CONTENTS
- Cryptococcal meningitis
- Dimorphic fungi (endemic mycoses)
- Molds
- Candidiasis
- Podcast
- Questions & discussion
- Pitfalls
basics
- Cryptococcus neoformans is a widespread opportunistic fungus found in soil and bird droppings.
- Cryptococcus gattii causes infection in immunocompetent patients, but it is restricted to specific geographic locales (British Columbia and the Pacific Northwest; figure below). The remainder of this section focuses predominantly on Cryptococcus neoformans.
- Cryptococcus has a proclivity for causing meningitis. Identification of Cryptococcus anywhere in the body should lead to a consideration of the possibility of simultaneous cryptococcal meningitis.
pathophysiology
- Pneumonia is the primary focus of infection, with secondary dissemination to other sites (especially the brain). However, patients may present initially with neurological abnormalities.
- A hallmark of cryptococcal meningitis is communicating hydrocephalus, with markedly elevated intracranial pressure.
- Meningeal inflammation may affect blood vessels, leading to ischemic strokes (figure below).
epidemiology
- Cryptococcal meningitis is by far the most common fungal CNS infection, and also the most common fungal infection in AIDS patients (it's the second most common CNS opportunistic infection, following toxoplasmosis).
- Risk factors for cryptococcus neoformans include:
- HIV (CD4 count usually <100/uL).
- Transplantation.
- Immunosuppressive medications, including chronic steroid use, TNF-inhibitors, azathioprine, cyclosporine, fingolimod (an S1P receptor modulator used for multiple sclerosis), ibrutinib.(33516057, 33896533)
- Malignancy (especially hematological).
- Cirrhosis, chronic renal failure, diabetes, sickle cell disease.
- Sarcoidosis.
- 💡 15% of patients have no underlying immunocompromising condition. This is quite rare considering the large denominator that includes all immunocompetent patients, but it is possible.(26633781)
clinical features of cryptococcal meningitis
- Usually patients present with subacute or chronic onset of mild symptoms, including headache, malaise, and fever. Symptoms may be insidious and may fluctuate over time.
- (1) Meningeal findings:
- Headache and fever are often present.
- Frank meningeal irritation is uncommon (e.g., nuchal rigidity).
- Basilar meningitis may cause cranial nerve abnormalities (e.g., mimicking Meniere's disease).(26633781)
- (2) Features of elevated intracranial pressure:
- Nausea and vomiting.
- Visual loss and abducens nerve palsy.
- Examination may reveal papilledema.
- Confusion, behavior changes, and eventually stupor/coma may occur.
- (3) Clinical effects of cryptococcomas:
- Invasion of the brain parenchyma may lead to focal lesions in the basal ganglia, thalamus, and subcortical white matter.(28466277)
- Symptoms may include seizures and other focal findings (e.g., weakness, sensory abnormalities).
- Patients may have other sites of involvement (e.g., pneumonia, skin manifestations). Skin manifestations may include papules, nodules, plaques, or ulcerations.(33516057)
CSF studies in cryptococcal meningitis
- CSF pressure is often extremely elevated (although it may be normal in a third of patients).(33516057)
- HIV-negative patients:
- Moderate lymphocytic pleocytosis is usually seen. However, cell counts can be extremely elevated in patients able to mount an immune response (e.g., >1,000/uL).(30273244)
- Protein is often highly elevated.
- Glucose is usually reduced.
- AIDS patients may have largely normal laboratories (or only mild elevation of white blood cell count or protein). Normal CSF chemistries don't exclude cryptococcal meningitis in the context of AIDS. Low cell count is actually a poor prognostic sign among patients with cryptococcal meningitis.(26633781)
- Testing for cryptococcus:
- CSF testing for cryptococcal antigen is both highly specific and sensitive (>97%).(34623105)
- Fungal culture has high yield, but takes several days.
other laboratory studies
- Cryptococcus grows readily in most lab media. It may often be isolated from the urine of patients with cryptococcal meningoencephalitis.
- Serum cryptococcal antigen may be useful if lumbar puncture is contraindicated, with sensitivity of ~90% and specificity of ~95%.(30921084; 31378872)
imaging: CT scan
- CT scan is often normal.(33516057)
- Hydrocephalus may be seen in some patients.
