Intraoperative Fluorescence Imaging for Personalized Brain Tumor Resection: Current State and Future Directions

Abstract

Introduction: Fluorescence-guided surgery is one of the rapidly emerging methods of surgical "theranostics." In this review, we summarize current fluorescence techniques used in neurosurgical practice for brain tumor patients as well as future applications of recent laboratory and translational studies.

Methods: Review of the literature.

Results: A wide spectrum of fluorophores that have been tested for brain surgery is reviewed. Beginning with a fluorescein sodium application in 1948 by Moore, fluorescence-guided brain tumor surgery is either routinely applied in some centers or is under active study in clinical trials. Besides the trinity of commonly used drugs (fluorescein sodium, 5-aminolevulinic acid, and indocyanine green), less studied fluorescent stains, such as tetracyclines, cancer-selective alkylphosphocholine analogs, cresyl violet, acridine orange, and acriflavine, can be used for rapid tumor detection and pathological tissue examination. Other emerging agents, such as activity-based probes and targeted molecular probes that can provide biomolecular specificity for surgical visualization and treatment, are reviewed. Furthermore, we review available engineering and optical solutions for fluorescent surgical visualization. Instruments for fluorescent-guided surgery are divided into wide-field imaging systems and hand-held probes. Recent advancements in quantitative fluorescence-guided surgery are discussed.

Conclusion: We are standing on the threshold of the era of marker-assisted tumor management. Innovations in the fields of surgical optics, computer image analysis, and molecular bioengineering are advancing fluorescence-guided tumor resection paradigms, leading to cell-level approaches to visualization and resection of brain tumors.

Keywords: 5-ALA; ICG; confocal; endomicroscopy; fluorescein; fluorescence-guided surgery; fluorescent probe; glioma.

Figure 1

A schematic diagram of the light spectrum and corresponding wavelengths. Quantum efficiency of the human eye, standard CCD camera, and EMCCD camera are plotted together to show the differences in the covered wavelengths and the sensitivity to light. Light with shorter wavelengths has higher energy than light with longer wavelengths. Light wavelengths below 300 nm may burn eyes and skin. UV light of 264 nm is germicidal. Longer wavelengths (infrared) have greater tissue penetration properties. EMCCD, electron multiplying charge-coupled device; CCD, charge-coupled device. Used with permission from Barrow Neurological Institute, Phoenix, AZ, USA.

Figure 2

Schematic view of the concept of PpIX-guided tumor visualization using a wide-field operative microscope with appropriate filters. Wavelength scales are in the same position in the figure. The illumination device emits light in the wavelength band less than 470 nm. The excitation filter then transmits light with the peak of about 405 nm. PpIX, which is accumulated in the tumor cells, absorbs photons in the spectrum band around 405 nm and then emits photons of lower energy at a wavelength of about 630 nm. The blue light from the illumination device and the emitted red fluorescence band are observed through the operative microscope optics equipped with an emission (observation) filter. This filter has a cut-off transmittance at about 450 nm and cut-on transmittance at about 570 nm. The two bands of light observed fall into the visible spectrum (with the naked eye) and are perceived as a violet–blue background and “pink-to-red” fluorescence. The light in between those two bands is blocked; therefore green, yellow, and orange colors are not visible. PpIX, protoporphyrin IX. Used with permission from Barrow Neurological Institute, Phoenix, AZ, USA.

Figure 3

Schematic view of the concept of ICG fluorescence visualization using a wide-field surgical microscope with appropriate filters. Wavelength scales are in the same position in the figure. The illumination device (xenon lamp) emits light in a wide range of wavelengths. The excitation filter cuts off the light longer than about 750 nm. ICG present in the tissue (vessels) absorbs photons in the available spectrum band below 750 nm and then emits photons in a NIR spectrum around 820 nm, invisible to the naked eye. The emission filter then transmits this NIR light to the CCD camera and blocks the light with other wavelengths. The CCD camera records the images during the desired period. After image processing, the resultant surgical picture is displayed on the monitor of the neurosurgical microscope in the grayscale as a short movie fragment. ICG, indocyanine green. Used with permission from Barrow Neurological Institute, Phoenix, AZ, USA.

Figure 4

Schematic view of the concept of fluorescein-guided tumor visualization using a wide-field operative microscope with appropriate filters (https://www.google.ch/patents/US8730601). Wavelength scales are in the same position in the figure. The illumination device (xenon lamp) emits light in a broad range of wavelengths. The excitation filter then transmits the light as narrow bands at about 450–520 nm and about 600–750 nm. The first (blue–green) transmittance band is significantly more intense (see log scale on the side of the filters in the figure) than the second (red) band of light. Fluorescein, which is accumulated in the tumor tissue, absorbs photons in the spectrum band around 485 nm (high-intensity band) and then emits photons with a wavelength around 514 nm (yellow) with a lower energy (new low-intensity yellow band). Blue–green and red bands of light from the illumination device, as well as the new yellow (around 514 nm) fluorescence band, are observed through the operative microscope optics equipped with an emission (observation) filter. This emission filter has a transmittance in two bands: first in the range of 475–515 nm with significantly lower transmittance (see log scale in the figure) and the second in the range of 530–700 nm with the maximum transmittance. The three bands of light, the blue–green emission band, red band, and emitted yellow band, all fall into the naked-eye-visible spectrum for observation. The transmittance of all filters together results in the uniform intensity of all bands, with a higher possible intensity of emitted yellow light. A portion of the spectrum between the bands could be blocked by the filters, but the remaining three primary color bands allow the surgeon to see the intraoperative picture with almost the full spectrum of colors. Used with permission from Barrow Neurological Institute, Phoenix, AZ, USA.

Figure 5

Intraoperative use of a hand-held confocal endomicroscopy probe co-registered with a StealthStation neuronavigation system during brain tumor surgery. Used with permission from Barrow Neurological Institute, Phoenix, AZ, USA.

Figure 6

Intraoperative images of meningioma and glioma after intravenous fluorescein sodium injection taken with the confocal endomicroscopy probe and shown with corresponding histopathological pictures. Used with permission from Barrow Neurological Institute, Phoenix, AZ, USA.