Fluorescein sodium guided resection of high-grade glioma

Naik et al. compared 5-aminolevulinic acid fluorescence guided resection of high-grade glioma, Fluorescein sodium guided resection of high-grade glioma. (FS), and Intraoperative magnetic resonance imaging-guided resection of high-grade glioma (IMRI) with no image guidance to determine the best intraoperative navigation method to maximize rates of gross total resection (GTR) and outcomes. A frequentist network meta-analysis was performed following standard PRISMA guidelines (PROSPERO registration CRD42021268659). Surface-under-the-cumulative ranking (SUCRA) analysis was executed to hierarchically rank modalities by the outcome of interest. Heterogeneity was measured by the I2 statistic. Publication bias was assessed by funnel plots and the use of Egger's test. Statistical significance was determined by p < 0.05. Twenty-three studies were included for analysis with a total of 2,643 patients. Network meta-analysis comparing 5-ALA, IMRI, and FS was performed. The primary outcome assessed was the rate of GTR. Analysis revealed the superiority of all intraoperative navigation to control (no navigation). SUCRA analysis revealed the superiority of IMRI + 5-ALA, IMRI alone, followed by FS, and 5-ALA. Overall survival (OS) and progression-free survival (PFS) were also examined. FS (vs. control) was associated with improved OS, while IMRI was associated with improved PFS (vs. control, FS, and 5-ALA). Intraoperative navigation using IMRI, FS, and 5-ALA lead to greater rates of GTR in HGGs. FS and 5-ALA also yielded improvement in OS and PFS. Further studies are needed to evaluate differences in survival benefit, operative duration, and cost ¹⁾.

Senders et al., systematically review all clinically tested fluorescent agents for application in fluorescence guided surgery (FGS) for glioma and all preclinically tested agents with the potential for FGS for glioma.

They searched the PubMed and Embase databases for all potentially relevant studies through March 2016.

They assessed fluorescent agents by the following outcomes: rate of gross total resection (GTR), overall and progression free survival, sensitivity and specificity in discriminating tumor and healthy brain tissue, tumor-to-normal ratio of fluorescent signal, and incidence of adverse events.

The search strategy resulted in 2155 articles that were screened by titles and abstracts. After full-text screening, 105 articles fulfilled the inclusion criteria evaluating the following fluorescent agents: 5 aminolevulinic acid (5-ALA) (44 studies, including three randomized control trials), fluorescein (11), indocyanine green (five), hypericin (two), 5-aminofluorescein-human serum albumin (one), endogenous fluorophores (nine) and fluorescent agents in a pre-clinical testing phase (30). Three meta-analyses were also identified.

5-ALA is the only fluorescent agent that has been tested in a randomized controlled trial and results in an improvement of GTR and progression-free survival in high-grade gliomas. Observational cohort studies and case series suggest similar outcomes for FGS using fluorescein. Molecular targeting agents (e.g., fluorophore/nanoparticle labeled with anti-EGFR antibodies) are still in the pre-clinical phase, but offer promising results and may be valuable future alternatives. ²⁾.

Fluorescein can be used as a viable alternative to 5-ALA for intraoperative fluorescent guidance in brain tumor surgery. Comparative, prospective, and randomized studies are much needed ³⁾.

5-ALA fluorescence-guided surgery has shortcomings such as drug's phototoxicity, extortionate price, and not being approved by Food and Drug Administration, which limited its widespread application.

Due to the above limitations, sodium fluorescein guided surgery had been paid more attention by neurosurgeons than 5-ALA. FL is an easily available and biosafe fluorescein dye with a peak excitation at 465 to 490 nm and emission between 500 and 550 nm and has been used extensively and safely for many years especially in ophthalmology ^{4) 5)}.

5-aminolevulinic acid is still the preferred and more established fluorescent dye used during high-grade gliomas resection, with Fluorescein sodium gaining-attention, really cheaper and more ductile alternative ⁶⁾.

The use of fluorescein fluorescence-guided stereotactic needle biopsy has been shown to improve diagnostic accuracy and to expedite operative procedure in the stereotactic needle biopsy of high-grade gliomas.

see Fluoropen.

