Renan Maximilian Lovato1, João Luiz Vitorino Araujo1,2 , José Carlos Esteves Veiga1

– BACKGROUND: Gross total resection for malignant brain neoplasms is challenging owing to the heterogeneity
of these lesions and infiltration in eloquent areas. Gross total resection is a very important part of treatment of these patients and is a crucial prognostic factor. Fluorescence-guided surgery is an important tool that improves the rate of total resection.

– METHODS: We built a device to use in surgical microscopes with an excitation and a barrier filter to perform fluorescence-guided surgery. All patients received a standard dose of 500 mg of sodium fluorescein before skin incision. Surgical view under white light was compared with use of the light filters.

– RESULTS: In all cases with use of the filters, the tumors showed a high fluorescence contrasting with the normal surrounding brain, making it easier to identify the limits of the lesion and to achieve gross total resection.

– CONCLUSIONS: The use of fluorescence for malignant brain tumor resection increases the rate of gross total resection. It is an important tool that makes it possible to identify the lesion in areas where it looks like normal tissue under white light. This device is a low-cost option that has shown good results in our experience.

INTRODUCTION

Fluorescein is an organic dye first synthesized by Adolf von Baeyer that is widely and safely used in humans.1,2 It is a
highly fluorescent molecule and is excited by light with a  wavelength between 465 nm and 490 nm and has a peak emission between 520 nm and 530 nm.3,4 To see it properly, a blue light source and an interposition of a yellow filter are needed.3-6 Fluorescein is widely used in ophthalmology and neurosurgery and is a drug with a safe profile. Severe anaphylactic reaction is seen in 1 of 15,000 cases, and the mortality rate is estimated to be 1 in 222,000 patients.2,7-10 This substance accumulates where the blood-brain barrier is broken. The use in central nervous system tumors have been studied in metastasis, high-grade gliomas, and skull base tumors.1,11-14

The first use in neurosurgery was reported by George Moore in 1948, who published 46 cases showing that fluorescein could help to identify malignant areas and improve total resection.15 More recent studies have shown the value of this dye in neurosurgery, including for vascular procedures.4,5,16 The sensitivity and specificity for intraoperative detection of malignancy are 79% e 97% and 81% e 100%, respectively.1,15,17-20. Studies have shown good results using fluorescence for resection of malignant brain tumors, increasing the cases that achieved gross total resection (GTR) to 80%,6,11,12,19,21-23 including brainstem lesions.24 Use of fluorescein to guide both microscopic and stereotactic biopsies has also been reported.20,24,25

Low-cost options using fluorescein instead of the commercially available commercial modules have been reported. In 1998, Kuroiwa et al.26 used excitatory and barrier filters inserted in a microscope for the use of fluorescein guidance in surgery of high-grade glioma. In 2012, Okuda et al.22 used a microscope with excitation and barrier filters for surgery of high-grade gliomas. In 2015, Ichikawa et al.4 published an article showing the use of a blue excitatory filter and a yellow barrier filter for vascular neurosurgery with good results. In 2016, Bongetta et al.27 reported an option using excitatory light in an endoscope and barrier filters superimposed to the microscope oculars or the use of yellow glasses. 5-Aminolevulinic acid (5-ALA) has a cost of up to V1000,19 whereas sodium fluorescein in our institution costs only V5 per patient, making it much more affordable in our public health system.

MATERIALS AND METHODS

We have designed and produced using 3-dimensional printing a device with light filters that could fit any microscope with a removable part that works like a drawer containing the filters. You
can easily alternate during the surgery between the white light and the fluorescence mode (Figure 1). The device has a band-pass filter (BP470; Midwest Optical Systems, Inc., Palatine, Illinois, USA) for an excitation filter for the light source with high transmission rate that allows wavelength only between 425 nm and 490 nm and, as a barrier, a long-pass filter (LP515; Midwest Optical Systems, Inc.) that cuts off light under 520 nm (blue and ultraviolet wavelengths), enhancing the fluorescence contrast (Figure 2). The total cost to build our device is V340, including the taxes to buy the filters from the United States.

A simple analogy for how our device works is it would be like entering a dark room using a flashlight with blue light and wearing glasses with yellow lens. The blue light will excite the fluorescein, and the barrier filter will make it easier to see it. Patients with either high-grade gliomas or metastatic lesions were operated on using this system. All patients signed an informed consent, and the study was approved by the ethics committee. Before the skin incision, the patients received a Q5 standard 500-mg dose of sodium fluorescein, administered intravenously in bolus. There are many protocols with different doses, ranging from the standard dose of 1000 mg14,15,17 to high doses of 20 mg/kg,22 most administered without the use of dedicated filters14,15,17 but also with them.22 Doses of 8 mg/kg and 5e10 mg/kg12,19,26 and low-dose protocols using 3 e 5 mg/kg1,5,27 have been reported. Based on the use of the standard 1000-mg dose without the filters, we decided to use 500 mg in our first cases using our device to evaluate our method. We are currently using a low-dose protocol for our new prospective study. The surgery was performed as usual until the beginning of the tumor resection, when the filters were then attached to the microscope when necessary to help to identify the tumor. Surgeries were performed using a Zeiss S8 or a Pentero microscope without Q6 the “Yellow 560” fluorescence module. All surgeries were performed by the same team (J.L.V.A. and R.M.L.).

