Central nervous system candidiasis beyond neonates: Lessons from a nationwide study.

Though candidiasis is the most frequent invasive fungal infection, Candida spp. central nervous system (CNS) infections are rare but severe. To further describe clinico-patho-radiological presentations of this entity, we report a retrospective study from January 2005 to December 2018 including patients aged ≥ 28 days with proven or probable CNS candidiasis in France. Twenty-four patients were included. Seventeen patients (70%) had CNS localization secondary to disseminated candidiasis (10 with hematologic malignancies [HM]; the seven other patients had infective endocarditis [IE]). Among patients with HM, seven previously had lumbar puncture for intrathecal chemotherapy, the three others had IE. Among patients with disseminated infection, magnetic resonance imaging (MRI) evidenced meningitis (17%), micro-abscesses (58%), or vascular complications (67%). Seven patients (30%) had isolated CNS involvement related to neurosurgery (n = 2), CARD9 deficiency (n = 2), intravenous drug use, diabetes mellitus, or no identified predisposing condition (n = 1 each). All evaluated patients with isolated CNS involvement had meningitis on cerebrospinal fluid (CSF) and intracranial hypertension. For the latter patients, MRI evidenced meningitis (71%) or abscesses (57%). Among all patients, cerebrospinal fluid (CSF) culture grew Candida spp. in 31% of cases. CSF ßDGlucan or mannan Ag were positive in respectively 86% and 80% of cases. Mortality attributed to CNS candidiasis was 42%: 53% in case of disseminated infection (70% for HM) and 14% in case of localized infection. CNS candidiasis are isolated or occur during disseminated infection in patients with HM and lumbar puncture for intrathecal chemotherapy or during IE. Clinical, radiological finding and outcome highly vary according to CNS localized versus disseminated candidiasis. LAY SUMMARY: Candida is a yeast and is the most common cause of fungal infections worldwide. Candida central nervous system (CNS) infections are rare, severe, and poorly described. We report a retrospective study from January 2005 to December 2018 including patients aged ≥ 28 days with proven or probable CNS candidiasis in France. Twenty-four patients were included (14 men, median age 51 years). Seventeen patients had CNS localization secondary to disseminated candidiasis from blood to CNS (10 with hematologic malignancies [HM], the seven other patients had infective endocarditis [IE]). Seven patients had isolated CNS involvement related to neurosurgery (n = 2), CARD9 deficiency (n = 2), intravenous drug use (n = 1), diabetes mellitus (n = 1), or no identified risk factor (n = 1).During Candida CNS infections, brain lesions were meningitis abscesses or vascular complications. Cerebrospinal fluid (CSF) culture grew Candida spp. in 31% of cases. Forty-two percent of patients died from infection: 53% in case of disseminated infection (70% for HM) and 14% in case of localized infection.

Role of microglia in fungal infections of the central nervous system.

Most fungi are capable of disseminating into the central nervous system (CNS) commonly being observed in immunocompromised hosts. Microglia play a critical role in responding to these infections regulating inflammatory processes proficient at controlling CNS colonization by these eukaryotic microorganisms. Nonetheless, it is this inflammatory state that paradoxically yields cerebral mycotic meningoencephalitis and abscess formation. As peripheral macrophages and fungi have been investigated aiding our understanding of peripheral disease, ascertaining the key interactions between fungi and microglia may uncover greater abilities to treat invasive fungal infections of the brain. Here, we present the current knowledge of microglial physiology. Due to the existing literature, we have described to greater extent the opportunistic mycotic interactions with these surveillance cells of the CNS, highlighting the need for greater efforts to study other cerebral fungal infections such as those caused by geographically restricted dimorphic and rare fungi.

Fungal Infections of the Central Nervous System.

PURPOSE OF REVIEW: This article summarizes current knowledge on the epidemiology, clinical presentations, diagnosis, and management of selected fungal infections of the central nervous system (CNS). Key syndromes, differential diagnoses, and therapeutic interventions according to host immune status and exposure are reviewed. RECENT FINDINGS: Advancements in imaging of the brain and spinal cord, and molecular DNA and antigen-based laboratory diagnostics afford improved sensitivity for CNS mycoses. Newer therapeutic strategies may improve outcomes if provided early and host immunosuppression is abrogated. Adjunctive corticosteroid use for disabling neuroinflammation and cerebral edema in the setting of microbiological control may be considered. In addition, nonspecific presentations and absence of fevers in patients without human immunodeficiency virus suggest that screening for Cryptococcus meningitis be performed in all patients with subcortical dementias using a simple CSF or serum antigen test. SUMMARY: CNS fungal infections comprise a wide spectrum of clinical syndromes, including abscesses, meningitis/meningoencephalitis, focal masses, stroke/vasculitides, immune reconstitution inflammatory syndrome (IRIS), and spinal pathologies such as arachnoiditis. The main etiologies include Aspergillus, Cryptococcus, Candida, Mucorales, dematiaceous molds, and dimorphic endemic fungi, with the route of acquisition being respiratory or traumatic inoculation with subsequent spread hematogenously or contiguously. Proper management focuses on early effective antifungal therapy and surgery for large or compressive mass lesions. While adjunctive recombinant cytokine or growth factor use has been supported in certain hosts with refractory infections, IRIS-like reactions may occur, suggesting alternative approaches such as high-dose pulse corticosteroids followed by taper.

