Cryptococcal Meningitis


Cryptococcal Meningitis Background and Pathophysiology

Cryptococcal meningitis is the most common cause of fungal meningitis and the most common cause of extrapulmonary cryptococcosis worldwide with over 220,000 cases per year and 181,000 deaths per year.1-5 In the United States alone, there are approximately 3,000 cases per year of cryptococcal meningitis, with 80% of those in occurring in HIV+ patients.6,7 Published incidence ranged from 0.04 to 12% per year among persons with HIV globally.8 Sub-Saharan Africa had the highest yearly incidence (median incidence 3.2%).8 While the lowest reported rates include the developed countries (</=0.1% each).  However, in the United States, the true incidence of cryptococcal meningitis is likely higher as cryptococcal meningitis is not a reportable disease in many states. While cryptococcal meningitis has the strongest association with patients suffering from HIV disease, other immunocompromised patients including those with cancer, iatrogenic immunosuppression, transplants, drug or alcohol abuse, chronic kidney disease, diabetes and other immunodeficiencies are at high risk as well.9-14

Cryptococcal meningitis is caused by inhalation of the etiologic agents Cryptococcus neoformans and Cryptococcus gatii, encapsulated fungi found in the environment, bird feces and decaying wood. Cryptococcal exposure is ubiquitous, especially in urban areas, as evidenced by high rates of antibody prevalence in adult and pediatric populations and is thought to be in-part a result of exposure to pigeon droppings.15,16 Globally, approximately 60% of HIV+ patients with CD4 counts less than 100 have cryptococcal antigenemia, though not all will develop disseminated disease.1 Despite high rates of antibody prevalence, Cryptococci primarily cause disease in immunocompromised hosts, but rarely lead to severe disease in immunocompetent patients.12

Cryptococcus neoformans and Cryptococcus gatti are fungi characterized by their high virulence and ability to cross the blood-brain-barrier, rapid antigenic variation in their polysaccharide capsule to evade host defenses, and environmentally stable spore form. After inhalation, Cryptococci colonize the lung parenchyma and in some patients, remain asymptomatic for prolonged periods. In others, especially those immunocompromised, they lead to local disease such as pneumonia. Their ability to evade host immune macrophage defenses, especially in the setting of an already impaired immune response, leads to disseminated infection and fungemia. From there, Cryptococci are uniquely capable of penetrating the blood brain barrier, leading to CNS infection and subsequent meningeal inflammation.17   

90-day mortality rate from cryptococcal meningitis continues to remain high, between 30–50% globally, even with appropriate antifungal therapy.8 There is an estimated 9% 3-month case-fatality rate among high-income regions, a 55% rate among low-income and middle-income regions, and a 70% rate in sub-Saharan Africa.8 Mortality is even higher in non-HIV patients because of the delayed diagnosis and dysfunctional immune responses.18 In addition to high mortality, cryptococcal meningitis carries substantial morbidity. Survivors can suffer from irreversible blindness and deafness, as well as neurocognitive impairments that impair their daily activities.19

Clinical Presentation of Cryptococcal Meningitis

The clinical course of cryptococcal meningitis is variable, although typically presents as a subacute meningoencephalitis characterized by an initially indolent course for days to weeks that progressively worsens.12,20 The average time from symptom onset to presentation for medical care is 2 weeks in HIV+ individuals and up to 6-12 weeks non-HIV associated cryptococcal meningitis cases.21  Additionally, cryptococcal meningitis may be the initial AIDS-defining illness in up to 84% of patients.22 Due to its inhalational spread, Cryptococcus may also present with the signs and symptoms of either a pneumonia or upper respiratory infection, in addition to typical meningitis symptoms. Patients may present with symptoms of subacute headache, fever, neck pain and stiffness, nausea, vomiting, lethargy, altered mental status, new-onset psychosis, vestibular disturbances, or photophobia. 12,13,23-31 Classical features of “meningism” (e.g., neck stiffness) occur in 20-30% of these patients.29 Altered mental status portends a worse prognosis.6,26,32