- Parenchymal cryptococcomas may be seen, most often in the basal ganglia.
imaging: MRI
- Hydrocephalus is the most common radiological abnormality (which may be communicating or noncommunicating).(Tang 2015)
- Nodular leptomeningeal enhancement is sometimes seen, especially involving the basal meninges. Ventriculitis may also be seen. However, this may be less likely in patients with more severe immunocompromise.
- Infarcts may be seen due to perivascular inflammation, most commonly in the basal ganglia and less often in the thalamus, frontal, temporal, parietal, and occipital lobes.(33516057)
- Pseudocysts may occur, especially in HIV:(34623100)
- Gelatinous pseudocysts develop within dilated Virchow-Robin spaces that surround penetrating blood vessels near the basal ganglia and the corticomedullary junction. Similar patterns may occur in coccidiomycosis or candidiasis.(31964490) Although the basal ganglia are most often involved, pseudocysts may be seen in the cerebral white matter, brainstem, and cerebellum.
- Cysts often lack vasogenic edema or enhancement. This may produce a “soap bubble” appearance. (bottom figure, below)
- Parenchymal cryptococcomas may be seen, typically within the basal ganglia.
- Unlike pseudocysts, cryptococcomas reflect parenchymal brain invasion that incites granulomatous inflammation.
- Lesions are hyperintense on T2 and hypointense on T1, with surrounding vasogenic edema.
- Contrast enhancement may occur.
management
- Antibiotics typically involves: (30770097)
- (#1) Induction therapy with a combination of liposomal amphotericin B plus flucytosine for ~2-6 weeks. Amphotericin may cause electrolyte abnormalities and renal failure, whereas flucytosine may cause neutropenia.
- (#2) Consolidation therapy with high-dose fluconazole (800 mg/day) for 8 weeks.
- (#3) Maintenance therapy with fluconazole (200 mg/day) for ~6-12 months.
- Elevated intracranial pressure due to communicating hydrocephalus often requires management with either a lumbar drain or serial lumbar punctures. Therapeutic lumbar puncture should be performed daily in patients with persistent opening pressures of >25 cm.(33896533) Some patients may require a long-term CSF shunt.
- ⚠️ Adjunctive steroids are not routinely recommended, as a recent trial showed an increase in adverse effects.(31378870)
going further
- Case report: 64-year-old man with subacute altered mental status and headache (Mehra et al. PMID 30770097) 📄
basics
- CNS disease can occur in immunocompetent patients, but it is more likely in the context of immunocompromise. CNS involvement occurs in the context of progressive, disseminated histoplasmosis.
epidemiology
- Histoplasmosis is an endemic mycosis concentrated especially around the Mississippi and Ohio River valleys (map below). Histoplasma grows in the soil, as well as in bird/bat droppings.
- Infection is generally limited to the lungs, without systemic dissemination. Among patients with disseminated disease, CNS involvement occurs in ~15% of cases.(31378870) Reactivation of latent disease is rare.(33516057)
- No underlying cause is identified in about a third of patients with CNS histoplasmosis.(30921084) Risk factors for disseminated infection include:
- Solid organ transplantation.
- Immunosuppressive medications (including steroid and TNF inhibitors).
- AIDS (usually with CD4 counts <150/uL).
- Hematologic malignancy.
- Diabetes.
clinical features of patients with CNS involvement
- Manifestations may include:
- Brain abscess (~1/3 of patients) and/or spinal cord lesions.
- Chronic or relapsing meningitis (which may cause ischemic strokes due to small vessel vasculitis).
- Symptoms of CNS histoplasmosis:
- Fever is extremely common.
- Headache.
- Reduced level of consciousness, confusion.
- Focal cranial nerve deficits.
- Seizure, personality change, ataxia, clonus.
CSF evaluation
- Histoplasma abscess(es):
- CSF analysis is poorly sensitive and may be misleading.
- Occasionally patients may have pleocytosis or elevated protein, but CSF chemistries can be normal.
