Abstract
Intracranial aspergillosis is uncommon but often lethal, especially in classically immunocompromised hosts. We report a 71-year-old man with poorly controlled diabetes (a non-classical risk factor) who developed bilateral frontal abscesses due to Aspergillus fumigatus. After an initial craniotomy with negative cultures and galactomannan, recurrent disease was confirmed by stereotactic biopsy with next-generation sequencing (NGS). Targeted azole therapy (voriconazole, isavuconazole) and multidisciplinary care led to marked clinical and radiographic improvement. We also pooled 343 published cases (2000–2024): overall mortality was 34.6%, and 21.8% among patients without classical immunosuppression (including some with non-classical factors such as diabetes). Improved survival in recent decades likely reflects earlier diagnosis and broader azole use, though inference is limited by case-based evidence. Early tissue diagnosis (including molecular testing), timely surgery when indicated, and CNS-penetrant azoles can yield favorable outcomes in non-classically immunosuppressed patients.
Background
Intracranial Aspergillus infection is a severe complication of invasive aspergillosis, primarily affecting immunocompromised patients (e.g., those with hematologic malignancies, transplant recipients, or on chronic corticosteroids) (–). Historically, reported mortality rates for intracranial aspergillosis were as high as 85% to 99%, especially in immunocompromised hosts, and when complicated by brain abscesses, the rate reportedly approaches 100% in such patients (–).
Aspergillus typically reaches the brain through hematogenous spread from a primary pulmonary focus or by direct extension from the paranasal sinuses (, ). The clinical manifestations of cerebral aspergillosis are often nonspecific, leading to delayed diagnosis (, ). Common symptoms include headache, altered mental status, focal neurological deficits, seizures, and visual disturbances. In patients without classical immunosuppression but with non-classical risk factors (e.g., diabetes), the course may be more indolent and may present as meningitis or granulomatous mass ().
Intracranial aspergillosis is an exceedingly rare condition, even more so among immunocompetent patients. The existing literature primarily comprises single case reports or small retrospective studies, which provide insufficient data for robust prognostic assessments. Over the last 20–25 years, medical diagnostics and treatments have improved significantly. To contextualize our case, we compiled a pooled individual-patient analysis of reports since 2000, explicitly comparing outcomes by immune status. For terminology consistency throughout, we use “non-classically immunosuppressed” to denote patients lacking classical immunosuppressive conditions (e.g., no hematologic malignancy, transplant, HIV/AIDS, active chemotherapy, prolonged high-dose steroids, or primary immunodeficiency) but who carry risk modifiers such as diabetes.
Case presentation
A 71-year-old man with a 17-year history of poorly controlled type 2 diabetes (HbA1c 9.5%) underwent endoscopic resection of a sphenoid sinus mass with sinusotomy for chronic sinusitis (15 months before definitive diagnosis). Histopathology showed inflammation without fungi, and symptoms initially improved. Six months later, he developed aphasia, cognitive slowing, and personality change without fever. MRI at a local hospital suggested bilateral frontal abscesses; mannitol partially improved speech.
Two months thereafter he presented to our center. MRI demonstrated bilateral frontal lesions with extensive edema and ring enhancement (Figures 1A–F); nasal endoscopy confirmed purulence (Figures 1G–I). Pre-operative CT showed anterior skull-base sclerosis and erosion consistent with osteomyelitis (Figure 3A). Laboratory tests revealed leukocytosis with neutrophilia and mildly elevated CRP; HIV screening was negative. Serum galactomannan (GM) was negative.
Figure 1
Given encapsulated abscesses with sinus and skull-base involvement, he underwent bilateral frontal craniotomy for evacuation and anterior skull-base reconstruction. Abundant pus was encountered; bacterial, fungal, and mycobacterial cultures and histopathology were negative.
Postoperatively, he received vancomycin and ceftriaxone plus fluconazole (guided by early nanopore reads suggesting possible Candida). He was discharged to complete IV antibiotics and fluconazole. Two weeks later he worsened neurologically. Follow-up MRI showed progression with persistent ring enhancement and diffusion restriction (Figures 2A–D); endoscopy again revealed purulence (Figures 2E–G).
