Clinical manifestations

Presentation and course

• The most common neurologic manifestation includes meningoencephalitis, with less common forms being micro/macro-abscesses, granuloma, mycotic aneurysm, vasculitis, strokes, pachymeningitis, myelitis, and arachnoiditis.

Meningitis is the most common form of CNS infection caused by Candida (35). The clinical symptoms are highly variable and range from acute to chronic forms (50). Typically, the onset of meningitis evolves subacutely over several days to weeks with fever, headache, meningismus, and diminished consciousness (42). More acute manifestations are often indistinguishable from bacterial meningitis (49). Focal neurologic signs, cranial nerve deficits, papilledema, and seizures are infrequent. A chronic form of Candida meningitis mimics tuberculous or cryptococcal meningitis. Patients infected with the species Candida glabrata are known to become progressively obtunded over weeks to months (46).

A variety of situations alter the clinical presentation. In newborns and especially, premature babies, respiratory distress is a common manifestation of Candida meningitis and is indistinguishable from that seen in bacterial meningitis or sepsis. Prognosis is grave (15). Hydrocephalus results from obstruction of cerebrospinal fluid pathways. In PLWH, Candida meningitis typically has a subacute evolution with headache and fever (42). Generally, the infection appears in patients with advanced infection and an average CD4 count of 135/mm3.

Candidal abscesses are less common than meningitis. The clinical picture consists of fever, altered level of consciousness, seizures, headaches, and focal manifestations depending on the size and site of the abscess (Fennelly and Slenker 2013). Signs of systemic infection are infrequent. Microabscesses are those under 3 mm in diameter. These occur in adults and present with a diffuse encephalopathy (42). Focal signs are infrequent, poorly expressed, and fluctuating. Papilledema and meningeal signs are not encountered. In these patients, systemic candidiasis is common, but neurologic involvement is oftentimes detected only at autopsy.

There are several additional infrequent forms of CNS candidiasis. Vascular complications include invasion of the arteries at the base of the brain that produce transitory (17) or permanent neurologic deficit (05). Mycotic aneurysms may rupture, resulting in subarachnoid hemorrhage or subdural hematoma. Candida pachymeningitis results in cranial nerve palsies. Patients with spinal disease complain of back pain and demonstrate variable neurologic signs and symptoms (09). In these patients with spinal disease, a preceding fungemia weeks to months before is often reported (35). Candida albicans may cause a severe myelitis (23). Syringomyelia is an extraordinary and particularly late manifestation of spinal arachnoiditis after Candida meningitis (41). Polyradiculopathy is reported in several patients (45).

In addition, hematogenous spread often involves other organs, which may cause manifestations pertaining to renal, skin, cardiac (endocarditis), and eye (endophthalmitis) involvement (42).

Prognosis and complications

For patients with Candida meningitis, a delay in diagnosis of more than 2 weeks after onset of symptoms, CSF glucose levels below 35 mg/dL, development of intracranial hypertension, and focal neurologic deficits are associated with a grave prognosis. Delay in the diagnosis and institution of therapy are attributed to a number of factors among which are a subacute course, lack of clinical findings, variable spinal fluid formula, negative CSF cultures, slow in vitro growth of Candida, and misinterpretation of positive cultures as contaminants. Mortality of CNS involvement may approach 90% (19). About 18% to 29% of patients end up with serious sequelae. A higher morbidity especially pertains to children who often develop psychomotor retardation and aqueductal stenosis with hydrocephalus (26). When patients who have microabscesses have been treated, results have not been favorable. Macroabscesses, however, respond favorably to antifungal therapy.

