Dual labeling with 5-aminolevulinic acid and fluorescein in high-grade glioma surgery with a prototype filter system built into a neurosurgical microscope: technical note

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OBJECTIVE

Recent efforts to improve visualization of 5-aminolevulinic acid (5-ALA)–induced protoporphyrin IX (PPIX) fluorescence resulted in a dual-labeling technique, combining it with fluorescein sodium in a prototype setup. Fluorescein identifies regions with blood-brain barrier breakdown in gliomas. However, normally perfused and edematous brain fluoresces unselectively, with strong background enhancement. The aim of this study was to test the feasibility of a novel, integrated filter combination using porphyrins for selective tumor identification and fluorescein for background enhancement.

METHODS

A microscope with a novel built-in filter system (YB 475) for visualizing both fluorescein and 5-ALA–induced porphyrins was used. Resection limits were identified with the conventional BLUE 400 filter system. Six patients harboring contrast ring-enhancing lesions were analyzed.

RESULTS

The complete surgical field could now be illuminated. Fluorescein was helpful for improving background visualization, and enhancing dura, edematous tissue, and cortex. Overlapping regions with both fluorophores harbored merged orange fluorescence. PPIX fluorescence was better visualized, even in areas beyond a normal working distance of approximately 25 cm, where the BLUE 400 filters recognized no or weak fluorescence.

CONCLUSIONS

The novel filter system improved general tissue brightness and background visualization, enhancing fluorescence-guided tumor resection. Furthermore, it appears promising from a scientific perspective, enabling the simultaneous and direct observation of areas with blood-brain barrier breakdown and PPIX fluorescence.

ABBREVIATIONS 5-ALA = 5-aminolevulinic acid; FGS = fluorescence-guided surgery; PPIX = protoporphyrin IX.

Article Information

Correspondence Eric Suero Molina: University Hospital of Münster, Germany. eric.suero@ukmuenster.de.

INCLUDE WHEN CITING Published online April 26, 2019; DOI: 10.3171/2018.12.JNS182422.

Disclosures Walter Stummer received speaker and consultant fees from Medac, Zeiss, Leica, Photonamic, and NXDC.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Fluorescence time kinetic estimation curves for fluorescein (green) and PPIX (red) fluorescence. This scheme estimates the fluorescein kinetics as previously published.39 First, we observe fluorescein fluorescence in hyperperfused vessels and brain tissue. Hereafter, we observe what we call the “pseudoselectivity” for fluorescein in tumor tissue,39,40 being finally observed in the peritumoral edema zone and zones of resection margins. In contrast, 5-ALA real-time kinetics (asterisk) was studied in a recent study from our group. We observed PPIX fluorescence to peak approximately 8 hours after administration (unpublished data). a.u. = arbitrary unit. Figure is available in color online only.

  • View in gallery

    Manufacturers’ specifications of the new YB 475 filter system demonstrating an excitation light band that ranges from approximately 390 to 475 nm, enabling light to be absorbed by PPIX and fluorescein simultaneously. The observation filter allows light to pass between 545 and 740 nm. This setting enables optimal visualization for 5-ALA and fluorescein. In addition, the emission filter also allowed passage of a small band of light between 430 and 455 nm, enabling remitted excitation light to pass and to further enhance background detail. a.u. = arbitrary unit. Figure is available in color online only.

  • View in gallery

    Intraoperative imaging of a 72-year-old woman with a right postcentral glioblastoma using white-light microscopy (A), BLUE 400 (B), and YB 475 (C and D). Light intensity was 100% and working distance approximately 25 cm. Panel C demonstrates a brighter background and a red/orange fluorescence. Panel D shows a brighter background and the extent of fluorescence that is perceived with more background illumination. Figure is available in color online only.

  • View in gallery

    Images obtained in a 43-year-old man with a left-frontal distant recurrence of a gliosarcoma. Intraoperative imaging was performed with a BLUE 400 (A) and YB 475 filter (B) after 5-ALA and fluorescein application as described in the Methods. The synergistic effects of fluorescein with 5-ALA could partly be appreciated using the standard BLUE 400 filter but was markedly enhanced using the filter moiety. Note the brighter background and the merged red-orange fluorescence observed during the dual-labeling technique with the YB 475 filter. Furthermore, observe yellow illumination of the cortex with negatively contrasted vessels, which were thus easily identified. Figure is available in color online only.

