Michael A. Mooney

Neurosurgical confocal endomicroscopy: A review of contrast agents, confocal systems, and future imaging modalities

Background: The clinical application of fluorescent contrast agents (fluorescein, indocyanine green, and aminolevulinic acid) with intraoperative microscopy has led to advances in intraoperative brain tumor imaging. Their properties, mechanism of action, history of use, and safety are analyzed in this report along with a review of current laser scanning confocal endomicroscopy systems. Additional imaging modalities with potential neurosurgical utility are also analyzed. Methods: A comprehensive literature search was performed utilizing PubMed and key words: In vivo confocal microscopy, confocal endomicroscopy, fluorescence imaging, in vivo diagnostics/neoplasm, in vivo molecular imaging, and optical imaging. Articles were reviewed that discussed clinically available fluorophores in neurosurgery, confocal endomicroscopy instrumentation, confocal microscopy systems, and intraoperative cancer diagnostics. Results: Current clinically available fluorescent contrast agents have specific properties that provide microscopic delineation of tumors when imaged with laser scanning confocal endomicroscopes. Other imaging modalities such as coherent anti-Stokes Raman scattering (CARS) microscopy, confocal reflectance microscopy, fluorescent lifetime imaging (FLIM), two-photon microscopy, and second harmonic generation may also have potential in neurosurgical applications. Conclusion: In addition to guiding tumor resection, intraoperative fluorescence and microscopy have the potential to facilitate tumor identification and complement frozen section analysis during surgery by providing real-time histological assessment. Further research, including clinical trials, is necessary to test the efficacy of fluorescent contrast agents and optical imaging instrumentation in order to establish their role in neurosurgery.

Laser scanning confocal endomicroscopy in the neurosurgical operating room: a review and discussion of future applications

Laser scanning confocal endomicroscopy (LSCE) is an emerging technology for examining brain neoplasms in vivo. While great advances have been made in macroscopic fluorescence in recent years, the ability to perform confocal microscopy in vivo expands the potential of fluorescent tumor labeling, can improve intraoperative tissue diagnosis, and provides real-time guidance for tumor resection intraoperatively. In this review, the authors highlight the technical aspects of confocal endomicroscopy and fluorophores relevant to the neurosurgeon, provide a comprehensive summary of LSCE in animal and human neurosurgical studies to date, and discuss the future directions and potential for LSCE in neurosurgery.

Impact of Timing of Intervention Among 397 Consecutively Treated Brainstem Cavernous Malformations

BACKGROUND Surgical resection of brainstem cavernous malformations (BSCMs) is challenging, and patient selection and timing of intervention remain controversial. OBJECTIVE To evaluate the impact of surgical timing and predictors of neurological outcome after surgical resection of BSCMs. METHODS Consecutive adult patients (≥18 years) with BSCMs undergoing surgical resection between 1985 and 2014 by the senior author (RFS) were retrospectively reviewed. Patient demographics, lesion characteristics, imaging results, surgical approach, and perioperative and long-term neurological morbidity were analyzed. RESULTS Data were analyzed for a total of 397 adult patients (160, 40% male). On univariate analysis, a greater proportion of patients treated within 6 weeks of hemorrhage had an improved Glasgow Outcome Scale score (P = .06). On logistic regression analysis, patients treated within 6 weeks of hemorrhage experienced improved clinical outcomes (odds ratio = 1.73; 95% confidence interval = 1.06-2.83; P = .03). CONCLUSIONS Although BSCM surgery is associated with significant perioperative morbidity and mortality, favorable long-term hemorrhage rates and symptom resolution can be achieved in a carefully selected group of patients. Overall, patients treated acutely, within 6 weeks, benefited the most from surgical intervention.

Immediate ex-vivo diagnosis of pituitary adenomas using confocal reflectance microscopy: a proof-of-principle study

OBJECTIVE The objective of this study was to evaluate the feasibility of using confocal reflectance microscopy (CRM) ex vivo to differentiate adenoma from normal pituitary gland in surgical biopsy specimens. CRM allows for rapid, label-free evaluation of biopsy specimens with cellular resolution while avoiding some limitations of frozen section analysis. METHODS Biopsy specimens from 11 patients with suspected pituitary adenomas were transported directly to the pathology department. Samples were immediately positioned and visualized with CRM using a confocal microscope located in the same area of the pathology department where frozen sections are prepared. An H & E-stained slide was subsequently prepared from imaged tissue. A neuropathologist compared the histopathological characteristics of the H & E-stained slide and the matched CRM images. A second neuropathologist reviewed images in a blinded fashion and assigned diagnoses of adenoma or normal gland. RESULTS For all specimens, CRM contrasted cellularity, tissue architecture, nuclear pleomorphism, vascularity, and stroma. Pituitary adenomas demonstrated sheets and large lobules of cells, similar to the matched H & E-stained slides. CRM images of normal tissue showed scattered small lobules of pituitary epithelial cells, consistent with matched H & E-stained images of normal gland. Blinded review by a neuropathologist confirmed the diagnosis in 15 (94%) of 16 images of adenoma versus normal gland. CONCLUSIONS CRM is a simple, reliable approach for rapidly evaluating pituitary adenoma specimens ex vivo. This technique can be used to accurately differentiate between pituitary adenoma and normal gland while preserving biopsy tissue for future permanent analysis, immunohistochemical studies, and molecular studies.

