Real-time intraoperative surgical telepathology using confocal laser endomicroscopy

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  • 1 The Loyal and Edith Davis Neurosurgical Research Laboratory, Department of Neurosurgery, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona; and
  • | 2 Departments of Neurosurgery and
  • | 3 Neuropathology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona
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OBJECTIVE

Communication between neurosurgeons and pathologists is mandatory for intraoperative decision-making and optimization of resection, especially for invasive masses. Handheld confocal laser endomicroscopy (CLE) technology provides in vivo intraoperative visualization of tissue histoarchitecture at cellular resolution. The authors evaluated the feasibility of using an innovative surgical telepathology software platform (TSP) to establish real-time, on-the-fly remote communication between the neurosurgeon using CLE and the pathologist.

METHODS

CLE and a TSP were integrated into the surgical workflow for 11 patients with brain masses (6 patients with gliomas, 3 with other primary tumors, 1 with metastasis, and 1 with reactive brain tissue). Neurosurgeons used CLE to generate video-flow images of the operative field that were displayed on monitors in the operating room. The pathologist simultaneously viewed video-flow CLE imaging using a digital tablet and communicated with the surgeon while physically located outside the operating room (1 pathologist was in another state, 4 were at home, and 6 were elsewhere in the hospital). Interpretations of the still CLE images and video-flow CLE imaging were compared with the findings on the corresponding frozen and permanent H&E histology sections.

RESULTS

Overall, 24 optical biopsies were acquired with mean ± SD 2 ± 1 optical biopsies per case. The mean duration of CLE system use was 1 ± 0.3 minutes/case and 0.25 ± 0.23 seconds/optical biopsy. The first image with identifiable histopathological features was acquired within 6 ± 0.1 seconds. Frozen sections were processed within 23 ± 2.8 minutes, which was significantly longer than CLE usage (p < 0.001). Video-flow CLE was used to correctly interpret tissue histoarchitecture in 96% of optical biopsies, which was substantially higher than the accuracy of using still CLE images (63%) (p = 0.005).

CONCLUSIONS

When CLE is employed in tandem with a TSP, neurosurgeons and pathologists can view and interpret CLE images remotely and in real time without the need to biopsy tissue. A TSP allowed neurosurgeons to receive real-time feedback on the optically interrogated tissue microstructure, thereby improving cross-functional communication and intraoperative decision-making and resulting in significant workflow advantages over the use of frozen section analysis.

ABBREVIATIONS

CLE = confocal laser endomicroscopy; FDA = US Food and Drug Administration; FNa = fluorescein sodium; OR = operating room; RBC = red blood cell; ROI = region of interest; SCU = site control unit; TSP = telepathology software platform.

OBJECTIVE

Communication between neurosurgeons and pathologists is mandatory for intraoperative decision-making and optimization of resection, especially for invasive masses. Handheld confocal laser endomicroscopy (CLE) technology provides in vivo intraoperative visualization of tissue histoarchitecture at cellular resolution. The authors evaluated the feasibility of using an innovative surgical telepathology software platform (TSP) to establish real-time, on-the-fly remote communication between the neurosurgeon using CLE and the pathologist.

METHODS

CLE and a TSP were integrated into the surgical workflow for 11 patients with brain masses (6 patients with gliomas, 3 with other primary tumors, 1 with metastasis, and 1 with reactive brain tissue). Neurosurgeons used CLE to generate video-flow images of the operative field that were displayed on monitors in the operating room. The pathologist simultaneously viewed video-flow CLE imaging using a digital tablet and communicated with the surgeon while physically located outside the operating room (1 pathologist was in another state, 4 were at home, and 6 were elsewhere in the hospital). Interpretations of the still CLE images and video-flow CLE imaging were compared with the findings on the corresponding frozen and permanent H&E histology sections.

RESULTS

Overall, 24 optical biopsies were acquired with mean ± SD 2 ± 1 optical biopsies per case. The mean duration of CLE system use was 1 ± 0.3 minutes/case and 0.25 ± 0.23 seconds/optical biopsy. The first image with identifiable histopathological features was acquired within 6 ± 0.1 seconds. Frozen sections were processed within 23 ± 2.8 minutes, which was significantly longer than CLE usage (p < 0.001). Video-flow CLE was used to correctly interpret tissue histoarchitecture in 96% of optical biopsies, which was substantially higher than the accuracy of using still CLE images (63%) (p = 0.005).

CONCLUSIONS

When CLE is employed in tandem with a TSP, neurosurgeons and pathologists can view and interpret CLE images remotely and in real time without the need to biopsy tissue. A TSP allowed neurosurgeons to receive real-time feedback on the optically interrogated tissue microstructure, thereby improving cross-functional communication and intraoperative decision-making and resulting in significant workflow advantages over the use of frozen section analysis.

Communication between neurosurgeons and pathologists is mandatory for intraoperative decision-making and optimization of patient care.1 Since its development, frozen section analysis of tumor biopsies has become standard practice by neurosurgeons to assess lesions intraoperatively. Yet this method is invasive, relying on physical extraction of tissue by the neurosurgeon. The process of frozen section preparation and diagnostic evaluation of these samples by a pathologist occurs outside of the operating room (OR), often requiring approximately 20–45 minutes and occasionally longer.2 Discrepancies during intraoperative consultation can also occur because of inaccurate or inadequate tissue biopsy, artifacts due to the frozen section preparation method, and sampling errors due to regional tumor heterogeneity.36

At present, telemedicine is chiefly used to overcome geographical barriers in healthcare.7,8 Telepathology involves the use of digital pathology systems to accelerate communication between surgeons and pathologists in order to make remote diagnoses outside the hospital setting; yet these communications are largely concerned with and depend on frozen sections. To overcome the limitations associated with frozen sections, we implemented telepathology using confocal laser endomicroscopy (CLE). CLE is a novel handheld endoscopic imaging modality that provides in vivo visualization of tissue at cellular resolution.911 CLE images are acquired with the intraoperative administration of a fluorophore that has been matched to the excitation energy of the emitting light source. CLE allows histopathological assessment in real time via optical biopsies obtained with a pen-sized imaging probe without the need to physically extract tissue samples. A fluorescein-based CLE system recently received US Food and Drug Administration (FDA) clearance for in vivo intraoperative use in human brain tumor surgery.12 This technology uses an innovative surgical telepathology software platform (TSP) that establishes real-time, remote, and secure web-based communication between the neurosurgeon using CLE and the pathologist. This combination of a TSP and CLE potentially enhances intraoperative communication and workflow between neurosurgeons and pathologists to improve surgical decision-making efficiency.