References

  • 1

    Acerbi FBroggi MBroggi GFerroli P: What is the best timing for fluorescein injection during surgical removal of high-grade gliomas? Acta Neurochir (Wien) 157:137713782015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Acerbi FBroggi MEoli MAnghileri ECavallo CBoffano C: Is fluorescein-guided technique able to help in resection of high-grade gliomas? Neurosurg Focus 36(2):E52014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Acerbi FBroggi MEoli MAnghileri ECuppini LPollo B: Fluorescein-guided surgery for grade IV gliomas with a dedicated filter on the surgical microscope: preliminary results in 12 cases. Acta Neurochir (Wien) 155:127712862013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Albert FKForsting MSartor KAdams HPKunze S: Early postoperative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis. Neurosurgery 34:45611994

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Coburger JHagel VWirtz CRKönig R: Surgery for glioblastoma: impact of the combined use of 5-aminolevulinic acid and intraoperative MRI on extent of resection and survival. PLoS One 10:e01318722015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Diaz RJDios RRHattab EMBurrell KRakopoulos PSabha N: 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 122:136013692015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Diez Valle RTejada Solis S: Answer to: "sodium fluorescein-guided resection under the YELLOW 560-nm surgical microscope filter in malignant brain tumor surgery-a feasibility study" (April 2013, volume 155, issue 4, pp 693–69). Acta Neurochir (Wien) 155:131913202013

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Eljamel S: 5-ALA fluorescence image guided resection of glioblastoma multiforme: a meta-analysis of the literature. Int J Mol Sci 16:10443104562015

  • 9

    Floeth FWStummer W: The value of metabolic imaging in diagnosis and resection of cerebral gliomas. Nat Clin Pract Neurol 1:62632005

  • 10

    Gröger UHuber PReulen HJ: Formation and resolution of human peritumoral brain edema. Acta Neurochir Suppl (Wien) 60:3733741994

  • 11

    Johnson DROmuro AMPRavelo ASommer NGuerin AIonescu-Ittu R: Overall survival in patients with glioblastoma before and after bevacizumab approval. Curr Med Res Opin 34:8138202018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Kreth FWThon NSimon MWestphal MSchackert GNikkhah G: Gross total but not incomplete resection of glioblastoma prolongs survival in the era of radiochemotherapy. Ann Oncol 24:311731232013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Lacroix MAbi-Said DFourney DRGokaslan ZLShi WDeMonte F: A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 95:1901982001

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    McGirt MJChaichana KLGathinji MAttenello FJThan KOlivi A: Independent association of extent of resection with survival in patients with malignant brain astrocytoma. J Neurosurg 110:1561622009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Montcel BMahieu-Williame LArmoiry XMeyronet DGuyotat J: Two-peaked 5-ALA-induced PpIX fluorescence emission spectrum distinguishes glioblastomas from low grade gliomas and infiltrative component of glioblastomas. Biomed Opt Express 4:5485582013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Neira JAUng THSims JSMalone HRChow DSSamanamud JL: Aggressive resection at the infiltrative margins of glioblastoma facilitated by intraoperative fluorescein guidance. J Neurosurg 127:1111222017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Orringer DLau DKhatri SZamora-Berridi GJZhang KWu C: Extent of resection in patients with glioblastoma: limiting factors, perception of resectability, and effect on survival. J Neurosurg 117:8518592012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Piccirillo SGDietz SMadhu BGriffiths JPrice SJCollins VP: Fluorescence-guided surgical sampling of glioblastoma identifies phenotypically distinct tumour-initiating cell populations in the tumour mass and margin. Br J Cancer 107:4624682012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Pogue BWGibbs-Strauss SValdés PASamkoe KRoberts DWPaulsen KD: Review of neurosurgical fluorescence imaging methodologies. IEEE J Sel Top Quantum Electron 16:4935052010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Roberts DWOlson J: Fluorescein guidance in glioblastoma resection. N Engl J Med 376:e362017