Clinical vignette

A 57-year-old woman with a history of alcohol use disorder was admitted with fever and pleuritic chest pain. A right-sided pneumonia was found. Subsequently, the patient became hypotensive and obtunded. Respiratory distress ensued. Initial therapy consisted of empiric intravenous antibiotics. Blood cultures were positive for Streptococcus pneumoniae. The hospital course was complicated by a cardiac arrest, upper gastrointestinal bleeding, Klebsiella superinfections, acute tubular necrosis, and subarachnoid hemorrhage. Seventeen days after admission, fever, confusion, and nuchal rigidity appeared. A lumbar puncture disclosed cloudy fluid with 1900 white blood cells/mm3 (100% neutrophils). CSF glucose was 119 mg/dL (blood glucose 135 mg/dL), and protein was 129 mg/dL. Gram stain and cultures were negative. On the presumption of a gram-negative meningitis, systemic and intrathecal antibiotics were administered. A later lumbar puncture showed 1900 polymorphonuclear leukocytes. Blood cultures were positive for Candida albicans. Intravenous amphotericin B was given, but 4 days later the patient died. At necropsy, examination of the spinal cord showed a 10 cm linear collection of pus. Microscopic examination and culture revealed C albicans.

Biological basis

	• Although Candida albicans remains the most likely pathogen, infections with nonalbicans species have been increasingly recognized in the last decade, especially in healthcare facilities, in patients with malignancy, and transplant recipients.
	• CNS invasion occurs via the hematogenous route, local spread from nearby structures, or after neurosurgical procedures or lumbar puncture.

Etiology and pathogenesis

Candida albicans is responsible for more than 90% of all clinically significant fungal infections (03). The source is from the skin, oropharynx, gut, and vaginal flora where the microorganism is normally found. Although there are approximately 160 species of Candida, less than 10 are of clinical importance (31). C albicans is the most common species involved in systemic candidiasis and neurocandidiasis (13). The prevalence of C albicans is decreasing with rising frequency of nonalbicans species over the past decade (77%), especially among patients with underlying malignant diseases or hematopoietic stem cell transplant (19). These consist mainly of C parapsilosis with lesser frequency of C tropicalis, C krusei, C stellatoidea, C pseudotropicalis, C guilliermondii, C glabrata, and C viswanathii. Infection with multidrug-resistant C auris has increased, especially in healthcare facilities (48).

Risk factors for developing candidiasis include prematurity, CARD9 (caspase recruitment domain-containing protein 9) deficiency, central lines, intensive care unit admission, administration of antibiotics, HIV infection, cancer, chemotherapy, steroids, diabetes mellitus, neurosurgery, placement of prosthetic material, severe burns, and injection drug use (22; 47). Commonly, the fungus spreads through the blood stream from contaminated intravenous lines or breaches in the gut (03). Involvement of the CNS usually results from hematogenous dissemination (05), but direct invasion may occur from the oral cavity, orbit, or middle ear (35). An extracranial focus of infection is identified in more than 70% of patients with CNS disease (35). CNS invasion after cranial surgery and even lumbar puncture is also reported by the same authors.

There are several forms of candidiasis affecting the CNS (46). Candida meningitis is a chronic process that is associated with dense exudates at the base of the brain. When candidemia is prolonged, seeding of the CNS is widespread. Consequent microabscesses are commonly found at the gray-white junction, basal ganglia, and cerebellum (39). They consist of foci of necrosis surrounded by polymorphonuclear leukocytes or noncaseating granulomas with giant cells that contain hyphae. Vascular invasion of the arterial lumen is found in 23% of patients with CNS candidiasis at autopsy (42). Cerebral infarcts often occur in the basal ganglia. Cerebral mycotic aneurysms are usually associated with Candida endocarditis. Mycotic aneurysms caused by C albicans and C parapsilosis are both reported. Candida parapsilosis rarely may cause meningitis (06). Like L monocytogenes, C albicans uses clathrin-dependent endocytosis for invasion as well as other proteins for internalization, such as dynamin, cortactin, and E-cadherin (32).

Spinal involvement occurs in the form of vertebral osteomyelitis, usually of the thoracic or lumbar spine (35). Epidural abscesses are encountered in the cervical and thoracic spine. A spinal cord involvement in the form of longitudinally extensive transverse myelitis by spinal cord candidiasis linked to CARD9 deficiency is also reported (24). Spinal disease most often occurs in patients with complex multisystem disorders after a prolonged period of hospitalization.

Epidemiology

• Conditions interfering with normal function of host immune function play an important role in the development of disseminated and CNS candidiasis.