Pathology of tropical diseases.

Tropical diseases affecting the central nervous system include infections, infestations, and nutritional deficiency disorders. This article discusses the commonly encountered diseases. The infections include bacterial, mycobacterial, fungal, parasitic, and viral infections with varied clinical manifestations. Imaging sensitivity and specificity for the prediction of the cause of infections has improved with application of advanced techniques. Microbial demonstration and histology remain the gold standard for diagnosis. Understanding the basis of imaging changes is mandatory for better evaluation of images. Nutritional disorders present with generalized and nonspecific imaging manifestations. The pathology of commonly encountered vitamin deficiencies is also discussed.

Outcomes of central nervous system cryptococcosis vary with host immune function: results from a multi-center, prospective study.

BACKGROUND: Central nervous system (CNS) cryptococcosis is most commonly encountered among HIV-infected and other immunosuppressed hosts but is less well-characterized among non-immunosuppressed patients. METHODS: We conducted a three year, prospective, observational study to compare the clinical manifestations and outcome of CNS cryptococcosis in three patient populations: HIV-infected patients (n = 54), HIV-negative immunosuppressed patients (n = 21), and non-immunosuppressed patients (n = 11). RESULTS: Time from initial symptoms to presentation did not differ between the groups. HIV-infected patients were significantly more likely to present with fevers (p < 0.0001), but were less likely to have abnormal mental status, CNS mass lesions and pulmonary involvement (p = 0.001, 0.01 and 0.03, respectively). The clinical manifestations among HIV-negative immunosuppressed patients were generally intermediate to the other groups. Overall, acuity of illness was worse among non-immunosuppressed patients, as measured by APACHE II scores (p = 0.02). Intracranial pressure was higher in HIV-infected and non-immunosuppressed patients than immunosuppressed patients (p = 0.008 and 0.01, respectively). Repeated lumbar punctures were more common among HIV-infected patients (p = 0.01). There was a trend toward more frequent placement of permanent CNS shunts among non-HIV patients (p = 0.05). The mortality rate was greatest for non-immunosuppressed patients (p = 0.04). CONCLUSION: CNS cryptococcosis in non-immunosuppressed patients was associated with poorer prognosis. Our findings suggest that host immune responses may contribute to pathogenesis of CNS cryptococcosis, with more intact immune function associated with increased CNS-related morbidity and overall mortality.

Fungal infections of the central nervous system: the clinical syndromes.

Fungal infections of the central nervous system (CNS) are being increasingly diagnosed both in immunocompromised and immunocompetent individuals. Sinocranial aspergillosis is more frequently described from countries with temperate climates, more often in otherwise immunocompetent individuals. The clinical syndromes with which fungal infections of the CNS can present are protean and can involve most part of the neuroaxis. Certain clinical syndromes are specific for certain fungal infections. The rhinocerebral form is the most common presenting syndrome with zygomycosis and skull-base syndromes are often the presenting clinical syndromes in patients with sinocranial aspergillosis. Subacute and chronic meningitis in patients with HIV infection is more likely to be due to cryptococcal infection. Early recognition of the clinical syndromes in an appropriate clinical setting is the first step towards achieving total cure in some of these infections.

Laboratory investigation of fungal infections of the central nervous system.

While fungal infections of the central nervous system (CNS) are relatively rare, fungal pathogens are increasingly being recognized as an important etiology of CNS infections, particularly amongst the growing immunocompromized population. In this paper we aim to provide a practical approach to the diagnosis of fungal infections of the CNS, review some of the diagnostic methods currently available and discuss diagnosis of certain pathogens of particular interest to the practicing neurologist.

Middle and posterior fossa aspergilloma.

BACKGROUND: Aspergilloma of the brain is a rare disease. Among its varied presentations, a solitary intracranial mass is very uncommon. A preoperative diagnosis of it is very difficult, but a perioperative squash smear/frozen section can identify the pathology. Because of its rarity in immunocompetent patients and the difficulty in preoperative diagnosis, we have illustrated this case and its presentation and management. METHODS: A 27-year-old man presented with an h/o right-sided weakness along with headache and ear discharge. A computed tomographic (CT) scan showed a large irregular, space-occupying lesion in the middle and posterior cranial fossa. He had a mastoidectomy done 3 years before for chronic suppurative otitis media. After a symptom-free interval of 1 year, he was investigated for severe earache on the same side. A CT scan at that time showed a space occupying mass in the right temporal bone and right inferior temporal lobe. A biopsy and histopathology of the lesion revealed a chronic granulomatous mass. He was started on antituberculous drugs and was on it for 7 months at the time of presentation. RESULTS: He underwent a suboccipital craniectomy and total excision of the mass. Postoperatively, his consciousness improved but began to deteriorate on the third postoperative day. A repeat CT scan showed hydrocephalus and total removal of the mass. An external ventricular drain was put and he was ventilated, but he died on the fourth postoperative day. Histopathology report came as aspergilloma. CONCLUSION: This report highlights the rare presentation of aspergilloma in an immunocompetent patient. It emphasizes the importance of suspecting this disease in such patients and the role of intraoperative squash smear preparations or frozen section in the diagnosis as routine diagnostic procedures that will help in early pharmacotherapeutic interventions in adjunct to surgery.