Figure 2
Four months after craniotomy, stereotactic biopsy confirmed A. fumigatus by NGS; serum GM and β-D-glucan were now positive. Sinonasal biopsies demonstrated invasive hyphae. DTI tractography showed marked frontal tract loss (Figures 3B,C). OCT was normal, while visual fields showed dense bilateral defects consistent with compressive optic neuropathy (Figures 3D–F).
Figure 3
Multidisciplinary management with CNS-penetrant azoles (voriconazole and isavuconazole), blood-pressure control, and supportive care led to steady improvement. One-month MRI showed smaller lesions and reduced mass effect (Figures 3H,I). At six months, he was independent in daily activities with mild residual cognitive impairment and persistent visual-field loss (Figure 4).
Figure 4
Methods for pooled analysis
Search strategy and eligibility
We searched PubMed for English-language reports from January 1, 2000 to May 10, 2024 using (“intracranial aspergillosis” OR “Aspergillus brain abscess” OR “central nervous system Aspergillus” OR “cerebral Aspergillus” OR “brain aspergillosis”). Inclusion required: (1) histopathological, culture, or molecular confirmation of intracranial aspergillosis; (2) radiologic evidence of an intracranial lesion (intraparenchymal or extradural); and (3) documented immune status and outcome. We excluded reviews, animal studies, conference abstracts, studies with insufficient intracranial data, and reports limited to extracranial infection. PRISMA flow: 639 records → 229 excluded at screening; after removing 258 duplicates/inaccessible texts, 152 full texts reviewed; 27 excluded; 125 studies included (343 cases) (Figure 5).
Figure 5
Terminology
“Classically immunocompromised” comprised hematologic malignancy, solid-organ or stem-cell transplantation, HIV/AIDS, active cytotoxic chemotherapy, prolonged high-dose corticosteroids (>20 mg/day prednisone-equivalent for >2 weeks), or primary immunodeficiency. “Non-classically immunosuppressed” included conditions such as diabetes that alter host defenses without meeting classical criteria. For clarity, we report outcomes for patients “without classical immunosuppression,” which may include non-classical factors.
Results
Among 343 patients (201 male, 107 female, 35 unspecified), there were 119 deaths, with 11 additional deaths unrelated to aspergillosis; 213 were recovered or stable at last follow-up. Overall mortality was 34.6%; mortality among patients without classical immunosuppression (including some with non-classical factors) was 21.8%. Detailed per-case data are provided in Supplementary Table S1.
Discussion and conclusion
This case underscores diagnostic pitfalls in intracranial aspergillosis, particularly when early biomarkers are negative. The GM assay has variable sensitivity: at an optical density index of 0.5, pooled sensitivity is ∼82% (≈18% false-negative rate); at 1.0, sensitivity declines to ∼72% (≈28% false-negative rate) (–). Thus, negative GM should not preclude biopsy or molecular testing when imaging and clinical evolution are concerning. The eventual detection of Aspergillus DNA via NGS on a biopsy specimen was pivotal, enabling targeted antifungal therapy and likely preventing a fatal outcome.
Surgery remains important for encapsulated collections, mass effect, or diagnostic uncertainty, both to decompress and to obtain tissue for definitive identification (culture, histology, PCR/NGS). In our patient, delayed confirmation by NGS ultimately enabled targeted therapy.
Therapeutically, outcomes have improved with CNS-penetrant triazoles—especially voriconazole—compared with amphotericin B or itraconazole, which historically showed poor CNS efficacy and tolerability (–). Isavuconazole may offer additional options, as illustrated by this case, though further CNS-specific data are needed (, ). Non-classical risk factors (e.g., diabetes), disruption of anatomic barriers (e.g., sinus surgery), and transient immune dysfunction can permit angioinvasion even without classical immunosuppression. Recognizing these scenarios can prompt earlier imaging, biopsy, and azole initiation ().
