Introduction
While it is estimated that 1.5 million fungal species exist, only about 70,000 have been formally described. Of the described species, 300 may show virulence to humans, and only 10–15% of these could influence the CNS [
1,
2]. Clinically relevant fungi being etiological agents of fungal infections of the CNS include yeasts, filamentous fungi, and dimorphic fungi. Yeasts are unicellular organisms and include the cosmopolitan fungal species of genera
Candida and
Cryptococcus (except endemic
C. gattii), and less common fungi such as
Trichosporon spp. The filamentous fungi, which are characterized by branching hyphae, include moniliaceous (light-colored) moulds with septate hyphae (
Aspergillus spp.,
Fusarium spp.) and Mucoromycetes with non-septate hyphae (
Rhizopus, Rhizomucor, and
Mucor). They have worldwide distribution and are common causes of fungal CNS infections [
3‐
5]. Pigmented moulds (darkly pigmented) are seen less common and include species which are considered as true neurotropic fungi such as
Cladophialophora bantiana (mainly in India),
Exophiala dermatitidis (encountered worldwide, common in East Asia),
Rhinocladiella mackenziei (mainly in Middle East), and
Verruconis gallopava (syn.
Ochroconis gallopava, worldwide). The dimorphic fungi with two morphological stages: mould in environment (25 °C) and yeast in tissue (37 °C) (
Blastomyces, Histoplasma, Coccidioides, and
Paracoccidioides) are geographically restricted to specific endemic areas (see part Dimorphic fungi) [
3‐
5].
The incidence of fungal infections is increasing every year, with greater numbers of infections noted among patients belonging to high-risk groups such as HIV-infected persons and AIDS patients, transplant recipients, and immunosuppressed patients treated with chemotherapeutics or corticosteroids, as well as those suffering from haematological disorders and chronically ill patients [
3,
4,
6,
7]. Certain conditions may predispose the patient to the development of a specific etiological agent: disease/treatment-associated and genetic factors (prolonged antibiotic therapy, neutropenia, steroid therapy, transplantation, chronic granulomatous disease, CARD9 deficiency, neurosurgery, contaminated devices, and prematurity in infants—
Candida; diabetic ketoacidosis, necrotic burns, renal failure, and intravenous drug use—Mucoromycetes; contact with birds—
Cryptococcus and
Histoplasma; deferoxamine therapy and iron overload—Mucoromycetes [
3,
5].
However, some fungi, such as
Cryptococcus, Coccidioides, and
Histoplasma, can also cause infection in immunocompetent patients. In USA, it was estimated that invasive mycoses caused by
Candida spp. are responsible for 72 to 228 infections per million population annually, while
Cryptococcus neoformans is responsible for 30–66 infections and
Aspergillus spp., 12–34 infections [
8]. The most common CNS fungal infection worldwide is cryptococcal meningoencephalitis. Disseminated mycosis is often associated with CNS involvement. It is estimated that between 67 and 84% of patients with invasive cryptococcosis develop CNS mycosis, 3–64% develop invasive candidiasis, 40% blastomycosis, 25% disseminated coccidioidomycosis, and 5–20% disseminated histoplasmosis, while 12% develop mucormycosis and 4–6% invasive aspergillosis [
3]. It is important to note that examples of FIs-CNS differ in clinical manifestation, depending on type of etiological factor (Table
1).
Table 1
Clinical syndromes of neuroinvasions caused by fungi
Meningitis |
Cryptococcus
Coccidioides
Exserohilum
Candida
Histoplasma
|
Meningoencephalitis |
Cryptococcus
Coccidioides
Candida
|
Brain abscess |
Aspergillus
Candida
Mucoromycetes
Blastomyces
Coccidioides
Histoplasma
|
Rhino-cerebral |
Mucor
Rhizopus
Absidia
Rhizomucor
Syncephalastrum
|
Skull-base syndromes |
Aspergillus
|
Stroke/infarction | Mucoromycetes
Aspergillus
|
Disseminated | Mucoromycetes
Candida
Cryptococcus
Aspergillus
Coccidioides
|
Depending on the size of the fungal forms developing in the human body, such as blastospores or hyphae, various forms of CNS lesion may exist. For example,
Blastomyces, Histoplasma, Coccidioides, Paracoccidioides, Cryptococcus, and
Candida enter the capillaries and subarachnoid spaces, causing meningitis and subpial ischemic lesions,
Candida enter the blood vessels and cause local necrotic lesions, while
Aspergillus, Cladosporium, and Mucoromycetes penetrate large blood vessels and can cause strokes [
9,
10].
