Clinical Neurology and Neurosurgery · F. Acerbi et al. / Clinical Neurology and Neurosurgery 146...

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Clinical Neurology and Neurosurgery 146 (2016) 123–129 Contents lists available at ScienceDirect Clinical Neurology and Neurosurgery jo ur nal home p age: www.elsevier.com/locate/clineuro Feasibility of simultaneous sodium fluorescein and indocyanine green injection in neurosurgical procedures F. Acerbi , F. Restelli, M. Broggi, M. Schiariti, P. Ferroli Department of Neurosurgery, Foundation IRCCS Istituto Neurologico Besta, Via Celoria 11, 20133 Milano, Italy a r t i c l e i n f o Article history: Received 2 March 2016 Received in revised form 23 April 2016 Accepted 3 May 2016 Available online 6 May 2016 a b s t r a c t Objective: The objective of this study is to assess the feasibility of simultaneous Sodium Fluorescein (SF) and Indocyanine Green (ICG) injection during neurosurgical procedures. Patients and methods: Three patients harboring a high-grade glioma (HGG) were retrospectively identified in the surgical database of the Neurosurgical Unit 2 at the Foundation IRCCS Istituto Neurologico C. Besta in Milan, by having received intraoperatively both SF for tumor resection and ICG for vasculature angiographic studies in the same surgical procedure. We identified 2 males and 1 female (age range 25–60). Lesions were located in the left temporo-polar area and hippocampus (1 case), right superior frontal gyrus (1 case), left supplementary motor area (1 case). All the three lesions showed Magnetic Resonance Imaging (MRI) characteristics of HGG and, for this reason, in all patients a fluorescein-guided tumor removal was proposed. In the same surgical procedure ICG videoangiography was considered necessary in order to study arterial and venous vasculature, given by the strict relation of the tumor with an unexpected Posterior Communicating Artery (PComA) aneurysm in one case and with cortical drainage veins complexes in the other two cases. In all cases a microscope equipped with both YELLOW560 and IR800 integrated filters (Pentero 900, Carl Zeiss, Oberkorchen, Germany) was used. Fluorescein was i.v. injected at a dose of 5 mg/kg immediately after patient intubation. ICG was i.v. injected in bolus on demand of the operating surgeon at a dose of 12.5 mg. Results: No side-effects related to simultaneous injection of SF and ICG were identified. In all three cases, the use of SF allowed to better visualize the tumor areas during surgical removal, thus leading to a radical resection until no macroscopic appearance of residual tumor mass and no fluorescence was visible in the surgical cavity. ICG videoangiography confirmed the patency of branches of internal carotid artery after clipping of an unexpected small PComA aneurysm found intraoperatively during tumor removal in one case, while in patient 2 and 3 it allowed to evaluate patency and study flow pattern in cortical drainage veins that were intimately related to the tumors and the way of the surgical approach. Postoperative MRI showed a Gross Total Resection of the tumors in all cases. Conclusions: This study showed for the first time the feasibility of intravenous SF injection and ICG videoangiography in the same surgical procedure. The presence of different fluorescence filters on the same surgical microscope allows the surgeon to recognize and safely resect the tumor and simultaneously evaluate local brain vascularization. © 2016 Elsevier B.V. All rights reserved. 1. Introduction Surgical removal of high-grade gliomas (HGG) may benefici- ate from the use of fluorescein-guided technique, that allows to better discriminate tumor tissue from normal brain parenchima at the tumor margin, due to its capability to concentrate in areas with blood-brain barrier disruption [1], thus obtaining a high per- Corresponding author. E-mail address: [email protected] (F. Acerbi). centage of complete resection [2–5]. Since July 2015, the use of sodium fluorescein (SF) as a tracer for all neurological malignant neoplasm was approved in Italy by the Italian Drug Agency (AIFA) (“Determination n. 905/2015, AIFA”), widening the possibilities of implementation of this fluorofore to all central nervous sys- tem (CNS) tumors, enhancing at pre-operative Magnetic Resonance Imaging (MRI). When operating on CNS tumors, the surgeon may also face the need to evaluate blood vessels in the tumor area and peri-tumor brain parenchima. Indocyanine green (ICG) videoangiography is an established technique to assess brain vascularization intraopera- http://dx.doi.org/10.1016/j.clineuro.2016.05.003 0303-8467/© 2016 Elsevier B.V. All rights reserved.