Likewise, intracranial pressure (ICP) is often elevated in up to 75% of these patients,33 and may present with cranial nerve lesions,34,35 dysarthria,36 ataxia, paraparesis, and hemiparesis.12,34,37,38 CNS infection may be complicated by a mass lesion (cryptococcomas), which are more common with C. gattii than C. neoformans. Clinical sequelae include hydrocephalus, elevated ICP, and blindness. Up to 40% of patients will have ophthalmic involvement, including papilledema, immune-mediated optic nerve dysfunction, and uveitis with multifocal chorioretinitis. 19,39,40 Patients may also have intracranial41-44 or spinal cord abscess formation.45

Many patients may also have signs of severe immunocompromised, including opportunistic infections. One study reported an incidence of co-infection with oral candidiasis of 52% in patients presenting with cryptococcal meningitis.46 Similarly, the presence of skin lesions often contain the infecting organism. In the severely immunocompromised, disseminated disease (involvement of two or more sites or organs) may present as an isolated rash with associated fever before other signs and symptoms. It must also be noted that immunosuppressed patients may not elicit a fever with cryptococcal meningitis. Other non-CNS manifestations of disseminated Cryptococcus include soft tissue infections, 23,47,48 and pulmonary involvement, including cavitating or nodular lesions.36,39,42,48-50 Clinical features of cryptococcal meningitis and their associated incidence is provided below (Table 1).

Clinical FeatureIncidence at presentation
Elevated intracranial pressureUp to 75%
Evidence of opportunistic infectionsUp to 50%
Ocular involvementUp to 40%
Evidence of disseminated infection (2 or more sites of cryptococcal infection)33%
Neck stiffness20-30%
Altered mental status25%
Focal neuologic deficits (including cranial neuropathies)6%

Table 1. Clinical features of cryptococcal meningitis.

Diagnosis and Investigations of Cryptococcal Meningitis

Diagnosis of cryptococcal meningitis in the acute setting is presumptive, as the initial clinical presentation may be indistinguishable from several different CNS pathologies (Table 2). Emergency providers must have a high index of suspicion for cryptococcal meningitis in the immunocompromised patient. This is especially true for patients with repeated visits for increasing and atypical neurological symptoms including headache. Many missed cases of cryptococcal meningitis are due to not considering cryptococcal meningitis on the differential.

– Bacterial meningitis
– Viral meningitis
– Intracranial hemorrhage
– Intracranial neoplasm
– Behçet syndrome
– Benign recurrent lymphocytic meningitis (Mollaret meningitis)
– Central nervous system abscess
– Drug-induced meningitis
– Ehrlichiosis
– Fungal meningitis
– Human immunodeficiency virus
– Leptomeningeal carcinomatosis
– Lymphomatous meningitis
– Neoplastic meningitis
– Neurosarcoidosis
– Systemic lupus erythematosus
– Multiple sclerosis
– Acute disseminated encephalomyelitis
– Anti-NMDA receptor encephalitis
– Vasculitis
– Lymphochoriomeningitis virus (LCMV)
– Paraneoplastic encephalomyelitis
– Neurosyphilis*
– Parasitic meningitis*
– Lyme disease (neuroborreliosis)*
– Tuberculous meningitis*

Table 2. Selected differential diagnosis for Cryptococcal meningitis. * More common in geographic areas with higher incidence of these infections.

Diagnostic evaluation in the ED includes a thorough history and physical examination, with special attention paid to subtle neurologic findings, evidence of disseminated cryptococcal meningitis, and evidence of any co-infections with opportunistic organisms (Table 1). While the physical exam may raise suspicion for cryptococcal meningitis, it is not diagnostic in-and-of itself.

