Lung aspergilloma with pituitary invasive aspergillosis presenting as headache and hyponatraemia.

Fungal infections involving the pituitary gland are rare and can be life threatening. A 75-year-old man with hypertension and diabetes mellitus presented with headache and hyponatraemia. Imaging study showed right upper lung mass, and mass resection showed aspergilloma without tissue invasion on histology. The patient developed visual impairment a few weeks later, and MRI of the brain revealed bilateral sphenoid sinusitis and pituitary invasion. The trans-sphenoidal biopsy confirmed invasive Aspergillus infection. His sphenoidal sinuses were endoscopically debrided, and he was treated with oral voriconazole. Pituitary aspergillosis should be considered in the differential diagnosis in patients with lung aspergilloma with headache and sinusitis. Prompt biopsy and antifungal treatment are important due to the high mortality rate of the infection.

Central nervous system aspergillosis in immunocompetent patients: Case series and literature review.

The aim of this study was to investigate the clinical characteristics of central nervous system (CNS) aspergillosis in immunocompetent patients.This study enrolled six immunocompetent patients diagnosed with CNS aspergillosis. Additionally, we reviewed the clinical profiles for 28 cases reported in the literature. The age, gender, etiology of Aspergillus infection, clinical manifestations, location of the lesion, treatment, and prognosis were analyzed.There were 19 men (average age, 54.6 ±â€Š14.3 years) and 15 women (average age, 47.0 ±â€Š19.4 years). The clinical manifestations included headache (55.9%; n = 19), visual impairment (32.4%; n = 11), diplopia (32.4%; n = 11), hemiplegia (20.6%; n = 7), fever (17.6%; n = 6), and epilepsy (8.8%; n = 3). According to the radiological features, CNS aspergillosis lesions were divided into two subtypes: parenchymal lesions in the cerebral lobes (n = 11), and meningeal lesions in the meninges (n = 23). The patients with meningeal lesions are easy to be complicated with more serious cerebrovascular diseases, such as subarachnoid hemorrhage and massive infarction. Most of the lesions in brain parenchyma were abscess formation, and magnetic resonance imaging showed ring enhancement. The clinical diagnosis of Aspergillus infection was mainly based on brain biopsy (n = 14), autopsy (n = 8), pathological examination of adjacent brain tissues (n = 7), cerebrospinal fluid (CSF) or tissue culture (n = 3), and second-generation sequencing analysis of the CSF (n = 3). Clinical improvement was achieved in 23 cases, and 11 patients succumbed to the disease. Voriconazole treatment was effective in 24 (70.6%) cases.Immunocompetent subjects are also at risk for Aspergillus infections. Concomitant cerebrovascular diseases are common in patients with CNS aspergillosis, especially in patients with meningeal aspergillosis. Parenchymal aspergillosis lesions are usually localized and manifest as brain abscesses with annular enhancement on magnetic resonance imaging. Biopsy, CSF culture, and next-generation sequencing are mainstream diagnostic modalities. Voriconazole is an effective treatment for Aspergillus infection, and early diagnosis and treatment should be highlighted.

Invasive rhino-orbital-cerebral aspergillosis in an immunocompetent patient.

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 ß-(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.

Holohemispheric Invasive Aspergillus Granulomatous Cerebritis of the Brain.

BACKGROUND: Invasive aspergillosis of the central nervous system, a saprophytic infection with a unique vascular tropism, carries the burden of increased morbidity and mortality. Early clinical and imaging findings can masquerade as an innocuous condition before a secondary inexorable progression. We highlight the clinical and imaging phenotype of a patient with fatal invasive granulomatous aspergillosis. CASE DESCRIPTION: A 39-year-old man presented with progressive weakness of the left upper and lower limb for 4 months. Imaging demonstrated right holohemispheric extensive, numerous, confluent, ill-defined, T2 hypointense foci with moderate perilesional edema. Numerous foci of microhemorrhages with cortical asymmetric mineralization were seen. Post-contrast heterogeneous, variegate, punctiform enhancement of the lesions was observed extending to the ventricular margins. Volume loss of the left cerebral peduncle and ipsilateral long white matter descending tracts was noted. Histopathologic examination of a stereotactic biopsy specimen from the frontal region lesion showed dense inflammatory infiltrate with granulomas, a few in a perivascular distribution and branching septate hyphae resembling Aspergillus. The patient was initiated on antifungal therapy and in the following week, he had progressive drowsiness. The patient succumbed the next day. CONCLUSIONS: Diffuse holohemispheric, progressive presentation of a granulomatous form of invasive aspergillosis is a rare entity. The miliary pattern of heterogenous enhancement, holohemispheric conglomerate T2 hypointensities, interspersed hemorrhage, juxtacortical punctate T2 hyperintense foci, low perfusion, and the relative absence of diffusion abnormality are distinctive features. Early diagnosis of this atypical imaging phenotype of Aspergillus infection and appropriate treatment is critical for better prognosis.

Isavuconazole Treatment of Cerebral and Pulmonary Aspergillosis in a Pediatric Patient With Acute Lymphoblastic Leukemia: Case Report and Review of Literature.

Invasive aspergillosis in hematologic pediatric patients is an opportunistic infection that is difficult to treat, with a high mortality rate when localized in the central nervous system. We are describing a 3-year-old girl who was affected by acute lymphoblastic leukemia who developed cerebral and pulmonary aspergillosis during induction chemotherapy. The patient failed first-line voriconazole treatment because of being a CYP2C19 ultrarapid metabolizer and received effective isavuconazole therapy with no notable side effects.