Intracranial fungal granuloma: analysis of 40 patients and review of the literature.

OBJECTIVE: To describe the characteristics of patients diagnosed with intracranial fungal granuloma (IFG) in the largest reported series to date (to our knowledge). METHODS: A 22-year retrospective, multi-institutional review of 40 patients, aged 16 to 62 years (mean, 40.2 years), was performed in patients with histopathologically confirmed IFG. The variables were symptoms/signs at presentation, predisposing factors, location of granuloma, involvement of paranasal sinuses, diagnostic studies including blood and urine cultures, surgical procedures performed, specific organism identified, treatment, and prognosis. Plain x-rays, computed tomography, and/or magnetic resonance imaging scans were performed. RESULTS: Predominant symptoms included headache (83%), vomiting (65%), proptosis (48%), and visual disturbances (48%). Other symptoms were fever, nasal congestion, and seizures (7 [18%]). Common signs included papilledema (12 [30%]), with cranial neuropathy (I, III/IV/VI, and V in 4, 7, and 2 patients, respectively), hemiparesis (3), and meningismus (3). Predisposing factors were diabetes (16 [40%]), tuberculosis (7 [18%]), and immunocompromise related to renal transplant (2), non-Hodgkin's lymphoma (1), and human immunodeficiency virus (1). Location was primarily frontal (10 [25%]), with anterior cranial fossa involved in 8 (20%) patients; 6 (15%) patients had sellar/parasellar involvement. Eighteen (40%) had paranasal sinus involvement. Twenty-nine patients underwent craniotomy for resection, with 11 undergoing biopsy (of which 3 were transsphenoidally approached). Histopathology revealed aspergilloma (25 [63%]), mucormycosis (7 [18%]), cryptococcoma (3), cladosporidium (3), Bipolaris hawaiiensis (1), and Candida species(1). Microbiological analysis of the specimen was positive in 28 (60%) patients. All patients were treated with amphotericin B, fluconazole, and/or flucytosine. Only 26 patients completed amphotericin B therapy (due to nephrotoxicity). Mortality was 63%, most commonly due to meningoencephalitis (16 [36%]). CONCLUSIONS: High index of suspicion of IFG should exist for the following groups: (1) immunocompromised patients with intracranial lesions and (2) diabetic patients with intracranial and rhinocerebral mass lesions. Early diagnosis, surgical decompression, and a complete course of promptly initiated antifungal therapy are associated with better prognosis.

Primary central nervous system phaeohyphomycosis: a review of 101 cases.

Phaeohyphomycosis refers to infections caused by darkly pigmented fungi. These fungi rarely cause life-threatening disease. We reviewed 101 cases of culture-proven primary central nervous system phaeohyphomycosis reported in the English-language literature from 1966 to 2002. The most frequently isolated species was Cladophialophora bantiana. The next most frequent isolate was Ramichloridium mackenziei, seen exclusively in patients from the Middle East. More than one-half of the cases occurred in patients with no known underlying immunodeficiency. Mortality rates were high regardless of immune status. Therapy is not standardized, although the combination of amphotericin B, flucytosine, and itraconazole may improve survival rates. Newer azoles, such as voriconazole, also have a broad spectrum of activity against these fungi, although clinical experience is limited. Complete excision of brain lesions may provide better results than simple aspiration. An aggressive medical and surgical approach is warranted in treating these infections to optimize outcomes.

S100B expression in and effects on microglia.

We evaluated the intracellular and extracellular biological role of S100B protein with respect to microglia. S100B, which belongs to the multigenic family of Ca2+-binding proteins, is abundant in astrocytes where it is found diffusely in the cytoplasm and is associated with membranes and cytoskeleton constituents. S100B protein is also secreted by astrocytes and acts on these cells to stimulate nitric oxide secretion in an autocrine manner. However, little is known about the relationship between S100B and microglia. To address this issue, we used primary microglia from newborn rat cortex and the BV-2 microglial cell line, a well-established cell model for the study of microglial properties. S100B expression was assessed by immunofluorescence in primary microglia and by RT-PCR, Western blotting, and immunofluorescence in BV-2 cells. S100B was found in microglia in the form of a filamentous network as well as diffusely in the cytoplasm and associated with intracellular membranes. S100B relocated around phagosomes during BV-2 phagocytosis of opsonized Cryptococcus neoformans. Furthermore, interferon-gamma (IFN-gamma) treatment caused cell shape changes and redistribution of S100B, and downregulation of S100B mRNA expression in BV-2 cells. Treatment of BV-2 cells with nanomolar to micromolar amounts of S100B resulted in increased IFN-gamma-induced expression of inducible nitric oxide synthase mRNA as well as nitric oxide secretion. Taken together, these data suggest a possible role for S100B in the accomplishment/regulation of microglial cell functions.