Journal of Photochemistry and Photobiology B: Biology 148 (2015) 302–309

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Fluorescence in neurosurgery: Its diagnostic and therapeutic use. Review of the literature Christian Ewelt a,⇑, Andrei Nemes b, Volker Senner b, Johannes Wölfer a, Benjamin Brokinkel a, Walter Stummer a, Markus Holling a a b

Department of Neurosurgery, University Hospital, Münster, Germany Institute of Neuropathology, University Hospital, Münster, Germany

a r t i c l e

i n f o

Article history: Received 7 December 2014 Accepted 7 May 2015 Available online 14 May 2015 Keywords: 5-aminolevulinic acid Indocyanin green Fluorescein Brain tumors Intraoperative angiography

a b s t r a c t Fluorescent agents, e.g. 5-aminolevulinic acid (5-ALA), fluorescein and indocyanine green (ICG) are in common use in neurosurgery for tumor resection and neurovascular surgery. Protoporphyrine IX (PPIX) as major metabolite of 5-ALA is a strong fluorescent substance accumulated within malignant glioma tissue and a very sensitive and specific tool for visualizing high grade glioma tissue during surgery. Furthermore, 5-ALA or rather PPIX also offers an intratumoral therapeutic option stimulated by laser light in specific wavelength. Fluorescein was demonstrated to show similar fluorescent reactions in neurosurgery, but is controversial in its use, especially in high grade tumor surgery. Intraoperative angiography during resection of arterio-venous malformations, extracranial–intracranial-bypass or aneurysm surgery is supported by ICG fluorescence. Generally ICG will provide beneficial information for both, exposure of the pathology and illustration of healthy structures. This manuscript shows an overview of the literature focussing fluorescence in neurosurgery. Ó 2015 Elsevier B.V. All rights reserved.

1. Introduction Fluorescent agents are in common use in neurosurgery for fluorescence guided tumor resection, e.g. by 5-aminolevulinic acid (5-ALA) or fluorescein, fluorescence based photodynamic therapy (PDT) as off-label treatment in recurrent gliomas, or for intraoperative angiography during resection of arterio-venous malformations, extracranial–intracranial-bypass or aneurysm surgery. One of the most used fluorescent agents is 5-ALA, which is a natural biochemical precursor of haemoglobin that elicits synthesis and accumulation of fluorescent porphyrins (PPIX) within malignant glioma tissues [101,102,105]. Intraoperative tumor fluorescence derived from 5-ALA has found to be a sensitive and specific tool for visualizing residual contrast-enhancing tumor during surgery for high grade gliomas [104,105], while cytoreductive surgery of these malignant gliomas is generally accepted to be of benefit for patients [65,87,103]. Further, if exposed at 635 nm, PPIX acts as a potent photosensitizer for photodynamic therapy of malignant gliomas and various cancers [80,46,41]. Because of its intratumoral

⇑ Corresponding author at: Department of Neurosurgery, Westfälische Wilhelms Universität Münster, Albert-Schweitzer-Campus 1, A1, 48149 Münster, Germany. Tel.: +49 251 83 47472; fax: +49 251 83 47479. E-mail address: [email protected] (C. Ewelt). http://dx.doi.org/10.1016/j.jphotobiol.2015.05.002 1011-1344/Ó 2015 Elsevier B.V. All rights reserved.

synthesis, 5-ALA differs from other fluorescent agents that have been investigated for tumor discrimination such as fluorescein. But, there are only a few numbers of published experiences with fluorescein for tumor resection. While 5-ALA’s main field of application is tumor surgery, indocyanine green (ICG) is of value in cerebrovascular procedures [55,88]. Similar to other neurosurgical purposes the main goal of intraoperative angiography by ICG is to understand and safely resect the pathology, and simultaneously to preserve cerebral perfusion [49]. ICG is widely used in ophthalmology [100,28] and hepatic surgery [116,61] due to similar reasons.

