5-aminolevulinic acid fluorescence-guided resection of pediatric brain tumor

• 5-Aminolevulinic acid (5-ALA) in paediatric brain tumour surgery-a systematic review and exploration of fluorophore alternatives
• How 5-ALA enlightens neurosurgery - results of a single centre study on high-grade gliomas
• Utility and Safety of 5-ALA Guided Surgery in Pediatric Brain Tumors: A Systematic Review
• Spontaneous intracerebral haemorrhage secondary to 5-ALA-induced thrombocytopaenia in a paediatric patient: case report and literature review
• 5-ALA fluorescence-guided resection of pediatric low-grade glioma using the ORBEYE 3D digital exoscope: a technical report
• 5-ALA fluorescence on tumors different from malignant gliomas. Review of the literature and our experience
• 5-ALA fluorescence-guided surgery in pediatric brain tumors-a systematic review
• The use of 5-aminolevulinic acid in resection of pediatric brain tumors: a critical review

5-aminolevulinic acid guided resection is a technique increasingly used to optimize tumor resection in neurosurgery. While it is well established in adult patients with high-grade gliomas, its application in pediatric brain tumors is still under investigation.

Mechanism: Orally administered 5-ALA is metabolized within cells into protoporphyrin IX (PpIX), a fluorescent compound that accumulates preferentially in tumor cells. Under blue-violet light (typically 400–410 nm), PpIX emits a red-violet fluorescence, allowing neurosurgeons to visualize tumor margins more clearly during surgery.

Applications in Pediatrics: In pediatric patients, the efficacy of 5-ALA varies depending on the tumor type. Studies have shown promising results in:

High-grade gliomas

Medulloblastomas

Ependymomas

Atypical teratoid/rhabdoid tumors (AT/RT)

However, fluorescence intensity and diagnostic accuracy tend to be lower in pediatric tumors compared to adult glioblastomas, possibly due to differences in tumor metabolism, blood-brain barrier integrity, and age-related enzyme activity.

Benefits:

Improves extent of resection, which correlates with better progression-free and overall survival.

Enhances intraoperative decision-making.

Minimizes damage to healthy brain tissue.

Limitations:

Not all pediatric tumors fluoresce reliably.

Off-label use in children; regulatory approval and standard dosing protocols are still evolving.

Requires specialized equipment and training.

Recent Evidence: Recent studies, including multi-institutional pediatric cohorts, have demonstrated the feasibility and relative safety of 5-ALA use in children, though further research is needed to standardize its use and confirm long-term oncological outcomes.

Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is well-established in adult high-grade gliomas, where it enhances intraoperative visualisation and extent of resection. However, its use in pediatric populations remains controversial due to variability in tumour biology and limited data on safety and efficacy. This systematic review aims to evaluate the clinical utility of 5-ALA fluorescence-guided surgery in paediatric brain tumours, while also exploring the potential of alternative fluorophores.

A comprehensive search of MEDLINE and EMBASE databases was performed up to October 2024, adhering to PRISMA guidelines. Data extracted included patient demographics, tumour histology, fluorescence intensity, extent of resection, and adverse effects. Statistical analyses focused on fluorescence frequency across tumour subtypes and variables related to administration protocols.

A total of 23 studies involving 281 paediatric patients (mean age: 10 years) were included. The most common tumour types were:

• Pilocytic astrocytomas (n = 45)
• Medulloblastomas (n = 45)
• Glioblastomas (n = 35)
• Ependymomas (n = 27)

Strong intraoperative fluorescence was significantly more frequent in high-grade gliomas compared to:

• Low-grade gliomas (p < 0.00001)
• Non-glioma tumours (p < 0.00001)
• High-grade non-glioma tumours (p = 0.000485)

Most adverse effects were transient, including mild transaminitis and dermatologic reactions ¹⁾.

This review confirms that 5-ALA fluorescence-guided surgery holds promise for resecting pediatric high-grade gliomas, enabling better delineation of tumour margins and potentially improving outcomes. However, the limited and inconsistent fluorescence observed in low-grade and non-glioma tumours raises concerns about the generalisability of 5-ALA use across the diverse landscape of pediatric brain tumors.

The rarity of serious side effects supports the relative safety of 5-ALA in children, though the pharmacokinetics and tumour uptake in younger patients require further clarification. Moreover, the variability in protocols for dosage and timing of administration across studies weakens the strength of pooled conclusions.

The review highlights the potential role of alternative fluorophores like fluorescein sodium and tozuleristide (BLZ-100), which may offer improved tumour contrast in non-glial lesions. These agents, though still under investigation, might provide better specificity for certain tumour types, justifying future comparative studies.

In summary, while 5-ALA remains a valuable adjunct in select paediatric neurosurgical cases, there is a clear need for tumour-specific strategies, protocol optimisation, and high-quality prospective trials before widespread adoption.