We have described and evaluated our experience integrating a TSP and CLE into the surgical workflow for virtual intraoperative consultation and discussion between the neurosurgeon and pathologist. We assessed differences in the durations of CLE application at certain stages and the diagnostic accuracy between standard histological section procedures and the surgical telepathology modality.

Methods

Study Design and Patient Population

Between May 2020 and June 2021, a prospective study was conducted at Barrow Neurological Institute at St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, to assess the tandem use of CLE imaging (CONVIVO, Carl Zeiss Meditec AG) and a TSP (ZEISS CONVIVO In Vivo Pathology Suite, Carl Zeiss Meditec) in patients undergoing brain tumor surgery. These patients constituted the last 11 of 30 patients who were enrolled in a study to assess the feasibility of the first FDA-cleared in vivo CLE system for neurosurgery when the TSP became available. This study was approved by the institutional review board of St. Joseph’s Hospital and Medical Center.

Adult patients with brain lesions requiring resection were enrolled in the current study after providing voluntary informed consent for treatment. Exclusion criteria were 1) a history of hypersensitivity to fluorescein sodium (FNa), 2) renal failure, 3) patient age < 18 years, 4) pregnancy or currently breastfeeding, and 5) inability to provide informed consent. A dose of 5 mg/kg FNa was administered intravenously within 5 minutes before CLE imaging. Optimal imaging parameters for CLE, FNa dose for optical biopsy acquisition, and the diagnostic accuracy of CLE were previously reported.13,14 The surgeons involved in the operations did not use a wide-field fluorescein-guided technique (e.g., FNa or 5-aminolevulinic acid) during tumor resection or CLE imaging. FNa injection was used for only tissue interrogation with CLE. The optical biopsy sites for CLE were selected on the basis of only the surgeon’s subjective judgment that the regions of interest (ROIs) were pathological under visualization with the operative microscope, without any additional fluorescence filters.

Tandem Integration of the TSP and CLE Into Surgical Workflow

As the neurosurgeon acquired the CLE images in the OR (i.e., the surgical workplace), the images were simultaneously transferred to a cloud-based platform (i.e., the pathology workplace) (Fig. 1). The consulting pathologist established a remote connection using the TSP between the pathology workplace and the OR; the CLE images were simultaneously displayed in both places as they were acquired. TSP functionality depends on a secure internet connection between the CLE at the surgical workplace, the pathology workplace, and the pathologist’s digital device. The site control unit (SCU) ensures secure data transmission and is the part of the TSP that is integrated into the hospital network only while the TSP is in use. The front-end connection involves transmitting the in vivo intraoperative images from the CLE station to the pathology workplace via the internet and SCU. The SCU maintains end-to-end data encryption and provides 2 network interfaces to separate the secured internal network from the external network with internet access. This setup ensures that the surgical workplace cannot connect to the external network or the internet. The back-end connection involves the mechanisms for authentication and authorization that allow the pathologist to access the pathology workplace. The SCU is not involved when the pathologist logs in to the pathology workplace and only engages between the surgical workplace and the internet or cloud. From the pathologist’s end, only regular internet access is needed to access the images on the display device.

FIG. 1.
FIG. 1.

Schematic illustration of frozen section processing (left) and the tandem utilization of CLE and the TSP (right). A standard clinical protocol for frozen section processing takes about 20 minutes and includes cryopreservation of tissue samples, sectioning, histological preparation, and evaluation by the pathologist. The tandem use of CLE and the TSP allows for the simultaneous, real-time intraoperative discussion of the tissue histoarchitecture between the surgical team and the pathologist who is physically located outside the OR. The TSP establishes a secure connection between the CLE station in the OR and the cloud-based pathology workplace via an internet connection and the SCU. The display device needs internet access to allow the pathologist to access the cloud-based pathology workplace, where the intraoperative CLE data are displayed. Used with permission from Barrow Neurological Institute, Phoenix, Arizona.

The neurosurgeons familiarized the pathologist with the patient’s medical history, cerebral location of the operation, and presumed lesion type at the beginning of the consultation. The neurosurgeon requested an intraoperative consultation with the neuropathologist via the TSP during exposure of the lesion. The neurosurgeon generated sequentially acquired CLE images within the operative field at a rate of 1.29 seconds/frame. Individual still images acquired in sequence mode were stored in the internal memory of the CLE device, processed within seconds into a video flow, and displayed on monitors in the OR. The CLE probe was coregistered with an intraoperative neuronavigation system to visualize and document the optical biopsy location. The pathologist was experienced with CLE technology and used a digital tablet to view the video-flow CLE images while simultaneously conversing with the surgical team in the OR. For these real-time consultations, the pathologist was physically located outside the OR (in another state [1 case], at home [4 cases], or in the hospital pathology department [6 cases]). As the surgical team acquired multiple optical biopsies of the ROIs, the pathologist and neurosurgeon simultaneously viewed the tissue histoarchitecture on the video-flow CLE images. The pathologist commented on and interpreted the histoarchitecture. Nonetheless, because this study was a pilot study, no intraoperative clinical decisions were made on the basis of the findings identified with this technology.

CLE Data Analysis and Interpretation

The assessed variables included the number of optical biopsies per patient, duration of CLE usage per optical biopsy and per patient, and time required to acquire the first image with identifiable histopathological features after CLE initiation. In addition, the time required for frozen section processing was analyzed per case and was defined from the time when the tissue samples were harvested in the OR to the conclusion of the frozen section evaluation by the pathologist (which required 5 minutes). The durations of CLE use and frozen section processing were compared.

The pathologist’s interpretations of the optical biopsies were based on identifiable histopathological features on video-flow CLE imaging. These features were categorized into 3 types: 1) presence of abundant cellular atypia or necrosis indicative of lesional tissue; 2) presence of hypocellular regions, debris, macrophages, and other reactive cells indicative of nonlesional or treatment-related changes; and 3) optical biopsies with substantial motion or red blood cell (RBC) artifacts and without any identifiable histopathological features, which were graded as noninterpretable. At the close of the clinical trial 6 months later, all optical biopsies composed of still CLE images were evaluated by the pathologist.

