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CRYPTOCOCCAL MENINGITIS

AYESHA FAREEDPHARM D

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The genus Cryptococcus contains at least 39 species of yeast, but few are able to cause disease in humans.

Most human infections are due to C. neoformans.

Infection with the fungus Cryptococcus (either C. neoformans or C. gattii) is called cryptococcosis.

Cryptococcosis is a global invasive mycosis associated with significant morbidity and mortality.

Cryptococcosis usually affects the lungs or the central nervous system (the brain and spinal cord), but it can also affect other parts of the body.

Brain infections due to the fungus Cryptococcus are called cryptococcal meningitis.

Cryptococcus neoformans is a fungus that lives in the environment throughout the world.

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Cryptococcus neoformans is dimorphic, existing in the asexual yeast form characterized by oval to spherical cells with a polysaccharide capsule, and in the sexual or perfect state characterized by the presence of basidiospores.

C. neoformans is readily cultured in the laboratory, producing mucoid colonies within 36–72 h, although growth is inhibited at 37 °C.

Colonies are white to cream in colour, but characteristic dark brown colonies are formed when grown on birdseed agar.

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C. neoformans infections are not contagious. Humans and animals can get the infection after inhaling the microscopic fungus from the environment.

Meningitis is the most common manifestation of cryptococcal infection.

The lung is the second most common organ to develop clinical disease, usually pneumonia, which can occur in the immunocompetent

The skin is the third most common organ to be affected by cryptococcal infection

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EPIDEMIOLOGY

Cryptococcosis is a rare infection in healthy human population

C. neoformans is a major cause of illness in people living with HIV/AIDS, with an estimated 1 million cases of cryptococcal meningitis occurring worldwide each year.

Most cases occur in the 20–50 years old age group.Global burden of HIV-related cryptococcal meningitis

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Causes of death in sub-Saharan Africa, excluding HIV/AIDS

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Most cases of C. neoformans infection occur in people who have weakened immune systems, such as people who:

• Have advanced HIV/AIDS,• Have had an organ transplant• Sarcoidosis;• Lymphoproliferative disorder;• Hypogammaglobulinaemia;• Systemic lupus erythematosus;• Cirrhosis;• Peritoneal dialysis• Are taking corticosteroids, medications to treat rheumatoid arthritis,

or other medications that weaken the immune system.

WHO ARE AT RISK?

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In the BRAIN (cryptococcal meningitis)

Cryptococcal meningitis is an infection caused by the fungus Cryptococcus after it spreads from the lungs to the brain. The symptoms of cryptococcal meningitis include:

• Headache• Fever• Neck pain; neck rigidity• Nausea and vomiting, lethargy, personality change, memory loss• Sensitivity to light• Confusion or changes in behavior

• The duration of symptoms before presentation is likely to be longer in non-AIDS patients, with a history of more than 2 weeks in only 25% of HIV positive patients.

CLINICAL PRESENTATION:

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DIAGNOSIS :

Definitive diagnosis of cryptococcal meningitis requires lumbar puncture with demonstration of yeasts with India ink stain, positive cryptococcal antigen testing or culture of the organism.

CSF EXAMINATION:

CSF examination generally reveals a mild mononuclear leucocytosis (50–500 cells/μL).

The CSF protein is rarely greater than 500–1000 mg/Dl and it may be normal, especially in HIV patients.

In HIV patients, the cell count is usually much lower, and often in single figures.

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IMAGING:

CT brain scan is normal in 50% of patients with cryptococcal meningitis. The most common abnormal finding is hydrocephalus

Magnetic resonance imaging is more likely to demonstrate abnormalities than CTScanning.

DIAGNOSTIC TECHNIQUES:

India ink test

The CSF India ink test is a simple and relatively sensitive test that enables the rapid diagnosis of cryptococcal meningitis.

Yeast cells are easily identified through the halo effect that occurs around them because of the glucuronoxylomannan capsule.

A concentration of yeasts less than 104 colony forming units (CFU) is unlikely to be detected.

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CSF smear examined for acid and alcohol fast bacilli to exclude TB.

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CULTUREC. neoformans from CSF or blood grows readily on blood or Sabouraud’s agar at 35 °C. Identification can be confirmed through the demonstration of capsule growth on corn meal agar, development of characteristic brown mucoid colonies on birdseed agar, and through commercially available sugar assimilation test kits.

C. neoformans grows easily in commercially available automated blood culture systems. Culture of CSF is more sensitive in detecting cryptococcal infection than the India ink test, with a sensitivity approaching 90%.

CRYPTOCOCCAL ANTIGENCryptococcal antigen testing is both sensitive and specific in identifying patients with cryptococcal disease.

The kits can be used on serum or CSF and the sensitivity in CSF is greater than 90% in cryptococcal meningitis.

SEROTYPINGThere are immunotyping kits to distinguish the various cryptococcal serotypes. However, they are expensive.

