Acute Stroke as First Manifestation of Cerebral Aspergillosis.

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.

Intracranial Fungal Infection After Solid-Organ Transplant.

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.

CNS aspergilloma mimicking tumors: Review of CNS aspergillus infection imaging characteristics in the immunocompetent population.

BACKGROUND AND PURPOSE: CNS Aspergillosis is very rare and difficult to diagnose clinically and on imaging. Our objective was to elucidate distinct neuroimaging pattern of CNS aspergillosis in the immunocompetent population that helps to differentiate from other differential diagnosis. METHODS: Retrospective analysis of brain imaging findings was performed in eight proven cases of central nervous system aspergillosis in immunocompetent patients. Immunocompetent status was screened with clinical and radiological information. Cases were evaluated for anatomical distribution, T1 and T2 signal pattern in MRI and attenuation characteristics in CT scan, post-contrast enhancement pattern, internal inhomogeneity, vascular involvement, calvarial involvement and concomitant paranasal, cavernous sinus or orbital extension. All patients were operated and diagnosis was confirmed on histopathology. RESULTS: The age range was 19-50 years with mean age of 33.7 years. Concomitant sinonasal disease was seen in six patients (75%). Three patients had orbital extensions. Most of the lesions (n=7) were profoundly hypointense in T2-weighted imaging. The most common enhancement pattern was bright, solid and homogenous enhancement (n=7). Cavernous extension with ICA encasement was always associated with paranasal sinus disease. Six patients showed demineralization or complete resorption of involved bone. All of the fungal masses appear hyperdense on available CT scan images. CONCLUSION: CNS aspergillus infection in immunocompetent patients has distinct imaging features as compared to CNS aspergillosis in immunocompromised patients. A high index of suspicion in proper clinical settings, even with immunocompetent status and typical imaging features allow us to diagnose CNS aspergillosis in such patients.

Aspergilosis cerebral como causa de lesión cerebral focal asociada SIDA: a propósito de un caso y revisión de la literatura / Focal brain lesion due to cerebral aspergillosis in a patient with AIDS: case report and literature review

Resumen La aspergilosis cerebral es una patología infrecuente, pero de elevada mortalidad en pacientes con SIDA. Es importante considerarla entre los diagnósticos diferenciales ante una lesión expansiva cerebral. Se requiere un alto grado de sospecha para poder realizar un diagnóstico precoz. Se presenta el caso de un paciente con infección por VIH con un cuadro neurológico rápidamente progresivo por Aspergillus sección flavi. Se realiza una revisión de 40 casos publicados de aspergilosis cerebral en pacientes con SIDA.

Cerebral aspergillosis is a rare disease with high mortality rates in AIDS patients. It is important to take this into account in the differential diagnosis of a brain expansive lesion. A high level of suspicion is required to make an early diagnosis. We present a case of an HIV-infected patient with progresive neurological disease caused by Aspergillus flavi. We review 40 previously published cases of central nervous system aspergillosis in patients with AIDS.

Angioinvasive Aspergillus-associated Stroke in an Immunocompetent Host Following Cardiac Surgery and ECMO.

INTRODUCTION: Invasive cerebral aspergillosis is an uncommon cause of stroke among immunocompetent patients and has not been reported in association with cardiac surgery or extracorporeal membrane oxygenation (ECMO). We report the case of an immunocompetent host who developed aspergillus-associated stroke following coronary artery bypass graft (CABG) and ECMO. CASE REPORT: A 59-year-old woman developed cardiogenic shock after 3-vessel-CABG requiring intra-aortic balloon pump placement and subsequent veno-arterial ECMO. Noncontrast computed tomography of the brain was suggestive of multiple bihemispheric ischemic infarcts. Postmortem pathologic analysis revealed aspergillus-associated inflammation of blood vessels and ischemic and petechial hemorrhagic strokes in the affected territories. DISCUSSION AND CONCLUSIONS: Ischemic infarcts in the setting of CABG or ECMO are often presumed to be thromboembolic from the heart or device, related to underlying hemodynamic instability, or due to a clinically apparent systemic infection such as endocarditis. This report suggests that invasive cerebral aspergillosis should be considered in seemingly immunocompetent patients following CABG or ECMO. The mechanism is unclear, but may be related to systemic inflammatory dysregulation resulting in increased susceptibility to uncommon pathogens.

Need of voriconazole high dosages, with documented cerebrospinal fluid penetration, for treatment of cerebral aspergillosis in a 6-month-old leukaemic girl.

This case report indicates the usefulness of voriconazole for the treatment of central nervous system (CNS) aspergillosis, also in paediatrics. However, it also confirms the need for therapeutic drug monitoring (TDM), especially in younger children that may require very high dosages in order to achieve plasma and cerebrospinal fluid (CSF) therapeutic concentrations.