Fungal interaction with the BBB and CNS invasion
The pathogenesis of FIs-CNS is not yet fully understood. Penetration of pathogen across the blood–brain barrier (BBB) is an essential step for CNS invasion. The circulating pathogens in the blood must first be arrested in the brain microvasculature and then transmigrate into the brain parenchyma across the blood–brain barrier BBB. Three mechanisms have been described for pathogens to cross the BBB: transcellular migration, paracellular migration, and the Trojan Horse Mechanism [
11,
12]. Those mechanisms are best understood for
Cryptococcus and
Candida. C. neoformans mechanically arrested in the brain vasculature can cross the BBB by both direct and indirect mechanisms [
13]. Direct way include BBB passage through transcytosis of endothelial cells [
13,
14], while indirect include transport inside of phagocytes as Trojan Horse Mechanism. In addition, paracellular passage of the
C. neoformans between endothelial cells has been also suggested [
13]. To trigger the translocation processes, mainly through paracellular and transcellular mechanisms, interactions between pathogen protein molecules and BBB are necessary. Recent studies indicate that using transcellular mechanism by
C. neoformans in brain microvascular endothelial cells (BMECs) requires protein kinase C-alpha activation. The CPS1 gene is required for
C. neoformans adherence to the surface protein CD44 of human BMECs [
15]. The dissemination of pathogen into the brain is controlled by Isc1 gene encoding an enzyme that hydrolyzes inositol. Recently, Huang et al. [
16] shown that invasion of
Cryptococcus neoformans into human BMECs is mediated through the lipid rafts- endocytic pathway via the intracellular kinase-DYRK3. Adherence of
C. albicans to extracellular matrix is facilitated by fibronectin, laminin, and vitronectin. It was demonstrated that
C. albicans invasion of brain endothelial cells is mediated by the fungal invasions Als3 and Ssa1 [
17]. Als3 binds to the gp96 heat shock protein that is expressed specifically on brain endothelium, promoting endothelial transcytosis by the fungus [
18]. Trojan horse pathway starts with an infection of a phagocyte in the periphery. Once internalized, the pathogen may actively manipulate the phagocyte to promote migration towards the brain. The infected phagocyte reaches the brain and adheres to the luminal side of brain capillaries and crosses the BBB, either paracellularly or transcellularly [
19].
In states of reduced immunity, the BBB permeability increases, which facilitates the penetration of fungi into the brain.The pathogens get to the brain parenchyma and proliferate causing brain inflammation. As the pathogenic factors have to overcome the effective barriers surrounding the brain, invasions are mostly associated with immunocompromised states. Hence, the activation of nerve cells by fungal cells and the expression of immune-enhancing and immune-suppressing cytokines and chemokines play a determining role in pathogenesis of FIs-CNS [
11]. CNS involvement takes place as the blood–brain barrier, and cerebral and subarachnoid spaces are crossed by the invading fungi [
12]. This process is favoured by various blood–brain barrier disruptions, such as trauma, surgery, or activation of microglia and cytokines: TNF-α disrupts the tight junctions of the barrier [
12]. The rate and extent of infection are influenced by the virulence of the fungus and the activity of the host immune system [
12]. T cells, microglia, astrocytes, and endothelial cells play important roles in preventing infection by inhibiting fungal growth through the production of cytokines (INF-γ, TNF-α, IL-1β, IL-6, and IL-12), chemokines, nitric oxide and superoxide anion, and by the expression of MHC I and II molecules [
1,
7,
11,
12]. TLR-2, 4, and 9 are responsible for the recognition of fungal antigens: polysaccharide capsule (
C. neoformans), pseudohyphae (
C. albicans), or conidia (
Aspergillus spp.); however TLR-2, Dectin-1, and CR-3 are responsible for the recognition of carbohydrates, such as mannose and β-glucans, present on the surface of
A. fumigatus and
C. albicans [
12]. Fungal pathogen-associated molecular patterns are connected with carbohydrates (chitin, mannoproteins, phospholipomannan, and β-glucans) in the cell wall which may allow fungal infections to be controlled by enabling the activation of microglia yielding pro-lymphatic and humoral responses. The activation of microglia cells depends on the presence of opsonins and T cells [
12].