Long-term Patient Outcomes After Microsurgical Treatment of Blister-Like Aneurysms of the Basilar Artery

BACKGROUND: Blister-like aneurysms (BLAs) are challenging lesions that require unique microsurgical strategies. BLAs are predominantly found along the internal carotid artery; however, BLAs of the basilar artery are a rare subset that requires a modified treatment strategy. OBJECTIVE: To discuss the microsurgical management and review the long-term outcomes of patients with BLAs of the basilar artery. METHODS: We retrospectively reviewed the surgical technique, postoperative results, and long-term outcomes of all patients with basilar artery BLAs treated at our institution from 2005 to 2011. RESULTS: Four patients with basilar artery BLAs were identified over this 6-year interval. All 4 patients were treated by direct microsurgical clipping. A thin layer of cotton reinforcement was used beneath the clip tines to minimize the risk of clip slippage in 2 of 4 patients; 1 patient required adjunctive endovascular stent placement for residual aneurysm after clipping. Complete obliteration of all aneurysms was achieved, and there has been no recurrence at mean clinical follow-up of 72 months (median, 74.5; range, 37-103) and imaging follow-up of 48 months (median, 54; range 12-72). CONCLUSION: Direct clipping with or without cotton reinforcement can obliterate basilar BLAs with excellent long-term outcomes. Clip wrapping is not an option for these lesions given the proximity to perforating branches. Endovascular techniques provide a useful adjunctive strategy; however, risks with antiplatelet therapy in the acute subarachnoid hemorrhage period must be considered. ABBREVIATIONS: BLA, blister-like aneurysms GOS, Glasgow Outcome Scale ICA, internal carotid artery PED, Pipeline Embolization Device SAH, subarachnoid hemorrhage

Use of a conformational switching aptamer for rapid and specific ex vivo identification of central nervous system lymphoma in a xenograft model

Improved tools for providing specific intraoperative diagnoses could improve patient care. In neurosurgery, intraoperatively differentiating non-operative lesions such as CNS B-cell lymphoma from operative lesions can be challenging, often necessitating immunohistochemical (IHC) procedures which require up to 24-48 hours. Here, we evaluate the feasibility of generating rapid ex vivo specific labeling using a novel lymphoma-specific fluorescent switchable aptamer. Our B-cell lymphoma-specific switchable aptamer produced only low-level fluorescence in its unbound conformation and generated an 8-fold increase in fluorescence once bound to its target on CD20-positive lymphoma cells. The aptamer demonstrated strong binding to B-cell lymphoma cells within 15 minutes of incubation as observed by flow cytometry. We applied the switchable aptamer to ex vivo xenograft tissue harboring B-cell lymphoma and astrocytoma, and within one hour specific visual identification of lymphoma was routinely possible. In this proof-of-concept study in human cell culture and orthotopic xenografts, we conclude that a fluorescent switchable aptamer can provide rapid and specific labeling of B-cell lymphoma, and that developing aptamer-based labeling approaches could simplify tissue staining and drastically reduce time to histopathological diagnoses compared with IHC-based methods. We propose that switchable aptamers could enhance expeditious, accurate intraoperative decision-making.

Convolutional neural networks: Ensemble modeling, fine-tuning and unsupervised semantic localization for neurosurgical CLE images

Abstract Confocal laser endomicroscopy (CLE) is an advanced optical fluorescence technology undergoing assessment for applications in brain tumor surgery. Many of the CLE images can be distorted and interpreted as nondiagnostic. However, just one neat CLE image might suffice for intraoperative diagnosis of the tumor. While manual examination of thousands of nondiagnostic images during surgery would be impractical, this creates an opportunity for a model to select diagnostic images for the pathologists or surgeons review. In this study, we sought to develop a deep learning model to automatically detect the diagnostic images. We explored the effect of training regimes and ensemble modeling and localized histological features from diagnostic CLE images. The developed model could achieve promising agreement with the ground truth. With the speed and precision of the proposed method, it has potential to be integrated into the operative workflow in the brain tumor surgery.