Transcript of Clinical Neurology and Neurosurgery · F. Acerbi et al. / Clinical Neurology and Neurosurgery 146...

Page 1: Clinical Neurology and Neurosurgery · F. Acerbi et al. / Clinical Neurology and Neurosurgery 146 (2016) 123–129 tively by the use of a dedicated filter in the surgical microscope

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Clinical Neurology and Neurosurgery 146 (2016) 123–129

Contents lists available at ScienceDirect

Clinical Neurology and Neurosurgery

jo ur nal home p age: www.elsev ier .com/ locate /c l ineuro

easibility of simultaneous sodium fluorescein and indocyanine greennjection in neurosurgical procedures

. Acerbi ∗, F. Restelli, M. Broggi, M. Schiariti, P. Ferroliepartment of Neurosurgery, Foundation IRCCS Istituto Neurologico Besta, Via Celoria 11, 20133 Milano, Italy

r t i c l e i n f o

rticle history:eceived 2 March 2016eceived in revised form 23 April 2016ccepted 3 May 2016vailable online 6 May 2016

a b s t r a c t

Objective: The objective of this study is to assess the feasibility of simultaneous Sodium Fluorescein (SF)and Indocyanine Green (ICG) injection during neurosurgical procedures.Patients and methods: Three patients harboring a high-grade glioma (HGG) were retrospectively identifiedin the surgical database of the Neurosurgical Unit 2 at the Foundation IRCCS Istituto Neurologico C.Besta in Milan, by having received intraoperatively both SF for tumor resection and ICG for vasculatureangiographic studies in the same surgical procedure. We identified 2 males and 1 female (age range25–60). Lesions were located in the left temporo-polar area and hippocampus (1 case), right superiorfrontal gyrus (1 case), left supplementary motor area (1 case). All the three lesions showed MagneticResonance Imaging (MRI) characteristics of HGG and, for this reason, in all patients a fluorescein-guidedtumor removal was proposed. In the same surgical procedure ICG videoangiography was considerednecessary in order to study arterial and venous vasculature, given by the strict relation of the tumor withan unexpected Posterior Communicating Artery (PComA) aneurysm in one case and with cortical drainageveins complexes in the other two cases. In all cases a microscope equipped with both YELLOW560 andIR800 integrated filters (Pentero 900, Carl Zeiss, Oberkorchen, Germany) was used. Fluorescein was i.v.injected at a dose of 5 mg/kg immediately after patient intubation. ICG was i.v. injected in bolus ondemand of the operating surgeon at a dose of 12.5 mg.Results: No side-effects related to simultaneous injection of SF and ICG were identified. In all three cases,the use of SF allowed to better visualize the tumor areas during surgical removal, thus leading to a radicalresection until no macroscopic appearance of residual tumor mass and no fluorescence was visible in thesurgical cavity. ICG videoangiography confirmed the patency of branches of internal carotid artery afterclipping of an unexpected small PComA aneurysm found intraoperatively during tumor removal in onecase, while in patient 2 and 3 it allowed to evaluate patency and study flow pattern in cortical drainageveins that were intimately related to the tumors and the way of the surgical approach. Postoperative MRI

showed a Gross Total Resection of the tumors in all cases.Conclusions: This study showed for the first time the feasibility of intravenous SF injection and ICGvideoangiography in the same surgical procedure. The presence of different fluorescence filters on thesame surgical microscope allows the surgeon to recognize and safely resect the tumor and simultaneouslyevaluate local brain vascularization.

© 2016 Elsevier B.V. All rights reserved.

. Introduction

Surgical removal of high-grade gliomas (HGG) may benefici-te from the use of fluorescein-guided technique, that allows to

etter discriminate tumor tissue from normal brain parenchimat the tumor margin, due to its capability to concentrate in areasith blood-brain barrier disruption [1], thus obtaining a high per-

∗ Corresponding author.E-mail address: [email protected] (F. Acerbi).

ttp://dx.doi.org/10.1016/j.clineuro.2016.05.003303-8467/© 2016 Elsevier B.V. All rights reserved.

centage of complete resection [2–5]. Since July 2015, the use ofsodium fluorescein (SF) as a tracer for all neurological malignantneoplasm was approved in Italy by the Italian Drug Agency (AIFA)(“Determination n. 905/2015, AIFA”), widening the possibilitiesof implementation of this fluorofore to all central nervous sys-tem (CNS) tumors, enhancing at pre-operative Magnetic ResonanceImaging (MRI).

