to humans, but it is virtually impossible to avoid inhaling the fungus at some point.

HIV/AIDS patients with severely weakened immune systems are advised to undergo regular screening to detect infections before they produce serious symptoms.

CNS Cryptococcosis Caregiver Tips

If you are a caregiver for a loved one with cryptococcosis, keep these tips in mind:

• Attend doctor appointments with your loved one to understand the diagnosis, the treatment plan, and the expectations for recovery.
• During recovery, provide a comfortable space for the sufferer free from noise, excessive stimulation, and stress.
• After treatment, work with your loved one’s medical providers to learn how you can best support them as they recuperate. Understand the goals of any long-term therapies, and be realistic about expectations.
• Call upon family and community to help out whenever possible. Don’t try to take sole responsibility for caregiving.

CNS Cryptococcosis Brain Science

When it enters the central nervous system, Cryptococcus can have a variety of effects, including:

• The fungus can infect the meninges, thin membranes surrounding the brain and spinal cord. This infection is called meningitis, and it can produce life-threatening complications.
• The infection can also affect brain tissue itself, leading to inflammation and swelling called encephalitis.
• Cryptococcus can also form lesions or cyst-like masses that put pressure on surrounding brain tissue and cause neurological symptoms.
• The infection can trigger a buildup of cerebrospinal fluid (CSF), resulting in a condition called hydrocephalus. This condition also may put pressure on brain tissue and cause symptoms.

CNS Cryptococcosis Research

Title: Cryptococcosis in Previously Healthy Adults

Stage: Recruiting

Principal Investigator: Peter R. Williamson, MD

National Institute of Allergy and Infectious Diseases (NIAID)

Bethesda, MD

Cryptococcus is a fungus that causes infections most commonly in immunocompromised patients, such as those with AIDS and solid organ transplant recipients, particularly renal transplant recipients (1-3). However, approximately one-third of cases fall outside these groups, and, overall, 12.9% to 17.9% have no readily identifiable immune defect (4, 5). The genetic factors which may predispose to cryptococcosis and the immune response in these patients have not been extensively studied.

This protocol is designed to examine the immune deficits that predispose to cryptococcosis as well as the clinical and immune responses among previously healthy adults. The patients included will have an unknown predisposing condition and cryptococcosis. Patients will undergo blood, saliva, and tissue sampling. Throughout the study, patients will be provided with standard medical care and will be seen as often as necessary to manage their condition. Patients with microbiologic control of the infection, but inflammation is causing neurologic damage, may be treated with corticosteroids or other immunosuppressive agents. Genetically related family members of patients will also be screened for clinical, in vitro, immune, and genetic correlates of immune abnormalities. Healthy adult volunteers, as a comparison group, will be enrolled as a source of blood samples for research testing. Moreover, with respect to cryptococcosis, patients with isolated non-central nervous system (CNS) disease (e.g., pulmonary) may serve as a subset comparator to those with (CNS) involvement, a major tissue tropism for Cryptococcus.

Genetic and immunologic testing will be performed on all subjects (patients, relatives, and healthy volunteers) to evaluate possible immunogenetic factors that lead to susceptibility to cryptococcosis. This protocol aims to better understand the pathophysiology and genetic factors that lead to defects in host defense and to use modern and evolving methods in molecular and cellular biology to elucidate the pathogenesis of this particular susceptibility. A better understanding of the underlying pathophysiology of immune defects and genetic susceptibility to fungal infections could allow for the rational development of novel therapies for such diseases and to benefit future patients.

Title: Etiology, Pathogenesis, and Natural History of Idiopathic CD4+ Lymphocytopenia

Stage: Recruiting

Principal Investigator: Irini Sereti, MD

National Institute of Allergy and Infectious Diseases (NIAID)

Bethesda, MD  

Idiopathic CD4+ lymphocytopenia (ICL) is a disorder characterized by decreased numbers of circulating CD4+ T lymphocytes in the absence of known causes of CD4+ lymphocytopenia. ICL is defined as an absolute CD4+ T cell count of fewer than 300 cells/microL in a patient with no human immunodeficiency virus infection or known immunodeficiency syndrome. The causes and frequency of the disorder remain unknown. The condition is typically diagnosed when patients present with a serious infection. In this natural history protocol, we will evaluate patients with CD4+ T cell counts below 300 cells/microL. We propose to follow 300 ICL patients for a minimum of 4 and a maximum of 20 years, focusing on the association between ICL and autoimmune disease. In addition to the ICL patients, we will enroll blood relatives and household contacts to better understand the pathogenesis and etiologies of the syndrome. We will collect blood and other tissues for immunologic, rheumatologic, and genetic testing in an effort to identify and understand the underlying defects that cause ICL and follow its course in a cohort of patients who will receive the best standard therapy for opportunistic infections.

Title: Evaluation of the Association of Polymorphisms in the Innate Immune System With the Risk for Cryptococcus Neoformans Infection in Patients Not Infected With HIV and Complications Associated With Cryptococcus Neoformans Infection

Stage: Completed

University of Alabama

Birmingham, AL

Innate immunity plays an important role in fungal recognition and initiation of fungicidal activity. We hypothesize that subtle differences in different molecules of innate immunity may contribute to either the predisposition or clinical course of infection with Cryptococcus neoformans. To test this hypothesis, we propose to analyze the allelic frequencies of 15 different genes (mannose binding lectin, Fc-gamma receptor IIa and IIb, Fc-gamma receptors IIIa and IIIb, myeloperoxidase, tumor necrosis factor-alpha and -beta, interleukin 1A and 1B, interleukin-1 receptor antagonist, interleukin-10, NRAMP-1, chitotriosidase, and chemokine receptor 5) and their intragenic polymorphic forms and to compare this data to the incidence and severity of C neoformans infection. With this study, we hope to identify a group of molecules of innate immunity which influence the risk and severity of invasive C neoformans infection.