2. Role of 5-aminolevulinic acid in glioma surgery The challenge in glioma surgery is to manage complete and safe removal of contrast enhancing tumor tissue which might help patients by reducing tumor volume and intracranial pressure. Malignant brain tumor tissue is usually difficult to distinguish from normal brain tissue and going too far might create neurological deficits after surgery. Beside other tools for optimizing resection like intraoperative MRI, neuro-navigation or ultrasound, 5-ALA is a natural biochemical precursor of haemoglobin that elicits synthesis and accumulation of strongly fluorescent PPIX within malignant glioma tissues. In a multicentre, randomized Phase III study,

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Stummer et al. could demonstrate a significant increase in rate of complete resection and progression free survival (PFS) controlled by postoperative MRI [104]. Their multivariate analysis showed that especially less or none residual tumor volume has a beneficial effect on overall survival (P = 0.0006⁄) more than Karnofsky Performance Score (KPS) (P = 0.0055⁄) and age (P = 0.0132⁄). However, intra-tumoral kinetic and accumulation of PPIX depends on different enzymes in the heme synthesis. There is also a serum-dependent export of PPIX by ATP-binding cassette transporter G2 and ferrochelatase (FECH) inhibition by nitrite oxide donor (NOC18) or deferoxamine, which increased cellular PPIX [79,110]. Further, Blake et al. showed in an in vitro comparison of the iron-chelating agents CP94 and dexrazoxane a significant effect on PPIX accumulation for photodynamic therapy and fluorescence guided resection [15]. Beside FECH, there may also be other mechanisms directly or indirectly responsible for 5-ALA uptake. Suzuki et al. could estimate an increased expression of Cadherin 13 in non-fluorescent tumor tissue [108], which influenced 5-ALA uptake into the cell by peptide transporter (Pept 1) [78] and 5-ALA efflux of the cell by ATP-transporter ABCG2 [106]. According to literature, ABCG2 is described as marker for tumor initiating cells (TICs) [16]. In contrast to ABCG2 as negative factor for intracellular PPIX fluorescence, another ATP-transporter ABCB6 is supposed to have a positive influence on tumor fluorescence [124]. A study about fluorescent and non-fluorescent glioma tissue, in which different TICs could be analyzed, underline our hypothesis that histologically, same tumor areas with different 5-ALA-induced fluorescence are also different regarding their molecular characterization [86]. There are only few studies, which correlate positive or negative fluorescent areas in astrocytomas to histological markers. Low grade fibrillary astrocytomas with slight proliferation rate mostly showed no fluorescence after 5-ALA incubation [119]. The same authors could even estimate that WHO Grade III tumors, like anaplastic astrocytomas, revealed no contrast enhancement in cerebral MRI, but fluorescence of intracellular PPIX in anaplastic foci with an increased cell amount and proliferation rate [118]. The value of Gadolinium-enhanced MRI, O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET and intraoperative, 5-ALA derived tissue fluorescence for anaplastic foci in diffuse gliomas is controversely discussed. Diffuse gliomas sometimes harbor anaplastic foci which determine final histopathological grading, are an indicator of prognosis and dictate adjuvant therapies such as radio- or chemotherapy. Undergrading as a consequence of sampling non-representative tumor may result in necessary therapies being deferred. Gadolinium-enhanced MRI is not always sensitive for detecting anaplastic foci. In an own study, we could show that in low grade gliomas 5-ALA fluorescence is the exception and FET PET is more sensitive. High grade areas in diffuse gliomas with anaplastic foci usually fluoresce, if they are FET PET positive. In consequence, FET PET appears valuable for pre-operative identification of anaplastic foci and hot spots are strongly predictive for 5-ALA-derived fluorescence, which highlight anaplastic foci during resection [36] (see Fig. 1).

3. Role of 5-aminolevulinic acid in photodynamic therapy Photodynamic therapy (PDT) in combination with the photosensitizer 5-ALA is an emerging treatment strategy for glioma as well as for other cancers including medulloblastoma, melanoma, lung, and breast cancer [17,21,112]. There are some pathobiologic factors with noteworthy impact on the clinical application of PDT: Even if a tumor consists of progeny developed from a single neoplastic cell, there will be heterogeneity of tumor cells in terms of their morphologies and differentiation status. Kushibiki et al.