- Histoplasma meningitis:
- Generally causes a lymphocytic CSF pleocytosis, with elevated protein and low glucose.
- CSF culture may be possible, if large volumes are sampled (but this lacks sensitivity).
other laboratory studies
- Serum antibodies are not entirely reliable.
- Urine or serum Histoplasma antigen may be detectable.
- Anemia, leukopenia, and thrombocytopenia may occur.(33516057) In this case, testing for bone marrow involvement should be considered. (Louis 2021)
imaging
- Contrast MRI may reveal abscess formation.
- Solitary or multifocal small (<2 cm), round, ring-enhancing mass lesions may be seen.
- Abscess is most often located subcortically (within the grey/white junction), or within the posterior fossa, or within the brainstem.
- Typically T1 hypointense.
- May show diffusion restriction (depending on the extent of inflammation and necrosis)
management
- High-dose liposomal amphotericin is generally used initially, as induction therapy.
- Surgical excision of abscesses is usually not necessary.(31378870)
basics
- Most patients will experience a pulmonary infection. Dissemination beyond the lungs is uncommon in immunocompetent patients, but occurs in the majority of immunocompromised patients.
epidemiology
- Coccidioidomycosis is an endemic mycosis present in the Southwestern United States, parts of Mexico, and South America (map below). Even a short trip to an endemic region may cause exposure.
- Only 1% of all patients progress from pneumonia to disseminated disease beyond the lungs. Among these 1% of patients with disseminated disease, only one-third have CNS involvement.(31378870)
- Some case series have found that a majority of patients with coccidioidal meningitis are immunocompetent.(30921084) Risk factors for the development of disseminated disease include:
- Pregnancy.
- HIV.
- Organ transplantation.
- Immunosuppressive medications (especially chronic steroid therapy).
- Hematologic malignancy.
- Diabetes.
- Older age.
clinical presentation
- Pneumonia is generally a central finding.
- Chronic basilar meningitis occurs in about a third of patients with disseminated disease, which may lead to hydrocephalus and/or vasculitic infarcts:
- Headache is common, but frank meningismus is rare.
- Mental status changes are frequently seen.
- Hearing or vision changes may occur.
- An adhesive arachnoiditis may occur, leading to compressive myelopathy, spinal subarachnoid block, and/or hydrocephalus.(33522738)
- May cause vasculitis, leading to ischemic stroke. CVT (cerebral venous thrombosis) has also been reported.
- Intraparenchymal abscess may result from spread of infection from the leptomeninges into the brain parenchyma.(33516057) This may lead to mass lesions that cause focal neurological deficits (e.g., seizure).(31378870) Spinal cord mass lesions may likewise occur.
- About half of patients with disseminated disease may also have skin or subcutaneous tissue involvement. Bone and joint infection may also occur.
laboratory findings
- CSF studies:
- Pleocytosis with mixed neutrophilic or lymphocytic predominance (and CSF eosinophilia in 15% of cases).(31378870)
- Glucose is often low.
- Protein is generally elevated.
- (CSF cultures are usually negative.)
- Serum antibody is generally positive.
imaging
- Basilar meningitis is a central finding:
- Ischemic areas occur in about a third of patients, typically in the deep cerebral matter.(33516057)
- Brain abscess(es) may be seen:
- Solitary or multifocal, 0.5-4 cm large.
- Most often in the posterior fossa, but may also involve juxtacortical and subcortical structures.(31378870)
treatment
- Fluconazole is the usual antibiotic therapy (800-1200 mg daily). Delayed recurrence is common, so guidelines recommend lifelong azole suppressive therapy following initial therapy.
- For patients with meningitis, hydrocephalus often requires interventional therapy (e.g., therapeutic lumbar punctures, and shunt placement if intracranial pressure is refractory to multiple therapeutic lumbar punctures).(31378870)
basics
- Blastomycosis is an endemic mycosis which is distributed within the Eastern United States (map below).
- Blastomycosis is somewhat unusual among fungal pathogens for the following reasons:
- (1) It often affects people with minimal or no immunosuppression.
