Central Nervous System Fungal Infections in Children With Leukemia and Undergoing Hematopoietic Stem Cell Transplantation: A Retrospective Multicenter Study.

BACKGROUND: Central nervous system fungal infections (CNSFI) are seen in patients with hematologic malignancies and have high morbidity and mortality. Because of their rarity, there is limited data on CNSFI in children with no established treatment protocols or guidelines. MATERIALS AND METHODS: In this multicenter retrospective study, 51 pediatric patients with leukemia, 6 of whom had undergone bone marrow transplantation, with proven or probable CNSFI were evaluated. Fungal infections were defined as proven or probable based on European Organisation for Research and Treatment of Cancer criteria. Proven CNSFI was diagnosed by appropriate central nervous system (CNS) imaging or tissue sample findings in combination with positive microbiological results of cerebrospinal fluid. A positive culture, microscopic evidence of hyphae, a positive result of the galactomannan assays are defined as positive microbiological evidence. Probable CNSFI was defined as appropriate CNS imaging findings together with proven or probable invasive fungal infections at another focus without CNS when there is no other explanatory condition. Data was collected by using the questionnaire form (Supplemental Digital Content 1, http://links.lww.com/JPHO/A541 ). RESULTS: Seventeen patients had proven, 34 patients had probable CNSFI. Headaches and seizures were the most common clinical findings. The median time between the onset of fever and diagnosis was 5 days. The most common fungal agent identified was Aspergillus . Sixteen patients received single-agent, 35 received combination antifungal therapy. Surgery was performed in 23 patients. Twenty-two patients (43%) died, 29 of the CNSFI episodes recovered with a 20% neurological sequelae. CONCLUSION: CNSFIs should be considered in the differential diagnosis in patients with leukemia and refractory/recurrent fever, headache, neurologicalocular symptoms, and a radiologic-serological evaluation should be performed immediately. Early diagnosis and prompt management, both medical and surgical, are essential for improving clinical outcomes.

Central Nervous System Infections in the Immunocompromised Adult Presenting to the Emergency Department.

Over the past 2 decades, the population of immunocompromised patients has increased dramatically in the United States. These patients are at elevated risk for both community-acquired and opportunistic central nervous system infections. We review the most common and serious central nervous system pathogens affecting these patients and outline a diagnostic and therapeutic approach to their management in the emergency department. We recommend a broad diagnostic evaluation, including neuroimaging and cerebrospinal fluid studies where appropriate, empiric antimicrobial therapy, and early involvement of subspecialists to provide comprehensive care for these complex patients.

Paracoccidioidomycosis in the Central Nervous System

Paracoccidioidomycosis is a systemicmycosis caused by the Paracoccidioides brasiliensis fungus, which is endemic in Latin America. Brazil is the country with the highest number of cases. The affection of the central nervous system (CNS), a potentially fatal condition, occurs in 12% of the cases. The following forms of presentation are identified:meningeal, which is unusual;meningoencephalitic; and pseudotumoral, the latter two being more frequent. Imaging tests are essential for the diagnosis, but the histological identification of the fungus is required for confirmation of the pathology. The clinical picture depends on the neuraxial location.We present a case of amale rural worker, with expansive lesions in the CNS compatible with paracoccidioidomycosis.

Angio-invasive Cerebral Aspergillosis Resulting in Hemispheric Infarct in an Immunocompetent Man.

BACKGROUND: Cerebral aspergillosis usually affects immunocompromised hosts and may rarely occur in immunocompetent individuals. Due to its angio-invasive nature, Aspergillus may cause various vascular complications, particularly mycotic aneurysms and infarcts. CASE PRESENTATION: A 22-year-old immunocompetent male with diagnosed case of sino-cerebral aspergillosis was taking voriconazole for two months. His headache worsened and repeat imaging showed an increase in the size of the lesion. The patient was managed with right frontal craniotomy and surgical debridement, and voriconazole was continued. After ten days of uneventful post-operative course, the patient developed left-sided hemispheric infarct. The patient is doing well at nine months' follow-up, and he is off voriconazole for three months after the follow-up imaging showed complete resolution of disease. CONCLUSION: Treatment of choice for cerebral aspergillosis is voriconazole. Surgical debridement may be a useful adjunct in patients not responding to voriconazole alone.

Prolonged survival after disseminated Rhinocladiella infection treated with surgical excision and posaconazole.