All the features predisposing to systemic candidiasis also favor the development of CNS candidiasis (42). According to a nationwide study conducted in France, hematological malignancy and infective endocarditis were mainly responsible for disseminated infection whereas CARD9 deficiency, diabetes mellitus, injection drug use, and neurosurgery accounted for localized CNS disease without evidence of candidemia or another location of invasive candidiasis (07). There is an increased incidence of both disseminated and CNS candidiasis in newborns, especially premature infants. CNS involvement is seen in up to 60% of invasive candidiasis pediatric cases (12). In some specific clinical situations, such as bone marrow transplant recipients or severe burn patients, Candida is a leading cause of CNS infection (56). Disimmune states contributing to CNS candidiasis include chronic granulomatous disease, neutrophilic myeloperoxidase deficiency, altered T lymphocytes in chronic mucocutaneous candidiasis, severe combined immunodeficiency, specific IgA deficiency, or CARD9 deficiency (27; 07). Although meningitis and abscesses occur in PLWH, the most common complication in PLWH is oral and pharyngeal candidiasis. These forms of candidiasis, however, are rarely invasive. There is increasing emergence of multidrug-resistance candida, especially C auris, in patients with COVID-19 (01; 20).

Prevention

Prophylactic treatment of all high-risk patients with anti-Candida antibiotics reduces the rate of infection and overall Candida mortality (38).

Differential diagnosis

The spectrum of diagnostic possibilities in presentations of CNS candidiasis covers almost all the infectious diseases of the CNS. Cases with acute evolution must be differentiated from bacterial meningitis and herpes simplex encephalitis. Chronic presentations must be distinguished from neurotuberculosis, brucellosis cryptococcosis, aspergillosis, coccidioidomycosis, histoplasmosis, cerebral embolisms, parameningeal suppuration, chronic subdural hematoma, borreliosis, and carcinomatous meningitis (42).

Diagnostic workup

	• The gold standard for diagnosis of CNS candidiasis is culture. However, nonculture diagnostic tests, tissue histopathology neuroimaging, and CSF analysis may further aid in correct clinical settings (31).
	• rRNA PCR of spinal fluid and metagenomic next generation sequencing are emerging techniques considered in diagnostically challenging cases.
	• Concurrent endophthalmitis, retinal exudates, and dermatological infection are often signs of widespread infection.

Macroabscesses have a variable CT density that becomes a nodular or ring-enhanced hyperdensity after the addition of contrast. However, MRI scanning frequently discloses widespread, small, ring-enhancing lesions with a hemorrhagic component (26). Microabscesses observed by MR usually disappear completely after systemic treatment (42). The CT scan in patients with Candida meningitis is usually normal except for hydrocephalus that occurs in approximately 20% of cases. Rarely, there can be associated meningeal enhancement. Cranial MR also reveals infarcts occurring in patients with Candida meningitis. Imaging studies following treatment reveal the residual complications, including cerebral atrophy (26). Calcifications around previous sites of infection are also frequent residual findings (10).

Similar to other causes of osteomyelitis, plain radiographic films illustrate end-plate irregularities with destruction of vertebral bodies and disc space narrowing (35). MRI is the imaging modality of choice with high sensitivity and negative predictive value. Radionuclide studies may be considered in patients who cannot get MRI or CT due to hardware to provide early evidence of disease (16).

In Candida meningitis, a pleocytosis approximates 600 white cells/mm3, and a neutrophilic or monocytic predominance is present. CSF protein is usually elevated. The fungus is identified by staining techniques in nearly 40% of cases and by culture in about 80% (42). Candida meningitis is caused by C albicans in about 90% of patients (50). Other species less frequently responsible are C glabrata (52), C tropicalis (41), or C lusitaniae (44). In exceptional cases, the CSF is completely normal, but stains or culture show the presence of a Candida species. Patients with candida microabscesses generally have a normal spinal fluid formula, and gram staining and culture of CSF are also usually unrevealing (39).