Successful Treatment of Combined Aspergillus and Cytomegalovirus Abscess in Brain and Lung After Liver Transplant for Toxic Fulminant Hepatitis.

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.

[Focal brain lesion due to cerebral aspergillosis in a patient with AIDS. Case report and literature review]. / Aspergilosis cerebral como causa de lesión cerebral focal asociada SIDA. A propósito de un caso y revisión de la literatura.

Cerebral aspergillosis is a rare disease with high mortality rates in AIDS patients. It is important to take this into account in the differential diagnosis of a brain expansive lesion. A high level of suspicion is required to make an early diagnosis. We present a case of an HIV-infected patient with progresive neurological disease caused by Aspergillus flavi. We review 40 previously published cases of central nervous system aspergillosis in patients with AIDS.

Magnetic Resonance Imaging of Cerebral Aspergillosis: Imaging and Pathological Correlations.

Cerebral aspergillosis is associated with a significant morbidity and mortality rate. The imaging data present different patterns and no full consensus exists on typical imaging characteristics of the cerebral lesions. We reviewed MRI findings in 21 patients with cerebral aspergillosis and correlated them to the immune status of the patients and to neuropathological findings when tissue was available. The lesions were characterized by their number, topography, and MRI signal. Dissemination to the brain resulted from direct spread from paranasal sinuses in 8 patients, 6 of them being immunocompetent. Hematogenous dissemination was observed in 13 patients, all were immunosuppressed. In this later group we identified a total of 329 parenchymal abscesses involving the whole brain with a predilection for the corticomedullary junction. More than half the patients had a corpus callosum lesion. Hemorrhagic lesions accounted for 13% and contrast enhancement was observed in 61% of the lesions. Patients with hematogenous dissemination were younger (p = 0.003), had more intracranial lesions (p = 0.0004) and had a higher 12-week mortality rate (p = 0.046) than patients with direct spread from paranasal sinuses. Analysis of 12 aneurysms allowed us to highlight two distinct situations. In case of direct spread from the paranasal sinuses, aneurysms are saccular and located on the proximal artery portions, while the hematogenous dissemination in immunocompromised patients is more frequently associated with distal and fusiform aneurysms. MRI is the exam of choice for cerebral aspergillosis. Number and type of lesions are different according to the mode of dissemination of the infection.

A case of hypertrophic cranial pachymeningitis associated with invasive Aspergillus mastoiditis.

We report a rare case of hypertrophic cranial pachymeningitis (HCP) associated with invasive Aspergillus mastoiditis. A 63-year-old man with diabetes mellitus underwent mastoidectomy because of chronic discharge from his left ear. The mastoidectomy was unsuccessful in resolving purulent otorrhea; moreover, 7 months later, the patient developed left abducens nerve palsy. Magnetic resonance imaging revealed HCP at the left middle cranial fossa. Although the pathogen could not be identified, an Aspergillus infection was considered based on elevated serum ß-d-glucan and a positive Aspergillus antigen test result. Voriconazole treatment resolved diplopia and left otorrhea and dramatically improved HCP.

Aspergillus flavus induces granulomatous cerebral aspergillosis in mice with display of distinct cytokine profile.

Aspergillus flavus is one of the leading Aspergillus spp. resulting in invasive aspergillosis of central nervous system (CNS) in human beings. Immunological status in aspergillosis of central nervous system remains elusive in case of both immunocompetent and immunocompromised patients. Since cytokines are the major mediators of host response, evaluation of disease pathology along with cytokine profile in brain may provide snapshots of neuro-immunological response. An intravenous model of A. flavus infection was utilized to determine the pathogenicity of infection and cytokine profile in the brain of male BALB/c mice. Enumeration of colony forming units and histopathological analyses were performed on the brain tissue at distinct time periods. The kinetics of cytokines (TNF-α, IFN-γ, IL-12/IL-23p40, IL-6, IL-23, IL-17A and IL-4) was evaluated at 6, 12, 24, 48, 72 and 96h post infection (hPI) in brain homogenates using murine cytokine specific enzyme linked immunosorbent assay. Histological analysis exhibited the hyphae with leukocyte infiltrations leading to formation of granulomata along with ischemia and pyknosis of neurons in the brain of infected mice. Diseased mice displayed increased secretion of IFN-γ, IL-12p40 and IL-6 with a concomitant reduction in the secretion of Th2 cytokine IL-4, and Th17 promoting cytokine, IL-23 during the late phase of infection. A.flavus induced inflammatory granulomatous cerebral aspergillosis in mice, characterized by a marked increase in the Th1 cytokines and neurons undergoing necrosis. A marked increase in necrosis of neurons with concurrent inflammatory responses might have led to the host mortality during late phase of infection.