Special scenarios in the management of central nervous system aspergillosis: a case series and review of literature.

Aspergillus is a rare but important opportunistic pathogen to invade the central nervous system (CNS). It is a significant pathogen of not only immunocompromised but also immunocompetent patients. Its manifestations are pleiotropic, reflecting multiple mechanisms of pathogenesis and host interactions. Despite significant advances in diagnostic methods and therapeutic options, the mortality remains high. Several advances have been made in medications and surgical management, yet, current treatment practices lack uniformity. Patient woes are further heightened by the high costs of treatment and prolonged duration of therapy. In view of the challenging aspects of this disease, we present a short review of four challenging cases touching on the varied aspects of management of CNS aspergillosis covering pathogenesis, diagnostic pitfalls, surgical and medical options and evidence-based guidelines for the management of the same.

Successful and safe long-term treatment of cerebral aspergillosis with high-dose voriconazole guided by therapeutic drug monitoring.

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.

Cerebral aspergillosis in a patient on ibrutinib therapy-A predisposition not to overlook.

Ibrutinib has revolutionized the treatment of B-cell malignancies since its approval for chronic lymphocytic leukemia. It is also used in mantle cell lymphoma, diffuse large B-cell lymphoma, Waldenstrom's macroglobulinemia, among others. It is a Bruton's tyrosine kinase inhibitor that acts on B-cell receptor signaling pathway and predisposes to various infections due to its effects on neutrophils, monocytes and T cells. We present a case of cerebral invasive aspergillosis in a patient being treated with ibrutinib for relapsed chronic lymphocytic leukemia. It was hard to associate the condition to ibrutinib versus the chronic lymphocytic leukemia. The patient was successfully treated with a combination of voriconazole and micafungin, resulting in complete recovery and no residual deficits. This highlights the importance of recognizing the rare complication in those on ibrutinib and initiating the treatment immediately with appropriate antifungal agents to improve prognosis of this potentially fatal condition.

Fatal case of cerebral aspergilloma complicated by ventriculitis and bacteremia due to Salmonella species in a sickle cell disease patient.

To describe a fatal case of invasive Aspergillus flavus sinusitis in a 43-year old female with sickle cell disease (SCD) complicated by intracerebral aspergilloma and invasive Salmonella infection. Cerebral aspergilloma carries a very high mortality rate. The patient developed post-craniotomy intracerebral hemorrhage at the site of biopsy, Salmonella species sepsis and ventriculitis. She presented with a 2-month history of headache, dizziness, personality and behavioral changes, and vomiting. Initial clinical evaluation raised the suspicion of brain tumor. Brain magnetic resonance imaging revealed a left frontal, thick-walled ring-enhancing lesion with extensive surrounding edema suggestive of a neoplastic lesion, or a contiguous inflammatory or infectious process from the skull base. Despite early diagnosis and appropriate antifungal and surgical management, she eventually died from severe infection and respiratory arrest. In conclusion, invasive aspergillosis should be included in the differential diagnosis of SCD patients with central nervous system (CNS) lesions.

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.

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.

Chronic Invasive Aspergillus Sinusitis and Otitis with Meningeal Extension Successfully Treated with Voriconazole.

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-ß-d-glucan test results were initially positive, in contrast to galactomannan antigen results.

Thoracic spinal cord intramedullary aspergillus invasion and abscess.

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.

[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.

Cerebral aspergillosis in a patient with leprosy and diabetes: a case report.

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.

Very prolonged liposomal amphotericin B use leading to a lysosomal storage disease.

Amphotericin B is a powerful polyene antifungal drug used for treating systemic fungal infections and is usually administered for a short period. Side effects after prolonged use are unknown in humans. Here we report the case of a 28-year-old man suffering from chronic granulomatous disease (CGD), treated for invasive cerebral aspergillosis with liposomal amphotericin B (L-AmB) for a very long time (8 consecutive years). We describe the efficacy and safety of this treatment in the long term. Aspergillosis was kept under control as long as L-AmB therapy was maintained, but relapsed when the dose was reduced. No overt renal toxicity was noted. The patient gradually developed hepatosplenomegaly and pancytopenia. Abnormalities of bone marrow were similar to the sea-blue histiocyte syndrome. Liver biopsy showed images of nodular regenerative hyperplasia related to CGD as well as a histiocytic storage disease. We discuss the very prolonged use of L-AmB leading to the development of a lysosomal storage disease.

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.

Aspergillus galactomannan antigen for diagnosis and treatment monitoring in cerebral aspergillosis.

Invasive aspergillosis, especially neuroaspergillosis, predominantly affects immunocompromised patients such as transplant recipients. Early diagnosis and subsequent early initiation of therapy may improve final outcome. In cerebral aspergillosis, samples for culture or histopathology, the diagnostic reference standard, are often impossible to obtain without risk. Because of these limitations, serological, nucleic acid amplification tests such as polymerase chain reaction or enzyme immunoassay from cerebrospinal fluid appear advantageous for early diagnosis and probably also for therapy monitoring. We report on the successful detection and treatment monitoring by serial testing of galactomannan in cerebrospinal fluid in a patient with neuroaspergillosis after heart transplant.

Antifungal therapy of aspergillosis of the central nervous system and aspergillus endophthalmitis.

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.