Cryptococcal Meningitis

Creator: Dr. Smitha S. Dutt
Keywords: Cryptococcal meningitis, Cryptococcus neoformans, fungal infection

Medically Reviewed by Dr. Lakshmi Venkataraman, MD on Apr 02, 2018

What is Cryptococcal Meningitis?

Cryptococcal meningitis is an infection of the meninges (membranes covering the spinal cord and brain), which is caused by the fungus Cryptococcus neoformans. This fungus is found in the environment (soil contaminated with bird excreta, e.g. pigeons; decaying wood) all over the world. Although many of us may inhale this fungus, only those with weak or compromised immune systems are prone to a serious infection in the brain.

There has been a rise in the incidence of cases of cryptococcal meningitis in the world due to immunosuppressive treatments and diseases such as late-stage HIV infection. Cryptococcal meningitis cases that are associated with HIV have been observed in large numbers in South and East Africa as well as Southeast Asia.

Every year, nearly 212 000 cases of cryptococcal meningitis cases are reported with nearly 181000 deaths. However, with the current antiretroviral therapy (ART), many HIV cases in developed countries are being protected from this infection.

What are the Causes of Cryptococcal Meningitis?

Cryptococcal meningitis is caused by the fungus (yeast) Cryptococcus neoformans. In addition, C. gattii (found in decaying wood and eucalyptus trees of the subtropical and tropical regions)is also known to cause cryptococcal meningitis in individuals with weak immune systems in certain specific regions of the world.

Cryptococcal meningitis usually occurs on its own (solitary) or in association with other conditions, such as focal skin lesions, HIV, or pneumonia.

Transmission of Cryptococcal Meningitis

Fungal meningitis does not spread from person to person. Instead, an individual acquires the infection following inhalation of soil particles contaminated by bird droppings.

The fungus first affects the body, and then spreads to the brain resulting in cryptococcal meningitis.

What are the Risk Factors of Cryptococcal Meningitis?

Cryptococcal meningitis occurs in individuals with compromised immune systems that arise due to illnesses or surgery. Following are the factors that increase the risk of being susceptible to cryptococcal infection:

Weak immune system as seen in conditions, such as HIV, lymphoma, leukemia
Immune suppressing medications
Congenital (present at birth) immunodeficiency states
Diabetes mellitus
Rheumatological diseases
Hematological conditions
Kidney and liver diseases
Organ transplants

What are the Symptoms and Signs of Cryptococcal Meningitis?

Some of the signs and symptoms of cryptococcal meningitis are:

Nausea
Headaches
Fever
Changes in mental status (confused state or coma)
Vomiting
Pain in the neck and stiffness
Hypersensitivity to light
Hallucinations
Increased pressure within the CSF (intracranial pressure - ICP) - ≥ 25 cm H2O
Abnormalities in the nerves of the cranium
Cerebral edema �C fluid accumulation occurs due to ICP in HIV-negative patients

Cryptococcal meningitis can cause complications, such as hydrocephalus, hearing loss, seizures and damage to the brain.

How do you Diagnose Cryptococcal Meningitis?

Cryptococcal meningitis is diagnosed by cell culture, staining and imaging methods.

The first step in diagnosing cryptococcal meningitis is to perform a physical examination and identify the relevant symptoms, such as high fever, stiffness of the neck, and altered mental condition.

Imaging: Brain magnetic resonance imaging or MRI may reveal lesions in different regions of the brain (basal ganglia, parenchyma, the meninges, and the midbrain). A CT scan does not reveal too many details but may allow detection of excess cerebrospinal fluid (CSF) in the brain (hydrocephalus), multiple or single lesions, and swelling within the brain (edema).

Staining: A quick and easy way to identify infection is to stain the CSF with India ink. However, the test is not sensitive enough and leads to misdiagnosis especially in patients where the infection is in its early stages.

Lumbar puncture: Fluid (CSF) from the spinal cord is obtained through lumbar puncture and tested for its cell count, antibodies to cryptococcal protein and glucose levels.

Cell culture: Culturing fungi (detecting fungal growth in medium using CSF samples) is an effective way to detect infection or understand the effect of treatment response.

Dipstick test: Detecting cryptococcal antigens (CrAg) in CSF is very sensitive and has been made cost effective through a cheap assay (CrAg LFA or dipstick test) that uses gold-linked anti-cryptococcal antibodies to detect the fungi. This point-of-care assay does not require extensive laboratory resources, is cheap, and provides the result in 10 minutes. The assay can be used to test a small amount of serum or plasma of blood to detect cryptococci. The test is able to screen infected individuals and helps to prevent death due to cryptococcal meningitis. This is a very useful test in low-income countries where resources are limited.

