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Introduction: Rhino-orbital-aspergillosis (ROA) is a rare but serious disease in immunocompetent patients. Diagnosis is often delayed due to the absence of specific clinical symptoms. We describe the case of a patient who presented initially with ROA which spread progressively to the right ethmoid-sphenoid sinuses and then to the brain., Observation: A 61-year-old patient with a history of well-controlled diabetes presented with a sudden severe decrease in right visual acuity. Cerebral MRI showed the presence of an infiltrate in the right orbital apex extending to the homolateral cavernous sinus without any cerebral involvement. A diagnosis of right orbital myositis was made and corticosteroid therapy was started. His symptoms worsened progressively leading to quasi-blindness. A new MRI showed the development of right sphenoid-ethmoid osteolytic lesions. A fungal aetiology was suspected and tests for fungal biomarkers found a β-(1-3)-D-glucan level of 99pg/ml but negative galactomannan. An ethmoid biopsy was performed for histological and mycological investigations, including the detection of Aspergillus DNA by qPCR. qPCR was positive and culture resulted in the isolation of multi-sensitive Aspergillus fumigatus. Treatment was initiated with voriconazole. Due to persistence of blindness and the appearance of a lesion extending to the right frontal lobe, surgical excision was performed followed by antifungal treatment for a total duration of 1year. The patient is currently stable, but has persistence of blindness in the right eye., Conclusion: Invasive ROA is a rare but serious disease in immunocompetent patients which should be evoked in the differential diagnosis of a tumour or vasculitis. Early diagnosis is essential for optimal management., (Copyright © 2020. Published by Elsevier Masson SAS.)

Background: Breakthrough invasive fungal infections (bIFIs) are an area of concern in the scarcity of new antifungals. The mixed form of bIFIs is a rare phenomenon but could be potentially a troublesome challenge when caused by azole-resistant strains or non-Aspergillus fumigatus. To raise awareness and emphasize diagnostic challenges, we present a case of mixed bIFIs in a child with acute lymphoblastic leukemia., Case Presentation: A newly diagnosed 18-month-old boy with acute lymphoblastic leukemia was complicated with prolonged severe neutropenia after induction chemotherapy. He experienced repeated episodes of fever due to extended-spectrum beta-lactamase-producing Escherichia coli bloodstream infection and pulmonary invasive fungal infection with Aspergillus fumigatus (early-type bIFIs) while receiving antifungal prophylaxis. Shortly after pulmonary involvement, his condition aggravated by abnormal focal movement, loss of consciousness and seizure. Cerebral aspergillosis with Aspergillus niger diagnosed after brain tissue biopsy. The patient finally died despite 108-day antifungal therapy., Conclusions: Mixed bIFIs is a rare condition with high morbidity and mortality in the patients receiving immunosuppressants for hematological malignancies. This case highlights the clinical importance of Aspergillus identification at the species level in invasive fungal infections with multiple site involvement in the patients on antifungal prophylaxis.

We report the case of a patient who had cerebral aspergillosis after otorhinolaryngologic surgery and who was successfully and safely treated with high-dose voriconazole (200 mg q6h) for more than 1 year thanks to a TDM-guided approach coupled with pharmacological review and with genotyping of CYP2C19 polymorphisms. The findings support the idea that personalized medicine based on TDM coupled with the need of avoiding drug-drug interactions may be helpful for maximizing the net benefit (probability of efficacy vs. probability of adverse events) of voriconazole in the management of long-term treatment of cerebral aspergillosis., (© 2018 The British Pharmacological Society.)

