Fluorescein sodium guided resection of high-grade glioma [Neurosurgery Wiki]

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====== Fluorescein sodium guided resection of high-grade glioma ======

Naik et al. compared [[5-Aminolevulinic Acid Fluorescence-Guided Resection in 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 plot]]s 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
((Naik A, Smith EJ, Barreau A, Nyaeme M, Cramer SW, Najafali D, Krist DT, Arnold PM, Hassaneen W. Comparison of fluorescein sodium, 5-ALA, and intraoperative MRI for resection of high-grade gliomas: A systematic review and network meta-analysis. J Clin Neurosci. 2022 Feb 22;98:240-247. doi: 10.1016/j.jocn.2022.02.028. Epub ahead of print. PMID: 35219089.)).
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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.
((Senders JT, Muskens IS, Schnoor R, Karhade AV, Cote DJ, Smith TR, Broekman ML.
Agents for fluorescence-guided glioma surgery: a systematic review of preclinical
and clinical results. Acta Neurochir (Wien). 2017 Jan;159(1):151-167. doi:
10.1007/s00701-016-3028-5. Review. PubMed PMID: 27878374; PubMed Central PMCID:
PMC5177668.
)).

----
[[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
((Hansen RW, Pedersen CB, Halle B, Korshoej AR, Schulz MK, Kristensen BW,
Poulsen FR. Comparison of 5-aminolevulinic acid and sodium fluorescein for
intraoperative tumor visualization in patients with high-grade gliomas: a
single-center retrospective study. J Neurosurg. 2019 Oct 4:1-8. doi:
10.3171/2019.6.JNS191531. [Epub ahead of print] PubMed PMID: 31585425.
)).

[[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 
((Novotny H. R., Alvis D. L. A method of photographing fluorescence in circulating blood in the human retina. Circulation. 1961;24:82–86. doi: 10.1161/01.cir.24.1.82.))
((Kwan A. S. L., Barry C., McAllister I. L., Constable I. Fluorescein angiography and adverse drug reactions revisited: the Lions Eye experience. Clinical and Experimental Ophthalmology. 2006;34(1):33–38. doi: 10.1111/j.1442-9071.2006.01136.x.)).

[[5-aminolevulinic acid ]] is still the preferred and more established fluorescent dye used during [[high-grade glioma]]s resection, with [[Fluorescein sodium]] gaining-attention, really cheaper and more ductile alternative
((Acerbi F, Restelli F, De Laurentis C, Falco J, Cavallo C, Broggi M, Höhne J,
Schebesch KM, Schiariti M, Ferroli P. Fluorescent tracers in neurosurgical
procedures: an European survey. J Neurosurg Sci. 2018 Jul 17. doi:
10.23736/S0390-5616.18.04494-6. [Epub ahead of print] PubMed PMID: 30014688.
)).

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 
((Moore GE, Peyton WT, French LA, Walker WW (1948) The clinical use of fluorescein in neurosurgery; the localization of brain tumors. J Neurosurg 5:392–398))
using [[fluorescein sodium]], a strongly fluorescing and non-toxic (apart from rare anaphylaxis 
((Dilek O, Ihsan A, Tulay H (2011) Anaphylactic reaction after fluo- rescein sodium administration during intracranial surgery. J Clin Neurosci 18:430–431))
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 
((Acerbi F, Broggi M, Eoli M, Anghileri E, Cuppini L, Pollo B, Schiariti M, Visintini S, Ori C, Franzini A, Broggi G, Ferroli P (2013) Fluorescein-guided surgery for grade IV gli- omas with a dedicated filter on the surgical microscope: pre- liminary results in 12 cases. Acta Neurochir (Wien) 155: 1277–1286))
((Schebesch KM, Proescholdt M, Höhne J, Hohenberger C, Hansen E, Reimenschneider MJ, Ullrich W, Doenitz C, Schlair J, Lange M, Brawanski A (2013) Sodium fluorescein-guided resection under the YELLOW 560 nm surgical microscope filter in malignant brain tumor surgery—a feasibility study. Acta Neurochir (Wien) 155:693–699)).
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.
((Schwake M, Stummer W, Suero Molina EJ, Wölfer J. Simultaneous fluorescein
sodium and 5-ALA in fluorescence-guided glioma surgery. Acta Neurochir (Wien).
2015 May;157(5):877-9. doi: 10.1007/s00701-015-2401-0. Epub 2015 Mar 28. PubMed
PMID: 25820632.
))
----
Sodium fluorescein (SF) was first used for the identification of different types of [[brain tumor]]s in 1948
((Moore GE, Peyton WT, French LA, Walker WW. The clinical use of fluorescein in neurosurgery. J Neurosurg. 1948;5:392–8. )).

Since then, the use of SF and others [[fluorescent tracer]]s have been described in literature particularly that dealing with [[glioblastoma multiforme]] resection
((Chae MP, Song SW, Park SH, Park CK. Experience with 5- aminolevulinic Acid in fluorescence-guided resection of a deep sylvian meningioma. J Korean Neurosurg Soc. 2012;52:558–60.))
((Kuroiwa T, Kajimoto Y, Ohta T. Development of a fluorescein operative microscope for use during malignant glioma surgery: A technical note and preliminary report. Surg Neurol. 1998;50:41–9.))
((Kuroiwa T, Kajimoto Y, Ohta T. Comparison between operative findings on malignant glioma by a fluorescein surgical microscopy and histological findings. Neurol Res. 1999;21:130–4.))

Metastatic lesion were also enhanced by SF
((Moore GE, Peyton WT, French LA, Walker WW. The clinical use of fluorescein in neurosurgery. J Neurosurg. 1948;5:392–8. )).
((Okuda T, Kataoka K, Taneda M. Metastatic brain tumor surgery using fluorescein sodium: Technical note. Minim Invasive Neurosurg. 2007;50:382–4.)).

Also in skull base tumors
((da Silva CE, da Silva JL, da Silva VD. Use of sodium fluorescein in skull base tumors. Surg Neurol Int. 2010;1:70.)).



"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 glioma]]s 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
((Diaz RJ, Dios RR, Hattab EM, Burrell K, Rakopoulos P, Sabha N, Hawkins C,
Zadeh G, Rutka JT, Cohen-Gadol AA. Study of the biodistribution of fluorescein in
glioma-infiltrated mouse brain and histopathological correlation of
intraoperative findings in high-grade gliomas resected under fluorescein
fluorescence guidance. J Neurosurg. 2015 Jun;122(6):1360-9. doi:
10.3171/2015.2.JNS132507. Epub 2015 Apr 3. PubMed PMID: 25839919.
)).
----
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
((Liu JG, Yang SF, Liu YH, Wang X, Mao Q. Magnetic resonance diffusion tensor
imaging with fluorescein sodium dyeing for surgery of gliomas in brain motor
functional areas. Chin Med J (Engl). 2013 Jul;126(13):2418-23. PubMed PMID:
23823811.
)).
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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
((Raza SM, Banu MA, Donaldson A, Patel KS, Anand VK, Schwartz TH. Sensitivity
and specificity of intrathecal fluorescein and white light excitation for
detecting intraoperative cerebrospinal fluid leak in endoscopic skull base
surgery: a prospective study. J Neurosurg. 2016 Mar;124(3):621-6. doi:
10.3171/2014.12.JNS14995. Epub 2015 Aug 21. PubMed PMID: 26295912.
)).