The gold standard of intracranial meningioma treatment is surgical removal based on the “three D” technique (devascularization-detachment, debulking, and dissection), but referral for preoperative embolization of the tumor is dependent on the personal preference of the neurosurgeon. Preoperative embolization of the meningioma expedites the surgical removal of the meningioma because of tumor softening and reduced bleeding, which allows removal of the meningioma in an inside-out fashion through the limited operative field in some particular cases such as lower falx meningioma . Our institution has used the nonadhesive liquid embolic agent Eudragid-E (methyl and butyl methacrylate and dimethylaminoethyl methacrylate copolymer) in ethanol solution as the preoperative embolization material of meningioma surgery. However, our personal experiences of preoperative embolization of the tumor suggest that better intraoperative visual awareness of the tumor demarcation with the white matter is needed because the embolized meningioma becomes whitish and soft like the white matter of the surrounding normal brain.
This study describes our technique of staining the tumor with indocyanine green (ICG) at the time of preoperative embolization with Eudragit so that the tumor tissue becomes green and fluorescent under near-infrared irradiation for increased safety during removal under the operating microscope. Although the number of cases is limited, our preliminary findings suggest that ICG staining facilitated better visualization and safety removal after preoperative liquid embolization. This technique of “green embolization” with ICG and Eudragit is the first example of biostaining of meningioma with fluorescent material.
Patients and methods
Our study protocol was approved by the institutional Ethics Committee of Juntendo University Shizuoka Hospital (No. 22–139) in accordance with the Declaration of Helsinki, and informed consent was obtained from all patients or their closest relatives. Ten patients (eight with convexity meningioma, one with lower falx meningioma, and one with sphenoid ridge meningioma) were enrolled in this study (Table 1).
Preparation of liquid embolic material
One gram Eudragit-E (Eudragit-E100; Evonic Industries AG, Essen, Germany) was dissolved in a mixture of 5 mL of 99.5% ethanol and 5 mL of iopamidol-370 (Bayer Schering Pharma AG, Berlin, Germany) to make 10% Eudragit in 50% ethanol. The 10% Eudragit mixture was filtered through a 0.2-μm FG filter and kept in a 10-mL glass ampoule until use. A total of 25 mg of ICG (Diagnogreen; Daiichi Sankyo Co., Ltd., Tokyo, Japan) was dissolved in 1.0 mL of 50% ethanol, and 0.1 mL of the ICG solution was mixed with 0.9 mL of 10% Eudragit solution. This green ICG/Eudragit solution was mixed with normal saline, and immediate formation of soft gel (precipitated Eudragit) was confirmed just before use.
Embolization procedure and near-infrared fluorescence image-guided tumor removal
Preoperative meningioma embolization was performed under local anesthesia with systemic heparinization induced to maintain the activated clotting time at 2–2.5 times higher than the control value until discontinued at the end of the procedure. A 6-F guiding catheter (Envoy; Cordis, Miami Lakes, FL, USA) was placed in the proximal external carotid artery through a 6-F sheath introduced into the femoral artery. A MALT Magic 1.5-F catheter (Balt, Montmorency, France) or Excelsior SL-10 (Stryker, Fremont, CA, USA) was used for microcatheterization to the terminal branch of the middle meningeal artery (MMA) in proximity to the tumor. After the catheter was irrigated with 0.3–1.7 mL of 70% ethanol, 0.1–0.8 mL of the ICG/Eudragit solution was injected several times until the tumor stain was not opacified by the contrast material injected via the guiding catheter. The total injected volume of the ICG/Eudragit solution was 0.1–0.8 mL.
The day before the surgery, magnetic resonance imaging (MRI) with gadolinium was performed to examine the tumor necrosis due to embolization. Three to 17 days after the tumor embolization, surgery for tumor removal was performed. During the tumor-removal process, fluorescence microimages were obtained with a near-infrared surgical microscope system (OPMI Pentero INFRARED 800 system, Carl Zeiss Co., Tokyo, Japan, or MM88, Mitaka Kohki Co., Ltd., Tokyo, Japan), which integrates the options of ICG-emitting light source and filter to detect fluorescence efficiency.
Table 1 shows the results of green embolization in the 10 patients with meningioma. The tumor volume ranged from 6 to 151 mL (mean±standard deviation: 47±44 mL). The volumes of flushing 70% ethanol and injected ICG/Eudragit solution ranged from 0.3 to 1.7 mL (0.7±0.4 mL) and from 0.1 to 0.65 mL (0.4±0.2 mL), respectively. The interval between embolization and tumor removal ranged from 3 to 17 days (7±4 days). Embolization resulted in only feeder occlusion, without tumor necrosis in three of the 10 patients. The tumor necrosis volume rate ranged from 0% to 80% (32%±32%). The tumor necrosis rate was not high, but partial necrosis of the tumor facilitated debulking because of the softened tumor with less bleeding. The status of tumor removal was classified by Simpson grading  and resulted in five patients with grade I, three patients with grade II, one patient with grade III, and one patient with grade IV. No adverse effects including hemorrhagic complication occurred after the embolization.