Objectives: To describe the neurological manifestations of invasive aspergillosis presenting with a focal neurological deficit compatible with an acute stroke., Materials and Methods: Retrospective analysis of a clinical series of patients between 2011 and 2017 with invasive aspergillosis and neurological symptoms compatible with an acute brain stroke. Clinical and epidemiological data, microbiological results, radiological findings, treatment, and course were recorded., Results: Five patients were selected with a mean age of 55.4years. All patients were immunosuppressed. In 4, systemic infection was unknown. In every case, neurology on call was alerted because of acute focal neurological symptoms. None of the patients received revascularization procedures. Galactomannan antigen was positive in all of the patients and culture was positive in 3. Mortality was 100% despite specific antifungal treatment., Conclusions: Acute stroke can be the first manifestation of disseminated aspergillosis. This form of presentation was frequent in our series and should be suspected in immunocompromised patients with acute neurological deficits., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Neurologic complications after solid-organ transplant reveal a great spectrum of pathologies. Intracranial hemorrhages, cerebral ischemic lesions, infarctions, lymphoproliferative disorders, and infections, including aspergillosis, have been observed after liver transplant. Fungi constitute nearly 5% of all central nervous system infections, mainly occurring in immunocompromised patients. The most common causative agent is Aspergillus species. It presents either as maxillary sinusitis or pulmonary infection. Brain involvement of Aspergillus carries a high rate of mortality. Aspergillosis presents in the forms of meningitis, mycotic aneurysms, infarctions, and mass lesions. Aspergillosis does not have a specific radiologic appearance. Parenchymal aspergillosis has heterogenous signal intensity (hypointense on T1-weighted and hyperintense on T2-weighted images). Here, we present 3 patients who underwent solid-organ transplant and developed central nervous system aspergillosis. Different modalities of neurosurgical intervention were performed in combination with chemotherapy as part of their fungal therapy.

Invasive aspergillosis is one of the most important and fatal complications after liver transplant, especially in patients with involvement of the central nervous system. We present a case of a patient who developed cerebral and pulmonary aspergillosis, coinfected with cytomegalovirus, after liver transplant for toxic fulminant hepatitis. The patient was treated successfully with neurosurgical intervention and voriconazole. Voriconazole is considered more effective in cerebral aspergillosis than other anti-fungal agents due to the greater penetration into central nervous system and higher cerebrospinal fluid and brain tissue levels.

Invasive aspergillosis (IA) is a severe disseminated fungal disease that occurs mostly in immunocompromised patients. However, central nervous system IA, combining meningitis and skull base involvement, does not occur only in groups with classic risk factors for IA; patients with chronic renal failure and diabetes mellitus are also at risk for more chronic forms. In both of our proven IA cases, voriconazole monotherapy was effective without surgery, and cerebrospinal fluid and serum 1,3-β-d-glucan test results were initially positive, in contrast to galactomannan antigen results., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Invasive central nervous system aspergillosis is a rare form of fungal infection that presents most commonly in immunocompromised individuals. There have been multiple previous reports of aspergillus vertebral osteomyelitis and spinal epidural aspergillus abscess; however to our knowledge there are no reports of intramedullary aspergillus infection. We present a 19-year-old woman with active acute lymphoblastic leukemia who presented with several weeks of fevers and bilateral lower extremity weakness. She was found to have an intramedullary aspergillus abscess at T12-L1 resulting from adjacent vertebral osteomyelitis and underwent surgical debridement with ultra-sound guided aspiration and aggressive intravenous voriconazole therapy. To our knowledge this is the first reported case of spinal aspergillosis invading the intramedullary cavity. Though rare, this entity should be included in the differential for immunocompromised patients presenting with fevers and neurologic deficit. Early recognition with aggressive neurosurgical intervention and antifungal therapy may improve outcomes in future cases., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Opportunistic fungi are dispersed as airborne, ground and decaying matter. The second most frequent extra-pulmonary disease by Aspergillus is in the central nervous system., Case Presentation: The case subject was 55 years old, male, mulatto, and an assistant surveyor residing in Teresina, Piauí. He presented with headache, seizures, confusion, fever and left hemiparesis upon hospitalization in 2006 at Hospital São Marcos. Five years previously, he was diagnosed with diabetes mellitus, and 17 months previously he had acne margined by hyperpigmented areas and was diagnosed with leprosy. Laboratory tests indicated leukocytosis and magnetic resonance imaging showed an infarction in the right cerebral hemisphere. Cerebrospinal fluid examination showed 120 cells/mm(3) and was alcohol-resistant bacilli negative. Trans-sphenoidal surgery with biopsy showed inflammation was caused by infection with Aspergillus fumigatus. We initiated use of parenteral amphotericin B, but his condition worsened. He underwent another surgery to implant a reservoir of Ommaya-Hickmann, a subcutaneous catheter. We started liposomal amphotericin B 5 mg/kg in the reservoir on alternate days. He was discharged with a prescription of tegretol and fluconazole., Conclusion: This report has scientific interest because of the occurrence of angioinvasive cerebral aspergillosis in a diabetic patient, which is rarely reported. In conclusion, we suggest a definitive diagnosis of cerebral aspergillosis should not postpone quick effective treatment.