Analysis of overlapping surgery in patients undergoing microsurgical aneurysm clipping: acute and long-term outcomes from the Barrow Ruptured Aneurysm Trial

OBJECTIVE Overlapping surgery is a controversial subject in medicine today; however, few studies have examined the outcomes of this practice. The authors analyzed outcomes of patients with acutely ruptured saccular aneurysms who were treated with microsurgical clipping in a prospectively collected database from the Barrow Ruptured Aneurysm Trial. Acute and long-term outcomes for overlapping versus nonoverlapping cases were compared. METHODS During the study period, 241 patients with ruptured saccular aneurysms underwent microsurgical clipping. Patients were separated into overlapping (n = 123) and nonoverlapping (n = 118) groups based on surgical start/stop times. Outcomes at discharge and at 6 months, 1 year, 3 years, and 6 years after surgery were analyzed. RESULTS Patient variables (e.g., age, smoking status, cardiovascular history, Hunt and Hess grade, Fisher grade, and aneurysm size) were similar between the 2 groups. Aneurysm locations were similar, with the exception of the overlapping group having more posterior circulation aneurysms (18/123 [15%]) than the nonoverlapping group (8/118 [7%]) (p = 0.0495). Confirmed aneurysm obliteration at discharge was significantly higher for the overlapping group (109/119 [91.6%]) than for the nonoverlapping group (95/116 [81.9%]) (p = 0.03). Hospital length of stay, discharge location, and proportions of patients with a modified Rankin Scale (mRS) score > 2 at discharge and up to 6 years postoperatively were similar. The mean and median mRS, Glasgow Outcome Scale, Mini-Mental State Examination, National Institutes of Health Stroke Scale, and Barthel Index scores at all time points were not statistically different between the groups. CONCLUSIONS Compared with nonoverlapping surgery, overlapping surgery was not associated with worse outcomes for any variable at any time point, despite the complexity of the surgical management in this patient population. These findings should be considered during the discussion of future guidelines on the practice of overlapping surgery.

Immediate Label-Free Ex Vivo Evaluation of Human Brain Tumor Biopsies With Confocal Reflectance Microscopy

Confocal microscopy utilizing fluorescent dyes is widely gaining use in the clinical setting as a diagnostic tool. Reflectance confocal microscopy is a method of visualizing tissue specimens without fluorescent dyes while relying on the natural refractile properties of cellular and subcellular structures. We prospectively evaluated 76 CNS lesions with confocal reflectance microscopy (CRM) to determine cellularity, architecture, and morphological characteristics. A neuropathologist found that all cases showed similar histopathological features when compared to matched hematoxylin and eosin-stained sections. RNA isolated from 7 tissues following CRM imaging retained high RNA integrity, suggesting that CRM does not alter tissue properties for molecular studies. A neuropathologist and surgical pathologist masked to the imaging results independently evaluated a subset of CRM images. In these evaluations, 100% of images reviewed by the neuropathologist and 95.7% of images reviewed by the surgical pathologist were correctly diagnosed as lesional or nonlesional. Furthermore, 97.9% and 91.5% of cases were correctly diagnosed as tumor or not tumor by the neuropathologist and surgical pathologist, respectively, while 95.8% and 85.1% were identified with the correct diagnosis. Our data indicate that CRM is a useful tool for rapidly screening patient biopsies for diagnostic adequacy, molecular studies, and biobanking.

Incidence of delivery wire recapture failure with the Pipeline Flex device

Background The Pipeline Flex embolization device has several advantages over the first-generation Pipeline embolization device (Covidien, Dublin, Republic of Ireland). Despite these advantages, we have observed frequent difficulty in recapturing the devices delivery wire. Objective To prospectively document the incidence of failure to recapture the delivery wire. Methods We tracked our experience in patients undergoing endovascular treatment with a flow-diverting stent for cerebral aneurysms between 1 May and 30 September 2016. Patient and lesion characteristics, device dimensions, and technical outcomes of delivery wire recapture were prospectively recorded for each device. Results Eighteen devices were deployed in 15 patients by the senior author (FCA) during this period. Failure to recapture the delivery wire occurred in 10 of 18 (56%) cases. No adverse outcomes of delivery wire recapture failure were encountered in this series. Conclusions The incidence of delivery wire recapture failure with the Pipeline Flex device is high. Failure to recapture the delivery wire carries a theoretical risk of stent displacement when re-navigating across the device, and endovascular surgeons should be aware of this limitation. Authors are encouraged to report delivery wire recapture failure rates in future clinical series in which the Pipeline Flex device is used.