Diagnosis of FIs-CNS
In accordance with EORTC/MSG criteria, the diagnosis of invasive fungal infections is made on the basis of a combined interpretation of risk factors, clinical symptoms, and imaging results. Symptoms of CNS invasion are in most cases not very specific and include headache, fever, convulsions, weakness, progressive confusion, changed mental status, and/or focal neurological deficits among others [
6,
7]. In addition, the image of mycosis in CT, MRI imaging may resemble changes caused by other pathogenic factors. For candidiasis or cryptococcosis, CT imaging is usually negative, and focal lesions are seen in the course of infections with mould fungi. Non-specific focal lesions, edema, or haemorrhagic lesions are found in the MRI image. In addition, therefore, CT and MRI techniques can only serve as additional aids in the diagnosis of FIs-CNS [
3,
7]. These imaging techniques can help localize the lesions, but tissue samples are still needed for objective diagnosis, especially in cases of fungal abscesses.
The diagnosis of invasive mycosis requires biopsy of the involved tissue, followed by culture and histopathology of clinical samples; however, CNS biopsies are regarded as too risky in severely ill patients, especially in populations of haematological patients with low platelet counts or neutropenia. Biopsy allows CNS specimens to be obtained, including those of the brain, meninges and cerebrospinal fluid (CSF) or ventricular fluid [
108]. Methods based on optical brighteners (Calcofluor or Blankophor) allow direct examination and have high sensitivity and specificity for detecting fungal elements. Biopsy material stained with hematoxylin and eosin (HE), particularly with Gomori methenamine silver (GMS) or periodic acid Schiff (PAS), is of great importance in the diagnosis of neuroinfections [
109‐
111]. Cell type depends on the pathogen causing neuroinfection: lymphocytic pleocytosis is associated with
Cryptococcus neoformans; neutrophils or monocytic predominance with
Candida spp.; neutrophilic predominance with
Aspergillus spp.; eosinophilia with
Coccidioides spp. [
3]. Diagnosis should be confirmed by culture, if possible, and serological tests of blood and cerebrospinal fluid. The cultures can be performed on Czapek-Dox and Sabouraud media, but their effectiveness varies depending on the etiological agent. Peripheral blood cultures are most likely to be useful when the etiologic agent is
Candida spp. It should be noted that
Fusarium and
Scedosporium species can easily be recovered from the bloodstream in patients with disseminated infections, which is rare for mould infections. Other fungi, such as
Histoplasma capsulatum and
Cryptococcus neoformans, can occasionally be isolated from blood cultures [
112].
Serological tests are mainly based on ELISA, EIA, and indirect hemagglutination techniques, and in recent years, immunofluorescence techniques have developed significantly [
3,
7,
113]. The sensitivity of antibody assays varies between 38% and 92% depending on the species, while the detection of fungal cell wall components (β-glucans, galactomannan, mannan, and chitin) in serum or CSF ranges from 64 to 90% [
37,
114]. Fungal antigens (e.g., mannan from
Candida spp., galactomannan from
Aspergillus spp., and galactoxylomannan from
Cryptococcus spp.) can be detected with commercially available kits. The detection of cryptococcal capsular polysaccharide antigen in serum or CSF by the latex agglutination test is an established method to diagnose cryptococcosis [
115], while serum assays for galactomannan are recommended for diagnosing invasive aspergillosis [
116]. However, it should be emphasized that as galactomannan antigens can also be expressed by
Fusarium, their positive detection in the serum or CSF does not constitute a definitive diagnosis of CNS aspergillosis [
5]. In addition, (1–3)-β-D-glucan being a cell wall constituent of
Candida and
Aspergillus species, and several other fungi, is not specific serum marker for invasive candidiasis or aspergillosis [
37,
111]. Although serological tests based on the detection of specific antibodies or antigens in body fluids (urine, serum) are commonly used in the diagnostics of CNS histoplasmosis, these methods show variable cross-reactions with other dimorphic fungi including
Blastomyces spp. and
Coccidioides spp. [
116]. A recent study found the CSF antigen test to be effective in the diagnosis of coccidioidal meningitis (sensitivity 93%, specificity 100%) [
117].
