A 53-year-old woman was admitted to Hannover Medical School after developing left-sided paresthesias and hemiparesis. Her medical history was remarkable for high-risk AML, which had been diagnosed 2 months earlier, with initially over 80% of blasts in bone marrow. In addition, she suffered from a chronic anxiety disorder and depression with a history of tranquilizer and antidepressant drugs intake.
The primary therapy had consisted in medication with daunorubicin, cytarabine, and gemtuzumab ozogamicin (DA + GO). On day 15, a good response to therapy was registered (<5% blasts in bone marrow). Nevertheless, the patient had a persistent cytopenia with prominent leukopenia (up to 0.1 103/microL). Thereafter, she developed pneumonia with recurring fever and an increasing CRP (up to 430 mg/L). A computed tomography (CT) scan of the chest performed on day 35 showed multiple nodules in both lungs, matching with a fungal pneumonia. Bronchoalveolar lavage (BAL) cultures however tested negative for fungi and tuberculosis. In particular, no Aspergillus antigen could be detected. Initial antifungal prophylaxis with Voriconazole was switched to Caspofungin. Subsequent bone marrow examination revealed no relapse of AML.
After the occurrence of paresthesias and hemiparesis, brain magnetic resonance imaging (MRI) showed multiple gadolinium-enhancing cerebral lesions [Figure 1a]. Differential diagnosis included metastases, lymphoma, bacterial, and fungal granulomatous lesions. Stereotactic biopsy was recommended for further diagnosis and to tailor therapy but was refused by the patient. The situation was complicated by a psychotic episode with limited judgment. Despite weekly white blood cells transfusions and antimycotic therapy escalation to Posaconazole and Amphotericin-B, neurological symptoms deteriorated and the patient became increasingly somnolent. A second brain MRI was carried out and showed progress of the lesions with involvement of the meninges. The lesions were characterized by signs of microhemorrhages and perifocal edema [Figures 1b-e]. The patient's family finally agreed to obtain a stereotactic biopsy and the patient was transferred to the department of neurosurgery.
On admission, the patient was in a poor general condition. She was obtunded and had a marked left-sided hemiparesis. Stereotactic serial biopsies were obtained (Riechert Mundinger frame with Zamorano-Dujovny application) targeting the right precentral lesion under general anesthesia. The collected samples were sent for microbiological and neuropathologic analyses. After surgery, the patient was transferred to the intensive care unit. Postoperative CT scan was unremarkable. Nevertheless, the patient had increasing cardiorespiratory problems, which led to her death on day 70. Autopsy was declined by her family.
Microscopic examination of the stereotactic biopsy specimen revealed gliotic central nervous system (CNS) parenchyma with sparse lymphomonocytic infiltrates. In addition, there were necrotic areas. Within the necrotic zones, fungal hyphae were detected by periodic acid Schiff (PAS) staining [Figure 2]. Some of these had a string-like appearance and developed bulbous beads. The hyphae branched and septations within the hyphae were visible. After deoxyribonucleic acid (DNA) extraction from the tissue, consensus primers for the 18S-Ribonucleic acid (RNA) gene were used to amplify the most important members of the fungal genera Aspergillus, Candida, Mucor, Rhizopus, Cryptococcus, Paecilomyces, Scedosporium, and Absidia and to specify them by hybridization of the polymerase chain reaction (PCR) product. Since the PCR product was strong but the hybridization signal was absent, the PCR product was sequenced directly. The resulting DNA sequences were then clearly assigned to the HA fungus species.