Cerebral abscess due to pigmented molds is a rare but usually fatal infection occasionally seen in transplant recipients. A 67-year-old man of Iraqi origin underwent a deceased donation renal transplant for renal failure and 2 months later was diagnosed with an abscess in the left posterior frontal lobe of his brain. Subsequent biopsy proved this to be due to the mold Rhinocladiella mackenziei. Further interventions included two operations to aspirate the lesion, voriconazole, then liposomal amphotericin B, then a combination of posaconazole and flucytosine which he continued for over 4 years. He also suffered from right ankle pain and was diagnosed with septic arthritis; R mackenziei was isolated from pus aspirated from the ankle joint. He responded well to the treatment and has had little loss of function, and on CT, the cerebral lesion has stabilized. Beta-D-glucan, initially at very high levels proved useful to monitor response over the 5 years and the latest sample was negative (38 pg/mL). This case is notable for the first disseminated case of this infection, its favorable outcome on a novel antifungal combination and a new approach to monitoring the course of disease.

Cerebral phaeohyphomycosis due to Cladophialophora bantiana in a French Guianese child.

We report a case of cerebral phaeohyphomycosis, a fungal brain infection due to a dark (dematiaceous) fungi in a 6-year-old French Guyanese boy. The child presented fever and drowsiness due to several paraventricular brain abscesses. Neurological surgeries were performed to reduce intracranial hypertension and to obtain abscess biopsies. Mycological cultures of intraoperative samples led to the diagnosis of cerebral phaeohyphomycosis due to Cladophialophora bantiana. The patient neurological status deteriorated and remained critical after several weeks of combination antifungal therapy with voriconazole 8mg/kg/day, liposomal amphotericin B 10mg/kg/day and flucytosine 200mg/kg/day. A complete surgical resection was not possible because of multiple small abscesses. A multidisciplinary ethical staff decided on home medical care with palliative ventriculoperitoneal shunt, nasogastric feeding and analgesics. One year later, the patient's neurological condition had improved and cerebral lesions had regressed, while he had not received any antifungal treatment but only traditional medicines. Cerebral phaeohyphomycosis are rare diseases affecting immunocompromised but also apparently non-immunocompromised patients, as in this case. A complete surgical resection is not always possible and mortality rates are high in spite of treatments with a combination of antifungals. The diagnosis may be difficult because of these dematiaceous fungi's slowly growing and their potential pathogenicity for laboratory staff.

Update on fungal infections of the central nervous system: emerging pathogens and emerging diagnostics.

PURPOSE OF REVIEW: Fungal infections of the central nervous system (CNS) are relatively uncommon but associated with significant morbidity and mortality. We reviewed recent literature highlighting new approaches to management of these complex patients. RECENT FINDINGS: Fungal infections are increasingly recognized as important causes of CNS disease in both immunocompromised and immunocompetent hosts. Globally, cryptococcal meningitis remains a leading cause of death in HIV-infected persons in resource-limited settings. Emerging fungal pathogens with increased virulence and resistance to numerous classes of antifungal agents have been identified and represent a management challenge. Newer diagnostic techniques focused on antigen detection or molecular amplification of fungal pathogens offer promise in the expediated diagnosis and treatment of CNS fungal infections. SUMMARY: Meningitis and brain abscess because of invasive fungal pathogens are frequently fatal infections. Newer laboratory tests allowing antigen detection or molecular amplification from cerebrospinal fluid are more sensitive than culture and allow earlier initiation of effective therapy.

The Frozen Brain State of Cryptococcus gattii: A Globe-Trotting, Tropical, Neurotropic Fungus.