Diagnostic Concordance Between the Optical and Tissue Biopsy Interpretations

For each ROI where optical biopsies were acquired, a tissue sample was also harvested with careful consideration for safety. Samples were processed using frozen and permanent methods, and both were stained with H&E and evaluated.

We performed separate concordance analyses to compare gold-standard frozen histology section analysis with optical biopsy based on still CLE images and video-flow CLE imaging. In 4 cases, the surgeon deemed tissue biopsy for a frozen section analysis as unnecessary; thus, the findings of the permanent H&E histology report were used in the analysis. Total concordance was defined as the identification of similar histopathological features indicative of a specific tissue type (atypical cells, reactive brain tissue, etc.) with both CLE and frozen or permanent histology sections. Partial concordance was characterized by findings on optical biopsy regarded as suggestive of histopathological features that were similar to those observed on the frozen or permanent sections. However, the presence of substantial artifacts (RBCs or motion) made interpretation of optical biopsy uncertain. Discordance was described as a lack of identifying histopathological features on optical biopsies due to artifact distortion created by motion or RBCs or as an interpretation completely different from that of the frozen or permanent section.

Statistical Analysis

Statistical analysis was performed using GraphPad Prism 9 (GraphPad Software, Inc.). Continuous variables are presented as mean ± SD. Categorical variables are described as count (percent). Durations of CLE use and frozen section processing were compared with the Mann-Whitney U-test. The chi-square test was used to compare diagnostic concordance between the interpretations of the optical biopsies based on still CLE images and those of frozen or permanent histology sections, as well as concordance between the interpretations of video-flow CLE imaging and those of frozen or permanent histology sections. CLE biopsies interpreted as partially concordant were included in the discordant group for these comparisons. A p value ≤ 0.05 was considered significant.

Results

Descriptive Analysis

Eleven patients with brain lesions—7 women (64%) and 4 men (36%)—underwent resection with integrated tandem use of CLE imaging and the TSP. The final histopathological diagnosis was consistent with 4 high-grade gliomas, 3 tissue treatment effects, and 4 other tumors (Table 1). No patient experienced any complications associated with CLE usage or FNa-related adverse effects.

TABLE 1.

Demographic data and general characteristics of 11 patients who underwent CLE with the TSP

Case No.Final DiagnosisSexAge (yrs)FNa Dose (mg)Optical Biopsies (no.)
1Breast adenocarcinoma metastasisF833503
2Anaplastic astrocytomaF413501
3HemangioblastomaF383701
4Choroid plexus papillomaM793502
5Mature teratomaF345003
6GlioblastomaM645003
7Treatment effectF423302
8Treatment effectM553001
9GlioblastomaF445002
10Treatment effectM684004
11Anaplastic astrocytomaM495002
Overall, 24 optical biopsies were acquired, with a mean of 2 ± 1 biopsies per case (Videos 1 and 2).

VIDEO 1. Recreated video-flow CLE images of the optical biopsies from cases 1–6 (only 1 of 3 optical biopsies is shown for case 6) that were acquired and discussed intraoperatively by the neurosurgeons and pathologist via tandem use of TSP and CLE. Currently, video-flow CLE images are not stored in the cloud and cannot be revised retrospectively during surgery if needed. Nonetheless, video-flow images can be easily reconstructed within minutes by using third-party software. Only digital images generated by CLE can be stored and reviewed on the CLE station after acquisition. In case 1, all 3 optical biopsies were discerned by the neuropathologist as lesional with atypical histoarchitecture, with the first 2 interpreted as suggestive of metastatic tumor cells. In case 2, optical biopsy of lesional tissue with atypical histoarchitecture was considered highly suggestive of high-grade glioma. In case 3, optical biopsy of lesional tissue with atypical histoarchitecture is shown. In case 4, the neuropathologist determined that the optical biopsies showed lesional tissue with atypical histoarchitecture packed with tumor cells. In case 5, optical biopsy of lesional tissue with atypical histoarchitecture is shown. In case 6, the optical biopsy shows lesional tissue with atypical histoarchitecture packed with tumor cells that are highly suggestive of high-grade glioma. Yellow areas show atypical lesional histoarchitecture, and arrows point to tumor cells. Used with permission from Barrow Neurological Institute, Phoenix, Arizona. Click here to view.

VIDEO 2. Recreated video-flow CLE images of the optical biopsies for cases 6–11 (including the second and third optical biopsies of case 6) that were acquired and discussed intraoperatively by the neurosurgeons and pathologist via tandem use of the TSP and CLE. In case 6, the optical biopsy shows lesional tissue with atypical histoarchitecture packed with tumor cells highly suggestive of high-grade glioma. In case 7, the neuropathologist saw both optical biopsies as nonlesional with hypocellular histoarchitecture consistent with treatment-related changes. In case 8, optical biopsy of nonlesional tissue with hypocellular histoarchitecture consistent with treatment-related changes is shown. In case 9, the first optical biopsy was interpreted as nonlesional tissue with hypocellular histoarchitecture consistent with treatment-related changes; the second was interpreted as lesional tissue with atypical cellular histoarchitecture because of the predominance of tumor cells mixed with treatment-related changes. In case 10, all 4 optical biopsies were discerned by the neuropathologist as nonlesional with hypocellular histoarchitecture consistent with treatment-related changes. In case 11, the first optical biopsy shows lesional tissue with atypical histoarchitecture; the second shows lesional tissue with atypical histoarchitecture packed with tumor cells highly suggestive of high-grade glioma. Yellow areas show atypical lesional histoarchitecture, green areas indicate nonlesional hypocellular histoarchitecture, and arrows point to tumor cells. Used with permission from Barrow Neurological Institute, Phoenix, Arizona. Click here to view.

Figure 2 shows the durations of optical biopsy acquisition and frozen section processing. The mean duration of CLE system use under pathologist guidance was 1 ± 0.3 minutes/case and 0.25 ± 0.23 seconds/optical biopsy. The first image with identifiable histopathological features was acquired within 6 ± 0.1 seconds. Frozen sections were processed within 23 ± 2.8 minutes, which was significantly longer than the time for CLE usage (1 ± 0.3 minutes) (p < 0.001).

FIG. 2.
FIG. 2.