When operating on CNS tumors, the surgeon may also face theneed to evaluate blood vessels in the tumor area and peri-tumorbrain parenchima. Indocyanine green (ICG) videoangiography is anestablished technique to assess brain vascularization intraopera-

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ively by the use of a dedicated filter in the surgical microscope6–11]. In tumor surgery, it can be used to evaluate tumor vascu-arization, to confirm arterial patency after tumor resection ando study brain regional perfusion [12–14]. In addition, our grouplready demonstrated that ICG videoangiography could help inssessing flow dynamic and patency of cortical drainage veins andn evaluating the possibility of venous sacrifice, by the use of apecific clipping test [12,13,15,16]. Furthermore, ICG videoangiog-aphy could be also useful for the study of arterial pathologies likentracranial aneurysms, that rarely could coexist with brain tumors17,18].

Both fluorescence studies require the use of a dedicated micro-cope, equipped with filters specific for fluorescein and ICGespectively.

In this report we presented three cases in which both SF and ICGere used during the removal of HGGs and we demonstrated for

he first time the feasibility of administration in the same patient,uring the same surgical procedure, of these two different fluores-ences dyes.

. Patients and methods

.1. Patients characteristics

Three patients harboring a HGGs were retrospectively identi-ed in the surgical database of the Neurosurgical Unit 2 at theoundation IRCCS Istituto Neurologico Besta, by having receivedntraoperatively both SF for tumor resection and ICG for vascula-ure studies in the same surgical procedure. There were 2 malesnd 1 female (age range 25–60). Patients complained for III nervealsy, diplopia and short-term memory disturbances (1 case), andeizures (2 cases). Lesions were located in the left temporo-polarrea and hippocampus (1 case), right superior frontal gyrus (1ase), left supplementary motor area (1 case) (Fig. 1). All threeesions showed MRI characteristics of HGGs; in particular, a certainegree of contrast enhancement was present in all cases (Fig. 1).or this reason, in all patients a fluorescein-guided tumor removalas proposed, following our specific protocol (see below). In the

ame surgical procedure, ICG videoangiography was consideredecessary in order to: (1) control arterial branches patency afterhe clipping of an unexpected posterior communicating (PComA)rtery aneurysm, found intraoperatively during tumor removal (1ase); (2) evaluate the patency and flow characteristics of corticalrainage veins to the superior sagittal sinuses that were in strictelationship to the tumor and in the way of the surgical approach2 cases). Histological diagnosis were Anaplastic Oligoastrocitoman 1 case, Anaplastic Oligodendroglioma in 1 case, and GlioblastomaGBM) in 1 case (Table 1).

One of the patients included in this analysis was part of theLUOGLIO phase II trial approved in our Institution (EudraCTo. 2011-002527-18); the other two patients were submitted touorescein-guided removal following AIFA determination after

uly 2015. The surgical database of Neurosurgical Unit 2 at the Foun-ation IRCCS Istituto Neurologico Besta has been approved by ourthical Committee.

.2. Intraoperative fluorescence protocol

.2.1. Fluorescein administrationSurgical removal of the lesions by fluorescein-guided technique

ollowed the protocol previously published by our group [2–4].

riefly, 5 mg/kg of SF were injected immediately after patient

ntubation. Tumor removal was carried out using a microsurgicalechnique under microscope and fluorescence visualization by YEL-OW 560 filter (Pentero microscope, Carl Zeiss, Germany), with the

eurosurgery 146 (2016) 123–129

aid of a neuro-navigation system (Stealth S7, Medtronic). Tumorwas removed in an inside-out fashion with the aid of ultrasonicaspiration or double aspiration technique, until no fluorescencewas left behind, as safely considered feasible by the operating sur-geon (FA).

2.2.2. ICG administrationICG was administered intravenously as a bolus (12.5 mg in 5 ml

of saline), when needed by the surgeon, into a central venousline. The same microscope, equipped also with infra-red sensi-tive filter and FLOW800 analysis software (Pentero microscope,Carl Zeiss, Germany) was used. Principles of ICG videoangiogra-phy using microscope-integrated technology were described indetail elsewhere [6,7,12,13,16]. Briefly, after the injection of ICGthe field of interest was illuminated with a near-infrared lightand real-time angiographic images were seen on video screen infew seconds, allowing to identify arterial, capillary and venousphases. The fluorescence was cleared within 10–15 min. The result-ing video was shown on the microscope screen during surgery andrecorded for further visualizations as well. With FLOW 800 soft-ware, fluorescence intensities are evaluated in arbitrary intensityunits corresponding to the intensity detected by the camera. Basedon maximal fluorescence intensities and delay times (time to reach50% of maximum fluorescence), the software is capable to recon-struct a map in grey-scale (maximal fluorescence intensities) anda colour map (delay time) outlining the blood flow sequence fromred to blue. In addition, a pin-point analysis of the course of fluo-rescence can be performed [16,19].

