Development and validation of a triple-LED surgical loupe device for fluorescence-guided resections with 5-ALA

Abstract

OBJECTIVE Fluorescence-guided resections performed using 5-aminolevulinic acid (5-ALA) have been studied extensively using the BLUE400 system. The authors introduce a triple–light-emitting diode (LED) headlight/loupe device for visualizing fluorescence, and compare this to the BLUE400 gold standard in order to assure similar and not more or less sensitive protoporphyrin-IX visualization. METHODS The authors defined the spectral requirements for a triple-LED headlight/loupe device for reproducing the xenon-based BLUE400 module. The system consisted of a white LED (normal surgery), a 409-nm LED for excitation, a 450-nm LED for background illumination, and appropriate observation filters. The prototype’s excitation and emission spectra, illumination and detection intensities, and spot homogeneity were determined. The authors further performed a prospectively randomized and blinded study for fluorescence assessments of fresh, marginal, fluorescing and nonfluorescing tumor samples comparing the LED/loupe device with BLUE400 in patients with malignant glioma treated with 20 mg/kg body weight 5-ALA. Tumor samples were immediately assessed in turn, both with a Kinevo and with a novel triple-LED/loupe device by different surgeons. RESULTS Seven triple-LED/loupe devices were analyzed. Illumination intensities in the 409- and 450-nm range were comparable to BLUE400, with high spot homogeneity. Fluorescence intensities measured distally to microscope oculars/loupes were 9.9-fold higher with the loupe device. For validation 26 patients with malignant gliomas with 240 biopsies were analyzed. With BLUE400 results as the reference, sensitivity for reproducing fluorescence findings was 100%, specificity was 95%, positive predictive value was 98%, negative predictive value was 100%, and accuracy was 95%. This study reached its primary aim, with agreement in 226 of 240 (94.2%, 95% CI 0.904–0.968). CONCLUSIONS The authors observed only minor differences regarding spectra and illumination intensities during evaluation. Fluorescence intensities available to surgeons were 9.9-fold higher with the loupe device. Importantly, the independent perception of fluorescence achieved using the new system and BLUE400 was statistically equivalent. The authors believe the triple-LED/loupe device to be a useful and safe option for surgeons who prefer loupes to the microscope for resections in appropriate patients.

The NXDC-MEN-301 Study on 5-ALA for Meningiomas Surgery: An Innovative Study Design for the Assessing the Benefit of Intra-Operative Fluorescence Imaging

“…Surgical microscopes adapted for detecting fluorescence are widely available (Zeiss Meditech Blue400, Leica FL400). The range of available devices has recently been expanded by a loupe-based system (DVI Reveal), which has been validated as achieving the same diagnostic performance as the established microscopes [ 15 ]. Given regulatory approval for 5-ALA by the European Medicines Agency in 2007, followed by FDA approval in 2017 [ 16 ], 5-ALA, which is marketed as Gliolan in the EU and Gleolan TM in the US, there has been considerable interest in extending FGR to other brain tumor types.…”

“…Widely used for fluorescence-guided resection of high-grade gliomas, 5-ALA is a well-characterized agent with low toxicity. Devices for visualizing fluorescence are similarly widely distributed, including neurosurgical microscopes adapted for fluorescence (e.g., Blue400, Zeiss Meditech, Oberkochen, Germany; FL400, Leica Microsystems, Heerbrugg, Switzerland) and a validated surgical loupe and illumination device [ 15 ]. Given past observations of specificity and sensitivity in meningiomas, 5-ALA appears to be an agent that qualifies for a larger-scale study in patients, not only for a prospective demonstration of diagnostic accuracy and safety, but also for providing an indication of clinical benefit.…”

5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy

“…New imaging devices are being developed and tested in clinical settings for easier and more sensitive visualization of PpIX fluorescence. As current glioma surgery is often performed with the aid of surgical loupes, a loupe device with three LED light sources has been developed for PpIX fluorescence-guided glioma resection [ 78 ]. This triple-LED loupe system includes a white LED for white light surgery, a 409-nm LED for PpIX excitation, a 450-nm LED for background illumination, magnifying lenses, and filters.…”

Comparison of minimal detectable protoporphyrin IX concentrations with a loupe device and conventional 5-ALA fluorescence microscopy: an experimental study

“…Intraoperative 5-ALA fluorescence is commonly visualized with assistance of a specifically modified neurosurgical microscope that is equipped with a certain module for fluorescence visualization 13 , 14 . This module typically consists of a xenon light source in conjunction with a 440 nm short-pass filter to provide violet-blue excitation light as well as a 440 nm long-pass filter added to the observer light path to selectively visualize the fluorescence signal 15 . Interestingly, some variance between illumination light intensities has been described even between different established microscope models 16 .…”

“…Recently, a specific loupe device consisting of a headlight and loupe spectacles tailored to facilitate intraoperative 5-ALA induced fluorescence visualization was successfully introduced to the neurosurgical field 15 . Instead of a filtered xenon light source typically utilized in the modified surgical microscope, this device relies on light-emitting diodes (LED) with wavelengths of 409 and 450 nm to provide excitation light 15 . First clinical observations demonstrated a successful implementation of this novel loupe device with a sufficient fluorescence signal 21 .…”