Scatterplot showing durations of acquisition of the optical biopsy with CLE and frozen section processing per case. On average, acquisition of the optical biopsy with CLE did not exceed 1 minute/case. The dashed line represents the 1-minute cutoff.

Interpretation of CLE Optical Biopsies

Of 24 optical biopsy interpretations based on video-flow CLE imaging, 16 (67%) were identified as lesional with histoarchitectural characteristics suggestive of a specific tumor type identified in 9 biopsies, whereas 8 (33%) were identified as nonlesional (Table 2). Of the optical biopsy interpretations based on still CLE images, 7 (29%) were identified as lesional (with 4 considered suggestive of a specific tumor type), 5 (21%) as presumably lesional, 8 (33%) as nonlesional, and 4 (17%) as uninterpretable.

TABLE 2.

Comparison of interpretations of optical biopsies and frozen or permanent sections

Case No.Optical Biopsies (no.)InterpretationStill CLE vs Frozen/Permanent H&EVideo-Flow CLE vs Frozen/Permanent H&EIntraop Decision*
Still CLEVideo-Flow CLEFrozen/ Permanent H&E
11Lesional; atypical tumor cells w/ foamy cytoplasmLesional; atypical tumor cells w/ foamy cytoplasmBreast adenocarcinoma metastasis w/ sheets of atypical tumor cells w/ mucin++Resection or biopsy
2Lesional; atypical tumor cells w/ foamy cytoplasmLesional; atypical tumor cells w/ foamy cytoplasm++Resection or biopsy
3Presumably lesional; RBCs w/ possible tumor cellsLesional; atypical tumor cells±+Resection or biopsy
21Presumably lesional; RBCs w/ possible tumor cellsLesional; atypical tumor cellsAnaplastic astrocytoma; infiltrative tumor cells w/ piloid features±+Resection or biopsy
31Presumably lesional; RBCs w/ possible tumor cellsLesional; atypical tumor cellsHemangioblastoma; proliferation of atypical vacuolated cells±+Resection or biopsy
41Uninterpretable; RBCs & motion artifactsLesional; atypical tumor cellsChoroid plexus papilloma; atypical cells w/ epithelial features arranged in a papillary architecture+Resection or biopsy
2Uninterpretable; RBCs & motion artifactsLesional; atypical tumor cells+Resection or biopsy
51Lesional; abnormal tissue w/ refractile materialLesional; atypical tumor cellsCystic teratoma; fragments of bone, fat, & hair admixed++Resection or biopsy
2Lesional; abnormal tissue w/ refractile materialLesional; atypical tumor cells++Resection or biopsy
3Lesional; abnormal tissue w/ refractile materialLesional; atypical tumor cells++Resection or biopsy
61Presumably lesional; suggestive of atypical cells w/ abundant RBCsLesional; atypical features consistent w/ tumorGlioblastoma; astrocytic tumor w/ highly pleomorphic cells & multinucleation±+Resection or biopsy
2Lesional; cellular tumor w/ edematous axonsLesional; atypical features consistent w/ tumor‡++Resection or biopsy
3Uninterpretable; RBCs, motion artifacts, & characteristics not definite for cellular tumorLesional; atypical features consistent w/ tumor+Resection or biopsy
71Nonlesional; hypocellular debrisNonlesional; hypocellular debrisAbundant necrosis, consistent w/ treatment-related changes++No resection or biopsy
2Nonlesional; hypocellular debrisNonlesional; hypocellular debris++No resection or biopsy
81Nonlesional; degenerating cellsNonlesional; degenerating cellsExtensive treatment-related changes; degenerating cells++No resection or biopsy
91Nonlesional; gliosisNonlesional; extensive gliosisExtensive treatment-related changes; degenerating cells++No resection or biopsy
2Presumably lesionalLesional; atypical cellsResection or biopsy
101Nonlesional; hypocellular debrisNonlesional; necrotic neuroglial tissueTreatment effect; largely necrotic material w/ reactive brain parenchyma++No resection or biopsy
2Nonlesional; hypocellular debrisNonlesional; necrotic neuroglial tissue++No resection or biopsy
3Nonlesional; hypocellular debrisNonlesional; necrotic neuroglial tissue++No resection or biopsy
4Nonlesional; hypocellular debrisNonlesional; hypocellular debris++No resection or biopsy
111Uninterpretable; RBC & motion artifactsLesional; atypical cellsAnaplastic astrocytoma; glioma w/ proliferation of cells bearing eccentrically located nuclei & abundant weakly eosinophilic cytoplasm+Resection or biopsy
2Lesional; atypical cells w/ cytoplasmic vacuolizationLesional; atypical cells w/ cytoplasmic vacuolization++Resection or biopsy

+ = total diagnostic concordance; ± = partial diagnostic concordance; − = diagnostic discordance.

The intraoperative decision was not based on the interpretation of CLE video-flow imaging.

Suggestive of metastasis.

Suggestive of high-grade glioma.

Diagnostic Concordance

Various histopathologic features seen on the optical biopsies and corresponding frozen or permanent H&E sections are shown in Fig. 3. Comparison of video-flow CLE imaging to H&E sections revealed total concordance in 23 of 24 optical biopsies (96%), whereas discordance was found in 1 optical biopsy (4%) (Table 2, Fig. 4). When still CLE images of the same optical biopsies were compared to frozen or permanent sections, total concordance was found in 15 of 24 optical biopsies (63%), partial concordance in 4 (16%), and discordance in 5 (21%). Video-flow CLE imaging interpreted tissue histoarchitecture correctly in 96% of optical biopsies, which was significantly higher than the interpretation accuracy of still CLE images (63%) (p = 0.005).

FIG. 3.
FIG. 3.