2.3. Post-operative follow-up

Patients were submitted to early post-operative MRI (within72 h from surgical procedure) in order to evaluate extent ofremoval. Clinical general and neurological evaluation were avail-able until hospital discharge, and during the follow-up, includinga throughout analysis of possible side effects related to fluoresceinadministration, as previewed in the FLUOGLIO study for patient 1and in the AIFA determination for patients 2 and 3.

3. Results

3.1. Fluorescence findings

3.1.1. Fluorescein-guided tumor resectionIn all three cases, the use of SF allowed to better visualize the

tumor areas during surgical removal. In particular, in patient 1, thetumor (anaplastic oligoastrocytoma) presented as a classical high-grade glioma at pre-operative MRI, with central necrotic core andintense peripheral enhancement on T1 sequences with gadolinium(Fig. 1A). The visualization with YELLOW560 filter allowed to iden-tify the tumor tissue that appeared intensively fluorescent and thatwas removed in an inside-out fashion until a minimal fluorescentremnant infiltrating the cerebral peduncle was identified and leftto avoid damages to the cortico-spinal tract (Fig. 2A,B).

In patient 2, the tumor (anaplastic oligodendroglioma) pre-sented as a huge hyperintense lesion in T2 and FLAIR with areasof contrast enhancement in T1 with gadolinium (Fig. 1C–F). In thiscase, the tumor presented some superficial fluorescent spots andsubcortical areas with intense fluorescent appearance under theYELLOW560 visualization, corresponding to the areas of enhance-ment at the pre-operative MRI, associated with non-fluorescenttumor areas that corresponded to non-enhancing tumor parts

(Fig. 2C,D). Also in this case, the tumor was progressively removedin an inside-out fashion until no macroscopic appearance of resid-ual tumor mass and no fluorescence was visible in the surgicalcavity.
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F. Acerbi et al. / Clinical Neurology and Neurosurgery 146 (2016) 123–129 125

Fig. 1. Preoperative and postoperative MRI of the patients. (A and B): Patient 1. Preoperative axial postcontrast T1 MRI (A) showing a left temporo-polar mass with anecrotic center and peripheral enhancement, involving also the mesencephalic surface. Early (<48 h after surgery) postoperative contrast enhanced axial T1-weighted MRI(B), showing a gross total resection of the lesion. (C–G): Patient 2. Preoperative axial Flair (C), T2-weighted (D), postcontrast T1-weighted (E, F) MRI showing a hyperintense(T2 and FLAIR) – hypointense (T1) lesion in the right superior frontal gyrus, with areas of contrast enhancement (red arrows in E–F). Postoperative axial T1-weighted imagewith contrast administration (G) showing a complete resection of the lesion. (H–L): Patient 3. Preoperative axial Flair (H), T2-weighted (I), postcontrast T1-weighted (J, K)MRI showing a left hyperintense (T2 and FLAIR) – hypointense (T1) lesion in the left supplementary motor area, with a clear nodule of contrast enhancement (red arrows inJ–K). Postoperative axial T1-weighted with contrast image (L) showing a complete resection of the lesion. (For interpretation of the references to colour in this figure legend,the reader is referred to the web version of this article.)

Table 1Detailed patient characteristics.