Initially reported in tropical regions, Cryptococcus gattii infection is now diagnosed globally. Methods: case report; Literature review. Although initial reports described outbreaks of pulmonary and central nervous system (CNS) disease in tropical regions such as Australia and New Guinea, it is now clear that Cryptococcus gattii is a global, neurotropic pathogen. In contrast with C. neoformans, C. gattii patients are more likely to present with cryptococcomas in the brain and lungs and are often HIV negative. Imaging findings can mimick cancer leading to delays in diagnosis and definitive treatment. Some experts have speculated that the spread of C. gattii is due to climate change, newly recognized genotypes that cause disease in temperate zones (genotype VGII), international travel, and improved awareness among physicians and veterinarians. We emphasize neurocritical and neurosurgical management, because patients with CNS involvement often have high intracranial pressures (ICP). Cryptococcus gattii patients often have elevated ICP without 'red flag' radiographic signs of elevated ICP such as ventriculomegaly, cerebral edema, or effaced basal cisterns. Therefore, diagnosis of high ICP should be suspected based on clinical symptoms such as incapacitating headaches, progressive visual loss and associated papilledema, and then confirmed by measuring the opening pressure with lumbar puncture (LP). Cerebral intraparenchymal deposition of the large cryptococcal polysaccharide capsule and cryptococcal organisms causes poor brain compliance leading to a 'frozen brain state.' Mortality rates and clinical outcomes are significantly improved with early diagnosis, antifungal therapies, steroids, and aggressive management of elevated ICP including cerebrospinal fluid (CSF) diversion by serial LP's, external ventricular drains and CSF shunts. Following institution of antifungal therapy, about 10% of patients can worsen due to immune reconstitution inflammatory syndrome which responds to steroids. We recommend neurocritical and neurosurgical management of C. gattii patients with CNS involvement and elevated ICP. There is often poor correlation between elevated ICP and neuroimaging due to the frozen brain state.

Fungal infections of the central nervous system and paranasal sinuses in onco-haematologic patients. Epidemiological study reporting the diagnostic-therapeutic approach and outcome in 89 cases.

Invasive fungal infections (IFI) of the Central Nervous System (IFI-CNS) and Paranasal Sinuses (IFI-PS) are rare, life-threatening infections in haematologic patients, and their management remains a challenge despite the availability of new diagnostic techniques and novel antifungal agents. In addition, analyses of large cohorts of patients focusing on these rare IFI are still lacking. Between January 2010 and December 2016, 89 consecutive cases of Proven (53) or Probable (36) IFI-CNS (71/89) and IFI-PS (18/89) were collected in 34 haematological centres. The median age was 40 years (range 5-79); acute leukaemia was the most common underlying disease (69%) and 29% of cases received a previous allogeneic stem cell transplant. Aspergillus spp. were the most common pathogens (69%), followed by mucormycetes (22%), Cryptococcus spp. (4%) and Fusarium spp. (2%). The lung was the primary focus of fungal infection (48% of cases). The nervous system biopsy was performed in 10% of IFI-CNS, and a sinus biopsy was performed in 56% of IFI-PS (P = 0.03). The Galactomannan test on cerebrospinal fluid has been performed in 42% of IFI-CNS (30/71), and it was positive in 67%. Eighty-four pts received a first-line antifungal therapy with Amphotericine B in 58% of cases, Voriconazole in 31% and both in 11%. Moreover, 58% of patients received 2 or more lines of therapy and 38% were treated with a combination of 2 or more antifungal drugs. The median duration of antifungal therapy was 60 days (range 5-835). A surgical intervention was performed in 26% of cases but only 10% of IFI-CNS underwent neurosurgical intervention. The overall response rate to antifungal therapy (complete or partial response) was 57%, and 1-year overall survival was 32% without significant differences between IFI-CNS and IFI-PS. The overall mortality was 69% but the IFI attributable mortality was 33%. Mortality of IFI-CNS/PS remains high but, compared to previous historical data, it seems to be reduced probably due to the availability of newer antifungal drugs. The results arising from this large contemporary cohort of cases may allow a more effective diagnostic and therapeutic management of these very rare IFI complications in haematologic patients.

Neuroinfections caused by fungi.