In the future, standardization of molecular diagnostics, therapeutic drug monitoring for azoles, and optimized combination/sequencing strategies may further lower mortality; exploratory immunomodulatory approaches merit study but lie beyond the scope of this report.
Conclusion
Intracranial aspergillosis remains a high-stakes neurosurgical and infectious-disease emergency, yet patients without classical immunosuppression—including those with non-classical risks such as diabetes—can achieve good outcomes when clinicians maintain suspicion despite early false-negative biomarkers, pursue early tissue diagnosis with biopsy/NGS, and combine indicated surgical management with CNS-penetrant azoles (e.g., voriconazole, isavuconazole) under multidisciplinary care.
Statements
Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.
Ethics statement
Written informed consent for publication (clinical details and images) was obtained from the patient. In accordance with institutional policy and journal guidance for single-patient case reports, IRB approval was not required.
Author contributions
MR: Formal analysis, Data curation, Writing – original draft, Writing – review & editing. SL: Writing – review & editing, Investigation. YD: Investigation, Writing – review & editing. JY: Conceptualization, Writing – review & editing, Funding acquisition, Resources. XC: Writing – review & editing, Resources. JY: Resources, Writing – review & editing. CY: Funding acquisition, Writing – review & editing, Conceptualization.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This work was supported by the National Natural Science Foundation of China (82371319 to CY), Beijing Nova Program (20230484356 to CY), Beijing Natural Science Foundation (7222217 to CY and QY24070 to MR), Peking University Clinical Scientist Training Program supported by “The Fundamental Research Funds for the Central Universities” (BMU2024PYJH017 to CY), Capital Health Research and Development of Special (2022-4-40918 to CY), Research Project of Peking University Third Hospital in State Key Laboratory of Vascular Homeostasis and Remodeling (2024-VHR-SY-06 to CY), Digital and Humanities Project supported by “The Fundamental Research Funds for the Central Universities” (7101503232 to J.Ye and CY), and Peking University Third Hospital Clinical Key Project (BYSYZD2021023 to CY). Funding sources had no involvement in the design of the study; in the collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.
Acknowledgments
We thank the patient and his family who trusted us, and all the physicians and staff members who helped in this study.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fsurg.2025.1674057/full#supplementary-material
Abbreviations
CT, computed tomography; MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery; Gd-DTPA, gadolinium-diethylenetriamine pentaacetic acid; DWI, diffusion-weighted imaging; GRE, gradient echo; PLT, platelet count; CRP, C-reactive protein; PCT, procalcitonin; HIV, human immunodeficiency virus; NGS, next-generation sequencing; DTI, diffusion tensor imaging; OCT, optical coherence tomography; CSF, cerebrospinal fluid; PCR, polymerase chain reaction; GM, galactomannan; CNS, Central Nervous System; IV, intravenous.
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Summary
Keywords
aspergillosis, brain abscess, non-classically immunosuppressed, voriconazole, isavuconazole
Citation
Regmi M, Liu S, Dai Y, Ye J, Chen X, Yang J and Yang C (2025) Case Report: Rare invasive aspergillosis with brain abscess in a non–classically immunosuppressed patient, and pooled analysis of individual patient data (2000–2024). Front. Surg. 12:1674057. doi: 10.3389/fsurg.2025.1674057
Received
27 July 2025
Accepted
30 September 2025
Published
23 October 2025
Volume
12 - 2025
Edited by
Katharina Feil, University of Tübingen, Germany
Reviewed by
Nicolas Padilla-Raygoza, Institute of Public Health of the State of Guanajuato (ISAPEG), Mexico
Yafei Guo, Tsinghua University, China
Updates
Copyright
© 2025 Regmi, Liu, Dai, Ye, Chen, Yang and Yang.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Chenlong Yang vik.yang@pku.edu.cn; vik.yang@bjmu.edu.cn Jun Yang yangjbysy@bjmu.edu.cn
† These authors have contributed equally to this work and share first authorship
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.