Patient Sex Age Tumor Localization Symptoms Hystological Analysis Indication for SFinjection

Indication for ICGvideoangiography

1 Female 62 Left temporo-polararea and hippocampus

III nerve palsyDiplopiaShort-term memorydisturbances

AnaplasticOligoastrocitoma

Contrast enhancementat preoperative MRI

Control of arterialbranches patency afterclipping of anunexpected PComAaneurysm that wasintraoperatively found

2 Male 24 Right superior frontalgyrus

Seizures AnaplasticOligodendroglioma

Contrast enhancementat preoperative MRI

Patency and flowevaluation of corticaldrainage veins to theSSS in strict relationwith the tumor

3 Male 57 Left supplementarymotor area

Seizures Glioblastoma Contrast enhancementat preoperative MRI

Patency and flowevaluation of corticaldrainage veins to theSSS in the way of visionof the surgical

iw

In patient 3, the tumor (GBM) presented as a hyperintense lesionn T2 and FLAIR, with a clear nodule of contrast enhancement in T1

ith gadolinium (Fig. 1H–K). Fluorescent visualization with YEL-

approach andmanipulated duringsurgical removal

LOW560 filter allowed to clearly identifiy the aggressive nodule(Fig. 2E,F). The tumor was progressively removed until no macro-

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126 F. Acerbi et al. / Clinical Neurology and Neurosurgery 146 (2016) 123–129

Fig. 2. Intraoperative images and fluorescein findings. (A and B): Patient 1. Intraoperative images with white-light illumination (A) and fluorescent visualization withYELLOW560 filter (B). The tumor appeared as an intensively fluorescent mass under the filter visualization (white arrow in B). (C and D): Patient 2. Intraoperative imageswith fluorescent visualization under YELLOW560 filter. Some cortical fluorescence spots were clearly visible on the brain surface after dural opening (white arrows in C);subcortically, other fluorescent part of the tumor were identified and removed (white arrow in D). (E and F): Patient 3. Intraoperative images with white-light illumination (E)a visibli h peritc

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nd fluorescent visualization with YELLOW560 filter (F); a reddish-greyish lesion iss larger and allows to more clearly identify the superficial margin of the lesion witolour in this figure legend, the reader is referred to the web version of this article.)

copic appearance of residual tumor mass and no fluorescence wasisible in the surgical cavity.

.1.2. Indocyanine-green videoangiographyIn patient 1 ICG videoangiography confirmed the patency of

ranches of internal carotid artery (PComA, anterior choroidalrtery (AChoA), small perforating branches) after clipping of annexpected small PComA aneurysm, found intraoperatively duringumor removal (Fig. 3A,B).

In patient 2 and 3 ICG videoangiography, with FLOW 800 anal-sis, allowed to evaluate patency and study flow pattern in corticalrainage veins that were intimately related to the tumors and theay of the surgical approach. In particular, in patient 2 the corti-

al drainage veins remained patent with anterograde flow towardhe superior sagittal sinus (SSS) after tumor removal (Fig. 3C,D);n patient 3, instead, the distal segment of the cortical drainageein thrombosed after tumor removal due to surgical manipula-ion for an inter-hemispheric approach, but ICG videoangiographyemonstrated retrograde flow through a collateral (Fig. 3E,F).

.2. Clinical and radiological results

Median follow-up was 4 months (range 1–15). No complicationelated to fluorescein and ICG administration was registered in thehree patients included in the study. All patients presented yel-ow fluorescent discoloration in the urine for 24–48 h. One patientn.3) presented leg motor weakness (1/5) that improved at 1 monthollow-up (4/5). One patient (n.1) died 15 months after a surgical

rocedure for tumor recurrence. Patients 2 and 3 are alive at the last

ollow-up, respectively 4 and 1 months after surgical procedure.All the postoperative MR images showed a Gross Total Resection

f the tumors (Fig. 1B,G,L).

e with white-light illumination (white arrow in E); fluorescein uptake of the lesionumor brain parenchima (white arrow in F). (For interpretation of the references to

4. Discussion

Our study confirmed for the first time the feasibility of simul-taneous intravenous SF and ICG injection during neurosurgicalprocedures. Indeed, the presence of two different fluorescence fil-ters (YELLOW 560 and FLOW 800) in the same surgical microscope(Pentero 900, Carl Zeiss Meditec, Germany) allowed the surgeon torecognize and safely resect tumor tissues, checking and preservingsimultaneously local brain vascularization.

In recent times, the implementation of fluorescence in neu-rosurgery has undergone a great interest by the neurosurgicalcommunity, given by the wide range of possible use, from neu-rovascular to oncological procedures [8,11,20–23].