BACKGROUND: Fungal infections of the central nervous system (FIs-CNS) have become significantly more common over the past 2 decades. Invasion of the CNS largely depends on the immune status of the host and the virulence of the fungal strain. Infections with fungi cause a significant morbidity in immunocompromised hosts, and the involvement of the CNS may lead to fatal consequences. METHODS: One hundred and thirty-five articles on fungal neuroinfection in PubMed, Google Scholar, and Cochrane databases were selected for review using the following search words: "fungi and CNS mycoses", CNS fungal infections", "fungal brain infections", " fungal cerebritis", fungal meningitis", "diagnostics of fungal infections", and "treatment of CNS fungal infections". All were published in English with the majority in the period 2000-2018. This review focuses on the current knowledge of the epidemiology, clinical presentations, diagnosis, and treatment of selected FIs-CNS. RESULTS: The FIs-CNS can have various clinical presentations, mainly meningitis, encephalitis, hydrocephalus, cerebral abscesses, and stroke syndromes. The etiologic factors of neuroinfections are yeasts (Cryptococcus neoformans, Candida spp., Trichosporon spp.), moniliaceous moulds (Aspergillus spp., Fusarium spp.), Mucoromycetes (Mucor spp., Rhizopus spp.), dimorphic fungi (Blastomyces dermatitidis, Coccidioides spp., Histoplasma capsulatum), and dematiaceous fungi (Cladophialophora bantiana, Exophiala dermatitidis). Their common route of transmission is inhalation or inoculation from trauma or surgery, with subsequent hematogenous or contiguous spread. As the manifestations of FIs-CNS are often non-specific, their diagnosis is very difficult. A fast identification of the etiological factor of neuroinfection and the application of appropriate therapy are crucial in preventing an often fatal outcome. The choice of effective drug depends on its extent of CNS penetration and spectrum of activity. Pharmaceutical formulations of amphotericin B (AmB) (among others, deoxycholate-AmBd and liposomal L-AmB) have relatively limited distribution in the cerebrospinal fluid (CSF); however, their detectable therapeutic concentrations in the CNS makes them recommended drugs for the treatment of cryptococcal meningoencephalitis (AmBd with flucytosine) and CNS candidiasis (L-AmB) and mucormycosis (L-AmB). Voriconazole, a moderately lipophilic molecule with good CNS penetration, is recommended in the first-line therapy of CNS aspergillosis. Other triazoles, such as posaconazole and itraconazole, with negligible concentrations in the CSF are not considered effective drugs for therapy of CNS fungal neuroinfections. In contrast, clinical data have shown that a novel triazole, isavuconazole, achieved considerable efficacy for the treatment of some fungal neuroinfections. Echinocandins with relatively low or undetectable concentrations in the CSF do not play meaningful role in the treatment of FIs-CNS. CONCLUSION: Although the number of fungal species causing CNS mycosis is increasing, only some possess well-defined treatment standards (e.g., cryptococcal meningitis and CNS aspergillosis). The early diagnosis of fungal infection, accompanied by identification of the etiological factor, is needed to allow the selection of effective therapy in patients with FIs-CNS and limit their high mortality.

Affinity of Mucormycosis for Basal Ganglia in Intravenous Drug Users: Case Illustration and Review of Literature.

Central nervous system mucormycosis is an aggressive fungal infection often ending in fatality. The usual circumstance is an immunocompromised individual presenting with rapidly progressive rhinocerebral involvement. An extremely rare variant of central nervous system mucormycosis isolated to the basal ganglia in an immunocompetent intravenous drug user is detailed in this manuscript. The patient was aggressively treated with aspiration of the fungal abscess and long-term intravenous antifungal agents.

An updated comprehensive systematic review of Cladophialophora bantiana and analysis of epidemiology, clinical characteristics, and outcome of cerebral cases.

Cladophialophora bantiana is a phaeoid fungus that only rarely has been isolated from sources other than the human brain. It has a particular tropism for the central nervous system (CNS). We have integrated and updated large-scale data related to several aspects of C. Bantiana and reviewed all the available reports on its cerebral infections, focusing on their geographical distribution, infection routes, immune status of infected individuals, type and location of infections, clinical manifestations and treatment and outcome, briefly looking over the spectrum of other disease entities associated with C. bantiana, that is, extra-cerebral and animal infections and on the environmental sources of this fungus. Among the agents of phaeohyphomycosis, a term used to describe an infection caused by a dark pigmented fungus, C. bantiana has some significant specific features. A total of 120 case reports were identified with a significantly higher percentage of healthy subjects than immune-debilitated patients (58.3% vs. 41.7%). Infections due to C. bantiana occur worldwide. The main clinical manifestations are brain abscess (97.5%), coinfection of brain tissue and meninges (14.2%) and meningitis alone (2.5%). Among immunocompetent patients, cerebral infection occurred in the absence of pulmonary lesions. The mortality rate is 65.0% regardless of the patient's immune status. The therapeutic options used include surgery or antifungals alone, and the combination of both, in most cases the fatal outcome being rapid after admission. Since the fungus is a true pathogen, laboratory workers should be made aware that BioSafety Level-3 precautions might be necessary.

[Dementia in Patients with Central Nervous System Mycosis].