How do you Treat Cryptococcal Meningitis?

Induction, consolidation phase and maintenance phase with drugs form the 3 stages of treatment.

Induction: The main goal is to sterilize the CSF. This is measured as the rate at which the fungus is cleared from each ml of CSF in a day. The measured indicator is called early fungicidal activity (EFA). The recommended drugs used are amphotericin B (0.7-1 mg/kg per day) and flucytosine (100 mg/kg/day) in combination for 2 weeks. In the absence of flucytosine, a combination of amphotericin B with fluconazole (�� 800 mg/day) is recommended. If amphotericin B and flucytosine are unavailable or highly restrictive due to costs, WHO recommends the use of fluconazole (1200 mg/day) for 10 to 12 weeks.

Consolidation: Following 2 weeks of induction therapy, patients should be placed on 400-800 mg/day fluconazole for a minimum of 8 weeks. The CSF should be tested regularly to see if it is sterile and free of infection. Following confirmation of CSF sterility, the fluconazole dose can be reduced to 400 mg/day.

Maintenance: Once induction and consolidation therapy results in sterile CSF, patients are maintained on 200 mg/day of fluconazole to prevent infection.

Antiretroviral Therapy (ART): Since many patients who develop cryptococcal meningitis are HIV-infected patients, they need to be first screened for cryptococcal infection (targeted screening) before being treated with antiretroviral therapy (ART). It has been observed that ART is effective only when administered 2 weeks following induction therapy. It has been noted that the optimal period to begin ART therapy is 4 weeks following diagnosis.

It is important to note that cryptococcal meningitis should first be treated before starting ART therapy. If meningitis is not treated initially before ART, there is an increased risk of mortality.

Voriconazole and IFN-g are used in patients who do not respond to the traditional amphotericin-flucytosine/fluconazole treatment.

How do you Prevent Complications due to Cryptococcal Meningitis?

Putting in place effective screening (targeted screening) measures in high risk population to diagnose cryptococcal infection (dipstick test) before meningitis sets in
Making available essential drugs such as amphotericin B and flucytosine, in Africa and other developing nations
Cryptococcal meningitis is characterised by increased ICP and this can lead to consequences such as vomiting, headaches, reduced vision, confusion, blindness, and coma. These complications can be avoided by performing regular lumbar punctures to reduce the pressure when it increases beyond 25 cm H₂O. Constant monitoring of ICP is a good way to reduce the risk of mortality.
Drugs, such as corticosteroids and mannitol should not be used on a regular basis to measure ICP.
Drug toxicities are common with amphotericin treatment. Increasing the administration of saline during IV administration of amphotericin helps to reduce kidney injury. Administering amphotericin once every 2 days is another effective strategy. Rigors and fever that sets in during IV administration of amphotericin can be treated with acetaminophen or hydrocortisone if it becomes severe.
Electrolyte supplementation should be provided to the patient to stem loss of magnesium and potassium that occurs due to amphotericin treatment.

References:

Meningitis � Cryptococcal. Published Nov 27, 2016; Accessed Mar 20, 2016; Cited Mar 20, 2016.
Bicanic T, Harrison TS. Cryptococcal meningitis. Br. Med Bull. 2004; 72(1):99-118.
Preventing deaths from cryptococcal meningitis. Published Sep 30, 2014. Updated Jul 20, 2017; Accessed Mar 20, 2016; Cited Mar 20, 2016.
Saag MS et al. Practice guidelines for the management of cryptococcal disease. Clin Infect Dis. 2000;30(4):710-718.
Tenforde MW, Scriven JE, Harrison TS, Jarvis JN (2017) Immune correlates of HIV-associated cryptococcal meningitis. PLoS Pathog 13(3): e1006207.
Cryptococcal meningitis. Published Nov 1, 1994; Accessed Mar 20, 2018; Cited Mar 20, 2018.
Cryptococcus: Screening for opportunistic infection among people living with HIV/AIDS. Accessed Mar 20, 2018.
Abassi M, Boulware DR, Rhein J. Cryptococcal Meningitis: Diagnosis and Management Update. Current tropical medicine reports. 2015;2(2):90-99. doi:10.1007/s40475-015-0046-y.
Vidal JE, Boulware DR. Lateral flow assay for cryptococcal antigen: An important advance to improve the continuum of HIV care and reduce cryptococcal meningitis-related mortality. Revista do Instituto de Medicina Tropical de S�o Paulo. 2015;57(Suppl 19):38-45. doi:10.1590/S0036-46652015000700008.
Govender NP et al. Guideline for the prevention, diagnosis and management of cryptococcal meningitis among HIV-infected persons: 2013 update. SAJHIVMED. 2013;Vol.14(2):76-86.

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