5-Aminolevulinic acid (5-ALA) and SF are the most used neuro-oncological fluorescent tracers. 5-ALA is a precursor of hemoglobinthat causes accumulation of fluorescent porphyrins in tumor cells,including gliomas. Since Stummer et al. presented the results oftheir phase III trial on 5-ALA guided technique for HGGs resec-tion, demonstrating a positive effect on extent of resection andprogression-free survival, it has been established as an importanttool for safe and extensive resection in HGG patients [24,25]. SF (thesodium salt of fluorescein), instead, is a fluorochrome that, wheninjected i.v., has the capability to concentrate in tumor areas of theCNS, due to their induced disruption of the blood-brain barrier [1].Given its low cost (about five euros per injection), its safety profile,and the preliminary data confirming the efficacy in terms of bettertumor visualization by the use of a dedicated filter on the surgi-cal microscope, has recently gained wide diffusion in neurosurgery[2–4,21,22,26–29]. Our group was the first to propose a phase II

prospective trial on fluorescein-guided resection of HGGs with adedicated filter on the surgical microscope (“FLUOGLIO” study) [2]and our report of 2014 on a 20 patients cohort showed a total resec-tion of the contrast-enhancing tissue in 80% of cases [3]. In addition,
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F. Acerbi et al. / Clinical Neurology and Neurosurgery 146 (2016) 123–129 127

Fig. 3. Intraoperative images and ICG findings. (A and B): Patient 1. During tumor removal, an unexpected small aneurysm of the left internal carotid artery at the originof PcomA was found (white arrow in A); ICG videoangiography was used after the clipping of the aneurysmal sac in order to assess patency of PComA, AChoA and otherperforating arteries (red arrow in B). (C and D): Patient 2. Intraoperative images with white-light illumination (C) and with IR800 filter activated (D) at the end of tumorremoval. Two large cortical drainage veins complexes were found superficial to the tumor mass and were dissected-free from the tumor during the removal (white arrowsin C). ICG videoangiography eventually confirmed the patency and the anterograde flow toward the SSS in these vessels after tumor resection (red arrows in D). (E and F):Patient 3. Intraoperative images with white-light illumination (E) and IR800 filter (F) at the end of tumor removal. A large cortical drainage vein was found at the posteriorc om thd in F)t gure l

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orridor of the inter-hemispheric approach for tumor removal and dissected-free fremonstrated the thrombosis of the distal segment of the vein’s complex (red arrowhe vein (white arrows in F). (For interpretation of the references to colour in this fi

reliminary data showed the possibility of using SF with a dedicatedlter on the surgical microscope for resection of other types of CNS

umors, including metastasis, lymphomas and hemangioblastomas22,27–29]. Finally, the use of SF has been also proposed, with aolus type of injection, in order to visualize intracranial vessels dur-

ng surgical procedures for arteriovenous malformations resection30] and aneurysm clipping [31], by the use of an integrated filtern the surgical microscope. Eventually, in July 2015 the use of SFs a tracer for all neurological malignant neoplasm was approvedn Italy by the AIFA (“Determina n. 905/2015, AIFA”), widening theossibilities of implementation of this fluorofore to all neurologicalnhancing tumors at MRI with contrast administration.

In the cases included in this report, the use of SF was consideredue to tumor characteristics, with contrast enhancement at the pre-p MRI; in fact, the visualization of tumor under YELLOW 560 filter

n the surgical microscope allowed to better visualize the tumorass and, in case 2 and 3, to identify high-grade spots in the con-

ext of the main tumor mass, thus leading to a macroscopic radicalemoval of the lesion (confirmed in all the cases by a postoperative

RI with intravenous contrast administration).ICG videoangiography is a simple, low cost and highly effective

ethod that offers real-time information about arterial and venousntracranial vessels, and brain parenchymal perfusion in the areahat is exposed during neurosurgical procedures [6,7,9,16,32]. Its

se has been implemented in vascular neurosurgery, specificallyuring aneurysm clipping [11,32,33], arteriovenous malformationemoval [34], dural arteriovenous fistulas closure [35], and verifica-ion of bypass patency [36]. Our group proposed for the first time

e arachnoid, without need for its section (white arrow in E). ICG videoangiography, with collateral and retrograde circulation that involved the proximal segments ofegend, the reader is referred to the web version of this article.)

the use of ICG videoangiography during tumor removal in orderto evaluate its pathological vascularization and check for arterialpatency and brain perfusion after resection [12,14]. In addition,we explored the usefulness of ICG videoangiography in studyingthe characteristics of venous flow and predicting the presence of asafe collateral circulation for veins that are at risk for intended orunintended damage during neuro-oncological procedures. We alsodesigned a specific test (“ICG temporary clipping test”) in which,after a baseline ICG videoangiography, a temporary clip is placedon the vein to be tested and flow direction and dynamic are againanalyzed by ICG videoangiography. Flow stagnation is consideredto be a sign of lack of collateral circulation whereas flow reversalis interpreted as a sign of the presence of collateral circulation andpossibility of venous sacrifice [15,16].