Importantly, several clinical situations alter the CSF profile. The pleocytosis and protein concentrations in postsurgical candida CNS infection tend to be in the range of 1 to 1000/mm3 (mean 276) with neutrophilic predominance and 42 to 666 g/dl (mean 155), respectively (34). In PLWH, pleocytosis is mostly lymphocytic (43).

A chronic meningitis with CSF neutrophilic predominance and hypoglycorrhachia is frequent in Candida meningitis and is often difficult to confirm (45). Isolation of Candida species is difficult because of the low concentration of organisms in the CSF (42). Therefore, repeated lumbar punctures with large samples of spinal fluid may be needed to increase the yield of positive cultures. A minimum of 5 mL and, more ideally, a sample of 15 mL are recommended (45). The ventricular CSF profile may be normal when lumbar CSF is abnormal (29). Smaller available amounts limit the identification of CNS candidiasis in the neonate. For positive cultures, contamination is not a reasonable consideration if risk factors for invasive candidiasis are present. Additionally, the presence of more than 1 pathogen in the CSF is not infrequent because of the clinical conditions in which Candida meningitis commonly appears. Multiple pathogens in the spinal fluid occur in neonates, postsurgical patients, individuals with shunt infections, and immunocompromised patients.

Positive Candida albicans germ tube specific antibodies, or CAGTA, proved to be the only protective factor associated with ICU mortality; however, its current role is limited due to low sensitivity and specificity (57; 54). Mannan is an immunodominant antigen on cell walls of C albicans. Sensitivity and specificity of mannan/antimannan antibody combined assay in serum for diagnosis of invasive candidiasis is 83% and 86%, respectively, but it is only approved in Europe; sensitivity is lower (approximately 60%) when mannan and antimannan IgG assay is used individually (37). β-D-glucan can help identify invasive candidiasis days to weeks prior to positive blood culture and shorten the time for initiation for appropriate treatment. Although serum β-D-glucan has approximately an 80% sensitivity and specificity diagnosis for invasive candidiasis (08), its use in CNS infection is not established, and this test can be negative in candida meningitis when the CSF concentration is elevated (29).

Once appropriate antifungal treatment is initiated, the spinal fluid becomes sterile in about 1 week (42). An altered CSF formula often persists for months, especially an elevated protein, and does not necessarily imply a need to prolong treatment (45).

An emerging modality to detect CSF Candida infection is metagenomic next-generation sequencing. Using this method, C dubliniensis meningitis was identified in a patient with normal serum β-D-glucan assay and negative culture of a lumbar meningeal biopsy after 20 months of Illness (55). Another case of C dubliniensis was reported in a liver transplant patient with negative culture and PCR of spinal fluid until the fourth CSF culture grew the offending agent on day 28 of illness, with simultaneous detection by 18s rRNA PCR of the CSF (18).

Nonculture-based U.S. Food and Drug Administration (FDA)-approved techniques include matrix-assisted laser desorption/ionization time of flight (MALDI-TOF), peptide nucleic acid fluorescent in situ hybridization (PNA-FISH), the β-D glucan (Fungitell) assay, the T2Candida assay, and the BioFire Filmarray blood culture identification (BCID) panel. These tests help clinical decision making for early intervention while culture results are still pending (31).

Histopathological analysis shows a wide spectrum of abnormalities, ranging from mild encephalitis to massive destruction of brain tissue. Lesions show perivascular cuffs of lymphocytes and plasma cell infiltrate with diffuse extracellular edema to necrosis; gliosis; and diffuse infiltration of lymphocytes, plasma cells, and macrophages. There can be giant multinucleated cells forming granuloma and thromboembolic infarcts with fungus invasion of necrotic tissue and blood vessels (07).

Management

	• Early identification and treatment initiation with a multidisciplinary approach is key to successful management of CNS candidiasis.
	• Initial treatment in the form of liposomal amphotericin B, with or without flucytosine in adults, and amphotericin deoxycholate in neonates is recommended.
	• After an initial positive response, step-down treatment with fluconazole can be considered until all signs, symptoms, and CSF and radiological abnormalities have been resolved.
	• If possible, infected CNS devices should be removed.