RESULTS

Case 1

A 50-year-old woman presented with a recurrent glioblastoma in the right temporal lobe. Surgery was performed to achieve a GTR, showing high fluorescence in the tumor but not in the sur
rounding brain. The hippocampus appeared normal without the fluorescence filter but showed a high concentration of fluorescein and was resected; histopathology confirmed hippocampal infil
tration (Figure 3). Preoperative and postoperative magnetic resonance imaging showed the area of resection (Figure 4).

Case 2

A 60-year-old woman presented with a history of ovarian cancer. Magnetic resonance imaging showed a metastatic lesion near the motor cortex on the right hemisphere. An awake craniotomy was
performed using the OsiriX tool (Pixmeo SARL, Bernex, Switzerland) for planning.28 The metastasis showed a high fluorescence, very distinct from the surrounding brain (Figure 5). Total resection was achieved without additional deficits (Figure 4).

Case 3

A 68-year-old man presented with a temporal glioblastoma. An awake craniotomy was performed with intraoperative monitoring. The tumor, but not the surrounding brain, showed high fluores-
cence (Figure 6). Total resection was not possible owing to worsening of speech (Figure 4).

 

DISCUSSION

The interest in fluorescence-guided surgery in neurosurgery is growing with the use of 5-ALA, indocyanine green, and fluorescein.6,16,29 5-ALA accumulates inside glioblastoma tumor cells as protoporphyrin IX6,29,30 and is fluorescent under blue excitation light (wavelength 400e410 nm), and its use has been shown to increase GTR and overall survival in high-grade gliomas.31 The patient takes an oral dose 2.5 e 3 hours before surgery and must avoid light in the next 24 hours because of the risk of skin lesions. 5-ALA costs up to $1000.19 (euro) ,32
Sodium fluorescein is a low-cost option19 with a very safe profile for intravenous use.2,7-10 It has been widely used in ophthalmology for retinal angiography.8,9,30 It accumulates in malignant brain tumors where the blood-brain barrier is broken.1,11-14,33 After intravenous administration, 80% binds to plasmatic proteins and is not visible, and 20% circulates freely and is responsible for the visible fluorescence.8,10 It takes 24 e 36 hours for fluorescein to be eliminated by renal excretion after its use.8,10,14,15

For high-grade gliomas, it is well established that the extent of resection is an important prognostic factor for survival; most studies suggest that resection of at least 98% is necessary.34-39 . Maximal resection of these tumors also optimizes the effectiveness of chemotherapy and radiotherapy.39,40 In 2006, Stummer et al.31 published data showing that under normal white light,
GTR of malignant gliomas was achieved in only 36% of patients, and with the aid of 5-ALA, GTR was possible in 65% of the cases. Fluorescence-guided surgery has promising results, achieving GTR in >80% of cases6,11,12,19,21-23 and even possible good results in brainstem lesions.24

Fluorescence-guided surgery is an amazing advance in neuro-surgery with a possible impact on patient overall survival. However, the high cost of commercially available fluorescence modules makes it impossible to use fluorescence-guided surgery in most hospitals in developing countries because the surgical microscopes needed to execute it include only the top models of the major manufacturers, with costs of approximately $300,000.32 (euro) Also, the cost of 5-ALA is very high19,32 compared with sodium fluorescein. In Brazil, sodium fluorescein is widely available, and 5-ALA is not sold in the oral form. With our method, we intend to make fluorescence guidance available for patients who otherwise would never benefit from this technology. The cost of the device is only $340 (euro) or less, and the device can be used in simple microscopes. We also use it in neurovascular surgery for aneurysms, bypass procedures, and arteriovenous malformations. When used in many surgeries, the cost for each patient becomes very low; for example, after 100 procedures, the cost would be only V8.40 per patient, including the dose of sodium fluorescein.

Further studies are necessary to evaluate the rates of GTR with our method. We are currently beginning a prospective evaluation using preoperative and postoperative magnetic resonance imaging
to assess rates of GTR in high-grade gliomas and metastasis Q7 .

CONCLUSIONS

Despite criticism of sodium fluorescein because it does not stain tumor cells except where it accumulates in areas where the blood-Q8 brain barrier is broken, it has a sensitivity for intraoperative detection of malignancy of 79%e97% and a specificity of 81% e 100%.1,15,17-20 Fluorescence-guided surgery improves rates of GTR to up to 80%.6,11,12,19,21-23 Maximal resection is an important prognostic factor for survival and improves the effectiveness of chemotherapy and radiotherapy.34-40 The low cost of this fluorophore and the possibility to use it in vascular neurosurgery with the same filters makes it a good choice for hospitals in developing countries.

 

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