Cerebral Aspergillosis is the most lethal manifestation of infection due to Aspergillus species arising most commonly as hematogenous dissemination from a pulmonary focus, direct extension from paranasal sinus infection or direct inoculation through trauma and surgery of the central nervous system (CNS). Voriconazole is currently considered the standard of treatment of CNS aspergillosis with liposomal amphotericin B being the next best alternative. Neurosurgical resection of infected cerebral tissue in addition to antifungal therapy is frequently performed in patients with CNS aspergillosis to prevent neurological deficits and improve outcome. Aspergillus endophthalmitis may occur endogenously mostly from a pulmonary focus or exogenously following eye surgery or trauma. Although amphotericin B is still described as the primary therapy, voriconazole is increasingly considered the first line treatment of Aspergillus endophthalmitis. Vitrectomy is recommended in most cases of Aspergillus endophthalmitis.

We have shown previously that high-dose lipid amphotericin preparations are not more efficacious than lower doses in aspergillosis. We studied toxicity, drug concentrations and localization, and quantitative infection concurrently, using a 4-day model of central nervous system (CNS) aspergillosis to assess early events. Mice given Aspergillus fumigatus conidia intracerebrally, under a cyclophosphamide immunosuppressive regimen, were treated for 3 days (AmBisome at 3 or 10 mg/kg of body weight, Abelcet at 10 mg/kg, amphotericin B deoxycholate at 1 mg/kg, caspofungin at 5 mg/kg, or voriconazole at 40 mg/kg). Sampling 24 h after the last treatment showed that AmBisome at 3 but not at 10 mg/kg, as well as Abelcet, caspofungin, and voriconazole, reduced brain CFU. All regimens reduced renal infection. Minor renal tubular changes occurred with AmBisome or Abelcet therapy, whereas heart, lung, and brain showed no drug toxicity. Amphotericin B tissue and serum concentrations did not correlate with efficacy. Endothelial cell activation (ICAM-1 and P-selectin in cerebral capillaries) occurred during infection. Amphotericin B derived from AmBisome and Abelcet localized in activated endothelium and from Abelcet in intravascular monocytes. In 10-day studies dosing uninfected mice, minor renal tubular changes occurred after AmBisome or Abelcet at 1, 5, or 10 mg/kg with or without cyclophosphamide treatment; nephrosis occurred only with Abelcet in cyclophosphamide-treated mice. Hepatotoxicity occurred with AmBisome and Abelcet but was reduced in cyclophosphamide-treated mice. Marked CFU reduction by AmBisome at 3 mg/kg occurred in association with relatively more intense inflammation. Abelcet renal localization appears to be a precursor to late nephrotoxicity. Hepatotoxicity may contribute to high-dose Abelcet and AmBisome failures. Our novel observation of endothelial amphotericin localization during infection may contribute to amphotericin mechanism of efficacy.

A voriconazole-resistant isolate of Aspergillus fumigatus was recovered from an immunocompetent patient receiving long-term antifungal therapy for cerebral aspergillosis. A G448S amino acid substitution in the azole target (Cyp51A) was identified as the cause of the resistance phenotype. This article describes the first isolation of a voriconazole-resistant A. fumigatus isolate from an immunocompetent patient in Spain.

Invasive aspergillosis, chronic pulmonary aspergillosis and allergic bronchopulmonary aspergillosis are the clinical forms of aspergillosis. Although there is a great number of Aspergillus species, Aspergillus fumigatus-complex is the more frequent aetiological agent, regardless of clinical form or baseline condition. The increase in immunosuppressive agents and the higher use of corticosteroids in chronic obstructive pulmonary disease have led to aspergillosis becoming more prominent in recent years. Galactomannan detection and radiological diagnostic images complement the limitations of microbiology cultures in these patients. Voriconazole and liposomal amphotericin B are the gold standard in patients requiring therapy, and posaconazole, itraconazole, caspofungin and other echinocandins are effective alternatives. The prognosis depends of clinical forms and characteristics of the host, but it is particularly poor in the disseminated invasive forms., (Copyright © 2011 Elsevier España, S.L. All rights reserved.)

