Journal of Neuro-Oncology

, Volume 141, Issue 3, pp 555–565 | Cite as

5-aminolevulinic acid induced protoporphyrin IX (ALA-PpIX) fluorescence guidance in meningioma surgery

  • Pablo A. ValdesEmail author
  • Matthias Millesi
  • Georg Widhalm
  • David W. Roberts
Topic Review



5-aminolevulinic acid induced protoporphyrin IX (5-ALA-PpIX) fluorescence guidance has emerged as a valuable surgical adjunct for resection of intracranial tumors.


Here we present a focused review on 5-ALA-PpIX fluorescence guidance for meningiomas.


We discuss the clinical studies and specific applications to date as well as the two main intraoperative fluorescence technologies applied to meningiomas.


The use of 5-ALA-PpIX in meningiomas holds promising potential so neurosurgeons can improve surgical outcomes for patients with meningiomas as well as be pioneers in developing improved fluorescence imaging technologies.


Fluorescence-guided surgery 5-Aminolevulinic acid Protoporphyrin IX Quantitative fluorescence Meningioma Spectroscopy 



This study was funded by National Institutes of Health (US) Grant No. R01 NS052274 (D.W. Roberts).

Compliance with ethical standards

Conflict of interest

D.W. Roberts and P.A. Valdes have multiple patents for intraoperative fluorescence imaging devices noted in this manuscript. D.W. Roberts has equity in InSight Surgical Technologies LLC. M. Millesi and G. Widhalm report no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional committees and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Kajimoto Y, Kuroiwa T, Miyatake S, Ichioka T, Miyashita M, Tanaka H, Tsuji M (2007) Use of 5-aminolevulinic acid in fluorescence-guided resection of meningioma with high risk of recurrence. Case report. J Neurosurg 106(6):1070–1074. CrossRefGoogle Scholar
  2. 2.
    Motekallemi A, Jeltema HR, Metzemaekers JD, van Dam GM, Crane LM, Groen RJ (2015) The current status of 5-ALA fluorescence-guided resection of intracranial meningiomas-a critical review. Neurosurg Rev 38(4):619–628. CrossRefGoogle Scholar
  3. 3.
    Valdes PA, Bekelis K, Harris BT, Wilson BC, Leblond F, Kim A, Simmons NE, Erkmen K, Paulsen KD, Roberts DW (2014) 5-Aminolevulinic acid-induced protoporphyrin IX fluorescence in meningioma: qualitative and quantitative measurements in vivo. Neurosurg 10 Suppl 1:74–82; discussion 82 – 73.
  4. 4.
    Simpson D (1957) The recurrence of intracranial meningiomas after surgical treatment. J Neurol Neurosurg Psychiatry 20(1):22–39CrossRefGoogle Scholar
  5. 5.
    Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ (2006) Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7(5):392–401. CrossRefGoogle Scholar
  6. 6.
    Bekelis K, Valdes PA, Erkmen K, Leblond F, Kim A, Wilson BC, Harris BT, Paulsen KD, Roberts DW (2011) Quantitative and qualitative 5-aminolevulinic acid-induced protoporphyrin IX fluorescence in skull base meningiomas. Neurosurg Focus 30(5):E8. CrossRefGoogle Scholar
  7. 7.
    Chae MP, Song SW, Park SH, Park CK (2012) Experience with 5-aminolevulinic Acid in fluorescence-guided resection of a deep sylvian meningioma. J Korean Neurosurg Soc 52(6):558–560. CrossRefGoogle Scholar
  8. 8.
    Coluccia D, Fandino J, Fujioka M, Cordovi S, Muroi C, Landolt H (2010) Intraoperative 5-aminolevulinic-acid-induced fluorescence in meningiomas. Acta Neurochir 152(10):1711–1719. CrossRefGoogle Scholar
  9. 9.
    Millesi M, Kiesel B, Mischkulnig M, Martinez-Moreno M, Wohrer A, Wolfsberger S, Knosp E, Widhalm G (2016) Analysis of the surgical benefits of 5-ALA-induced fluorescence in intracranial meningiomas: experience in 204 meningiomas. J Neurosurg 125(6):1408–1419. CrossRefGoogle Scholar
  10. 10.
    Bradley RS, Thorniley MS (2006) A review of attenuation correction techniques for tissue fluorescence. J R Soc Interface 3(6):1–13. CrossRefGoogle Scholar
  11. 11.
    Valdes PA, Jacobs VL, Paulsen KD, Roberts DW, Leblond F (2011) In vivo fluorescence detection in surgery: a review of principles, methods, and applications. Curr Med Imaging Rev 8(3):211–232Google Scholar