  • 21

    Sanai NBerger MS: Extent of resection influences outcomes for patients with gliomas. Rev Neurol (Paris) 167:6486542011

  • 22

    Schucht PBeck JAbu-Isa JAndereggen LMurek MSeidel K: Gross total resection rates in contemporary glioblastoma surgery: results of an institutional protocol combining 5-aminolevulinic acid intraoperative fluorescence imaging and brain mapping. Neurosurgery 71:9279362012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Schwake MStummer WSuero Molina EJWölfer J: Simultaneous fluorescein sodium and 5-ALA in fluorescence-guided glioma surgery. Acta Neurochir (Wien) 157:8778792015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Sjoback RNygren JKubista M: Absorption and fluorescence properties of fluorescein. Spectrochim Acta A Mol Biomol Spectrosc 51:L7L211995

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Stummer W: Factors confounding fluorescein-guided malignant glioma resections: edema bulk flow, dose, timing, and now: imaging hardware? Acta Neurochir (Wien) 158:3273282016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Stummer W: Poor man’s fluorescence? Acta Neurochir (Wien) 157:137913812015

  • 27

    Stummer WGötz CHassan AHeimann AKempski O: Kinetics of Photofrin II in perifocal brain edema. Neurosurgery 33:107510821993

  • 28

    Stummer WMeinel TEwelt CMartus PJakobs OFelsberg J: Prospective cohort study of radiotherapy with concomitant and adjuvant temozolomide chemotherapy for glioblastoma patients with no or minimal residual enhancing tumor load after surgery. J Neurooncol 108:89972012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Stummer WNovotny AStepp HGoetz CBise KReulen HJ: Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. J Neurosurg 93:100310132000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Stummer WPichlmeier UMeinel TWiestler ODZanella FReulen HJ: Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7:3924012006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Stummer WStepp HWiestler ODPichlmeier U: Randomized, prospective double-blinded study comparing 3 different doses of 5-aminolevulinic acid for fluorescence-guided resections of malignant gliomas. Neurosurgery 81:2302392017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Stummer WStocker SNovotny AHeimann ASauer OKempski O: In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid. J Photochem Photobiol B 45:1601691998

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Stummer WStocker SWagner SStepp HFritsch CGoetz C: Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence. Neurosurgery 42:5185261998

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Stummer WSuero Molina E: Fluorescence imaging/agents in tumor resection. Neurosurg Clin N Am 28:5695832017

  • 35

    Stummer WTonn JCGoetz CUllrich WStepp HBink A: 5-Aminolevulinic acid-derived tumor fluorescence: the diagnostic accuracy of visible fluorescence qualities as corroborated by spectrometry and histology and postoperative imaging. Neurosurgery 74:3103202014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Stupp RMason WPvan den Bent MJWeller MFisher BTaphoorn MJ: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:9879962005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Suero Molina ESchipmann SMueller IWölfer JEwelt CMaas M: Conscious sedation with dexmedetomidine compared with asleep-awake-asleep craniotomies in glioma surgery: an analysis of 180 patients. J Neurosurg 129:122312302018

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38

    Suero Molina ESchipmann SStummer W: Maximizing safe resections: the roles of 5-aminolevulinic acid and intraoperative MR imaging in glioma surgery—review of the literature. Neurosurg Rev [epub ahead of print] 2017

    • Search Google Scholar
    • Export Citation
  • 39

    Suero Molina EStummer W: Where and when to cut? Fluorescein guidance for brain stem and spinal cord tumor surgery—technical note. Oper Neurosurg (Hagerstown) 15:3253312018

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40

    Suero Molina EWölfer JEwelt CEhrhardt ABrokinkel BStummer W: Dual-labeling with 5-aminolevulinic acid and fluorescein for fluorescence-guided resection of high-grade gliomas: technical note. J Neurosurg 128:3994052018

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41

    Zhang XFZhang JLiu L: Fluorescence properties of twenty fluorescein derivatives: lifetime, quantum yield, absorption and emission spectra. J Fluoresc 24:8198262014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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