Aspergillosis of the central nervous system (CNS) is an uncommon infection, mainly found in immunocompromised patients but rarely seen among immunocompetent patients. Herein we describe a 57 year-old immunocompetent man who suffered intracranial aspergillosis spread by the pterygopalatine fossa (PPF) following a tooth extraction. Based on magnetic resonance imaging (MRI) characteristics, in this report we focus on the spreading routes of CNS aspergillosis via communicative structures of the PPF, the relationship between clinical manifestations and the locations of the lesion, and propose a therapeutic strategy to improve the prognosis.

A 59-year-old male with acute lymphoblastic leukemia developed sinus, tracheobroncheal, pulmonary, and intracerebral aspergillosis. All lesions except the intracerebral aspergillosis healed after combination antifungal treatment. Long-term voriconazole--but not posaconazole--therapy induced partial regression of the cerebral manifestations. At the time of writing, 3.5 years after the initial diagnosis, the patient is working half-time and suffers from a possible voriconazole-induced polyneuropathy.

Introduction: Invasive aspergillosis is a life-threatening infectious complication in hematological patients undergoing immunosuppressive chemotherapy., Patients and Methods: We report 29 cases of invasive aspergillosis diagnosed in the Sousse Farhat Hached hospital Hematology unit, Tunisia, between 2002 and 2010., Results: The most frequent disease (65.5%) was acute myeloid leukemia. All patients were severely neutropenic (<500/mm(3), mean duration=27 days). Pulmonary invasive aspergillosis was suggested in 28 (96.5%) cases. The most frequent respiratory signs were cough (64.3%), chest pain (53.6%), and hemoptysis (50%). The chest X-ray showed suggestive lesions in 60.7% of cases. CT scans revealed nodules with cavitation in 65% of cases, a halo sign in 20% of cases, and nodules in 15% of cases. Galactomannan antigenemia was positive in 88%, mycological examination positive in 51.6%, and seroconversion was noted in 35.7% of the cases. Invasive pulmonary aspergillosis was classified, according to EORTC/MSG criteria, as probable in 26 cases, possible in one case, and proven in one case. Aspergillus flavus was the dominant species in pulmonary invasive aspergillosis accounting for 73.7% of isolates. Extrapulmonary involvement was suggested in 39.3% of cases, the most frequent were sinusitis and brain abscess. Primary cutaneous aspergillosis was observed in one case. The overall mortality rate was 64.2%; the 12-week survival rate was 71.4%., Conclusion: Our results are correlated to published data. A. flavus was the most frequent species in our region., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Infection of the central nervous system (CNS) is a rare but devastating complication of invasive aspergillosis. We report a case of invasive aspergillosis with spinal involvement in a human immunodeficiency virus (HIV)-infected patient without neutropenia. A 42-year-old, antiretroviral-naïve, HIV-infected man presented with progressive weakness in the lower limbs and urinary and faecal incontinence for 2 weeks. The patient had been prescribed broad-spectrum antibiotics and prednisone. He had upper motor neuron signs and a sensory level at T1, with accompanying neck stiffness on flexion. Magnetic resonance imaging revealed diffuse abnormal signals of the vertebral bodies in the lower cervical and thoracic areas, with cord compression in the C2 and C3 region and signal distortions of the T2 and T3 vertebral bodies. Chest X-ray and computerized tomography demonstrated post-tuberculous apical cavities with suspected fungal colonization. Histopathology of an extradural spinal lesion at T1/T2 suggested invasive aspergillosis. The patient was started on fluconazole in response to the histopathological evidence of Aspergillus infection, but died within 3 weeks. Post-mortem analysis of the biopsy sample by PCR identified the infectious agent as Aspergillus fumigatus. Atypically, his CD4(+) T-cell count was 239 cells mm(-3) and he had no evidence of neutropenia. Invasive aspergillosis should be considered as part of the differential diagnosis among HIV-infected patients with non-specific, focal CNS symptoms, even among those without classical risk factors such as neutropenia, and aggressive antifungal therapy should be instituted as early as possible.

In contrast with the common hematogenous dissemination of invasive aspergillosis (IA), we present case with a protracted course through anatomical planes in an immunocompromised adult male. The unusual clinical features and laboratory findings led to fungal genotyping and identification of the mold as Aspergillus viridinutans. It appears to be the first described case of IA caused by this agent in an adult patient.