Fig. 1. 5-ALA-mediated fluorescence guided resection. Salmon like fluorescence inside the resection cavity shows malignant glioma tissue (A/B). There is a difference in fluorescence grading: strong fluorescence (A) for highly specific malignant tissue with necrosis and high tumor cell density, mild fluorescence (B) for the infiltration zone between malignant and normal brain tissue. Intraoperative microscope view in (C) with white light and (A/B) with fluorescent light. One part of fluorescending specimen is always directly checked by neuropathologists concerning their tumor entity.

found differential effects and sensitivity of PDT on morphologically distinct tumor cells derived from a single precursor cell [64] by separating two subclones from a tumor cell line after

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photodynamic therapy which showed differences in their migratory activity to other tissues. Other authors could demonstrate effects after photodynamic therapy on nuclei and nucleoli of HL-60 leukemic granulocytic precursors [98] and on leukemia stem cells [11,50]. Barth et al. evaluated the cytotoxic effect of PDT with the photosensitizer calcium phosphosilicate nanoparticles (CPSNPs) encapsulating the near-infrared fluoroprobe indocyanine green (ICG) and specifically targeting CD117 or CD96 as surface features enhanced on leukemia stem cells. He could dramatically enhance the disease-free survival by 29% in a murine leukemia model in vivo [11]. Another stem cell effect of PDT was documented by Huang et al. They used a special photosensitizer with PDT targeting murine erythroblastic leukemic EL9611 cells to purge leukemic cells and their precursors from bone marrow autografts and likewise retained sufficient progenitor cells for the hematopoietic activity [50]. Thus, the effect of PDT is multifaceted on different tissue and tumor cells. The combination of 5-ALA and photodynamic therapy in gliomas in vivo and in vitro was also described by several authors. In a case report of a patient with non-resectable, recurrent GBM in whom multimodal therapies had previously failed, stereotactic 5-ALA/PDT resulted in a long-sustaining response [103]. A recent Phase III study combining 5-ALA- and Photofrin-mediated fluorescence-guided resection and PDT constated a clear benefit in survival and progression free survival (PFS) [31]. The essential phototoxic effect is apoptosis and necrosis in glioma cells which are induced by suppression of survival signals, activation of proteolytic pathways [56] and generating highly reactive oxygen species, particularly singlet oxygen [120,62]. 5-ALA based PDT causes mitochondrial and nuclear DNA damage [81] and apoptosis occurs due to mitochondrial release of cytochrome c, endoplasmatic reticulum stress, decrease in Bcl-3 and Bcl-xL, and activation of caspase-9 and caspase-3 [62,41]. Moreover, an in vitro study by Etminan et al. could conclude that ALA/PDT has a long-lasting effect on glioblastoma cells, affecting their migratory and invasive activity, possibly mediated by changes induced in the cytoskeleton and the expression of molecules involved in matrix invasion [34]. Thus, this 5-ALA-derived fluorescent treatment option with excitation light in wavelength of 635 nm by a laser diode does not only eliminate glioblastoma cells by phototoxicity, might target the tumor vasculature, and might result in an antitumoral immune response [18,26], but it also effects on one of the most significant characteristics of glioblastomas, their invasiveness. Moreover, other authors could confirm this theory. PDT may generate regional and systemic anti-tumor immunity in mice with G422 gliomas in the brain, because infiltration of immune cells and the release of inflammatory factors, such as TNF-a and IFN-c, were increased in animals with G422 gliomas following PDT when compared with those without receiving PDT [67]. Further, 5-ALA/PDT-treated spheroids induced dendritic cell maturation as indicated by the up-regulation of CD83 and co-stimulatory molecules as well as increased T-cell stimulatory activity of the dendritic cells. In another experimental trial, Etminan and co-workers could estimate that the uptake of tumor antigens and dendritic cell maturation induced by the 5-ALA/PDT-treated spheroids were inhibited when heat-shock protein-70 (HSP-70) was blocked [35]. But in the literature so far, no studies have reported about analyzing glioblastoma stem-like cells treated by photodynamic therapy and its phototoxic and probably immune-modulating effects in vitro or in vivo. Unpublished own data showed that PDT within experimental glioblastoma stem-like cell line results in significant cell death after exposure to laser light and this might be an explanation for its observed effect in recurrent glioblastomas in vivo. Despite these in vitro studies only on cell lines, further studies evaluating the accumulation of PPIX and its effects on primary glioblastoma cancer stem cells (GB-CSC) as well as in vivo studies