This feasibility study explored the identification of tumor types that are ideal candidates for tissue histoarchitecture visualization with CLE. Hence, conclusions regarding the optimal tumor features for CLE imaging must be drawn after feasibility studies have been performed that include other tumor types. Other tumors must be included to evaluate the efficacy and advantages of CLE with the TSP. Histological features identified with optical biopsies (left) and the corresponding H&E–stained histological tissue samples (right) are shown. A: Cellular tumor showing scattered atypical cells with foamy cytoplasm (dashed outline) that corresponds to metastasis of breast adenocarcinoma. Bar = 60 μm. B: Infiltrative cellular tumor of the cerebellum (dashed outline) that is consistent with anaplastic astrocytoma. The arrowhead indicates a blood vessel with RBCs inside. Bar = 100 μm. C: An extensively hemorrhagic tumor with atypical cells corresponding to hemangioblastoma. Bar = 100 μm. This patient with hemangioblastoma had a history of renal cell carcinoma and a second lesion in the cerebellum in the setting of von Hippel–Lindau disease; thus, the application of the CLE-TSP system was of clinical interest. D: Necrotic neuroglial tissue and isolated tumor cells (arrowheads) consistent with a treatment effect are shown. Bar = 100 μm. E: High-grade astrocytic tumor with highly pleomorphic cells with multinucleation indicative of glioblastoma. Bar = 100 μm. F: Atypical tumor cells with abundant eosinophilic cytoplasm and nuclei on the periphery (arrowheads) indicative of anaplastic astrocytoma. Bar = 100 μm.

FIG. 4.
FIG. 4.

Diagnostic concordance between video-flow CLE imaging and still CLE image interpretation and frozen or permanent histological analysis.

Discussion

William Mayo and his chief of pathology, Louis B. Wilson, first published their frozen section technique used to hasten the time required for intraoperative diagnoses.1517 Wilson’s technique in 1905 simply used methylene blue to stain frozen tissue specimens and rapidly return a diagnostic interpretation to the OR.18 At present, telemedicine has been implemented across many medical and surgical specialties to improve the efficacy of diagnosis and patient care.19 Recent studies that investigated neurosurgery-specific telemedicine applications focused on the implementation of telemedicine for transfer triage and follow-up patient care after elective neurosurgical procedures.2024

Although telemedicine is conventionally used for patient-doctor communication, it was also used as early as 1993 for communication between doctors, particularly for imaging consultations in neurosurgical care.25 A 1997 report by Gray et al. describes a telemedicine network that allowed the rapid transmission of radiology images so that the neurosurgeon and referring doctor could view them while simultaneously talking over the telephone.25 Current advances in technology such as the TSP promote a similar paradigm for communication between a pathologist and a neurosurgeon in the OR that aids in rapid intraoperative decision-making. Because optical biopsies produced with CLE are digital, they can be successfully transmitted across interconnected devices via the internet. CLE is well suited for integration with a TSP, producing a fully digital communication system.

Integration of a TSP into the workflow allowed pathologists to establish their real-time virtual presence in the OR. The TSP showed feasibility to assist neurosurgeons who are using CLE and providing a consultative service for tissue discrimination at the cellular level. The pathologist in our study was informed of the date and time of the surgery and received a notification from the OR shortly before CLE imaging started. Coordination with the OR and a secure internet connection allow the pathologist to view the CLE optical biopsies remotely with a personal computer, tablet, or smart handheld device. Therefore, a TSP is not bound by limitations in geographical location, allowing flexibility in consultation and accommodating urgent cases when the pathologist is not available on-site.

TSP for Intraoperative Decisions

Powsner et al. found an overall discordance rate of 30% between surgeons’ interpretations of pathology reports and pathologists’ intended meanings.26 Tandem application of CLE and the TSP establishes closer cooperation between neurosurgeons and pathologists for rapid, optimal intraoperative interpretation of optical biopsies. The two neurosurgeons interviewed about their experiences with the TSP rated the technology highly (5 points on a 1- to 5-point scale). The TSP was considered very useful as a convenient way to receive an experienced pathologist’s intraoperative consultation on tissue histoarchitecture. When questioned about the ease of following the pathologist’s guidance, both surgeons were satisfied with the quality of communication (4 points on a 1- to 5-point scale). Optical biopsy acquisition for a specific ROI occurred within about 1 minute; the mean ± SD time to the first image with interpretable histopathological features was 6 ± 0.1 seconds. CLE technology is under investigation for its effect on workflow efficiency in the OR and direct communication between the surgeon and pathologist.

In its current stage of development, CLE is not regarded as a substitute for the frozen section procedure. Although CLE has obvious applications for the treatment of invasive primary brain tumors, this feasibility study explored the identification of tumor types that are ideal candidates for tissue histoarchitecture visualization with CLE. The diversity of cases in this study is the result of our deliberate inclusion in order to understand the usability of CLE and the TSP for the identification of different tumor types. Thus, CLE and the TSP were applied in various scenarios where a typical frozen section may not have been acquired.

However, CLE has revealed characteristics of cellular architecture that are not visualized at the resolution of an operating microscope. Neurosurgeons use CLE to visualize live histoarchitecture in real time, whereas pathologists use the TSP to assist and guide them in tissue interrogation and identification of optimal tissue-harvesting sites, thereby obtaining a more accurate diagnosis. Lesions that are visually unremarkable or near eloquent areas may require multiple tissue biopsies to establish the intraoperative diagnosis and decrease sampling error. In such cases, the TSP is beneficial because it allows pathologists to be virtually present in the OR, evaluate histoarchitectural features, and request additional locations for optical biopsies if needed. Additionally, the TSP may be particularly beneficial for guiding intraoperative navigation at the demarcation zone of a lesion. CLE and the TSP could increase the yield of positive findings on frozen histological section analysis, with less time needed to acquire sections and less tissue transgressed by exploration.

Diagnostic Accuracy

The diagnostic accuracy of CLE has been investigated in preclinical and clinical settings.2730 The sensitivity of using still CLE imaging to interpret brain tumors has varied from 71% to 91%. Although still CLE images convey information on various histoarchitectural tissue characteristics, their interpretation by the pathologist is limited by the retrospective nature of the evaluation. An abundance of RBCs often obscures cellular discrimination and may lower diagnostic accuracy. In our experience, video-flow CLE imaging for optical biopsy results in higher diagnostic accuracy (96%) than interpretation of still CLE images, thus providing a significant advantage over evaluation of still CLE images. Although CLE was not designed for the diagnostic assessment of tissue, the pathologist discerned the exact tumor type in 9 patients with the current generation of video-flow CLE imaging. A possible explanation for this result is that video-flow imaging enhances the perception of tissue histoarchitecture. For instance, the pathologist can differentiate RBC artifacts from tumor cells because RBCs are in motion and can be washed away from the field while the tumor cells remain. Additionally, structures such as vessels can be identified to show blood flow within them. Discordant diagnosis between video-flow CLE imaging and H&E analysis was noted for 1 (4%) optical biopsy. In this case of recurrent glioblastoma, the optical biopsy was conclusive of high-grade glioma, whereas the frozen section showed signs of extensive treatment effect. The explanation for this discrepancy could be associated with the small scanning field of CLE, which may have scanned a different region of tissue than was harvested.