More accurate confirmation of diagnoses, and identification of fungi, could be achieved by polymerase chain reaction (PCR) assays. Unfortunately, there are still no standardized and validated detection methods based on PCR; most PCR protocols have been developed for the diagnosis of invasive fungal infections, mainly for
Aspergillus and
Candida species [
108,
116,
118‐
121]. The retrospective analysis of CSF samples from patients with suspected CNS-invasive aspergillosis found the nested PCR assay to have high sensitivity [
118]. PCR positivity in CSF was observed for 8/8 proven/probable, in 4/22 possible and in 2/25 patients without invasion yielding sensitivity and specificity values of 100% and 93%, respectively. PCR techniques performed on cerebrospinal fluid samples may well become the new gold standard for the diagnosis of CNS infection, especially for patients whose clinical condition does not allow invasive diagnostic procedures; however, validation is first needed. In addition, other molecular diagnostic tools for the rapid detection of fungi directly from CSF, such as fluorescence in situ hybridization (FISH), have proved promising in clinical trials but still need to undergo standardization before clinical use [
113,
122].
Treatment of FIs-CNS
Fungal neuroinfections are characterized by higher mortality rates and poorer prognosis than viral and bacterial infections, and parasitic invasions. Rapid diagnosis and the use of appropriate therapy are crucial in helping prevent an often fatal outcome. The choice of antifungal therapy depends on the fungistatic and fungicidal action of drug. The fungal cell membrane or wall components (ergosterol, chitin, and β-glucans) are major targets of the main groups of antifungal agents in current use, with the exception of flucytosine (antimetabolic effects) [
1,
3]. The mode of action of selected antifungal drugs and their spectrum of activity against fungal species is summarized in Table
2. Amphotericin B deoxycholate (AmBd) is highly toxic and has poor CNS penetration, but is an effective treatment for cryptococcal meningoencephalitis, in combination with flucytosine, and neuroinfections caused by other fungi which are not susceptible to agents with good CNS penetration (e.g., voriconazole); in these cases lipid formulations of amphotericin B (L-AmB) should be preferred [
123‐
125]. Treatment recommendations (IDSA, ESCMID, and ECMM) for the most common fungal CNS infections are presented in Table
3 [
37,
110,
111,
125‐
130]. Among antifungal drugs, voriconazole, fluconazole, and flucytosine readily penetrate into the CNS, but itraconazole and posaconazole only penetrate to a minor degree [
131]. Voriconazole is recommended as primary therapy for CNS aspergillosis, while liposomal amphotericin B (L-AmB) are reserved for intolerant or refractory patients [
111,
132,
133]. Clinical data indicate that isavuconazole shows satisfactory activity in invasive aspergillosis [
134] and disseminated mucormycosis with location in CNS [
135].
Table 2
Principle properties of selected antifungal drugs used for treatment of central nervous system infections [
1,
3,
39,
54,
80,
123,
124,
130,
133]
Amphotericin B (Polyene antibiotic) Amphotericin B formulations Deoxycholate—AmBd Lipid complex—ABLC Colloidal dispersion—ABCD Liposomal—L-AmB | Concentration-dependent pharmacokinetics—for all formulations Plasma protein binding—95–99%—for all formulations T1/2 of AmBd of 15–27 h T1/2 of ABLC of ~ 24 h T1/2 of L-AmB of 12–24 h T1/2 of ABCD of ~ 18 h Vd (L/kg) of AmBd—0.5–2.0 Vd (L/kg) of L-AmB—0.05–2.2 | Binding and interaction with ergosterol and destabilization of fungal cell membrane; increase in cell membrane permeability for mono- and divalent cations, which leads to cell death |
Mucor
Absidia
Aspergillus
Cryptococcus
Candida
Histoplasma
Blastomyces
Coccidioides
Paracoccidioides
Sporothrix
|
Fluconazole (Triazole) | Dose-proportional pharmacokinetics (except in patients with renal impairment) Plasma protein binding—12% T1/2 of 24–30 h Vd (L/kg)—0.7 | Inhibition of cytochrome P-450 14 α-lanosterol demethylase; accumulation of lanosterol leading to disorders in the cell membrane | Candida (except C. glabrata and C. krusei)
Cryptococcus
Histoplasma
Blastomyces
Coccidioides
|
