Cryptococcal Meningitis

Incidence
1. United States: 2-7 cases per 1000 AIDS patients
2. Worldwide: 1 Million cases annually (especially sub-Sahara Africa)
  1. 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

Insidious onset
1. Typically starts as occult, asymptomatic infection in 50% of cases
2. Typically develops over a 2 week period
3. Symptoms are often nonspecific at onset
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. Glucose usually normal
  2. Protein mildly elevated
  3. White Blood Cell Count usually less than 20
2. Definitive Diagnosis
  1. India Ink stain usually shows organism (Test Sensitivity 60 to 80%)
    1. Indicated when CSF Cryptococcal Ag test is unavailable
  2. CSF Cryptococcal Ag 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)
First-Line Combination Antibiotic Therapy
1. Amphotericin B (High dose) 0.7 mg/kg/day AND
2. Flucytosine (100 mg/kg/day)
Continue to lower Intracranial Pressure as needed
1. Serial Lumbar Puncture
2. Lumbar drain
3. VP Shunt
Fluconazole (200 to 400 mg/day) Indications
1. Normal Mental Status at baseline
2. Time to sterilization of CSF is slower
3. Prefer Amphotericin B (short course first)
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]