The mycotoxin gliotoxin is an important metabolite produced by Aspergillus fumigatus, but its precise role in the pathogenesis of cerebral aspergillosis is not yet determined. We could demonstrate that growth in cerebrospinal fluid (CSF) induced the production and secretion of significant amounts of gliotoxin by A. fumigatus. These concentrations of 590-720nM were sufficient to reduce the viability of astrocytes and neurons, as well as of primary microglia, already after few hours of incubation. Annexin staining and electron microscopy revealed the induction of apoptosis rather than necrosis as the relevant mode of gliotoxin action in the brain. Furthermore, even a low gliotoxin concentration of 100nM, which was subtoxic for astrocytes, was able to significantly down-modulate the phagocytic capacity of astrocytes. In order to improve the current antimycotic therapy of cerebral aspergillosis by supporting innate immunity in the fight against Aspergillus, we aimed to neutralize the toxic potency of gliotoxin towards different brain cell types. Compounds such as dithiothreitol (DTT) or glutathione that reduce the internal disulfide bond of gliotoxin were shown here to be able to interfere with the gliotoxin-induced decrease of cell viability and to save the cells from induction of apoptosis. Thus, exploration of these substances may lead to novel approaches for adjunctive treatment of cerebral aspergillosis., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The central nervous system (CNS) is the most common site of dissemination during Aspergillus infection. PCR has the potential to facilitate early diagnosis of CNS aspergillosis, which could assist in reducing disease mortality. In two experiments, neutropenic CD-1 male mice were infected intracranially with 5×10⁶ conidia of Aspergillus fumigatus. At time points up to 120 h after infection, mice were euthanized and samples of blood, brain, spinal cord and cerebrospinal fluid (CSF) were taken. The brain fungal burden was determined by quantitative culture, and fungal DNA was detected by quantitative PCR. Plating for A. fumigatus from the brain confirmed that all mice had burdens of log₁₀>3 from 4 to 120 h after infection. A. fumigatus DNA was detected in blood (88 %), brain (96 %), CSF (52 %) and spinal cord (92 %) samples. The brain and spinal cord contained the highest concentrations of fungal DNA. Adapting the extraction protocol to maximize yield from small sample volumes (10 µl CSF or 200 µl blood) allowed PCR detection of A. fumigatus in infected mice, suggesting the use of CSF and blood as diagnostic clinical samples for CNS aspergillosis.

Presentation of an unusual case of cerebral aspergillosis in an immune competent patient who was treated successfully but symptoms and signs of a demyelinating process following initial recovery has been occurred. A 29-year-old male with focal seizure. Brain MRI revealed small multiple hemispheric and dural lesions. An open biopsy was conducted. Histological evaluation revealed hyphe-like structure in the necrotic area, within vessel walls, and lumina, suggestive aspergillus fumigatus . Furthermore, brancheal hyphae in potassium hydrxide 15% and colonies on sabourud dextrose agar were observed. Based of the above findings the patient underwent anti fungal therapy. The patient recovered and continued a normal life however a follow up MRI was performed after 3 months from recovery. No significant abnormality was observed from the MRI procedure. One month later the patient developed signs and symptoms of spinal cord involvement which seemed to be the result of myelitis. A brain MR showed no abnormalities .Therefore it seemed reasonable to administer corticosteroid as a treatment for suspected active demyelinating process. During the above treatment, signs and symptoms of myelopathy disappeared and a whole spine MRI showed remarkable improvement.

Complement represents a central immune weapon in the brain, but the high lethality of cerebral aspergillosis indicates a low efficacy of the antifungal complement attack. Studies with cerebrospinal fluid (CSF) samples derived from a patient with cerebral aspergillosis showed a degradation of complement proteins, implying that Aspergillus might produce proteases to evade their antimicrobial potency. Further investigations of this hypothesis showed that Aspergillus, when cultured in CSF to simulate growth conditions in the brain, secreted a protease that can cleave various complement proteins. Aspergillus fumigatus, the most frequent cause of cerebral aspergillosis, destroyed complement activity more efficiently than other Aspergillus species. The degradation of complement in CSF resulted in a drastic reduction of the capacity to opsonize fungal hyphae. Furthermore, the Aspergillus-derived protease could diminish the amount of complement receptor CR3, a surface molecule to mediate eradication of opsonized pathogens, on granulocytes and microglia. The lack of these prerequisites caused a significant decrease in phagocytosis of primary microglia. Additional studies implied that the complement-degrading activity shares many characteristics with the previously described alkaline protease Alp1. To improve the current therapy for cerebral aspergillosis, we tried to regain the antifungal effects of complement by repressing the secretion of this degrading activity. Supplementation of CSF with nitrogen sources rescued the complement proteins and abolished any cleavage. Glutamine or arginine are of special interest for this purpose since they represent endogenous substances in the CNS and might be included in a future supportive therapy to reduce the high lethality of cerebral aspergillosis., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Cerebral aspergillosis is a rare complication of liver transplantation. We present the case of a 34-year-old woman with multiple brain lesions discovered 8 days after orthotopic liver transplant for autoimmune hepatitis. The epidemiology, differential diagnosis, diagnostic strategies, and management of cerebral aspergillosis are discussed.