Itraconazole (Triazole) | Concentration-dependent pharmacokinetics Plasma protein binding 99.8% T1/2 of 34 h Vd (L/kg)—11 | Inhibition of ergosterol synthesis in the fungal cell membrane like other triazoles |
Aspergillus
Cryptococcus
Candida
Histoplasma
Paracoccidioides
Blastomyces
Sporothrix
|
Voriconazole (Triazole) | Concentration-dependent pharmacokinetics Plasma protein binding—58% T1/2 of ~ 6 h Vd (L/kg)—45 | The mechanism of action on fungi is similar for fluconazole |
Candida
Aspergillus
Fusarium
Scedosporium
|
Posaconazole (Triazole) | Dose-proportional pharmacokinetics Plasma protein binding > 98% T1/2 of 20–31 h Vd (L/kg)—20 (oral suspension) Vd (L/kg)—5 (tablet formulation) Vd (L/kg)—3.7 (intravenous) | Fungicidal action similar to other triazoles |
Aspergillus
Candida
Coccidioides
Fusarium
Rhizomucor
Mucor
Rhizopus
|
Isavuconazole (Triazole) | Dose-proportional pharmacokinetics Plasma protein binding > 98% T1/2 of 80–120 h Vd (L/kg)—65 | The mechanism of action on fungi is similar for fluconazole |
Candida Aspergillus
Mucor
Rhizopus
Rhizomucor
Fusarium
Sporothrix
|
Flucytosine/5-FC/(Nucleoside) | Dose-proportional pharmacokinetics (except in patients with renal impairment) Plasma protein binding—5% T1/2 of 3–5 h Vd (L/kg)—0.4–0.8 | Weakening of nucleic acid synthesis by formation of toxic, fluorine pyrimidine antimetabolites It enters the fungal cell by cytosine permease where it is deaminated to the active form of 5-fluorocytosine, which weakens the synthesis of DNA and RNA |
Cryptococcus
Candida
Cladophialophora Fonsecaea
Phialophora
|
Table 3
Treatment recommendations (IDSA, ESCMID, and ECMM) for fungal CNS infections
Cryptococcal meningoencephalitis | Initial therapy (for the non–HIV-infected and non-transplant patients): AmBd (0.7–1.0 mg/kg/day IV) plus flucytosine (100 mg/kg/day) ≥ 4 weeks AmBd (0.7–1.0 mg/kg/day IV) ≥ 6 weeks—for flucytosine-intolerant patients L-AmB (3–4 mg/kg/day) or ABLC (5 mg/kg/day IV) combined with flucytosine ≥ 4 weeks—for AmBd-intolerant patients Consolidation therapy: fluconazole (400–800 mg /day) ≥ 8 weeks Maintenance therapy: fluconazole (200 mg/day) for 6–12 months | Initial therapy: AmBd (1 mg/kg/day IV) plus flucytosine (100 mg/kg/day orally in 4 divided doses) for 2 weeks L-AmB (5 mg/kg/day) or ABLC (5 mg/kg/day) for AmBb-intolerant patients Consolidation therapy: fluconazole (10–12 mg/kg /day orally) for 8 weeks Maintenance therapy: fluconazole (6 mg/kg/day orally) for 6–12 months | IDSA |
Cerebral cryptococcomas | Initial therapy: AmBd (0.7–1 mg/kg/day IV), or L-AmB (3–4 mg/kg/day IV), or ABLC (5 mg/kg/day IV) plus flucytosine (100 mg/kg/day orally in 4 divided doses) ≥ 6 weeks Consolidation and maintenance therapy: fluconazole (400–800 mg/day orally) for 6–18 months Adjunctive therapies Corticosteroids for mass effect and surrounding edema Surgery: for large (≥ 3 cm lesion), accessible lesions with mass | No recommendation | IDSA |
Candidiasis | Initial therapy: L-AmB (5 mg/kg/day), with or without oral flucytosine (25 mg/kg 4 times daily) for several weeks Step-down therapy: fluconazole, 400–800 mg (6–12 mg/kg) daily. Therapy should continue until all signs and symptoms and CSF and radiological abnormalities have resolved | Initial therapy for the neonatal patients: AmBd (1 mg/kg/day IV) or L-AmB (5 mg/kg/day IV) for several weeks Step-down therapy: fluconazole (12 mg/kg/day). Therapy should continue until all signs, symptoms, and CSF and radiological abnormalities, have resolved |
IDSA
|
Aspergillosis | Voriconazole: loading dose, 6 mg/kg IV every 12 h for 1 day, maintenance dose 4 mg/kg IV every 12 h L-AmB (3–5 mg/kg/day IV) for intolerant or refractory to voriconazole Therapy should continue until all signs and symptoms and CSF and radiological abnormalities have resolved | Voriconazole: loading dose, 9 mg/kg IV every 12 h for 1 day; maintenance dose, 8 mg/kg IV every 12 h L-AmB (3–5 mg/kg/day IV) for intolerant or refractory to voriconazole Treatment duration is determined on a case-by-case basis |
IDSA
|
Mucormycosis | L-AmB (10 mg/kg/day IV), initial 28 days The duration of antifungal treatment should be determined on an individual basis, usually continues for at least 6–8 weeks | L-AmB (5–10 mg/kg/day IV). Treatment duration is determined on a case-by-case basis | ESCMID and ECMM |