In the first patient of this report, ICG administration wasperformed because of unexpected intraoperatively finding ofa small PComA aneurysm during tumor resection. Associationbetween intracranial aneurysms and tumors is uncommon (inci-dence ranged between 0, 3% and 4%) but sometime they couldcoexist. A combination of GBM and cerebral aneurysms is even rarer[37–40]. The pathogenesis has been debated: a theory proposedthat an increase in flow inside pathological low-resistance ves-sels feeding the tumor could contribute to the development of theaneurysmal [18,37]; another theory suggested that tumor invasion

of blood vessels could play a role in the development of vascularmalformations as aneurysms [41]. In our case, the aneurysm wasfound only intraoperatively during tumoral resection in the deepof the surgical cavity. Due to its proximity to the surgical field, rel-
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tively easiness of clipping and the thin-wall appearance, it waslipped straightforward. ICG confirmed the complete occlusion ofhe aneurysmal sac and the preservation of the blood flow in theeft PComA, AChoA and other perforating arteries (Fig. 3A,B). In thether two cases ICG videoangiography was used for the study of theuperficial venous system, because of tumor location and tumorpproach, and relationship with cortical draining veins. Specifi-ally, in case n. 2 the dye was administered during the last steps ofhe surgery, confirming the patency of two large cortical drainageeins complexes found intimately related to the tumor that couldave been unintentionally damaged during the surgery (Fig. 3C,D).ost-operative finding was uneventful. In case n. 3, the videoan-iographic study showed the thrombosis of the distal segment of aortical drainage vein related to surgical manipulation during sur-ical approach and removal, with a good collateral flow through theroximal segments of the vein complex (Fig. 3E,F). In this case a legotor weakness related to close proximity to the primary motor

ortex developed, that improved at the last follow-up; no venousnfarction was found at post-operative MRI.

We recognized the possibility of using SF also for vascular stud-es in our series of patients. However, in the case n.1, this was notonsidered because the aneurysm was incidentally found duringumor resection when still some tumor remnant was present. Thetilization of a bolus type of SF injection, that causes brain perfusionnd intense fluorescent appearance of all normal brain parenchima,asting minutes after injection [4], could have induced a difficultumor discrimination, with a significant impact on extent of resec-ion. Furthermore, at least in Italy, SF is not yet approved for usage inascular neurosurgery. It could be used off-label requiring a specificonsent by the patient, or in the context of a specific research pro-ram. Thus, even if theoretically in case n. 2 and n. 3 SF could haveeen used with two different indications (tumor resection and veintudy after tumor removal), we were not allowed to do so without

specific consent by the patient.Our study still has certain limitations. First of all, in order to

se the two dyes in the same surgical procedure, the microscopein our case Pentero 900, Carl Zeiss) needs to be equipped withoth surgical filters (specifically YELLOW 560 for fluorescein visu-lization and FLOW 800 for ICG videoangiography) and this surelyncreases its cost. We could only hypothesize, due to the lack ofpecific experience, that an association of 5-ALA and ICG, with aicroscope equipped with both filters for these fluorescent tracer

BLU 400 for 5-ALA), could have a similar possible application ineurosurgery, but this is far beyond the scope of this manuscript.

n addition, and more importantly, due to the analysis of the pro-edure in only three patients, larger-scale systematic studies andlinical researches enrolling more patients are required to furtherssess the value and the benefits given by the use of both theseuorescence technologies during the same surgery. Nevertheless,he aim of the study is not to propose the systematic use of bothyes during resection of brain tumors, but to report the feasibil-

ty of using in the same surgical procedures SF assistance and ICGideoangiography, when indicated by the complexity of the specificase.

To our knowledge, this is the first paper showing this possibility.

. Conclusions

This study showed for the first time the feasibility of intravenousF injection and ICG videoangiography in the same surgical pro-

edure. The presence of different fluorescence filters on the sameurgical microscope allows the surgeon to recognize and safelyesect the tumor and simultaneously evaluate local brain vascu-arization.

[

eurosurgery 146 (2016) 123–129

Acknowledgment

Dr. Acerbi has received fees for lectures by Carl Zeiss Meditec.

References

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