Disseminated disease by Aspergillus granulosus has been reported only once previously in a cardiac transplant recipient. We report a fatal central nervous system infection in a lung transplant recipient. Key features of this species in the section Usti include growth at 37 degrees C and large, randomly spaced aggregates of variably shaped Hülle cells.

We report 2 patients showing invasion of aspergillosis into the central nerve system (CNS). Patient 1, an 81-year-old woman, underwent surgery for sphenoidal sinusitis. She developed cerebral infarction with unconsciousness on 12th postoperative day. CSF examination demonstrated pleocytosis with increased protein and aspergillus antigen. She was diagnosed as having invasion of aspergillosis into the CNS, and was treated with voriconazole. Her clinical manifestations and CSF findings markedly improved. However, the effects of voriconazole gradually attenuated and she demonstrated recurrence of the cerebral infarction. After 2 months, she died of systemic aspergillosis and sepsis. Autopsy studies. Severe atherosclerotic changes with calcification were demonstrated in the bilateral carotid and basilar arteries, and many aspergillus were clustered in the vessel walls. Granulomatous inflammatory lesions with aspergillus were also demonstrated in the area surrounding the chiasm. There were no massive infarcts or bleeding in the brain, but multiple small infarcts were present. Patinet 2, a 64-year-old man, showing bilateral visual loss, was receiving treatment with corticosteroids under a diagnosis of optic neuritis. Two weeks later, he developed cerebral infarction. CSF examination showed pleocytosis with increased protein and aspergillus antigen. He was diagnosed as having invasive aspergillosis from the sphenoidal sinusitis into the CNS. He was treated with voriconazole, and unconsciousness and CSF findings improved transiently. However, he developed a recurrence of the brain infarction and pneumonia and finally died 6 months later. Treatment by voriconazole was definitely effective in both patients, but both patients died of recurrent cerebral infarction, possibly due to resistance for voriconazole, or developing multicellular filamentous biofilms. Voriconazole is recommended as the first choice of antifungal agents for aspergillosis. Aspergillus infection is strongly invasive into arterial vessels. It is important to consider the possible occurrence of cerebrovascular disease when treating invasion of aspergillosis into the CNS.

A healthy postnatal woman succumbed to fulminant iatrogenic Aspergillus infection of the central nervous system, following accidental inoculation into the subarachnoid space at spinal anesthesia, during an outbreak of Aspergillus meningitis in Sri Lanka. Autopsy revealed extensive Aspergillus meningitis and culture confirmed Aspergillus fumigatus. The thalamic parenchyma in the brain was invaded by fungal hyphae producing necrotizing angitis with thrombosis, thalamic infarcts and fungal abscesses. The directional growth of fungal hyphae from the extra-luminal side of blood vessels towards the lumen favored extension from the brain parenchyma over hematogenous spread. The spinal parenchyma was resistant to fungal invasion in spite of the heavy growth within the spinal meninges and initial inoculation at spinal level. Modulation of the immune response in pregnancy with depression of selective aspects of cell-mediated immunity probably contributed to rapid spread within the subarachnoid space, to involve the brain parenchyma leading to clinical deterioration and death.

Chronic granulomatous disease (CGD) is characterized by a defect in phagocytic cells that lead to recurrent bacterial and fungal infections. The etiology of most common fungal infections in CGD are Aspergillus species. Aspergillus nidulans is one of several species of Aspergillus with low pathogenicity. However, it was reported to cause fatal invasive Aspergillosis in patients with CGD. Here we report the first cured invasive Aspergillus nidulans infection with extensive involvement of the spinal cord in a five-year-old child with CGD.

