5-Aminolevulinic Acid-Guided Glioma Resection During Awake Craniotomy: Systematic Review of Functional Safety and Surgical Benefit

Background: Maximal safe resection remains the cornerstone of glioma surgery, particularly in eloquent regions where oncologic gain must be balanced against functional preservation. While 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery improves extent of resection in high-grade gliomas under general anesthesia, its role during awake craniotomy (AC) remains underdeveloped. We aimed to evaluate the oncologic and functional outcomes of 5-ALA-guided tumor resection during AC. Methods: PubMed, Scopus, and Web of Science were searched from inception to February 2026 for studies reporting original data on AC using 5-ALA following PRISMA guidelines. Results: Across ten studies comprising 108 patients, fluorescence positivity was 79.2% in high-grade gliomas (Grade III-IV) and 24.1% in low-grade gliomas (Grade II), among the 83 patients with both grade and fluorescence data available (grade was not reported for 19 patients in one case series, and 6 patients in one cohort study did not receive 5-ALA and were excluded from grade- and fluorescence-stratified analyses). Gross total resection was achieved in 62.2% of patients with evaluable extent-of-resection data (56.5% of the full cohort), reaching 66.7% in the largest comparative cohort. Transient aphasia occurred in 32.6% of evaluable patients, while permanent aphasia and persistent hemiparesis were observed in 14.6% and 16.9%, respectively. In multiple studies, resection was intentionally halted despite persistent fluorescence when functional mapping identified an eloquent cortex, underscoring that mapping remained the decisive determinant of surgical boundaries. No study reported conversion to general anesthesia. Conclusions: 5-ALA-guided resection during AC appears feasible and clinically useful, particularly for high-grade gliomas in eloquent regions. Permanent neurological morbidity was observed in a minority of patients, within a range broadly consistent with awake glioma surgery generally, but the absence of a non-5-ALA comparator group means that functional safety relative to awake mapping alone cannot yet be established with confidence. Across the available literature, 5-ALA consistently enhances intraoperative tumor visualization, supports identification of residual fluorescent disease, and integrates well with cortical and subcortical mapping without clear evidence of increased permanent neurological morbidity. Although functional mapping remains the decisive determinant of the final resection boundary, the available evidence supports 5-ALA as a valuable complementary adjunct in onco-functional glioma surgery.