Treatment of CNS candidiasis is challenging. It often requires a multidisciplinary approach, prompt initiation of treatment, and reversal of defects in the host immune system (47). Untreated or inadequately treated, the mortality rate approaches 80% (35). Additionally, a higher frequency of resistance to antifungal therapy and greater mortality occur with infections by non-albicans species (40).

In adults, the treatment of choice for Candida meningitis is a combination of liposomal amphotericin B, 5 mg/kg intravenously daily, with or without oral flucytosine 25 mg/kg 4 times daily (37). Amphotericin B destabilizes fungal cell membranes and increases permeability leading to cell death. Intravenous liposomal formulation is preferred in adults due to higher CNS availability compared to amphotericin B deoxycholate (19). However, in neonates amphotericin B deoxycholate (1 mg/kg once daily intravenous) is used due to better tolerance, and flucytosine is typically reserved for only salvage therapy if there is no response to initial treatment due to frequent development of side effects (37; 30). Flucytosine weakens nucleic acid synthesis by formation of toxic, fluorine pyrimidine antimetabolites. Due to flucytosine’s major side effect of myelosuppression, careful monitoring of serum levels and frequent monitoring of blood counts is warranted. Additionally, if there is development of nephrotoxicity, the dose needs to be modified (02). Flucytosine has a synergistic action with amphotericin and has excellent CSF penetration compared to amphotericin B. With this combination, recovery rates of 88% to 100% are reported (35).

Therapy should be continued until all signs, symptoms, and CSF (negative culture and resolution of pleocytosis with downward trending protein) and radiological abnormalities resolve. With clinical improvement, step-down therapy with fluconazole 400 to 800 mg (6 to 12 mg/kg) daily orally or intravenously (for those who cannot take oral medications) can be used if the isolate is sensitive to fluconazole. This approach is particularly important in the neutropenic patient, who is likely to relapse in the absence of continued antifungal therapy (03).

The resistance of Candida species to fluconazole is mainly associated with the previous administration of this drug during prolonged periods of immunosuppression (42) and with infection by species of Candida other than C albicans (42). Less frequently, treatment failure is associated with interactions of fluconazole with other drugs such as antiepileptic agents (11).

In a study, 4 years of fluconazole prophylaxis significantly reduced the incidence of invasive candidiasis and its death rates in low birth weight infants, without any fluconazole-resistant Candida species (21). Other azole agents and echinocandins have a limited role in CNS candidiasis. Voriconazole could be considered in rare cases of susceptible C glabrata infection or as a step-down treatment for C krusei due to excellent CSF concentrations (51). However, posaconazole and echinocandins have no role in CNS candidiasis (37).

In addition to antifungal therapy, removal of infected CNS devices, including ventriculostomy drains, shunts, stimulators, prosthetic reconstructive devices, and biopolymer wafers that deliver chemotherapy, is highly recommended, if possible, for individuals with CNS candida infection (37).

Because of the infrequent occurrence of CNS candidiasis in children, experience with dual fungal agents is limited in this population. The treatment regimen should be constantly monitored with serum levels of flucytosine to prevent myelotoxicity. As noted above, flucytosine is not recommended in neonates. Echinocandins only achieve sufficient concentrations in CSF to treat Candida if the blood brain barrier is breached. They are reserved for refractory cases only in children. Posaconazole in not recommended to be used in children (30).

The initial treatment of Candida brain abscess (05), epidural abscess (04), and intramedullary abscess (28) is with amphotericin B and flucytosine (49). This regimen is usually followed by surgical resection of persisting cerebral mass lesions.

Although treatment of vertebral candida osteomyelitis consists primarily of medical therapy with amphotericin B, surgery is indicated in patients with neurologic deficits, spinal instability, large abscesses, or persistent or worsening symptoms during therapy (16).

A strong progress in fungal vaccine research is being made. However, mounting a protective immune response in immune-compromised individual remains one of many challenges (53).

Outcomes

Flucytosine treatment needs close monitoring for liver- and bone marrow–related toxicity (37). Mortality approaches 10% in neurosurgical procedure-related candida chronic meningitis (33).

Special considerations

Pregnancy

The fungus may be transmitted from an infected mother to her newborn at delivery.