Limitations

The small sample size could have affected the reliability of diagnostic accuracy and led to bias. The inclusion of additional cases would increase the power of future studies. Because of the small scanning field of the CLE probe, we acknowledge the possibility of tissue sampling errors that may have affected the correlation between CLE imaging and H&E histology sections. Motion artifacts can further exacerbate the difficulty in discerning the histoarchitecture of lesions. This limitation is predominantly associated with superficially located lesions and may be overcome by attaching the CLE probe to a stationary support.

Because the fluorescein signal used for CLE depends on extravasation via blood-brain barrier permeability, there are varying degrees of applicability and usefulness of CLE that depend on the histopathological tumor type. Neurosurgeons and pathologists new to CLE technology must overcome the learning curves for probe use and image interpretation. In this study, the surgeons were trained for CLE employment and experienced with the intraoperative use of the CLE imaging system. The neuropathologist was similarly trained and experienced in CLE imaging interpretation. Given the learning curve, a limitation of the CLE-TSP system is the technical training and experience required for optimal use, imaging interpretation, and accuracy. Despite these limitations, this study was the first to quantitatively analyze the combined intraoperative application of the TSP and CLE and to indicate the feasibility of this integrated diagnostic imaging process.

Conclusions

When employed in tandem with the TSP, neurosurgeons and pathologists can confer remotely and simultaneously view and interpret CLE images in real time without the need for physically biopsied tissue. At the same time, the system can increase the accuracy of tissue harvesting. The TSP allows neurosurgeons to receive real-time feedback about optically interrogated tissue microstructure that improves cross-functional communication and intraoperative decision-making, thereby delivering significant workflow advantages over frozen section processing. Future development of the CLE-TSP technology should expand its functionality and potential for broader applications in neurosurgery.

Acknowledgments

We thank the staff of Neuroscience Publications at Barrow Neurological Institute for assistance with manuscript preparation.

Disclosures

This study was funded in part by funds from the Newsome Chair in Neurosurgery Research held by Dr. Preul and by the Barrow Neurological Foundation. The technology system reported in this study was provided by Carl Zeiss Meditec AG. Carl Zeiss Meditec provided funds to offset administrative study costs but was not involved in patient recruitment, performance of the study, data analysis, or the conclusions reached in this report. Dr. Lawton is a consultant for Carl Zeiss Meditec. Dr. Lawton and Carl Zeiss Meditec were not involved in the data analysis or conclusions reached in this report. Dr. Smith owns stock in Gammatile; receives royalties from OsteoMed; and received clinical or research support for the described study from Medtronic.

Author Contributions

Conception and design: Preul, Abramov. Acquisition of data: Abramov, Park, Gooldy, Xu, Lawton, Little, Porter, Smith, Eschbacher. Analysis and interpretation of data: Preul, Abramov, Park, Eschbacher. Drafting the article: Preul, Abramov. Critically revising the article: Preul, Abramov, Eschbacher. Reviewed submitted version of manuscript: Preul. Statistical analysis: Abramov, Xu. Study supervision: Preul.

Supplemental Information

Previous Presentations

This paper was presented at the 90th Annual Scientific Meeting of the American Association of Neurological Surgeons, Philadelphia, PA, April 29 to May 2, 2022.

References

  • 1

    Wright JR Jr. The development of the frozen section technique, the evolution of surgical biopsy, and the origins of surgical pathology. Bull Hist Med. 1985;59(3):295326.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Novis DA, Zarbo RJ. Interinstitutional comparison of frozen section turnaround time. A College of American Pathologists Q-Probes study of 32868 frozen sections in 700 hospitals. Arch Pathol Lab Med. 1997;121(6):559567.

    • Search Google Scholar
    • Export Citation
  • 3

    Plesec TP, Prayson RA. Frozen section discrepancy in the evaluation of central nervous system tumors. Arch Pathol Lab Med. 2007;131(10):15321540.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4

    Plesec TP, Prayson RA. Frozen section discrepancy in the evaluation of nonneoplastic central nervous system samples. Ann Diagn Pathol. 2009;13(6):359366.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Chatterjee S. Artefacts in histopathology. J Oral Maxillofac Pathol. 2014;18(1)(suppl 1):S111S116.

  • 6

    Friedmann-Morvinski D. Glioblastoma heterogeneity and cancer cell plasticity. Crit Rev Oncog. 2014;19(5):327336.

  • 7

    Snyder SR. Editorial. Telemedicine for elective neurosurgical routine follow-up care: a promising patient-centered and cost-effective alternative to in-person clinic visits. Neurosurg Focus. 2018;44(5):E18.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    James HE. Pediatric neurosurgery telemedicine clinics: a model to provide care to geographically underserved areas of the United States and its territories. J Neurosurg Pediatr. 2016;25(6):753757.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Sankar T, Delaney PM, Ryan RW, et al. Miniaturized handheld confocal microscopy for neurosurgery: results in an experimental glioblastoma model. Neurosurgery. 2010;66(2):410418.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Sanai N, Eschbacher J, Hattendorf G, et al. Intraoperative confocal microscopy for brain tumors: a feasibility analysis in humans. Neurosurgery. 2011;68(2 Suppl Operative):282290.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Eschbacher J, Martirosyan NL, Nakaji P, et al. In vivo intraoperative confocal microscopy for real-time histopathological imaging of brain tumors. J Neurosurg. 2012;116(4):854860.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    US Food & Drug Administration. K181116. October 25, 2018. Accessed April 6, 2022. https://www.accessdata.fda.gov/cdrh_docs/pdf18/K181116.pdf

    • Search Google Scholar
    • Export Citation
  • 13

    Belykh E, Miller EJ, Carotenuto A, et al. Progress in confocal laser endomicroscopy for neurosurgery and technical nuances for brain tumor imaging with fluorescein. Front Oncol. 2019;9 554.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Abramov I, Dru AB, Belykh E, Park MT, Bardonova L, Preul MC. Redosing of fluorescein sodium improves image interpretation during intraoperative ex vivo confocal laser endomicroscopy of brain tumors. Front Oncol. 2021;11 668661.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Gal AA. The centennial anniversary of the frozen section technique at the Mayo Clinic. Arch Pathol Lab Med. 2005;129(12):15321535.