are needed to document efficacy of 5-ALA/PDT in the treatment of glioma tumors (see Fig. 2). 4. Role of 5-aminolevulinic acid in other intracranial or intraspinal tumors 5-ALA induced fluorescence is not only showed in malignant gliomas, but also in different tumors outside the central nervous system [57,60,95,6,39,42,51]. There have been detected several treatment options for using 5-ALA as diagnostic and therapeutic tool. Kamp et al. reported even a retrospective analysis of 52 patients with intracerebral metastasis from different cancer primaries [54]. More complete resection for local tumor control is as important as in the combined treatment options like in malignant gliomas. The majority of intracerebral metastasis showed a 5-ALA-induced fluorescence (5-AIF), whereas 20 metastasis were 5-ALA-negative and 61.5% exhibited an inhomogeneous fluorescence pattern with strongly fluorescent parts as well as 5-ALA-negative areas. Furthermore, Utsuki et al. reported that 9 of 11 (82%) metastatic brain tumors demonstrated 5-AIF [113]. In conclusion, these findings indicate that 5-AIF is neither associated with the histological type nor with the origin of intracerebral metastases. Better local tumor control might be achieved by extending the resection of intracerebral metastases to a depth of about 5 mm, as Yoo et al. could report in non-eloquent areas [123] and should be an aim in metastasis intracranial surgery. Because of infiltrating growth pattern into the adjacent brain of cerebral metastases, the surrounding brain tissue needs to be considered as a therapeutic target and the border between tumor tissue expending in a tong-like pattern into the adjacent brain parenchyma and normal brain tissue as well as edematous brain areas needs to be defined. Although 5-ALA could be a useful tool for metastatic brain surgery. A sufficient identification of peritumoral infiltrating cells is not always possible because of an unspecific leakage of PPIX and fluorescence being detectable in the peritumorous edematous brain tissue in a considerable fraction of patients. Therefore, further investigations in this part of brain surgery is needed. For primary or secondary intracerebral lymphomas, there are few data in the literature. Alone, Grossman et al. could describe a 5-AIF during resection of an intracerebral tumor with a mass occupying effect in the posterior fossa as a first case report on this topic [43]. Standard of intracerebral lymphoma surgery includes a

Fig. 2. 5-ALA-mediated fluorescence used for photodynamic therapy as off-label treatment for recurrent glioblastoma multiforme. Excitation light in wavelength of 635 nm by a laser diode implanted via stereotactical targeting does not only eliminate glioblastoma cells by phototoxicity, but might target the tumor vasculature, and might result in an antitumoral immune response.