Three patients with central nervous system aspergillosis due to azole-resistant Aspergillus fumigatus (associated with a leucine substitution for histidine at codon 98 [L98H] and a 34-base pair repeat in tandem in the promoter region) are described. The patients were treated with combination therapy or with polyenes, but all patients died. Azole resistance significantly complicates the management of aspergillosis by delaying the initiation of adequate therapy and because effective alternative antifungal drugs are lacking.

Fungal infections of the ear are recognised quite rarely, but they make sometimes, for many reasons, very important diagnostic-therapy issue. Cantagion may developes in every elements of the ear, ranging from external ear (external canal ear, sometimes auricle), middle ear (every pneumatic structure) to iner ear (extra ordinary rarely). Every states, which weaken general and punctual immunity (like immunosupression, chemo-sterydotherapy, blood disease, pregnancy and HIV) are circles, which give facilities to invansion. After penetrated organism, course of infections, in case of type of patogens, trim of the patient and localization, can have without symptoms, sharp, chronic or fulminant shape. For the sake of morphological differentiation fungal, in their developing cycle, treatment mycosis recommends serious difficulty, extra factor, which impeds therapy, is a must of prolongely antifungal treatment and repeated (to total elimination) remove hyphae from ear, which stay sometimes even for week. Progress of the mycotic infections ear, remain bacterial infections and is often reason of bad diagnosis and incorrect treatment.

Fungal infections of the ear and paranasal sinus, are recognised quite rarely, but they make sometimes, for many reasons, very important diagnostic-therapy issue. Cantagion may developes near every paranasal sinus. Facilities to invasion give every states, which weaken general and punctual immunity (like immunosupression, chemo-sterydotherapy, blood disease, pregnancy and HIV). After penetrated organism, course of infections, in case of type of patogens, trim of the patient and localization, can have without symptoms, sharp, chronic or fulminant shape. The hardest course with the highest mortality occur in the cases of mucormycosis and aspergillosis. Actually curiosity occur cases of fungal infections, since this times consider to be unpathogenic for humans. For treatment of sinus mycosis in majority chirurgical treatment is required. In addition or the sake of morphological differentiation fungal, in their developing cycle, treatment mycosis recommends serious difficulty, extra factor, which impeds therapy, is a must of prolongely antifungal treatment and repeated (to total elimination) remove hyphae from sinus, which stay sometimes even for week. Progress of the mycotic infections in paranasal sinus, remain bacterial infections and is often reason of bad diagnosis and incorrect treatment.

Central nervous system aspergillosis is an often fatal complication of invasive Aspergillus infection. Relevant disease models are needed to study the pathophysiology of cerebral aspergillosis and to develop novel therapeutic approaches. This study presents a model of central nervous system aspergillosis that mimics important aspects of human disease. Eleven-day-old non-immunosuppressed male Wistar rats were infected by an intracisternal injection of 10 mul of a conidial suspension of Aspergillus fumigatus. An inoculum of 7.18 log(10) colony-forming units (CFU) consistently produced cerebral infection and resulted in death of all animals (n = 25) within 3-10 days. Median survival time was 3 days. Histomorphologically, all animals developed intracerebral abscesses (2-26 per brain) containing abundant fungal hyphae and neutrophils. Fungal culture of cortical homogenates yielded maximal growth on day 3 after infection (5.4 log(10) CFU/g, n = 15) that declined over time. Galactomannan concentrations in cortical homogenates, assessed as an index for hyphal burden, peaked on days 3-5. Fungal infection spread to peripheral organs in 83% of animals. Fungal burden in lung, liver, spleen and kidney was two orders of magnitude lower than in the brain. The successful establishment of a model of cerebral aspergillosis in a non-immunosuppressed host provides the opportunity to investigate mechanisms of disease and to develop novel treatment regimens for this commonly fatal infection.

Cerebral aspergillosis has rarely been reported in immunocompetent patients. We herein describe a unique case of cerebral aspergillosis in a healthy adult that led to his death despite aggressive antifungal therapy. Sequencing of ribosomal 18S-28S internal transcribed spacer identified the organism as Eurotium herbariorum, the teleomorph of Aspergillus glaucus.