  12. 12.
    Valdes PA, Leblond F, Kim A, Harris BT, Wilson BC, Fan X, Tosteson TD, Hartov A, Ji S, Erkmen K, Simmons NE, Paulsen KD, Roberts DW (2011) Quantitative fluorescence in intracranial tumor: implications for ALA-induced PpIX as an intraoperative biomarker. J Neurosurg 115(1):11–17. CrossRefGoogle Scholar
  13. 13.
    Hadjipanayis CG, Widhalm G, Stummer W (2015) What is the Surgical Benefit of Utilizing 5-Aminolevulinic Acid for Fluorescence-Guided Surgery of Malignant Gliomas? Neurosurgery 77(5):663–673. CrossRefGoogle Scholar
  14. 14.
    Pogue BW, Gibbs-Strauss S, Valdes PA, Samkoe K, Roberts DW, Paulsen KD (2010) Review of neurosurgical fluorescence imaging methodologies. IEEE J Sel Top Quantum Electron 16(3):493–505. CrossRefGoogle Scholar
  15. 15.
    Stummer W, Stepp H, Moller G, Ehrhardt A, Leonhard M, Reulen HJ (1998) Technical principles for protoporphyrin-IX-fluorescence guided microsurgical resection of malignant glioma tissue. Acta Neurochir 140(10):995–1000CrossRefGoogle Scholar
  16. 16.
    Stummer W, Novotny A, Stepp H, Goetz C, Bise K, Reulen HJ (2000) Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. J Neurosurg 93(6):1003–1013. CrossRefGoogle Scholar
  17. 17.
    Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ, Group AL-GS (2006) Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7(5):392–401. CrossRefGoogle Scholar
  18. 18.
    Stummer W, Reulen HJ, Novotny A, Stepp H, Tonn JC (2003) Fluorescence-guided resections of malignant gliomas—an overview. Acta Neurochir Suppl 88:9–12Google Scholar
  19. 19.
    Stummer W, Stocker S, Wagner S, Stepp H, Fritsch C, Goetz C, Goetz AE, Kiefmann R, Reulen HJ (1998) Intraoperative detection of malignant gliomas by 5-aminolevulinic acid-induced porphyrin fluorescence. Neurosurgery 42(3):518–525 (discussion 525–516)CrossRefGoogle Scholar
  20. 20.
    Roberts DW, Valdes PA, Harris BT, Fontaine KM, Hartov A, Fan X, Ji S, Lollis SS, Pogue BW, Leblond F, Tosteson TD, Wilson BC, Paulsen KD (2011) Coregistered fluorescence-enhanced tumor resection of malignant glioma: relationships between delta-aminolevulinic acid-induced protoporphyrin IX fluorescence, magnetic resonance imaging enhancement, and neuropathological parameters. Clinical article. J Neurosurg 114(3):595–603. CrossRefGoogle Scholar
  21. 21.
    Valdes PA, Angelo JP, Choi HS, Gioux S (2017) qF-SSOP: real-time optical property corrected fluroescence imaging. Biomed Opt Express 8(8):3597–3605. CrossRefGoogle Scholar
  22. 22.
    Valdes PA, Jacobs V, Harris BT, Wilson BC, Leblond F, Paulsen KD, Roberts DW (2015) Quantitative fluorescence using 5-aminolevulinic acid-induced protoporphyrin IX biomarker as a surgical adjunct in low-grade glioma surgery. J Neurosurg 123(3):771–780. CrossRefGoogle Scholar
  23. 23.
    Valdes PA, Roberts DW, Lu FK, Golby A (2016) Optical technologies for intraoperative neurosurgical guidance. Neurosurg Focus 40(3):E8. CrossRefGoogle Scholar
  24. 24.
    Valdes PA, Leblond F, Jacobs VL, Wilson BC, Paulsen KD, Roberts DW (2012) Quantitative, spectrally-resolved intraoperative fluorescence imaging. Sci Rep 2:798. CrossRefGoogle Scholar
  25. 25.
    Kim A, Khurana M, Moriyama Y, Wilson BC (2010) Quantification of in vivo fluorescence decoupled from the effects of tissue optical properties using fiber-optic spectroscopy measurements. J Biomed Opt 15(6):067006. CrossRefGoogle Scholar
  26. 26.
    Valdes PA, Kim A, Leblond F, Conde OM, Harris BT, Paulsen KD, Wilson BC, Roberts DW (2011) Combined fluorescence and reflectance spectroscopy for in vivo quantification of cancer biomarkers in low- and high-grade glioma surgery. J Biomed Opt 16(11):116007. CrossRefGoogle Scholar
  27. 27.
    Bravo JJ, Olson JD, Davis SC, Roberts DW, Paulsen KD, Kanick SC (2017) Hyperspectral data processing improves PpIX contrast during fluorescence guided surgery of human brain tumors. Sci Rep 7(1):9455. CrossRefGoogle Scholar
  28. 28.