- (2) It can progress relatively rapidly. For example, pulmonary blastomycosis may resemble a typical bacterial pneumonia (and is often misdiagnosed as such).
epidemiology
- Blastomycosis is acquired by inhaling fungus from soil or rotting vegetation (e.g., when camping, hunting, or logging).
- The incubation period may extend up to about 100 days after exposure. Additionally, latent disease may become reactivated in the context of immunosuppression.
- Only ~25% of infections will disseminate beyond the primary site of inoculation (which is usually the lungs, less often the skin). Among patients with disseminated disease, the CNS is involved in 5-10% of patients.(31378870) Disseminated infection that involves the CNS often occurs in immunocompetent patients, but it may be more likely in patients with the following risk factors:
- Transplantation.
- AIDS.
- Immunosuppression (especially chronic steroid use, TNF-inhibitors).
- Malignancy.
- Diabetes.
clinical features
- Pneumonia is generally the primary manifestation, with CNS manifestations being relatively uncommon.
- Potential manifestations of CNS blastomycosis include:
- Intracranial and/or epidural abscess.
- Meningitis (acute or chronic).
- Symptoms may include:(31378870)
- Headache (~75%).
- Focal neurologic deficits (~60%).
- Altered mental status, seizures, nausea/vomiting.
- ~80% of patients with CNS blastomycosis have involvement of other organs.(30921084)
- Skin manifestations are common (including subcutaneous nodules, ulcers, and painless vegetating plaques).
- The genitourinary tract and skeleton may also be involved (e.g., causing purulent vertebral osteomyelitis).(26633781)
CSF studies
- Pleocytosis is common (with neutrophilic predominance initially and a subsequent transition to lymphocytic predominance).
- Protein is elevated.
- Glucose is reduced.
- CSF cultures are often negative, or extremely sluggish to return (requiring up to a month to grow).(31378870)
other investigations
- Blastomyces serum and urine antigen have a sensitivity of ~80%. This isn't entirely specific (since it cross-reacts with other endemic fungi such as Histoplasma), but it may be extremely useful to direct the evaluation towards an endemic fungus.(31378870)
- Skin lesions may be biopsied.
- Brain abscess may require aspiration to yield a diagnosis.
imaging
- (1) MRI may show meningeal enhancement among patients with meningitis.
- (2) Brain abscess(es) may occur in ~60% of patients with CNS involvement:
- Lesions may be solitary or multiple.
- Tendency to involve the cerebellum, midbrain, basal ganglia, and pituitary stalk.
- MRI may show restricted diffusion in a heterogeneous, peripheral ring, or central pattern.(31378870)
management
- Initial induction therapy is generally with liposomal amphotericin.
basics
- Aspergillus species are ubiquitous, opportunistic pathogens.
- Further general discussion regarding invasive pulmonary aspergillosis here.
sino-cranial aspergillosis
- Rarely, a primary infection occurs within the sinuses, nose, or ear with direct invasion of the brain.
- This often occurs in immunocompetent patients. Pathology is marked by well-formed granulomas (as the immune system attempts to contain the fungus).
- Initial symptoms may include nasal/sinus congestion, ear discharge, or periorbital pain. This may evolve locally (e.g., with the development of proptosis, ophthalmoplegia, chemosis, and visual loss).(26633781) These features may resemble rhinocerebral mucormycosis (discussed below).
- Patients can eventually develop an intracranial mass lesion, or skull-base syndromes (cavernous sinus syndrome, orbital apex syndrome, proptosis with or without ocular nerve palsies, polyneuritis cranialis, orbitocranial syndromes).
- Neuroimaging may be highly suggestive of the diagnosis.
angioinvasive aspergillosis
- In this situation, the primary site of infection is pneumonia with subsequent hematogenous spread to the brain. Fungus invades blood vessels, leading to ischemic infarcts and hemorrhages.
- Epidemiologically, this is restricted to immunocompromised patients, with risk factors including:
- Neutropenia (especially if prolonged).
- Transplantation (especially allogeneic stem-cell transplantation).
- Malignancy (hematologic > solid tumors).
- Steroid use (especially if high-dose and prolonged).
- Treatment with cytotoxic chemotherapy, T-cell immunosuppressive medications, or Burton tyrosine kinase inhibitors (e.g., ibrutinib).(33273175)
- Advanced AIDS (e.g., CD4 count <50/uL or neutropenia due to antiviral therapies).
