Intraoperative confocal laser endomicroscopy: prospective in vivo feasibility study of a clinical-grade system for brain tumors

Abstract

OBJECTIVE The authors evaluated the feasibility of using the first clinical-grade confocal laser endomicroscopy (CLE) system using fluorescein sodium for intraoperative in vivo imaging of brain tumors. METHODS A CLE system cleared by the FDA was used in 30 prospectively enrolled patients with 31 brain tumors (13 gliomas, 5 meningiomas, 6 other primary tumors, 3 metastases, and 4 reactive brain tissue). A neuropathologist classified CLE images as interpretable or noninterpretable. Images were compared with corresponding frozen and permanent histology sections, with image correlation to biopsy location using neuronavigation. The specificities and sensitivities of CLE images and frozen sections were calculated using permanent histological sections as the standard for comparison. A recently developed surgical telepathology software platform was used in 11 cases to provide real-time intraoperative consultation with a neuropathologist. RESULTS Overall, 10,713 CLE images from 335 regions of interest were acquired. The mean duration of the use of the CLE system was 7 minutes (range 3–18 minutes). Interpretable CLE images were obtained in all cases. The first interpretable image was acquired within a mean of 6 (SD 10) images and within the first 5 (SD 13) seconds of imaging; 4896 images (46%) were interpretable. Interpretable image acquisition was positively correlated with study progression, number of cases per surgeon, cumulative length of CLE time, and CLE time per case (p ≤ 0.01). The diagnostic accuracy, sensitivity, and specificity of CLE compared with frozen sections were 94%, 94%, and 100%, respectively, and the diagnostic accuracy, sensitivity, and specificity of CLE compared with permanent histological sections were 92%, 90%, and 94%, respectively. No difference was observed between lesion types for the time to first interpretable image (p = 0.35). Deeply located lesions were associated with a higher percentage of interpretable images than superficial lesions (p = 0.02). The study met the primary end points, confirming the safety and feasibility and acquisition of noninvasive digital biopsies in all cases. The study met the secondary end points for the duration of CLE use necessary to obtain interpretable images. A neuropathologist could interpret the CLE images in 29 (97%) of 30 cases. CONCLUSIONS The clinical-grade CLE system allows in vivo, intraoperative, high-resolution cellular visualization of tissue microstructure and identification of lesional tissue patterns in real time, without the need for tissue preparation.

Characterization of ex vivo and in vivo intraoperative neurosurgical confocal laser endomicroscopy imaging

“…Six patients from the ex vivo study received an additional FNa dose at some point during the surgery. Data on the diagnostic performance of in vivo and ex vivo CLE imaging were published previously ( 17 , 20 ) and are presented in Table 2 .…”

“…During the in vivo scanning process, movement between probe and tissue, imaging depth change, and scanning fiber disturbance introduce artifacts that make the images uninterpretable. Interestingly, in the in vivo study, deeply located digital biopsy spots were associated with a higher percentage of interpretable images than superficial ones, which may be attributed to more support of the probe and less range of scanning movement allowed when used on deeper spots ( 18 , 20 ).…”

“…Between August 2016 and May 2019, samples from 43 adult patients (≥ 18 years) undergoing FNa fluorescence-guided brain tumor surgery were imaged ex vivo with CLE ( ex vivo feasibility study) ( 17 ). Between May 2020 and July 2021, 30 adult patients (≥18 years) who had brain tumor surgery were imaged in vivo with CLE after FNa administration during the operation ( 18 , 20 ). Both studies were approved by the St. Joseph’s Hospital and Medical Center Institutional Review Board for Human Research (IRB No.…”

“…One patient received a one-time dose of 40 mg/kg of FNa at the induction of anesthesia ( 17 ). For the in vivo study, a 5-mg/kg dose of FNa was given intravenously approximately 5 minutes before the first images were acquired, and surgeons did not order to redose FNa ( 18 , 20 ).…”

“…A 515 to 577-nm bandpass filter was used, with the gain maintained at 2400. The resulting images were 1920 × 1080-pixel resolution, with a 267 × 475-μm field of view ( 18 , 20 ).…”