[Cerebral aspergillosis in an immunocompromised patient with follicular lymphoma].

We present a case of central nervous system aspergillosis in an immunocompromised 69-year-old male with a history of chemotherapeutic treatment for follicular lymphoma. The patient presented with aphasia, apraxia and confusion. An MRI of the central nervous system and Aspergillus antigen in the spinal fluid was suggestive for this invasive fungal infection. Despite treatment with voriconazole the patient succumbed to the infection. A rise in rare, severe infectious complications as presented is expected due to increasing dose-intensity of chemotherapy.

Progressive intracranial hypertension and cerebral hypoperfusion in a fatal case of cerebral aspergilloma.

We report a case of cerebral aspergilloma in a 25-year-old immunoincompetent man admitted to a general intensive care unit. Monitoring of intracranial pressure was instigated and revealed hour-long epochs of severe intracranial hypertension, despite a normal opening pressure, with decreases in cerebral perfusion pressure. We documented that this was associated with cerebral hypoperfusion by transcranial Doppler ultrasound. The present case illustrates that severe intracranial hypertension may evolve despite a normal opening pressure; it furthermore shows that continuous monitoring of intracranial pressure may be used to predict changes in cerebral haemodynamics in critically ill patients with neuroinfection.

Aspergillosis after liver transplantation in the context of common variable immunodeficiency: case report.

Common variable immunodeficiency (CVID) is the most common primary immune defect, resulting in hypogammaglobulinemia as well as deficits in cell-mediated immunity. Although it mainly manifests in immunodeficiency and related infection, CVID can also be associated with autoimmune phenomena such as immune thrombocytopenic purpura, hemolytic anemia, rheumatoid arthritis, lupus, primary biliary cirrhosis, and autoimmune hepatitis (AIH). AIH is a less common but serious complication of CVID, which can result in early cirrhosis, ascites, and even hepatocellular carcinoma. Here, we discuss a recent case of transplantation for cirrhosis secondary to AIH in the context of CVID. Although the patient's surgery occurred without complication, he rapidly developed fulminant alveolar hemorrhage and seizures, and died secondary to disseminated neuroaspergillosis.

Diffuse myelitis after treatment of cerebral aspergillosis in an immune competent patient.

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.

Importancia de las imágenes y el diagnóstico etiológico en el paciente inmunocomprometido con afección del SNC / Importance of images and etiological diagnosis of central nervous system envolvement in immunocompromised patient

We report a 16 years old boy with diagnosis of Acute Myeloid Leukemia with severe immune suppression secondary to his primary disease and to leukemia's treatment. Early during the course of his chemotherapy he developed symptoms and signs compatible with invasive fungal disease (IFD). Lungs were primarily compromised followed by CNS involvement with manifestations of intracranial hypertension. Laboratory exams were remarkable for prolonged neutropenia and indirect evidence of Aspergillus sp infection, with successive detection of positive and increasing levels of galactoman antigen in serum. With this case we want emphasize the great importance of invasive fungal disease in immune suppressed patients and particularly the CNS compromise. This represents a medical emergency which deserves to start a complete and comprehensive microbiology diagnosis and concomitantly start an empiric antifungal treatment. The importance of neuroimaging for a correct identification of the number, location and size of CNS lesions must be highlighted. The election of MRI, if available, should be preferred due to a better performance than CT scan. Brain biopsy should be discussed when all the non invasive attempts for etiology identification have failed. The invasive fungal CNS compromise has medical treatment and the surgical drainage has to be considered for lesions greater than 2 cm or for those making a mass effect or have failed with medical treatment.

Comunicamos el caso de un adolescente de 16 años, con una leucemia mieloide aguda y una grave inmunosupresión secundaria a su enfermedad y el tratamiento. Precozmente post-quimioterapia desarrolló síntomas y signos compatibles con una enfermedad fúngica invasora (EFI). Inicialmente se afectaron sus pulmones y a continuación el SNC con hipertensión intracraneal. Los exámenes de laboratorio indicaron una neutropenia prolongada y evidencias indirectas de una infección por Aspergillus sp mediante la medición sucesiva de galactomanano positivo en sangre y un segundo valor en ascenso. Con este caso enfatizamos la gran importancia que tienen las EFI en pacientes inmunocomprometidos, particularmente sobre el SNC. Ellas representan una emergencia médica que requiere de una confín-nación microbiológica y el inicio temprano de terapia anti-fúngica empírica. Debe destacarse la importancia que tienen las neuro-imágenes en la correcta identificación del número de lesiones, su localization y tamaño. La RM, si está disponible, debiera ser la elección, para una mejor definición, por sobre el uso de la TAC. Igualmente, debiera discutirse la indicación de biopsia cerebral cuando todos los métodos no invasores han fracasado en precisar la etiología. La EFI del SNC es de tratamiento médico, debiéndose considerar el drenaje quirúrgico de las lesiones con más de 2 cm de diámetro o aquellas que ejercen efecto de masa o, finalmente, cuando ha fracasado el manejo con anti-fúngicos.