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stereotactical biopsy for histopathological confirmation with following chemotherapy or irradiation. So, less experiences have been given with 5-AIF in this surgery, but according to these findings it could be an option for PDT, as other authors could show in systemic lymphoma treatment regiments [107]. Concerning meningiomas as one of the most frequent intracranial tumor, which is in most cases WHO Grade I or Grade II, but could also invade into adjacent bone structures or sometimes into brain tissue, literature showed some case reports [53,76,117,19] and few clinical studies about the fluorescence effect of PPIX after 5-ALA application [23,115,30]. The last one was published by Della Puppa and co-workers in Journal of Neurosurgery, in which they revealed in 12 patients with invading meningiomas (7 with skull base and 5 with convexity meningiomas) a clear 5-AIF with a sensitivity of 89.06% and a specificity of 100% compared to histopathological results in detecting meningioma bone invasion [25]. Another author group could show in 15 patients that 5-ALA induced PPIX fluorescence is a promising adjunct and potential in accurately detecting neoplastic tissue during meningioma resective surgery [114]. Further, these results suggest a broader reach for PPIX as a biomarker for meningioma than was previously noted in the literature. However, in meningiomas 5-AIF might prove itself a treatment option not only for resection control, but also for PDT, just as it does in high grade gliomas. Hefti and colleagues could conclude in their experimental setting that differences in intracellular PPIX concentrations between HBL-52 and BEN-MEN-1 benign meningioma cells were mainly due to differences in FECH activity and that these differences correspond to their susceptibility to 5-ALA-induced PDT [45]. The last experience was made by Cornelius and his group for analyzing the photodynamic effect enhanced by ciprofloxacin in malignant meningioma cell line (KT21-MG). Although preliminary work indicated that meningiomas are more resistant to PDT than gliomas, they demonstrated that efficacy of 5-ALA PDT was increased by adjunction of ciprofloxacin in conventional clinical dosing and by prolongation of 5-ALA incubation time [24]. Clear visualization of solid intraspinal tumor tissue, identification of tumor borders and safe differentiation of normal neuronal tissue in extra- and intra-medullary gliomas, recurrent or infiltrative meningiomas and extra- and intra-medullary ependymomas can also be challenging in neurosurgery. As for the intracerebral gliomas, meningiomas and ependymomas, 5-AIF might improve extent of tumor resection and PFS. Eicker and co-workers reported about 26 intraspinal extra- and intra-medullary tumors and that the vast majority of meningiomas, all gliomas and one ependymoma showed a clear fluorescence after pre-operative application of 5-ALA [30]. Before this, extension of this technique to spinal intradural pathologies was only described in a few case reports. In an own case report, we demonstrated clear 5-AIF and its possible clear identification of tumor borders in a young female patient with an anaplastic astrocytoma WHO Grade III and recurrent situation, performing a cordectomy sub level T9/10 for complete resection and pre-operatively documented complete senso-motoric deficit [37]. However, gross total resection, especially in invasive pituitary adenomas, is not always possible and requires adjuvant treatment modalities, such as radiotherapy [38,72], specific drug therapy, or particularly in the last ten years, gamma-knife surgery [40,1]. Failure of surgery in invasive pituitary adenomas could be minimized when visualizing of adenoma tissue invading the cavernous sinus or the suprasellar region is provided. So, our proposal in an own experimental setting was to establish a new diagnostic tool in pituitary adenoma surgery by using 5-ALA in order to distinguish between normal tissue and adenoma tissue and therefore, to improve cure rate and preservation of pituitary functions. So far in the literature, there is only one observational study in which