Laboratory investigations should be guided by clinical presentation, but may include a CBC, serum chemistries, urinalysis, urine pregnancy, and inflammatory markers (CRP and ESR). In addition, blood, urine and sputum cultures (with special attention towards obtaining appropriate fungal cultures) should be sent. Blood cultures are positive for cyptococci in approximately 66% of cryptococcal meningitis cases.51 Similarly, HIV testing may be sent in order to ascertain HIV status, although this may not result while the patient is in the ED.12 In the case of suspected co-infection with tuberculosis (TB), sputum studies and culture may be obtained. Traditional testing for cryptococcal meningitis includes lumbar puncture with cerebral spinal fluid (CSF) analysis including cell culture, protein, glucose, India ink staining, and fungal culture.12,13 CSF studies characteristically show an elevated white blood cell count (WBC) with a predominant lymphocytosis, elevated protein levels and distinctive low glucose levels.12,13 However, CSF may be normal in up to 17% of patients, especially in HIV-positive populations.22,26,52 Similarly, India ink staining of CSF is between 42-86% sensitive for diagnosing cryptococcal meningitis, and is largely dependent on the microbiologist’s expertise.53,54 Although readily available, the use of the India ink as the sole means of diagnosis resulted in a misdiagnosis in 1 of every 11 persons presenting with cryptococcal meningitis in one Ugandan study.53 It is important to remember that normal CSF studies are inadequate to rule out cryptococcal meningitis in any patients. CSF culture is the current gold-standard, but commonly takes up to 10 days to result.12 Additional CSF testing in immunocompromised individuals at risk for cryptococcal meningitis are provided below (Table 3).

Standard cerebrospinal fluid studies
– Opening pressure
– White blood cell count
– Protein level
– Glucose level
– Gram stain
– India ink stain
Additional cerebrospinal fluid studies in immunocompromised individuals
– Cryptococcal studies (dependent on availability):
o Polymerase chain reaction
o Cryptococcal antigen
o Lateral flow assay
o Latex agglutination
o Culture
– Cytomegalovirus polymerase chain reaction
– Epstein bar virus polymerase chain reaction
– Human herpes virus 6 polymerase chain reaction
– Varicella zoster virus polymerase chain reaction and antibodies (IgG and IgM)
– Listeria polymerase chain reaction
– Wright or Giemsa stain (toxoplasmosis)
Additional studies to consider in appropriate clinical context
– West nile virus IgG/IgM and polymerase chain reaction (seasonal risk)
– Acid fast bacilli stain and culture (Tuberculosis)
– Coccidioides IgG/IgM and coccidioidal antigen levels (geographical risk)

Table 3. Cerebrospinal fluid testing in suspected cryptococcal meningitis.

Recently, newer diagnostic studies have evolved, including cryptococcal antigen (CrAg) testing, which is primarily used to screen for subclinical cryptococcal infection prior to initiating ART in HIV+ patients.12 Cryptococcal antigen (CrAg) can be detected in CSF or peripheral blood samples via latex agglutination testing also with over 99% sensitivity and specificity with results in several hours.53 Newer point-of-care (POC) diagnostic studies include the Lateral Flow Assay (LFA) which gives results within in minutes and can be performed on CSF, blood or urine.12 LFA is over 99% sensitive and specific for diagnosis of cryptococcal meningitis when CSF is obtained.53,55 There is increased sensitivity with increasing amounts of CSF sampled.55 Similar sensitivity to CSF was seen on LFA with serum and urine samples.56 Fingerstick LFA has reported 100% concordance with serum results.57 However, both latex agglutination and LFA testing requires laboratory infrastructure and resources which may not be available in every ED.

Imaging has little role in the diagnosis of cryptococcal meningitis, but may be obtained to evaluate for other potential diagnoses and complicaitons.13 A chest x-ray may be useful, as crytpococcus initially infects the lungs. Chest x-ray findings can include pulmonary nodules, most commonly in the middle and upper lobes.58 There may be diffuse micronodular opacities mimicking TB or pulmonary nodules with central cavitation.59 Decision to perform computed tomography (CT) imaging of the brain prior to LP should be considered. Data supporting routine head CT prior to LP in suspected meningitis is limited.60 Physicians should consider selective CT for those patients at risk for intracranial mass effect lesions based on decision rules or clinical gestalt. Importantly, imaging should never delay appropriate management, and patients undergoing head CT must receive immediate antibiotic therapy. Leptomeningial enhancement is classically seen on CT consistent with cryptococcal meningitis, but CT findings may be normal, or nonspecific.13 CT imaging with contrast enhancement may show multiple small nodules, it is easy to be misdiagnosed as cerebral metastasis.61 Complications of cryptococcal meningitis may also be seen- most commonly cryptococcomas with associated mass effect, and non-communicating hydrocephalus.12