The first use of fluorescence for brain tumour surgery was in 1948 by G.E. Moore ⁷⁾ using fluorescein sodium, a strongly fluorescing and non-toxic (apart from rare anaphylaxis ⁸⁾ compound). In malignant brain tumours with their inherent blood-brain barrier breakdown, fluorescein is extravasated and might serve to mark tumours.

Today, fluorescein sodium is again under scrutiny ^{9) 10)}. using a novel filter system by Zeiss (YELLOW 560) for the microscope. This filter visualises fluorescein and allows good background discrimination. Furthermore, fluorescein can be injected any time and is low in cost. Nevertheless, its use in brain tumour surgery is off-label and thus restricted to clinical studies. Little is known about the best timing of i.v. fluorescein application before resection. Injecting fluorescein too early might result in unspecific propagation with oedema, whereas acute injections might be useful for detecting abnormally perfused tumour tissue. Levels in the blood will be high, especially with acute injections, leading to fluorescence of all perfused brain tissue. Such time-resolved in- formation on the specificity of fluorescein are not available.

Overall, Schwake et al observed no clear value of fluorescein in a small study, which they closed prematurely. Clearly, further work elucidating optimal timing and dosing of fluorescein is warranted. ¹¹⁾

Sodium fluorescein (SF) was first used for the identification of different types of brain tumors in 1948 ¹²⁾.

Since then, the use of SF and others fluorescent tracers have been described in literature particularly that dealing with glioblastoma multiforme resection ^{13) 14) 15)}

Metastatic lesion were also enhanced by SF ¹⁶⁾. ¹⁷⁾.

Also in skull base tumors ¹⁸⁾.

“Fluorescein sodium”, the sodium salt of fluorescein, is used extensively as a diagnostic tool in the field of ophthalmology and optometry, where topical fluorescein is used in the diagnosis of corneal abrasions, corneal ulcers and herpetic corneal infections. It is also used in rigid gas permeable contact lens fitting to evaluate the tear layer under the lens. It is available as sterile single-use sachets containing lint-free paper applicators soaked in fluorescein sodium.

Intravenous or oral fluorescein is used in fluorescein angiography in research and to diagnose and categorize vascular disorders including retinal disease macular degeneration, diabetic retinopathy, inflammatory intraocular conditions, and intraocular tumors. It is also being used increasingly during surgery for brain tumors.

Diluted fluorescein dye has been used to localise multiple muscular ventricular septal defects during open heart surgery and confirm the presence of any residual defects.

Intravenous fluorescein sodium has been used during resection of high-grade gliomas to help the surgeon visualize tumor margins. Several studies have reported improved rates of gross total resection (GTR) using high doses of fluorescein sodium under white light. The introduction of a fluorescein-specific camera that allows for high-quality intraoperative imaging and use of very low dose fluorescein has drawn new attention to this fluorophore.

Fluorescein sodium does not appear to selectively accumulate in astrocytoma cells but in extracellular tumor cell rich locations, suggesting that fluorescein is a marker for areas of compromised blood brain barrier within high grade astrocytoma. Fluorescein fluorescence appears to correlate intraoperatively with the areas of MR enhancement, thus representing a practical tool to help the surgeon achieve GTR of the enhancing tumor regions ¹⁹⁾.

Magnetic resonance diffusion tensor imaging (MR-DTI) and fluorescein sodium dyeing guiding for surgery of glioma located in brain motor functional areas can increase the gross total resection rate, decrease the paralysis rate caused by surgery, and improve patient quality of life compared with traditional glioma surgery ²⁰⁾.

Intrathecal fluorescein (ITF) is extremely specific and very sensitive for detecting intraoperative Cerebrospinal fluid fistulas. Although false negatives can occur, these patients do not appear to be at risk for postoperative Cerebrospinal fluid fistula. The use of ITF may help surgeons prevent postoperative Cerebrospinal fluid fistulas by intraoperatively detecting and confirming a Water-tight repair ²¹⁾.