    Morofuji Y, Matsuo T, Hayashi Y, Suyama K, Nagata I (2008) Usefulness of intraoperative photodynamic diagnosis using 5-aminolevulinic acid for meningiomas with cranial invasion: technical case report. Neurosurgery 62 (3 Suppl 1):102–103 (discussion 103–104). Google Scholar
  29. 29.
    Cornelius JF, Slotty PJ, Stoffels G, Galldiks N, Langen KJ, Steiger HJ (2013) 5-Aminolevulinic acid and (18)F-FET-PET as metabolic imaging tools for surgery of a recurrent skull base meningioma. J Neurol Surg Part B Skull Base 74(4):211–216. CrossRefGoogle Scholar
  30. 30.
    Scheichel F, Ungersboeck K, Kitzwoegerer M, Marhold F (2017) Fluorescence-guided resection of extracranial soft tissue tumour infiltration in atypical meningioma. Acta Neurochir 159(6):1027–1031. CrossRefGoogle Scholar
  31. 31.
    Wilbers E, Hargus G, Wolfer J, Stummer W (2014) Usefulness of 5-ALA (Gliolan(R))-derived PPX fluorescence for demonstrating the extent of infiltration in atypical meningiomas. Acta Neurochir 156(10):1853–1854. CrossRefGoogle Scholar
  32. 32.
    Cornelius JF, Slotty PJ, Kamp MA, Schneiderhan TM, Steiger HJ, El-Khatib M (2014) Impact of 5-aminolevulinic acid fluorescence-guided surgery on the extent of resection of meningiomas–with special regard to high-grade tumors. Photodiagn Photodyn Ther 11(4):481–490. CrossRefGoogle Scholar
  33. 33.
    Bekelis K, Valdés PA, Erkmen K, Leblond F, Kim A, Wilson BC, Harris BT, Paulsen KD, Roberts DW (2011) Quantitative and qualitative ALA-induced PpIX fluorescence in skull base meningiomas. Neurosurg FocusGoogle Scholar
  34. 34.
    Whitson WJ, Valdes PA, Harris BT, Paulsen KD, Roberts DW (2011) Confocal microscopy for the histological fluorescence pattern of a recurrent atypical meningioma: case report. Neurosurgery 68(6):E1768–E1772. (discussion E1772–E1763)CrossRefGoogle Scholar
  35. 35.
    Eljamel MS (2009) Which intracranial lesions would be suitable for 5-aminolevulenic acid-induced fluorescence-guided identification, localization, or resection? A prospective study of 114 consecutive intracranial lesions. Clin Neurosurg 56:93–97Google Scholar
  36. 36.
    Marbacher S, Klinger E, Schwyzer L, Fischer I, Nevzati E, Diepers M, Roelcke U, Fathi AR, Coluccia D, Fandino J (2014) Use of fluorescence to guide resection or biopsy of primary brain tumors and brain metastases. Neurosurg Focus 36(2):E10. CrossRefGoogle Scholar
  37. 37.
    Potapov AA, Goryaynov SA, Okhlopkov VA, Shishkina LV, Loschenov VB, Savelieva TA, Golbin DA, Chumakova AP, Goldberg MF, Varyukhina MD, Spallone A (2016) Laser biospectroscopy and 5-ALA fluorescence navigation as a helpful tool in the meningioma resection. Neurosurg Rev 39(3):437–447. CrossRefGoogle Scholar
  38. 38.
    Della Puppa A, Rustemi O, Gioffre G, Troncon I, Lombardi G, Rolma G, Sergi M, Munari M, Cecchin D, Gardiman MP, Scienza R (2014) Predictive value of intraoperative 5-aminolevulinic acid-induced fluorescence for detecting bone invasion in meningioma surgery. J Neurosurg 120(4):840–845. CrossRefGoogle Scholar
  39. 39.
    Borovich B, Doron Y (1986) Recurrence of intracranial meningiomas: the role played by regional multicentricity. J Neurosurg 64(1):58–63CrossRefGoogle Scholar
  40. 40.
    Muroi C, Fandino J, Coluccia D, Berkmann S, Fathi AR, Landolt H (2013) 5-Aminolevulinic acid fluorescence-guided surgery for spinal meningioma. World neurosurgery 80(1–2):223–e1. Google Scholar
  41. 41.
    Eicker SO, Floeth FW, Kamp M, Steiger HJ, Hanggi D (2013) The impact of fluorescence guidance on spinal intradural tumour surgery. European spine journal: official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical. Spine Res Soc 22(6):1394–1401. Google Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of NeurosurgeryHarvard Medical School/Brigham and Women’s HospitalBostonUSA
  2. 2.Department of NeurosurgeryMedical University of ViennaViennaAustria
  3. 3.Department of Neurosurgery, Dartmouth Hitchcock Medical Center1 Medical Center DriveLebanonUSA

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