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TREATMENT

Anti-fungal drug options for cryptococcal disease are limited.

There are three phases – induction, consolidation and maintenance (also known as secondary prophylaxis).

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Continuation of combination induction therapy beyond 2 weeks may be considered if:

(1) A patient remains comatose; (2) The patient is clinically deteriorating;(3) The patient has not improved, with persisting elevated, symptomatic intracranial pressure; and/or (4) The results of CSF culture obtained after 2 weeks of induction therapy is anticipated to remain positive.

These patients may require additional weeks (eg, 1–6 weeks) of the induction phase oftreatment.

Maintenance (suppressive) and prophylactic therapy:

Maintenance therapy should be initiated after completion of primary therapy with an induction and consolidation regimen.

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ORGAN TRANSPLANT RECIPIENTS:

Regimen Duration Evidence Induction therapy:(a)

liposomal AmB (3–4 mg/kg per day) orABLC (5 mg/kg per day) plus flucytosine (100 mg/kg per day)

2 weeks B-III

Alternatives for induction therapy:

Liposomal AmB (6 mg/kg per day) or ABLC (5 mg/kg per day)

4–6 weeks B-III

AmBd (0.7 mg/kg per day)b 4–6 weeks B-III

Consolidation therapy:

fluconazole (400–800 mg per day)f 8weeks B-III

Maintenance therapy:

fluconazole (200 mg per day)b 6 - 12weeks B-III

a Immunosuppressive management may require sequential or step-wise reductions.b Many transplant recipients have been successfully treated with AmBd; however, issues of renal dysfunction with calcineurin inhibitors are important and the effective dose is imprecise.

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Regimen Duration Evidence

Induction therapy:AmBd (0.7–1.0 mg/kg per day) plus flucytosine (100 mg/kg per day)

≥4 weeks a,b

B-II

AmBd (0.7–1.0 mg/kg per day)c ≥6 weeks a,b

B-II

Liposomal AmB (3–4 mg/kg per day) or ABLC (5 mg/kg per day) combined with flucytosine, if possible d

≥4 weeks a,b

B-III

AmBd (0.7 mg/kg per day) plus flucytosine (100 mg/kg per day)e

2 weeks B-II

Consolidation therapy:fluconazole (400–800 mg per day)f 8weeks B-IIIMaintenance therapy:fluconazole (200 mg per day)b 6 -

12weeksB-III

Non–HIV Infected and Nontransplant Patients:

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a Four weeks are reserved for patients with meningitis who have no neurological complications, who have no significant underlying diseases or immunosuppression, and for whom the cerebrospinal fluid culture performed at the end of 2 weeks of treatment does not yield viable yeasts; during the second2 weeks, lipid formulations of AmB may be substituted for AmBd.

b Fluconazole is given at 200 mg per day to prevent relapse after induction therapy, and consolidation therapy is recommended.

c For flucytosine-intolerant patients.

d For AmBd-intolerant patients.

e For patients who have a low risk of therapeutic failure. Low risk is defined as an early diagnosis by history, no uncontrolled underlying condition orsevere immunocompromised state, and an excellent clinical response to initial 2-week antifungal combination course.

f A higher dosage of fluconazole (800 mg per day) is recommended if the 2-week induction regimen was used and if there is normal renal function

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NONMENINGEAL CRYPTOCOCCOSISPatient group Initial

antifungal regimen

Duration Ev.

Immunosuppressed patients and immunocompetentpatients with mild-to-moderate pulmonarycryptococcosis

Fluconazole (400 mg per day)

6–12 months

B-III

Immunosuppressed patientsa and immunocompetent patientswith severe pulmonary cryptococcosis

Same as CNS disease

12 months B-III

Patients with nonmeningeal, nonpulmonary cryptococcosisPatients with cryptococcemia Same as CNS

disease12 months B-

III

Patients for whom CNS disease has been ruled out with no fungemia, with a single site of infection, and with no immunosuppressive risk factors

Same as CNS disease

6-12 months

B-III

A Should directly rule out CNS disease with lumbar puncture.

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REFERENCES:

1. John R. Perfect, et.al. Clinical Practice Guidelines for the Management of Cryptococcal Disease: 2010 Update by the Infectious Diseases Society of America.

2. Jeremy N Day Clinical Research Fellow, Oxford University Clinical Research Unit, Hospital for Tropical Diseases, 190 Ben Ham Tu, Quan 5, Ho Chi Minh City, Viet Nam; Practical Neurology, 2004, 4, 274–285.

3. Southern African HIV Clinicians Society, Guideline for the prevention, diagnosis and management of cryptococcal meningitis among HIV-infected persons: 2013 update , S Afr J HIV Med 2013;14(2):76-86. DOI:10.7196/SAJHIVMED.930

4. http://www.cdc.gov/fungal/diseases/cryptococcosisneoformans/