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the authors used 5-ALA applied pre-operatively for visualizing tumor tissue (optical biopsy system) by putting a laser diode into the sellar cavity during surgery and by measuring the light emission by photodiagnostic filters in 30 patients [32]. This study provided evidence that this is a feasible and reliable way to localize the adenomas and may lead to improved outcome. But basic research for 5-ALA derived fluorescence-guided surgery in pituitary adenomas is required. In unpublished data, we could demonstrate that 5-ALA accumulate as protoporphyrine IX in pituitary adenoma cells after incubation in cell culture which offers surgical possibilities for this method in skull base surgery. In most cases, gross total and safe cytoreductive surgery for pediatric brain tumors, such as medulloblastoma, ependymoma, astrocytoma and cPNET, followed by adjuvant radio- and chemotherapy, is an important part of the interdisciplinary therapy concept of this very special patient population and could provide a better prognosis. Many therapeutic protocols require an initial resection to be as complete as possible [92,27]. In children with suspected medulloblastoma, a residual tumor of more than 1.5 cm2 is considered as high risk for relapse with metastatic disease in the brain, spine or cerebrospinal fluid [3]. The extent of resection of both, non-metastatic medulloblastoma and cPNET, correlates with patients’ outcome [47,83]. Concerning other pediatric brain tumors, such as ependymoma and malignant glioma, gross total resection also confers a better prognosis for overall survival [2,4]. Indeed, two published cases indicate that fluorescence-guided surgery in pediatric brain tumors is possible [29,93]. One case report was about a 15-year-old girl with a childhood classic medulloblastoma; the other 9-year-old girl was operated because of a pleomorphic xanthoastrocytoma without adverse events. But no further studies exists about this item. Consecutively, we could reveal the first systematical analysis of intracellular PPIX accumulation after incubation with 5-ALA in pediatric tumor cell lines in experimental studies [96]. Thus, there are clear limitations due to differences between the in vitro conditions and the in vivo micro environment of the cells, concerning nutritions, vascularization, extra cellular matrix (ECM) composition, cytoarchitecture, cytokines and particularly oxygen supply, what may result in different effects on 5-ALA. Further in vivo studies are necessary in order to analyze pharmacokinetics of 5-ALA in young patients and their dependence on tumor blood supply and blood–brain-barrier. Moreover, the phenomenon of porphyrin accumulation in pediatric brain tumors could be used as an alternative therapeutic option for selective PDT in cases where complete removal of the tumor is impossible or tumor recurs and resection is not an option. 5. Role of fluorescein in neurosurgery In 1948, George Moore and co-workers already analyzed fluorescence with sodium fluorescein, which appeared to be helpful in the detection of malignancies, particularly in the recognition in brain tumors. In 46 operated patients, fluorescein technique could confirm complete removal of infiltrating gliomas and determined the presence and absence of tumor tissue in needle biopsies of brain tissue [75]. Recently published data by Rey-Dios showed technical principles and neurosurgical applications of fluorescein fluorescence using a microscope-integrated fluorescence module. They employed this technology in three representative cases to maximize resection of tumors and perform intraoperative angiography to guide microsurgical management of aneurysms and arteriovenous malformations [91]. Further, in a review of 37 appropriate articles by Lane and Cohen-Gadol, the authors could estimate that sodium fluorescein is generally safe with few reports of severe complications and useful in neurosurgical application for tumor resection and vascular surgery [66]. However, fluorescein

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enters the tumor via a broken down blood–brain barrier and is unspecific. Fluorescence is detected not only in any areas of surgical injury, but also in any zone of brain edema. Wherever blood could be seen intra- or extravascular, fluorescein shows fluorescence. Concerning neurovascular neurosurgery, fluorescein is directly visible within the vessels, which the surgeon can inspect and directly manipulate (see Fig. 3). 6. Role of indocyanine green (ICG) in aneurysm surgery Intracranial aneurysm surgery aims at occluding aneurysms completely from brain circulation without any residues and maintaining blood flow in all participating vessels [84,7]. Confirmation of neurosurgical results is impossible by visual microscopic inspection. Examination of surgical results can be performed by postoperative angiograms, and if residuals are left, a second surgery may be required [5,20,63,85,109]. Angiographic studies demonstrate a risk of residual filling of aneurysms from 2% to 8%, while occlusion of other neighbouring vessels was seen in 4–12% of cases [88,7,71,111]. Therefore intraoperative methods to validate the success of operative procedures were recommended. ICG was already invented during World War II as a dye for photographic purposes and was tested in 1957 for medical use in the US. In the 1960s renal blood flow was determined by ICG and diagnosis of subretinal processes was done by ICG. As a tricarbocyanine ICG has a molecular weight of 774.96 Da – the structural formula is 2,20 -indo-6,7,60 ,70 -dibenzocarbocyanine sodium salt [69,82]. Maximum near-infrared light absorption is at 790 nm with a maximum emission at 835 nm [14]. 98% of ICG is bound to plasma proteins [13] and therefore rests in blood vessels for 20–30 min meanwhile extravasation is very slow. Intraoperative ICG application in order to assess cerebral vascular flow was described initially by Raabe et al. [88]. They could report successful investigation of 12 aneurysm cases without any