Management of Cryptococcal Meningitis

Proper management of cryptococcal meningitis is dependent on prompt diagnosis. Emergency physicians must have a high clinical suspicion for cryptococcal meningitis, especially in patients who are immunocompromised, with subacute symptoms. Have a low threshold to perform LP on these patients with risk factors or signs and symptoms of cryptococcal meningitis. As a definitive diagnosis of cryptococcal meningitis will not be made in the ED, patients should be treated empirically for bacterial, fungal, and viral meningitis. Potential regimens are provided below in Table 4. Additionally, appropriate resuscitation and supportive care, including advanced airway management, antipyretics, intravenous fluids, and isolation should be initiated. Patients should be evaluated for elevated ICP and aggressive management should be pursued if indicated. Of note, intravenous dexamethasone administration has not been shown to reduce mortality but rather has been associated with higher rates of mortality, disability, and adverse events.62 As such, it is not recommended in the treatment of cryptococcal meningitis.18,63

Antibacterial regimen
– Ceftriaxone 2 grams IV q12hr
o If the patient has a history of penicillin anaphylaxis or cephalosporin allergy, may substitute with meropenem 2g IV q8hr.

– Listeria coverage in patients >50 years old, pregnant, or immunocompromised
o Ampicillin 2 grams IV q4hr
o Note: ampicillin is not required for patients receiving meropenem

– Cephalosporin-resistant pneumococcus coverage
o Vancomycin 15 to 20 mg/kg IV q8-12hr (not to exceed 2 g per dose or a total daily dose of 60 mg/kg)
o Rifampin 600 mg q12hr
Antiviral regimen
– Acyclovir 10 mg/kg IV
– Consider doxycycline 100 mg q12hr if rocky mountain spotted fever or tick-borne encephalitis is possible
Antifungal regimen
– Preferred regimen:
o Amphotericin B deoxycholate 0.7 to 1.0 mg/kg/day AND flucytosine 100 mg/kg/day
o Liposomal amphotericin B 3 to 4 mg/kg/day AND flucytosine 100 mg/kg/day
o Amphotericin B lipid complex 5 mg/kg/day AND flucytosine 100 mg/kg/day

– If unable to obtain flucytosine:
o Amphotericin B deoxycholate 0.7 to 1.0 mg/kg/day
o Liposomal amphotericin B 3 to 4 mg/kg/day
o Amphotericin B lipid complex 5 mg/kg/day
o Amphotericin B deoxycholate 0.7 to 1.0 mg/kg/day AND fluconazole 800-1,200 mg/day

– If unable to obtain amphotericin:
o Flucytosine 100 mg/kg/day AND fluconazole 800-1,200 mg/day
o Fluconazole 800-1,200 mg/day

Table 4. Empiric regimen for suspected cryptococcal meningitis.

Antifungal therapy in the ED is focused on initial induction intended to rapidly sterilize the CSF.12,13 Recommended induction therapy for all patients with suspected cryptococcal meningitis irrespective to immunosuppressed status is with intravenous Amphotericin B and oral flucytosine for two weeks.18 Flucytosine is only available in oral form, and if the patient is too obtunded to swallow, it will need to be given via enteric access. Alternative antifungal regimens can be considered in resource-limited settings or depending on hospital formulary.18 Either Amphotericin B alone, or amphotericin B and high dose fluconazole high (800-1,200 mg/day) is recommended if flucytosine is unavailable.18 Amphotericin B is relatively easy to obtain in the United States, although two weeks of oral flucytosine (100 mg/kg/day) and fluconazole (800-1,200 mg/day) as a substituted if amphotericin B is unavailable.18 In the absence of both amphotericin B and flucytosine, high dose fluconazole at 800-1,200 mg/day is recommended for two weeks.12  