Objective: Central nervous system (CNS) aspergillosis is a life-threatening disease that has had a published mortality of >80%. Little is known about this serious infection in the pediatric population. We conducted this study to analyze characteristics of CNS aspergillosis in infants and children., Methods: The English literature was reviewed and all CNS aspergillosis cases in patients younger than 18 years of age were analyzed., Results: Ninety cases were recorded up to June 2005. The median age of the patients was 9 years, ranging from 18 days to 18 years (15.6% younger than 1 year). CNS aspergillosis most commonly presented as brain abscess(es), either single or multiple. While prematurity was the predominant underlying condition among infants, leukemia was the most frequent underlying disease in children. Aspergillus fumigatus was isolated from 75.5% of the cases. The overall mortality in published cases was 65.4%. In multivariate analysis, surgical treatment was independently associated with survival., Conclusion: CNS aspergillosis in infants and children predominantly presents as brain abscess(es) and has significantly better outcome compared to published adult data. The findings of this systematic review could assist future investigations for improved outcome of this life-threatening infection in pediatric patients.

Recently, improved response and survival rates in patients treated with voriconazole and neurosurgery for central nervous system (CNS) aspergillosis have been reported. We assessed retrospectively the outcome in 17 patients with definite or probable CNS aspergillosis treated with amphotericin B alone (n = 15) or in combination with 5-fluorocytosine (n = 3) or itraconazole (n = 2). Four patients underwent neurosurgery. The mortality rate was 100% with a median survival of only 10 days (range: 3-60) after onset of first symptoms or first radiological evidence of CNS aspergillosis. In conclusion, treatment with amphotericin B and itraconazole has negligible efficacy in CNS aspergillosis.

Cerebral angioinvasive aspergillosis is a rare manifestation of disseminated aspergillosis which may result in stroke in immunocompromised individuals. Reports of such disease in patients with diabetes mellitus are rare. We describe a 45-year-old man with diabetes mellitus who presented with a three-day history of right-sided limb weakness and aphasia. Cerebral computed tomography showed features of an acute infarct involving the left anterior and middle cerebral arteries. He was initially treated for an acute ischaemic stroke. Further history revealed that he was investigated for a growth in the sphenoid sinus two months earlier. Culture of the biopsied material from the sphenoid sinus grew Aspergillus fumigatus. Magnetic resonance imaging showed an extension of the growth to the brain, causing the acute ischaemic stroke. He was subsequently diagnosed with angioinvasive cerebral aspergillosis and was commenced on intravenous amphotericin B. Unfortunately, he succumbed to his illness despite treatment.

Aspergillosis of the central nervous system (CNS) is an uncommon infection, mainly occurring in immunocompromised patients. We report a case of neuroaspergillosis caused by Aspergillus flavus in an immunocompetent patient presenting as a space-occupying lesion of the CNS. The patient was responding favorably to voriconazole at the time of this report.

Aspergillosis of central nervous system is an uncommon infection mainly occurring in immunocompromised patient. It may be present in several forms: abscess, meningitis, mycotic aneurysm, infarction and in tumoral form. Here we report a case of cerebral aspergillosis presenting as bilateral frontal lobe abscess without evidence of any underlying systemic disorder or extracranial disease.

Invasive aspergillosis of the central nervous system has a mortality rate exceeding 90%. We describe a 29-year-old woman with a medical history of chronic polyarthritis who developed a proven rhinocerebral Aspergillus fumigatus infection refractory to first-line treatment with liposomal amphotericin B. The patient responded successfully to salvage combination treatment with voriconazole and caspofungin. Furthermore, for the first time, voriconazole levels in an intracerebral abscess were measured in this patient undergoing voriconazole oral therapy.

Aspergillus infection of the central nervous system (CNS) is an uncommon disease. Most of the reported cases are of sinocranial spread and cases with contiguous spread to spinal cord from lung and other organs are uncommon. A case of pulmonary aspergillosis with extension to thoracic vertebrae forming a paraspinal mass resulting in neurological deficit due to Aspergillus flavus, is reported. The 43 year old patient did not have any obvious predisposing condition. He presented with loss of motor function and succumbed to the infection despite operative intervention and antifungal therapy. A brief update on CNS aspergillosis is presented along with detailed clinical, radiological and laboratory work up of the patient.