Secretion of a fungal protease represents a complement evasion mechanism in cerebral aspergillosis.

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.

Imaging findings in intracranial aspergillus infection in immunocompetent patients.

AIM: To study the neuroimaging features of craniocerebral aspergillosis infection in immunocompetent patients. MATERIALS AND METHODS: The clinical and imaging data of 12 patients of aspergillus fungal infection were retrospectively reviewed. Diagnosis of fungal infection was confirmed by histopathologic examination of surgically excised specimen, stereotactic biopsy material, or endoscopic sinus biopsy. The radiologic studies were evaluated for anatomic distribution of lesions, signal intensity, contrast enhancement, presence of hemorrhage, diffusion restriction, perfusion, and spectroscopy characteristics. Medical records, biopsy reports, and autopsy findings were also reviewed. RESULTS: Twelve cases of aspergillosis infections in immunocompetent patients were diagnosed at our hospital over a period of 10 years. Lesions could be classified based on imaging of lesions of sinonasal origin, intracranial mass lesion including both parenchymal or extraparenchymal meningeal based and stroke. Coexisting meningitis was also noted in one patient. Disease of sinonasal origin commonly showed invasion of the cavernous sinus and orbital apex resulting in visual symptoms and multiple cranial nerve palsies. Intracranial mass lesions without sinonasal involvement were seen in five cases that included isolated parenchymal lesion in two patients and dural-based mass lesions in three patients. Isolated intraparenchymal lesions included two cases of fungal cerebritis. Dural-based lesions were large granulomas with a significant mass effect. Infarcts were seen in three patients and angiography showed vessel narrowing or occlusion in all the three patients. CT demonstrated isodense to hyperdense attenuation of primary sinus disease with evidence of bone destruction in all the cases of sinonasal origin. Primary parenchymal lesions showed heterogenous attenuation with predominantly low-density areas. Dural-based lesions showed isodense to hyperdense attenuation. Magnetic resonance imaging revealed isointense to hypointense signal intensity on both T(1)-weighted (T1W) and T(2)-weighted (T2W) images in all lesions of sinonasal origin and isolated dural-based mass lesions. Primary parenchymal lesions showed heterogenous signal intensity pattern with predominantly hypointense signal on T1W and hyperintense signal on T2W images. Diffusion weighted imaging, magnetic resonance spectroscopy, and perfusion-weighted imaging gave valuable ancillary information in these cases. CONCLUSION: Sinonasal disease with intracranial extension is the commonest pattern of aspergillus infection followed by intracranial mass lesions. Hyperdense sinonasal disease with bone destruction and intracranial extension on computed tomography, hypointense signal intensity of the lesions on T2W magnetic resonance images, presence of areas of restricted diffusion, decreased perfusion on perfusion-weighted imaging, and presence of hemorrhages are key to the imaging diagnosis of fungal infection.

[Importance of images and etiological diagnosis of central nervous system involvement in immunocompromised patient]. / Importancia de las imágenes y el diagnóstico etiológico en el paciente inmunocomprometido con afección del SNC.

We report a 16 years old boy with diagnosis of Acute Myeloid Leukemia with severe immune suppression secondary to his primary disease and to leukemia's treatment. Early during the course of his chemotherapy he developed symptoms and signs compatible with invasive fungal disease (IFD). Lungs were primarily compromised followed by CNS involvement with manifestations of intracranial hypertension. Laboratory exams were remarkable for prolonged neutropenia and indirect evidence of Aspergillus sp infection, with successive detection of positive and increasing levels of galactoman antigen in serum. With this case we want emphasize the great importance of invasive fungal disease in immune suppressed patients and particularly the CNS compromise. This represents a medical emergency which deserves to start a complete and comprehensive microbiology diagnosis and concomitantly start an empiric antifungal treatment. The importance of neuroimaging for a correct identification of the number, location and size of CNS lesions must be highlighted. The election of MRI, if available, should be preferred due to a better performance than CT scan. Brain biopsy should be discussed when all the non invasive attempts for etiology identification have failed. The invasive fungal CNS compromise has medical treatment and the surgical drainage has to be considered for lesions greater than 2 cm or for those making a mass effect or have failed with medical treatment.