Note that amphotericin B comes in multiple forms, and liposomal Amphotericin B is the recommended form (dosing is 3-4mg/kg/day).18,63 Amphotericin B deoxycholate is the most commonly used form worldwide and is comparatively less-expensive. It is important to note that the recommended dosage is 0.7-1 mg/kg/day for the deoxycholate form.18,63

Elevated ICP in CM is caused by failure of CSF resorption in the arachnoid villa due to obstruction from the Cryptococcal polysaccharide capsule. Elevated ICP should be aggressively managed in the setting of suspected cryptococcal meningitis. Opening pressure should be measured during LP and therapeutic CSF drainage should be performed for pressures ≥25 cm H20.12,13,30 This is especially important in the setting of cranial nerve palsies, papilledema or other symptoms of elevated ICP (headaches, nausea, vomiting, or visual changes). Up to 30 mL of CSF can be safely drained via LP.  For persistent hydrocephalus, a neurosurgery consult is warranted for ventriculoperitoneal shunt placement.18 Serial LP’s and antifungal therapy are adequate for treatment of elevated ICP in the majority of patients. Shunt placement is considered for refractory headache after LP, no decrease in opening pressure after three serial LP’s and patient inability to tolerate serial lumbar punctures.64   The usage of mannitol, hypertonic saline, acetazolamide and corticosteroids in the setting of hydrocephalus are not indicated for management of elevated ICP.65

Prognosis is variable, with a an estimated 9% 3-month case-fatality rate among high-income regions, a 55% rate among low-income and middle-income regions, and a 70% rate in sub-Saharan Africa.8 Poor prognostic indicators are provided below (Table 5).

Prognostic factors in cryptococcal meningitis
– Abnormal mental status (due to encephalitis and/or increased intracranial pressures)
– Cerebrospinal fluid (CSF) antigen titer >1:1024 (high burden of yeasts)
– CSF white blood cell count <20/microL
– CSF opening pressure of ≥25 cm of water
– Sensory impairment
– Delayed diagnosis
– Rate of infection clearance
– Non-HIV-related patients and the prognostic factors in these patients, in addition to the already mentioned:
o Markers of a poor inflammatory response
o Absence of headache
o Underlying hematological malignancy
o Chronic renal or liver disease

Table 5. Prognostic factors for cryptococcal meningitis.

Take Home Points

  • Cryptococcal meningitis is the most common cause of fungal meningitis and the most common cause of extrapulmonary cryptococcosis worldwide with over 220,000 cases per year, and a mortality of ~30% worldwide.1-5
  • Cryptococcal meningitis occurs primarily in immunocompromised patients. Patients with HIV, cancer, iatrogenic immunosuppression, transplants, drug or alcohol abuse, chronic kidney disease, diabetes and other immunodeficiencies are at high risk.9-14
  • The clinical course of cryptococcal meningitis is variable, although it typically presents as a subacute meningoencephalitis characterized by an initially indolent course of neurological symptoms including headache, altered mental status, lethargy, fever, meningismus, nausea and vomiting for days to weeks that progressively worsens.12,20
  • Cryptococcal meningitis may be the initial AIDS-defining illness in up to 84% of patients.22 
  • Emergency providers must have a high index of suspicion for cryptococcal meningitis in the immunocompromised patient. This is especially true for patients with repeated visits for increasing and atypical neurological symptoms including headache.
  • Initial CSF studies (including India ink stain) may be normal in up to 17% of patients, especially in HIV-positive populations.22,26,52 CSF culture is the current gold-standard for ruling in or out cryptococcal meningitis , but commonly takes up to 10 days to result.12
  • Patients should be treated empirically for bacterial, fungal, and viral meningitis.
  • Initial antifungal regimen for cryptococcal meningitis includes Amphotericin B deoxycholate (0.7 to 1.0 mg/kg/day) + flucytosine (100 mg/kg/day orally) for 2 weeks.

FOAM Resources


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