Case 3: A 78-year-old woman suffered from gradual worsening of right leg weakness until she could not walk. Neurological examination showed motor weakness in the right leg. MR imaging showed a lower falx tumor under the left frontoparietal lobe (Figure 1A and B). Angiography showed tumor stain fed by the bilateral MMAs and left occipital artery. After flushing the microcatheter with 0.5 mL of 70% ethanol, the branch of the left MMA was embolized with 0.2 mL of the ICG/Eudragid solution. The day before the surgery, MRI imaging was repeated and showed that approximately 80% of the tumor was necrotic without hemorrhagic evidence (Figure 1C and D). Five days after embolization, surgical tumor removal was performed. The small branches of the MMA on the dura appeared green with prominent fluorescence under near-infrared microscopic examination (Figure 2). The dura was opened between the Rolandic veins and the ascending parietal veins. The postcentral gyrus was retracted, and the tumor was exposed via the narrowed surgical corridor. The surface of the tumor appeared whitish with heterogeneous green staining. Under near-infrared laser excitation, the tumor showed remarkable fluorescence except for the partially unembolized part (Figure 2). The demarcation between the tumor and the surrounding brain tissue was clear under fluorescence microscopic observation, and the tumor was removed completely in an inside-out fashion without bleeding except for the partially unembolized part. The embolized part of the tumor was soft enough to be removed by a suction tube. After the operation, no adverse events occurred and the patient fully recovered from leg weakness, and so she was discharged ambulatory (Figure 1E and F). The histological diagnosis was meningothelial meningioma.
Eudragit-E is a cationic polymer that was originally developed as a surface-coating material for medication tablets and granules. Eudragit is soluble in ethanol solution but forms sponge gel within 2–3 s after contact with normal saline or blood after the ethanol solvent diffuses [10, 13]. A total of 5%–10% Eudragit in ethanol solution has suitable viscosity for microcatheter injection [11, 13]. In vivo, 7.5%–10% of the Eudragit solution forms a stable precipitate within 3 s after contact with blood [11, 13]. This precipitated gel is nonadhesive to the microcatheter. Eudragit is neither metabolized nor absorbed in the body. Histological examination showed that embolization using Eudragit in ethanol solution caused acute vasculitis in the experimental animals and solidified Eudragit remained in the arterial lumen without recanalization up to 3 months [10, 13]. Furthermore, embolized Eudragit did not reach the venules, and no histological evidence of hemorrhage was detected [1, 13]. Hemorrhagic complication occurs in 3.2%–5.1% of particle embolizations of meningiomas and causes formidable consequences [2, 3]. Our institutional experience of 83 consecutive meningioma patients preoperatively embolized with Eudragit in ethanol solution did not include any cases of hemorrhagic complication (data not shown). The biological characteristics of Eudragit such as long-term retention in the artery without recanalization and no occlusion of the venous side are beneficial for the embolization of meningioma without hemorrhagic complication due to recanalization or venous stagnation. In the present study, the 10 patients with meningioma embolized by the ICG/Eudragit solution did not show any hemorrhagic complication.
ICG is a near-infrared fluorescent material (absorption peak at about 800 nm) and has been used for the examination of liver function and cardiac output, as well as retinal angiography. Recently, near-infrared video angiography after intravenous injection of ICG has become widely accepted as an intraoperative tool to assess the flow of the cerebral arteries including perforators and completeness of obliteration of aneurysms during clipping surgery [7, 8]. Sentinel lymph node can be detected by fluorescence after intradermal application of ICG for lymphatic mapping and lymph node biopsy in patients with breast cancer and malignant lymphoma [4, 6]. Intraoperative sentinel lymph node detection after the topical application of ICG is a type of real-time fluorescence navigation surgery. ICG tends to degrade with exposure to light, but such photodegradation proceeds slowly (days) if the ICG is bound to albumin . We verified the stability of fluorescence at 7 days after subcutaneous injection of ICG in rats (data not shown). Therefore, ICG injected with Eudragit in ethanol solution will maintain fluorescence activity in the tumor for at least several days after the embolization. In the present study, we injected ICG 3–17 days before tumor removal and the tumors showed adequate fluorescence during the surgery.
The present preliminary study with a limited number of cases demonstrated the feasibility of “green embolization” using the ICG/Eudragit solution for staining meningioma before surgery. The softened tumor can be aspirated and removed in an inside-out fashion without bleeding, and the green-stained tumor can be easily distinguished from the surrounding brain tissue. Furthermore, the fluorescence emitted by the tumor can be detected under near-infrared microscope examination, facilitating complete removal and reducing the possibility of tumor remnant.
In the present study, tumor embolization failed in three of the 10 cases, resulting in feeder occlusion. The necrotic volume rate was not high. We have to establish the embolization technique to achieve efficient tumor embolization with high necrotic rate. The risks of complications such as postembolization hemorrhage and ischemia, the appropriate amount of the ICG/Eudragit solution, the best timing for tumor removal, duration of the fluorescence activity, and recurrence rate are not clear and require more investigation.
The present study evaluated a new method for preoperative embolization of meningioma with liquid material containing green fluorescent material (ICG) to stain the tumor with green and fluorescent dye for better identification during tumor removal. Preoperative embolization of meningioma with the ICG/Eudragit solution achieves improved visual identification during tumor removal.
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The authors stated that there are no conflicts of interest regarding the publication of this article.
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Published Online: 2013-10-13
Published in Print: 2013-06-01