Cryptococcal Meningitis

Cryptococcus
1. Fungal organisms, primarily of 2 species important to humans
  1. Cryptococcus neoformans
  2. Cryptococcus gatti
2. Cryptococcus is most commonly found in soil, decaying wood, tree hollows, bird droppings
Cryptococcosis
1. Fungal infection acquired via spore inhalation
2. Invasive fungal infection (esp. Meningitis) in Immunocompromised patients (esp. AIDS)
3. Infection may occur in immunocompetent patients, but is contained without hematogenous spread
  1. However, should that patient become Immunocompromised later, reactivation may occur

Invasive fungal infection in Immunocompromised patients
Facultative intracellular organisms
Most commonly caused by Cryptococcus neoformans
1. Cryptococcus gatti is less common, and may affect immunocompetent patients

Incidence
1. United States: 2-7 cases per 1000 AIDS patients (90% are Meningitis cases, 12% case fatality rate)
2. Worldwide: 1 Million cases annually (especially sub-Sahara Africa)
  1. Worldwide Deaths per year >600,000
  2. Responsible for 15% of AIDS related dealths worldwide

Consider in all at risk and known HIV patients with Headache
Advanced HIV (AIDS)
1. CD4 < 50 to 100 cells per mm3 or
2. AIDS-Defining Illness
Other Immunocompromised patients
1. Diabetes Mellitus
2. Chonic liver disease
3. Chronic Kidney Disease
4. Immunosuppression (e.g. longterm Corticosteroids, status-post organ transplant)

Insidious onset
1. Typically starts as occult, asymptomatic infection in 50% of cases, or non-specific symptoms
2. Inhalation of spores results in asymptomatic lung infection, and then spreads hematogenously
3. Typically develops over a 2 week period, ultimately manifesting as meningoencephalitis
Headache (91%)
Weight Loss (90%)
Fever (52%)
Malaise
Altered Level of Consciousness or confusion

Fever (91%)
Muscle wasting (90%)
Motor weakness (40%)
Cranial Nerve palsy (29%)
1. Hearing Loss
2. Vision Loss (Optic Neuritis related)
  1. May progress within 12 hours following onset of Optic Neuritis
Organ Involvement
1. Neurologic involvement (Meningitis) (85-90%)
2. Lung or skin involvement (25%)

Do not rely on lack of meningismus (meningeal signs) to exclude Cryptococcal Meningitis
1. Meningeal signs are only present in one quarter of Cryptococcal Meninigitis
Best outcomes are for early diagnosis and treatment (including lowering of Intracranial Pressure)

CT Head
1. Typically performed prior to Lumbar Puncture to exclude Brain Mass
2. Lumbar Puncture is considered safe when there is no brain shift or significant space occupying lesion

Blood Cultures positive (>75%)
Serum cryptococcal Antigen
1. Test Sensitivity: 98 to 99%
2. Test Specificity: 94%
3. High titer (>1024:1)
CSF Exam
1. General Findings
  1. CSF Glucose usually normal
  2. CSF Protein mildly elevated
  3. CSF White Blood Cell Count usually less than 20
2. Definitive Diagnosis
  1. India Ink stain usually shows organism (Test Sensitivity 60 to 80%)
    1. Cream-colored fungal colonies develop within 3-7 days on culture
    2. Indicated when CSF Cryptococcal Antigen test is unavailable
  2. CSF Cryptococcal Antigen test (>95% Test sensitive, specific)
3. Increased CSF Opening Pressure
  1. Typically CSF Opening Pressure >350 mm H2O in Crytococcal Meningitis
    1. Increased pressure results from high fungal burden in CNS interfering with CSF reabsorption
  2. Differential diagnosis (other causes of increased CSF Opening Pressure in HIV)
    1. Toxoplasma Encephalitis
    2. CNS Lymphoma
    3. Tuberculous Meningitis
  3. Risk of obstructrive Hydrocephalus presenting as cognitive deficit and ataxic gait
    1. High pressure responsible for adverse sequelae
  4. Therapeutic CSF removal is indicated when opening pressure >30 mm H2O
    1. Treat with serial LPs, lumbar drain or VP Shunt
    2. Goal CSF Pressure reduction by 50% or to <20 mm H2O (normal pressure)

Precautions
1. Start empiric therapy while awaiting definitive diagnosis when Cryptococcal Meningitis is suspected
2. Lower Intracranial Pressure as soon as possible (initially via Lumbar Puncture)
  1. Critical factor in best neurologic outcomes
  2. Goal CSF Pressure reduction by 50% or to <20 mm H2O (normal pressure)
Step 1: Initial Induction Phase - Combination Antimicrobial Therapy for 2 to 8 weeks
1. Amphotericin B (High dose) 0.7 mg/kg/day AND
2. Flucytosine (100 mg/kg/day)
Step 2: Repeat CSF with opening pressure at 2 weeks (or sooner depending on status)
1. Obtain repeat CSF Culture
  1. If positive, then continue combination therapy (as in step 1)
  2. If negative, then may transition to Fluconazole (see step 3 below)
2. Lower Intracranial Pressure as needed
  1. Serial Lumbar Puncture
  2. Lumbar drain
  3. VP Shunt
Step 3: Maintenance Antifungal after initial induction (in step 1)
1. Fluconazole (200 to 400 mg/day) for up to 1 year
Step 4: Prophylaxis after maintenance (if indicated)
1. Start after maintenance completed (step 3) if CD4 <100 cells/uL
2. Relapse occurs in >80% if no suppression given (if CD4 <100 cells/uL)
3. Fluconazole 200 mg/day

Immunocompetent Patients with Suspected Pulmonary Crytopococcus
1. Exclude Crytopococcal Meningitis with Lumbar Puncture first
2. Fluconazole 400 mg daily for 6 to 12 months
Avoid harmful measures
1. Avoid Dexamethasone
  1. Associated with increased mortality
  2. Beardsley (2016) N Engl J Med 374(6): 542-4 +PMID: 26863355 [PubMed]

Mada (2023) Cryptococcus, StatPearls, Treasure Island, FL
1. https://www.ncbi.nlm.nih.gov/books/NBK431060/