The Role of 5-ALA in Low-Grade Gliomas and the Influence of Antiepileptic Drugs on Intraoperative Fluorescence

Abstract

Objectives: Intraoperative tumor visualization with 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX) fluorescence is widely applied for improved resection of high-grade gliomas. However, visible fluorescence is present only in a minority of low-grade gliomas (LGGs) according to current literature. Nowadays, antiepileptic drugs (AEDs) are frequently administered to LGG patients prior to surgery. A recent in-vitro study demonstrated that AEDs result in significant reduction of PpIX synthesis in glioma cells. The aim of this study was thus to investigate the role of 5-ALA fluorescence in LGG surgery and the influence of AEDs on visible fluorescence. Patients and Methods: Patients with resection of a newly diagnosed suspected LGG after 5-ALA (25 mg/kg) administration were initially included. During surgery, the presence of visible fluorescence (none, mild, moderate, or bright) within the tumor and intratumoral fluorescence homogeneity (diffuse or focal) were analyzed. Tissue samples from fluorescing and/or non-fluorescing areas within the tumor and/or the assumed tumor border were collected for histopathological analysis (WHO tumor diagnosis, cell density, and proliferation rate). Only patients with diagnosis of LGG after surgery remained in the final study cohort. In each patient, the potential preoperative intake of AEDs was investigated. Results: Altogether, 27 patients with a histopathologically confirmed LGG (14 diffuse astrocytomas, 6 oligodendrogliomas, 4 pilocytic astrocytomas, 2 gemistocytic astrocytomas, and one desmoplastic infantile ganglioglioma) were finally included. Visible fluorescence was detected in 14 (52%) of 27. In terms of fluorescence homogeneity ( n = 14), 7 tumors showed diffuse fluorescence, while in 7 gliomas focal fluorescence was noted. Cell density ( p = 0.03) and proliferation rate ( p = 0.04) was significantly higher in fluorescence-positive than in fluorescence-negative samples. Furthermore, 15 (56%) of 27 patients were taking AEDs before surgery. Of these, 11 patients (73%) showed no visible fluorescence. In contrast, 10 (83%) of 12 patients without prior AEDs intake showed visible fluorescence. Thus, visible fluorescence was significantly more common in patients without AEDs compared to patients with preoperative AED intake (OR = 0,15 (CI 95% 0.012–1.07), p = 0.046). Conclusions: Our study shows a markedly higher rate of visible fluorescence in a series of LGGs compared to current literature. According to our preliminary data, preoperative intake of AEDs seems to reduce the presence of visible fluorescence in such tumors and should thus be taken into account in the clinical setting.

Lighting Up the Tumor—Fluorescein-Guided Resection of Gangliogliomas

“…In a study by Valdes et al in which 5-ALA was evaluated in 12 cases of LGG, including two gangliogliomas, faint visual and quantitative probe-based fluorescence could only be detected in one of the two [ 14 ]. In another series with 27 LGG, including one desmoplastic infantile ganglioglioma, moderate diffuse fluorescence was reported by Goryaynov et al, using a slightly higher 5-ALA dose (25 mg/kg) [ 15 ]. Another retrospective study by Preuss et al evaluating 5-ALA in 18 pediatric patients with suspected brain tumors found minimal positive staining of the internal parts of the tumor but no enhancement of the tumor in one of three gangliogliomas [ 13 ].…”

“…Apart from standard microsurgical resection utilizing the operating microscope, 5-aminolevulinic acid (5-ALA) fluorescence has been evaluated as an intraoperative tool for improved visualization with limited to no benefit [ 13 , 14 , 15 ]. Near-infrared optical imaging in one study could visualize tumors with preoperative gadolinium enhancement on MRI [ 16 ].…”

Blood-Brain Barrier, Blood-Brain Tumor Barrier, and Fluorescence-Guided Neurosurgical Oncology: Delivering Optical Labels to Brain Tumors

“…So far, it is hard to elucidate which mechanism is most determinate of 5-ALA accumulation. Observed foci of fluorescence in low-grade gliomas were correlated with anaplastic transformation and increased cellularity (216,217), which in turn may result in a less competent BBTB that is permeable to 5-ALA but not to gadolinium-based contrast.…”

Photodynamic therapy, priming and optical imaging: Potential co-conspirators in treatment design and optimization — a Thomas Dougherty Award for Excellence in PDT paper

“…PSs have been utilized for their fluorescence for decades since the pioneering works of R. L. Lipson and S. Schwartz in the 1960s [25,26,185,186]. The most impactful use of Photosensitizer Fluorescence Detection (PFD) to date has been for image-guided resection of brain and bladder cancers [187][188][189][190][191], which are now approved by regulatory authorities worldwide. These approvals were based on clinical trials using ALA-PpIX (5-aminolevulinic acid induced protoporphyrin IX conversion) based PFD for guiding resection, which demonstrated a significant increase in tumor-free survival as compared to white-light based tumor resection surgery (Figs 7a-7d) [187,192,193].…”

“…Images in (c) and (d) were acquired by neurosurgical microscope equipped with a fluorescent 400 nm UV light module. Figures adapted from Zaak et al (2005)[191] and Goraynov et al (2019)[190].…”