Fig. 3. Fluorescein fluorescence during tumor surgery. Not only tumor tissue, but also vascular structures could be made visible (A). But it is less specific concerning tumor grading and tumor entity. (B) Resection cavity in white light.

side effects. The method could easily be integrated into the surgical microscope [89]. In order to validate ICG angiography, results were compared with intra-/postoperative digital substraction angiography (DSA) [90]. Usefullness of intra-operative ICG application has been published manifold [90,74,68,58,52]. Results of intraoperative ICG angiography were well correlated with intra/postoperative DSA (more than 90%) [88,90,52]. Other than DSA, intraoperative ICG angiography can be performed within two minutes after injection of the dye. Therefore clip position can be changed before critical cerebral ischemia occurs. Spatial resolution is superior to other methods and blood flow/patency can even assessed in vessels

Fig. 4. ICG fluorescence flow in neurovascular neurosurgery. Results of intraoperative ICG angiography were well correlated with intra/postoperative DSA. Intraoperative preparation of the aneurysm before clipping in white light microscopy (A) and in ICG angiography (B). After aneurysm clipping complete occlusion was presented by ICG angiography (C).

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smaller than 1 mm in diameter [88,90]. Complications of intraoperative ICG angiography comprise hypotension, tachycardia, nausea, pruritus as well as skin eruptions and are with 0.05–0.2% less frequent compared to other invasive methods [22,12] (see Fig. 4).

7. Role of Indocyanine green in arteriovenous-malformation (AVM) surgery Although several techniques including embolization, electrophysiological monitoring, neuronavigation and intraoperative angiography are available nowadays, excision of AVMs is still challenging [97,99]. Although intraoperative DSA technique is widespread [10,8,77], operation time is increased in comparison to ICG angiography [59]. AVM arteries and veins are easily identified using ICG angiography. Vessels in both physiological and pathological states can be distinguished by the timing of fluorescence, e.g. arterialized veins are emitting fluorescence in the late arterial phase [59]. It has to be noted that ICG angiography has especially limitations in deep seated AVMs as these lesions, approached by a narrow corridor as well as in vessels covered by brain tissue and blood clots [59]. Atherosclerosis is also an unfavourable condition for ICG angiography. Under these conditions DSA is the method of choice.

8. Role of Indocyanine green in extracranial–intracranial bypass surgery In EC–IC bypass surgery, the main complication is early graft occlusion and subsequent bypass failure [73,94]. If early bypass failure is not detected, this can lead to cerebral ischemia [73,94]. For this application intraoperative ICG angiography is most helpful. Historically ultrasonography and thermal artery imaging have been performed, but image quality and spatial resolution are poor [121,9]. Although intraoperative DSA is the method of choice [122], ICG angiography has also been reported to reliably detect stenosis and dysfunction of bypass [70,121,9]. ICG angiography can also be applied in high flow bypasses [121]. Because of high spatial resolution, anatomical relationships at the anastomotic site can be assessed [9]. Patency rates reached 100% after usage of ICG angiography [121].

9. Preview: Role of fluorescent agents 5-ALA/ICG Although 5-ALA is standard as diagnostic tool in glioma surgery for safe and effective resection, it offers more potential, even for therapeutic options in different cerebral tumors. This evidence would be the challenge in future studies. Similar to 5-ALA Indocyanine green angiography might be of value for different tumors/vascular malformations like hemangioblastomas [44,48] or cavernous hemangiomas [33]. In contrast to aneurysm-, bypass- and AVM-surgery above-mentioned indications failed to provide evidence of usefulness until now – this might change with increasing sample sizes. Generally ICG will provide beneficial information for both exposure of the pathology and illustration of healthy structures. Acknowledgments The corresponding author Christian Ewelt and author Volker Senner are supported by the fund ‘‘Innovative Medical Research’’ of the University of Münster Medical School (grant SE 111120).

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