Central nervous system (CNS) mycosis is a potentially life-threatening but treatable neurological emergency. CNS mycoses progress slowly and are sometimes difficult to distinguish from dementia. Though most patients with CNS mycosis have an underlying disease, such as human immunodeficiency virus (HIV) infection, cancer, diabetes mellitus, and/or use of immunosuppressants, cryptococcosis can occur in non-immunosuppressed persons. One of the major difficulties in accurate diagnosis is to detect the pathogen in patients' cerebrospinal fluid (CSF) cultures. Thus, the clinical diagnosis is often made by combining circumstantial evidence, including mononuclear cell-dominant pleocytosis with low glucose and protein elevation in the CSF, as well as positive results from an antigen-based assay and a (1-3)-beta-D-glucan assay using plasma and/or CSF. Polymerase chain reaction (PCR)-based diagnostics, which are not performed as routine examinations and are mostly performed as part of academic research in Japan, are sensitive tools for the early diagnosis of CNS mycosis. Mognetic resonance imaging (MRI) is useful to assess the complications of fungal meningitis, such as abscess, infarction, and hydrocephalus. Clinicians should realize the advantages and disadvantages of these diagnostic tools. Early and accurate diagnosis, including identification of the particular fungal species, enables optimal antifungal treatment that produces good outcomes in patients with CNS mycosis.

A retrospective analysis of eleven cases of invasive rhino-orbito-cerebral mucormycosis presented with orbital apex syndrome initially.

BACKGROUND: Rhino-orbito-cerebral mucormycosis(ROCM) is an invasive fungal infection that usually occurs in immunocompromised patients and sometimes presents as orbital apex syndrome(OAS) initially. It is rapidly fatal without an early diagnosis and treatment. We report the cases of invasive ROCM presenting with OAS initially in order to raise the attention of clinicians. METHODS: We retrospectively investigated eleven cases of invasive ROCM presenting initially with OAS admitted between January 2006 and December 2013. We analyzed clinical features, results of laboratory and radiological examinations, nasal endoscopy, aggressive surgical excision and debridement, and medical management outcomes of each case. RESULTS: A total of eleven cases of invasive ROCM with OAS as an initial sign were presented. Mucormycosis was accompanied by type II diabetes mellitus in nine cases, renal transplant in one case, and injury caused by traffic accident in one case. Anterior rhinoscopy revealed palatine or nasal necrotic lesions in all patients, and transethmoidal optic nerve decompression was carried out in three patients at the same time. CT scan revealed rhino-orbital-cerebral involvement in every patient. All patients were given intravenous amphotericin B. Nine patients underwent surgical debridement of necrotic tissue. Three patients survived. CONCLUSIONS: ROCM is a severe, emergent and fatal infection requiring multidisciplinary management. It may often present with OAS initially. For ophthalmologist, mucormycosis must be considered in immunocompromised patients presenting with OAS initially, and anterior rhinoscopy is imperative before hormonotherapy, even in the cases absent of ketoacidosis induced by diabetes mellitus.

A CLADOPHIALOPHORA BRAIN ABSCESS IN A RENAL TRANSPLANT RECIPIENT.

Cladophialophora bantiana is a dematiceous fungus with neurotrophic propensity for which therapy is not standardized and mortality is high. We report here a 49 year old non-diabetic renal transplant patient on triple immunosuppressant therapy who presented with a history of falls, weakness and headaches. A computed tomography scan of the brain revealed a 30 mm diameter abscess in the brain which was removed surgically and diagnosed on culture as C. bantiana. The patient was successfully treated medically post-operatively with chronic posaconazole. We review the literature regarding central nervous system infections due to C. bantiana.

Clinical management of infectious cerebral vasculitides.

A wide range of infections (virus, bacteria, parasite and fungi) may cause cerebral vasculitides. Headache, seizures, encephalopathy and stroke are common forms of presentation. Infection and inflammation of intracranial vessels may cause pathological vascular remodelling, vascular occlusion and ischemia. Vasculitis in chronic meningitis may cause ischemic infarctions, and is associated with poor outcome. Appropriate neuroimaging (CT-angiography, MR-angiography, conventional 4-vessel angiography) and laboratory testing (specific antibodies in blood and CSF, CSF culture and microscopy) and even brain biopsy are needed to quickly establish the aetiology. Enhancement of contrast, wall thickening and lumen narrowing are radiological signs pointing to an infectious vasculitis origin. Although corticosteroids and prophylactic antiplatelet therapy have been used in infectious cerebral vasculitis, there are no randomized clinical trials that have evaluated their efficacy and safety. Stable mycotic aneurysms can be treated with specific antimicrobial therapy. Endovascular therapy and intracranial surgery are reserved for ruptured aneurysms or enlarging unruptured aneurysms.

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.