Hyalohyphomycosis Fusarium species and Scedosporium apiospermum infection | Voriconazole: loading dose (6 mg/kg IV every 12 h for 1 day) maintenance dose (4 mg/kg IV every 12 h) for long-term | Voriconazole: 4 mg/kg IV every 12 h (13–18 years old) and 8 mg/kg IV every 12 h (2–12 years old) | ESCMID and ECMM |
Histoplasmosis | Initial therapy: L-AmB (5.0 mg/kg/day for a total of 175 mg/kg given over 4–6 weeks) Step-down therapy: itraconazole (200 mg 2 or 3 times daily) for at least 1 year and until resolution of CSF abnormalities, including Histoplasma antigen levels | Initial therapy: AmBd (1 mg/kg/day IV) for 2 weeks Step-down therapy: itraconazole (5.0–10.0 mg/kg/day in 2 divided doses), not to exceed 400 mg daily; for at least 1 year |
IDSA
|
Blastomycosis | Initial therapy: L-AmB (5 mg/kg/day) over 4–6 weeks Step-down therapy: fluconazole (800 mg/day), itraconazole (200 mg 2 or 3 times per day), or voriconazole (200–400 mg twice per day) for at least 12 months and until resolution of CSF abnormalities | Initial therapy: AmBd (0.7–1.0 mg/kg/ day), or L-AmB (3–5 mg/kg/day) Step-down therapy: oral itraconazole, 10 mg/kg/ day (up to 400 mg/day) for a total of 12 months |
IDSA
|
Coccidioidal meningitis | Fluconazole (400–1200 mg /day orally) for patients with normal renal function and without substantial renal impairment; lifelong treatment In patients who clinically fail initial therapy with fluconazole, higher doses are a first option, and second—change of therapy to another orally administered azole, or to initiate intrathecal AmBd therapy | Fluconazole (12 mg/kg/day IV) or ABLC (3–5 mg/kg/day IV), lifelong treatment | IDSA |
Cerebral phaeohyphomycosis | No strong recommendation for antifungal treatment When surgery (complete excision) is not possible voriconazole (400 mg) or posaconazole (800 mg) or combination therapy including a triazole plus an echinocandin plus flucytosine are proposed | No recommendation | ESCMID and ECMM |
In addition to pharmacological treatment, surgical removal of lesions is also possible. In most cases, a combination of surgical intervention and antifungal therapy increases the survival rate of patients with FIs-CNS [
1,
3]. It has been shown that neurosurgery is associated with an improved outcome in patients treated with voriconazole for CNS fungal infections [
48]. Surgical intervention can be used in cases of focal or localized superficial cortico-subcortical lesions (such as abscesses and granulomas) in the non-eloquent areas of the brain, while invasive multifocal lesions, deep cerebral, and/or brain stem lesions involving large parts of the brain, and major vascular invasions are not an indication for using surgical therapies.
Summary
Fungal infections of the central nervous system (FIs-CNS) are rare but pose a threat to life of patients. They are still a significant challenge for diagnosis and treatment. Their prevalence spans a wide array of hosts including immunosuppressed and immunocompetent individuals, mainly hospitalized persons and patients undergoing neurosurgical procedures. Cryptococcus neoformans, Aspergillus spp. and Rhizopus spp. remain the most common pathogens responsible for neuroinvasions. Recently, the number of newly detected fungal species in the CNS has been increasing, which requires the use of more advanced diagnostic methods to establish an etiology of emerging mycoses. Because the manifestations of FIs-CNS are often non-specific, diagnosis of the infection is very difficult. The clinical picture may mimic other CNS infectious diseases, especially tubercular meningitis, and therefore, precise diagnosis is needed. The routine diagnosis includes direct microscopic examination of clinical samples, histopathology, culture, and serology. The use of PCR-based assays still needs to undergo standardization. Although the radiological characteristics of FIs-CNS are often non-specific, some neurological changes caused by the presence of these pathogens can be revealed by CT and MRI. The choice of appropriate therapy is crucial in helping prevent the high mortality associated with fungal neuroinfections, and the choice of drug depends on its extent of CNS penetration, mode of action, and spectrum of activity.