Cryptococcal Meningitis: ED presentations, evaluation, and management

Authors: Kathryn Fisher (@KatieFisherEM, McGovern Medical School at UT Health Emergency Medicine Residency Program) and Tim Montrief, MD (@EMinMiami), University of Miami/Jackson Memorial Hospital Emergency Medicine Residency Program // Edited by Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

Case:

A 49-year-old man with a history of HIV (unknown CD4 count) and alcohol abuse presents to the ED. He complains of persistent headache and chills for the past three weeks with mild photophobia. He states that he recently began anti-retroviral therapy three months prior. His heart rate is 104 beats per minute, but all other vitals are within normal range. His neurologic exam is notable for an isolated cranial nerve VI palsy on the left side. What is on your differential for this patient? What are your next steps?

Background

Cryptococcal meningitis (CM) 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 CM, with 80% of those in occurring in HIV+ patients.^6,7  Published incidence ranged from 0.04-12% per year among persons with HIV globally.⁸  Sub-Saharan Africa has the highest yearly incidence (median incidence 3.2%),⁸  though the lowest reported rates include developed countries (</=0.1% each).  However, in the United States, the true incidence of CM is likely higher, as CM is not a reportable disease in many states. While CM 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

CM 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 < 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 CM 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, CM carries substantial morbidity. Survivors can suffer from irreversible blindness and deafness, as well as neurocognitive impairments that impair their daily activities.¹⁹

Clinical Presentation

The clinical course of CM is variable, although it typically presents as a subacute meningoencephalitischaracterized 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 CM cases.²¹ Additionally, CM 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 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 is 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 intracranial^41-44 or spinal cord abscess formation.⁴⁵

Many patients may also have signs of severe immunocompromise, including opportunistic infections. One study reported an incidence of co-infection with oral candidiasis of 52% in patients presenting with CM.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. Immunosuppressed patients may not have a fever with CM. 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 CM and their associated incidence is provided below (Table 1).

Table 1. Clinical features of cryptococcal meningitis.

Diagnosis and Investigations

Diagnosis of CM 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 CM 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 CM are due to not considering CM on the differential, leading to significant cases of medical malpractice.

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 CM, and evidence of any co-infections with opportunistic organisms (Table 1). While the physical exam may raise suspicion for CM, 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 CM 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 CM 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 CM, 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 CM in one study.⁵³  It is important to remember that normal CSF studies are inadequate to rule out CM 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 CM are provided below (Table 3).

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 CM 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, latex agglutination testing requires laboratory infrastructure which may not be available in every ED and LFA testing is not widely used throughout the US.

Imaging has little role in the diagnosis of CM, 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. For more on CT before LP, see this emDocs post. Leptomeningeal enhancement is classically seen on CT consistent with CM, 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 CM may also be seen- most commonly cryptococcomas with associated mass effect, and non-communicating hydrocephalus.¹²

Management

Proper management of CM is dependent on prompt diagnosis. Emergency physicians must have a high clinical suspicion for CM, 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 CM. As a definitive diagnosis of CM 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 CM.^18,63

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 CM 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 CM. 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).

Table 5. Prognostic factors for cryptococcal meningitis.

Case Conclusion: Given his multiple risk factors (alcohol abuse, HIV status), concerning history, and physical exam findings, you  CM. You place the patient in isolation, and empirically treat for meningitis with Ceftriaxone, Acyclovir, Amphotericin B and oral flucytosine. His CT brain showed nonspecific, scattered nodules that enhanced with contrast. A lumbar puncture is performed, revealing an opening pressure of 20 cm H₂O, and appropriate studies are sent. The patient is admitted for further evaluation and management.

From Dr. Katelyn Hanson and Hanson’s Anatomy:

Take Home Points:

• Cryptococcal meningitis (CM) 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. 
• CM 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. 
• The clinical course of CM 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. 
• CM may be the initial AIDS-defining illness in up to 84% of patients. 
• Emergency providers must have a high index of suspicion for CM 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. CSF culture is the current gold-standard for ruling in or out CM, but commonly takes up to 10 days to result.
• Patients should be treated empirically for bacterial, fungal, and viral meningitis.
• Initial antifungal regimen for CM includes amphotericin B + flucytosine for 2 weeks

References/Further Reading:

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