  • 16

    Wilson LB. A method for the rapid preparation of fresh tissues for the microscope. J Am Med Assoc. 1905;XLV(23):17371737.

  • 17

    Lechago J. The frozen section: pathology in the trenches. Arch Pathol Lab Med. 2005;129(12):15291531.

  • 18

    Gal AA, Cagle PT. The 100-year anniversary of the description of the frozen section procedure. JAMA. 2005;294(24):31353137.

  • 19

    Ryu WHA, Kerolus MG, Traynelis VC. Clinicians’ user experience of telemedicine in neurosurgery during COVID-19. World Neurosurg. 2021;146(e359):e367.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Klein Y, Donchik V, Jaffe D, et al. Management of patients with traumatic intracranial injury in hospitals without neurosurgical service. J Trauma. 2010;69(3):544548.

    • Search Google Scholar
    • Export Citation
  • 21

    Wong HT, Poon WS, Jacobs P, et al. The comparative impact of video consultation on emergency neurosurgical referrals. Neurosurgery. 2006;59(3):607613.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Reider-Demer M, Raja P, Martin N, Schwinger M, Babayan D. Prospective and retrospective study of videoconference telemedicine follow-up after elective neurosurgery: results of a pilot program. Neurosurg Rev. 2018;41(2):497501.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    Dadlani R, Mani S, A U JG, et al. The impact of telemedicine in the postoperative care of the neurosurgery patient in an outpatient clinic: a unique perspective of this valuable resource in the developing world—an experience of more than 3000 teleconsultations. World Neurosurg. 2014;82(3-4):270283.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24

    Thakar S, Rajagopal N, Mani S, et al. Comparison of telemedicine with in-person care for follow-up after elective neurosurgery: results of a cost-effectiveness analysis of 1200 patients using patient-perceived utility scores. Neurosurg Focus. 2018;44(5):E17.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Gray W, O’Brien D, Taleb F, Marks C, Buckley T. Benefits and pitfalls of telemedicine in neurosurgery. J Telemed Telecare. 1997;3(2):108110.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    Powsner SM, Costa J, Homer RJ. Clinicians are from Mars and pathologists are from Venus. Arch Pathol Lab Med. 2000;124(7):10401046.

  • 27

    Acerbi F, Pollo B, De Laurentis C, et al. Ex vivo fluorescein-assisted confocal laser endomicroscopy (CONVIVO® System) in patients with glioblastoma: results from a prospective study. Front Oncol. 2020;10 606574.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Belykh E, Zhao X, Ngo B, et al. Intraoperative confocal laser endomicroscopy ex vivo examination of tissue microstructure during fluorescence-guided brain tumor surgery. Front Oncol. 2020;10 599250.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Höhne J, Schebesch KM, Zoubaa S, Proescholdt M, Riemenschneider MJ, Schmidt NO. Intraoperative imaging of brain tumors with fluorescein: confocal laser endomicroscopy in neurosurgery. Clinical and user experience. Neurosurg Focus. 2021;50(1):E19.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30

    Martirosyan NL, Eschbacher JM, Kalani MY, et al. Prospective evaluation of the utility of intraoperative confocal laser endomicroscopy in patients with brain neoplasms using fluorescein sodium: experience with 74 cases. Neurosurg Focus. 2016;40(3):E11.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • View in gallery

    Schematic illustration of frozen section processing (left) and the tandem utilization of CLE and the TSP (right). A standard clinical protocol for frozen section processing takes about 20 minutes and includes cryopreservation of tissue samples, sectioning, histological preparation, and evaluation by the pathologist. The tandem use of CLE and the TSP allows for the simultaneous, real-time intraoperative discussion of the tissue histoarchitecture between the surgical team and the pathologist who is physically located outside the OR. The TSP establishes a secure connection between the CLE station in the OR and the cloud-based pathology workplace via an internet connection and the SCU. The display device needs internet access to allow the pathologist to access the cloud-based pathology workplace, where the intraoperative CLE data are displayed. Used with permission from Barrow Neurological Institute, Phoenix, Arizona.

  • View in gallery

    Scatterplot showing durations of acquisition of the optical biopsy with CLE and frozen section processing per case. On average, acquisition of the optical biopsy with CLE did not exceed 1 minute/case. The dashed line represents the 1-minute cutoff.

  • View in gallery

    This feasibility study explored the identification of tumor types that are ideal candidates for tissue histoarchitecture visualization with CLE. Hence, conclusions regarding the optimal tumor features for CLE imaging must be drawn after feasibility studies have been performed that include other tumor types. Other tumors must be included to evaluate the efficacy and advantages of CLE with the TSP. Histological features identified with optical biopsies (left) and the corresponding H&E–stained histological tissue samples (right) are shown. A: Cellular tumor showing scattered atypical cells with foamy cytoplasm (dashed outline) that corresponds to metastasis of breast adenocarcinoma. Bar = 60 μm. B: Infiltrative cellular tumor of the cerebellum (dashed outline) that is consistent with anaplastic astrocytoma. The arrowhead indicates a blood vessel with RBCs inside. Bar = 100 μm. C: An extensively hemorrhagic tumor with atypical cells corresponding to hemangioblastoma. Bar = 100 μm. This patient with hemangioblastoma had a history of renal cell carcinoma and a second lesion in the cerebellum in the setting of von Hippel–Lindau disease; thus, the application of the CLE-TSP system was of clinical interest. D: Necrotic neuroglial tissue and isolated tumor cells (arrowheads) consistent with a treatment effect are shown. Bar = 100 μm. E: High-grade astrocytic tumor with highly pleomorphic cells with multinucleation indicative of glioblastoma. Bar = 100 μm. F: Atypical tumor cells with abundant eosinophilic cytoplasm and nuclei on the periphery (arrowheads) indicative of anaplastic astrocytoma. Bar = 100 μm.

  • View in gallery

    Diagnostic concordance between video-flow CLE imaging and still CLE image interpretation and frozen or permanent histological analysis.

  • 1

    Wright JR Jr. The development of the frozen section technique, the evolution of surgical biopsy, and the origins of surgical pathology. Bull Hist Med. 1985;59(3):295326.