- Cirrhosis, diabetes, renal failure, malnutrition, alcoholism.
- Only 5% of patients with invasive Aspergillus have CNS involvement, so this is a rare complication of a rare disease.(31378870) Patients will generally first be diagnosed with aspergillosis involving the lungs, prior to recognition of CNS involvement.
- Pathological manifestations include:
- (1) Brain abscess.
- (2) Cerebral infarction, including hemorrhagic infarcts. These may be located within the cerebral hemispheres, the cerebellum, or regions supplied by lenticulostriate and thalamoperforating arteries (basal ganglia, thalamus, and corpus callosum).(33516057)
- Mycotic aneurysm formation.
- Meningitis and meningoencephalitis are rare.(31378870; 33516057)
- Clinical features may include fever, focal neurological deficits, encephalopathy, and seizure.(33516057)
- Since meningitis is uncommon, CSF cultures, PCR, and galactomannan antigen are often unhelpful.(33516057) Investigating other sites of infection may be more fruitful (e.g., bronchoscopy for evaluation of pneumonia). Serum galactomannan may be positive in 44-90% of patients.(33516057) Serum levels of 1,3-beta-D-glucan may also be elevated, although this is less specific for Aspergillosis.(33273175)
- Neuroimaging:(Torbey, 2019)
- Abscesses are typically ring-enhancing with restricted diffusion (although patients with severe immunocompromise may lack ring enhancement).
- May show areas of infarction, which may have secondary hemorrhagic transformation.
- Vascular imaging may reveal mycotic aneurysms.
treatment
- Voriconazole is front-line therapy.
- Surgical resection may be required (e.g., for sino-cranial aspergillosis, or for brain abscess management).
- Immunosuppression should be reduced, if possible.
basics
- Zygomycetes species are opportunistic pathogens found ubiquitously in soil and decaying organic matter (e.g., rotting food).
- The most common species belong to the phylum Mucor, with others including species of Rhizopus, Rhizomucor, Absidia, and Cunninghamella.
pathophysiology
- Infection begins in the sinuses and nasal mucosa.
- Infection may extend in numerous directions, to affect nearby structures:(31378870)
- Inferior invasion into the hard palate.
- Posterior invasion into the sphenoid sinus.
- Lateral invasion into the cavernous sinus and orbits.
- Superior invasion into the brain.
- Spread to the CNS occurs via direct extension in ~15% of cases, or via hematogenous spread and abscess formation in ~10% of cases.(31378870)
epidemiology
- Invasive rhinocerebral mucormycosis is restricted to patients with immunosuppression. Risk factors include the following:
- Diabetes, especially DKA (diabetic ketoacidosis).
- Leukemia (especially with prolonged neutropenia, or if undergoing allogeneic stem cell transplantation).
- Organ transplantation.
- Iron overload, or prior chelation therapy with deferoxamine.
- Chronic steroid use.
- Exposure to voriconazole (may select for Mucorales, rather than Aspergillus).
clinical presentation
- Initial symptoms may mimic bacterial sinusitis:
- Fever.
- Facial/sinus pain.
- Nasal congestion/discharge (which may be bloody).
- Orbital cellulitis may be seen, which may be extensive (e.g., causing impaired orbital motion and proptosis).
- Facial numbness.(26633781)
- Progressive disease may lead to:
- Carotid artery involvement may lead to MCA-territory acute ischemic strokes (e.g., contralateral hemiplegia).
- Cranial nerve palsies
- Meningoencephalitis.
- Coma, obtundation.
- Black, necrotic areas on the nasal turbinates or hard palate are highly suggestive of diagnosis, if seen.
diagnosis
- 💡 Nasal endoscopic biopsy for histologic evaluation can provide a rapid diagnosis. This should be performed as soon as possible, once Mucor is suspected.(33516057) Sinus lesions are generally necrotic but not always, so biopsy should still be performed even in the absence of necrosis.(26633781)
- CSF fungal cultures have variable sensitivity.
imaging
- CT or MRI may reveal paranasal sinus mucoperiosteal thickening and facial soft tissue edema.(31378870)
- MRI may reveal hyperintense T2-weighted lesions, and complications (e.g., thrombosis of the carotid artery or cavernous sinus).
management
- Antifungal therapy usually involves high-dose amphotericin B.
