Near-infrared fluorescent image-guided surgery for intracranial meningioma

Abstract

OBJECTIVE Meningiomas are the most common primary tumor of the central nervous system. Complete resection can be curative, but intraoperative identification of dural tails and tumor remnants poses a clinical challenge. Given data from preclinical studies and previous clinical trials, the authors propose a novel method of localizing tumor tissue and identifying residual disease at the margins via preoperative systemic injection of a near-infrared (NIR) fluorescent contrast dye. This technique, what the authors call "second-window indocyanine green" (ICG), relies on the visualization of ICG approximately 24 hours after intravenous injection. METHODS Eighteen patients were prospectively identified and received 5 mg/kg of second-window ICG the day prior to surgery. An NIR camera was used to localize the tumor prior to resection and to inspect the margins following standard resection. The signal to background ratio (SBR) of the tumor to the normal brain parenchyma was measured in triplicate. Gross tumor and margin specimens were qualitatively reported with respect to fluorescence. Neuropathological diagnosis served as the reference gold standard to calculate the sensitivity and specificity of the imaging technique. RESULTS Eighteen patients harbored 15 WHO Grade I and 3 WHO Grade II meningiomas. Near-infrared visualization during surgery ranged from 18 to 28 hours (mean 23 hours) following second-window ICG infusion. Fourteen of the 18 tumors demonstrated a markedly elevated SBR of 5.6 ± 1.7 as compared with adjacent brain parenchyma. Four of the 18 patients showed an inverse pattern of NIR signal, that is, stronger in the adjacent normal brain than in the tumor (SBR 0.31 ± 0.1). The best predictor of inversion was time from injection, as the patients who were imaged earlier were more likely to demonstrate an appropriate SBR. The second-window ICG technique demonstrated a sensitivity of 96.4%, specificity of 38.9%, positive predictive value of 71.1%, and a negative predictive value of 87.5% for tumor. CONCLUSIONS Systemic injection of NIR second-window ICG the day before surgery can be used to visualize meningiomas intraoperatively. Intraoperative NIR imaging provides higher sensitivity in identifying meningiomas than the unassisted eye. In this study, 14 of the 18 patients with meningioma demonstrated a strong SBR compared with adjacent brain. In the future, reducing the time interval from dye injection to intraoperative imaging may improve fluorescence at the margins, though this approach requires further investigation. Clinical trial registration no.: NCT02280954 ( clincialtrials.gov ).

Keywords: 125IR; 5-ALA = 5-aminolevulinic acid; EPR = enhanced permeability and retention; ICG = indocyanine green; NIR = near-infrared dye; NPV = negative predictive value; PPV = positive predictive value; ROC = receiver operating characteristic; SBR = signal to background ratio; brain tumor; fluorescence; indocyanine green; meningioma; near infrared; oncology.

FIG. 1.

Case 1S. Convexity meningioma displaying NIR fluorescence. Sagittal (A) and coronal (B) Gd-enhanced T1-weighted MR images. Axial T2-weighted MR image (C) demonstrating minimal adjacent edema. Visible-light image (D), NIR fluorescence superimposed and color-mapped onto the visible-light view (E), and NIR image (F) showing closure of the dura, although some NIR signal can be seen through the dura and localized to tumor. Visible-light image (G), NIR fluorescence superimposed and color-mapped onto the visible-light view (H), and NIR image (I) showing dura reflected away and the tumor-brain interface. The SBR of NIR tumor signal is 6.05. Visible-light image (J), NIR fluorescence superimposed and color-mapped onto the visible-light view (K), and NIR image (L) showing residual fluorescence in anterior and posterior margins after resection of the main tumor. No fluorescence is seen in the midline falx.

FIG. 2.

Case 22. Convexity meningioma displaying inverted fluorescence signal. Axial (A) and coronal (B) contrast-enhanced T1-weighted MR images. In the visible-light view (C), the brain parenchyma can be identified and the tumor is just starting to be seen as the dura is peeled back. The NIR fluorescence superimposed and color-mapped onto the visible-light view (D) demonstrates an inverted pattern with more NIR signal in adjacent brain parenchyma than in tumor. The SBR of NIR tumor signal is 0.30. When tumor was removed from the patient (E), there was still accumulation of ¹²⁵IR dye within the meningioma as compared with the attached dura (F). Ex vivo analysis confirms the presence of residual dye within tumor.

FIG. 3.

Linear regression plot of SBR of NIR tumor signal versus time from intravenous (IV) infusion. The SBR decreases as the length of time progresses after infusion. The 4 cases with inversion are seen as the 4 cases with an SBR < 1. p = 0.022, R² = 0.2876.

FIG. 4.

Case 13S. Automatic gain function may contribute to false positives. The visible-light image (A), NIR fluorescence superimposed and color-mapped onto the visible-light view (B), and NIR image (C) reveal the main specimen displaying strong NIR signal with a gain percentage at 15%. The visible-light image (D), NIR fluorescence superimposed and color-mapped onto the visible-light view (E), and NIR image (F) obtained after resection of the main tumor, showing a gain percentage increase to 71%. Notice the presence of a significant increase in background NIR signal in the skin edges partially obscured by Raney clips, bone, and so forth. Biopsy did not confirm the presence of meningioma.