    • Search Google Scholar
    • Export Citation
  • 2

    Novis DA, Zarbo RJ. Interinstitutional comparison of frozen section turnaround time. A College of American Pathologists Q-Probes study of 32868 frozen sections in 700 hospitals. Arch Pathol Lab Med. 1997;121(6):559567.

    • Search Google Scholar
    • Export Citation
  • 3

    Plesec TP, Prayson RA. Frozen section discrepancy in the evaluation of central nervous system tumors. Arch Pathol Lab Med. 2007;131(10):15321540.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4

    Plesec TP, Prayson RA. Frozen section discrepancy in the evaluation of nonneoplastic central nervous system samples. Ann Diagn Pathol. 2009;13(6):359366.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    Chatterjee S. Artefacts in histopathology. J Oral Maxillofac Pathol. 2014;18(1)(suppl 1):S111S116.

  • 6

    Friedmann-Morvinski D. Glioblastoma heterogeneity and cancer cell plasticity. Crit Rev Oncog. 2014;19(5):327336.

  • 7

    Snyder SR. Editorial. Telemedicine for elective neurosurgical routine follow-up care: a promising patient-centered and cost-effective alternative to in-person clinic visits. Neurosurg Focus. 2018;44(5):E18.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    James HE. Pediatric neurosurgery telemedicine clinics: a model to provide care to geographically underserved areas of the United States and its territories. J Neurosurg Pediatr. 2016;25(6):753757.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Sankar T, Delaney PM, Ryan RW, et al. Miniaturized handheld confocal microscopy for neurosurgery: results in an experimental glioblastoma model. Neurosurgery. 2010;66(2):410418.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Sanai N, Eschbacher J, Hattendorf G, et al. Intraoperative confocal microscopy for brain tumors: a feasibility analysis in humans. Neurosurgery. 2011;68(2 Suppl Operative):282290.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Eschbacher J, Martirosyan NL, Nakaji P, et al. In vivo intraoperative confocal microscopy for real-time histopathological imaging of brain tumors. J Neurosurg. 2012;116(4):854860.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    US Food & Drug Administration. K181116. October 25, 2018. Accessed April 6, 2022. https://www.accessdata.fda.gov/cdrh_docs/pdf18/K181116.pdf

    • Search Google Scholar
    • Export Citation
  • 13

    Belykh E, Miller EJ, Carotenuto A, et al. Progress in confocal laser endomicroscopy for neurosurgery and technical nuances for brain tumor imaging with fluorescein. Front Oncol. 2019;9 554.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Abramov I, Dru AB, Belykh E, Park MT, Bardonova L, Preul MC. Redosing of fluorescein sodium improves image interpretation during intraoperative ex vivo confocal laser endomicroscopy of brain tumors. Front Oncol. 2021;11 668661.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Gal AA. The centennial anniversary of the frozen section technique at the Mayo Clinic. Arch Pathol Lab Med. 2005;129(12):15321535.

  • 16

    Wilson LB. A method for the rapid preparation of fresh tissues for the microscope. J Am Med Assoc. 1905;XLV(23):17371737.

  • 17

    Lechago J. The frozen section: pathology in the trenches. Arch Pathol Lab Med. 2005;129(12):15291531.

  • 18

    Gal AA, Cagle PT. The 100-year anniversary of the description of the frozen section procedure. JAMA. 2005;294(24):31353137.

  • 19

    Ryu WHA, Kerolus MG, Traynelis VC. Clinicians’ user experience of telemedicine in neurosurgery during COVID-19. World Neurosurg. 2021;146(e359):e367.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Klein Y, Donchik V, Jaffe D, et al. Management of patients with traumatic intracranial injury in hospitals without neurosurgical service. J Trauma. 2010;69(3):544548.

    • Search Google Scholar
    • Export Citation
  • 21

    Wong HT, Poon WS, Jacobs P, et al. The comparative impact of video consultation on emergency neurosurgical referrals. Neurosurgery. 2006;59(3):607613.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Reider-Demer M, Raja P, Martin N, Schwinger M, Babayan D. Prospective and retrospective study of videoconference telemedicine follow-up after elective neurosurgery: results of a pilot program. Neurosurg Rev. 2018;41(2):497501.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    Dadlani R, Mani S, A U JG, et al. The impact of telemedicine in the postoperative care of the neurosurgery patient in an outpatient clinic: a unique perspective of this valuable resource in the developing world—an experience of more than 3000 teleconsultations. World Neurosurg. 2014;82(3-4):270283.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24

    Thakar S, Rajagopal N, Mani S, et al. Comparison of telemedicine with in-person care for follow-up after elective neurosurgery: results of a cost-effectiveness analysis of 1200 patients using patient-perceived utility scores. Neurosurg Focus. 2018;44(5):E17.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Gray W, O’Brien D, Taleb F, Marks C, Buckley T. Benefits and pitfalls of telemedicine in neurosurgery. J Telemed Telecare. 1997;3(2):108110.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    Powsner SM, Costa J, Homer RJ. Clinicians are from Mars and pathologists are from Venus. Arch Pathol Lab Med. 2000;124(7):10401046.

  • 27

    Acerbi F, Pollo B, De Laurentis C, et al. Ex vivo fluorescein-assisted confocal laser endomicroscopy (CONVIVO® System) in patients with glioblastoma: results from a prospective study. Front Oncol. 2020;10 606574.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Belykh E, Zhao X, Ngo B, et al. Intraoperative confocal laser endomicroscopy ex vivo examination of tissue microstructure during fluorescence-guided brain tumor surgery. Front Oncol. 2020;10 599250.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Höhne J, Schebesch KM, Zoubaa S, Proescholdt M, Riemenschneider MJ, Schmidt NO. Intraoperative imaging of brain tumors with fluorescein: confocal laser endomicroscopy in neurosurgery. Clinical and user experience. Neurosurg Focus. 2021;50(1):E19.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30

    Martirosyan NL, Eschbacher JM, Kalani MY, et al. Prospective evaluation of the utility of intraoperative confocal laser endomicroscopy in patients with brain neoplasms using fluorescein sodium: experience with 74 cases. Neurosurg Focus. 2016;40(3):E11.

    • Crossref
    • Search Google Scholar
    • Export Citation

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