- Immunocompromised states should be reversed if possible, for example:
- Hyperglycemia should be treated aggressively, if present.
- Neutropenic patients may benefit from GM-CSF.
- Aggressive surgical debridement of necrotic tissue is necessary.
basics
- Candida is part of the normal gut flora. It rarely causes invasive disease.
- Candida may cause meningitis or brain abscesses (e.g., microabscesses throughout the brain parenchyma). These may be accompanied by candidal endophthalmitis.
epidemiology
- (1) Systemic candidemia may seed the meninges, leading to candidal meningitis.
- Risk factors for candidemia include:
- Neutropenia.
- Older age.
- Indwelling catheters.
- Total parenteral nutrition.
- Malignancy.
- Immunosuppressive medications.
- Broad-spectrum antibiotics.
- Intravenous drug use.(30921084)
- Among patients with candidemia, endocarditis may be a risk factor for neurologic involvement.(26633781)
- Risk factors for candidemia include:
- (2) CNS infection may follow direct inoculation via neurosurgery or (rarely) head trauma.
clinical presentations in the context of systemic candidiasis
- Acute or chronic meningitis:
- Acute meningitis can occur with features resembling bacterial meningitis (with fever, headache, nuchal rigidity, and altered mental status.)(33516057)
- However, the course is generally subacute. Subacute/chronic meningitis can present more insidiously (e.g., with hydrocephalus).
- Cerebral micro-abscesses:
- This is the most common form of CNS candida, but it's often diagnosed postmortem since symptoms may be absent or subtle.(35419124)
- CSF analysis and culture may be unrevealing.
- Imaging may reveal multiple diffusion-restricting microabscesses in the basal ganglia, cerebellum, and gray-white junction, often with a hemorrhagic component on GRE/SWI sequences.(31378872)
- Cerebral macro-abscesses:
- Vascular complications may occur, including infarcts, mycotic aneurysms, or subarachnoid hemorrhage.(34623105)
- Visual abnormalities may reflect simultaneous candidal endophthalmitis.
- 💡 CNS involvement should be suspected whenever a patient with known invasive Candida develops neurological findings.(33516057)
clinical presentation following direct inoculation or neurosurgery
- Infection usually presents within three months after the initial inoculation.
- Infection may present acutely with encephalopathy and fever.(30921084) Alternatively, some patients may present with ventriculoperitoneal shunt dysfunction, leading to hydrocephalus and altered mental status (without meningeal symptoms).(33516057)
laboratory evaluation
- CSF may be relatively unremarkable among immunocompromised patients.(35419124)
- CSF pressure may be normal or moderately elevated.
- CSF studies often show pleocytosis (either lymphocytic or neutrophilic), elevated protein, and moderately reduced glucose.(30921084)
- CSF often reveals a positive culture for Candida, especially with repeat sampling.
- Blood cultures may reveal candidemia.
- Serum 1,3-beta-D-glucan is ~80% sensitive and specific for invasive disease.(31378872) CSF 1,3-beta-D-glucan may be superior for candidal meningitis, if this assay is available.
neuroimaging findings may include:
- Hydrocephalus in up to 20% of patients.(31378872)
- Leptomeningeal enhancement may occur. To confuse matters, subarachnoid hemorrhage may also occur. Meningeal vascular complications may also be seen (e.g., vasculitic infarctions or mycotic aneurysm).
treatment
- Induction therapy usually involves amphotericin B, with or without flucytosine.
- 💡Echinocandins (e.g., micafungin) achieve low levels in the CNS, so they are not adequate.(26633781)
- Any infected devices (e.g., ventriculostomy drains and shunts) should be removed.
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To keep this page small and fast, questions & discussion about this post can be found on another page here.
- The primary pitfall is failing to consider CNS fungal infections. Notably, infections may occur even in immunocompetent patients (especially blastomycosis or coccidioidomycosis).
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