Indocyanine Green and Cerebral Aneurysms

18 Indocyanine Green and Cerebral Aneurysms

David Bervini and Andreas Raabe

Abstract
When performing aneurysm clipping, the surgeon has to ensure that the aneurysm is completely obliterated and the parent, branching, and perforating vessels are patent. Several techniques are available for assessing whether aneurysm clipping has been done correctly. However, disadvantages such as their invasiveness, incomplete effectiveness, and spatial and temporal limitations, as well as their costs, are causes of concern for both patients and surgeons. Indocyanine green (ICG) videoangiography is a reliable, fast, repeatable, noninvasive, and cost-effective technique that allows real-time intraoperative assessment of vascular anatomy and analysis of flow dynamics. This chapter describes the principles of ICG videoangiography and its value in aneurysm surgery, and presents a critical appraisal of the validity and limitations of intraoperative ICG videoangiography. The focus is on practical aspects helpful during aneurysm surgery. ICG videoangiography represents a technical innovation meeting an important need in the microsurgical management of aneurysms, and it should be part of the state-of-the-art neurosurgical armory.

Keywords: indocyanine green, intraoperative technique, intracranial aneurysm, surgery

18.1 Introduction

Surgical clip ligation is a reliable treatment modality for intracranial aneurysms. The effectiveness of surgery depends on the clip(s) position, which needs to occlude the aneurysm and maintain blood flow in parent, branching, and perforating arteries. Several techniques are available for determining whether these goals have been achieved. Their value has to be balanced against their invasiveness, spatial and temporal limitations, as well as their costs. Indocyanine green (ICG) videoangiography has become a useful way to allow real-time assessment of intraoperative vascular anatomy and analysis of flow dynamics.

18.1.1 Surgical Clipping of Intracranial Aneurysms

Intracranial aneurysms are the most frequently diagnosed and increasingly common cerebrovascular malformation with a prevalence of 2 to 3% in the overall population.1,2 Aneurysm rupture has an incidence of about 9 per 100,000, accounting for approximately 5% of all strokes,^3,4 and has a high case fatality and morbidity rate. Due to its occurrence at a young age^3,5,6 and its poor outcome, the loss of productive life-years in the general population as a result of aneurysmal subarachnoid hemorrhage is as large as that from ischemic cerebral infarction, the most common type of stroke.^{4,7,8,9,10,11}

Surgical clip ligation is a validated treatment modality for intracranial aneurysms. Approximately 90% of such aneurysms are smaller than 10 mm¹ and surgery is routinely performed under microscope magnification. The technique consists of the dissection of the brain and vessels and the placement of one or more metallic clips in order to occlude and exclude the aneurysm from the normal arterial blood circulation of the brain.^12,13 The size, shape, number, and arrangement of clips depend on each patient’s unique vascular anatomy. Aneurysms have a close anatomical relationship to their parent vessels and to branching or perforating arteries. Surgical manipulation and aneurysm clipping put these vessels at risk for stenosis, occlusion, or insult, potentially leading to brain ischemia and infarction.^14,15,16,17 These risks can be minimized by the surgeon only by error avoidance and prompt error correction. As a rule of thumb, neurosurgeons consider that there is a time limit of 8 to 10 minutes before an ischemic event becomes irreversible.

Proven aneurysm remnants may regrow and lead to recurrent symptoms of hemorrhage or mass effect.^18,19,20,21 Together with the need for retreatment, this has a negative impact on the postoperative natural history.

When routinely performing postoperative angiography after clipping, the incidence of residual aneurysm filling reportedly ranges from 4 to 19%,^{22,23,24,25,26,27} and the incidence of parent or branching arteries ranges from 0.3 to 12%.^{22,23,24,25,26} Most of these findings (~10% combined incidence) are unexpected by the surgeon.

To lower this rate, diagnostic imaging of the vascular anatomy has to be made available in the operating room to allow assessment of clip position and to improve surgical results when suboptimal or wrong clip placement is detected. In light of the above-mentioned challenges faced during surgery, the ability to immediately evaluate and correct an imperfectly placed clip and/or cerebrovascular flow obstruction is highly desirable.

18.1.2 Techniques in Cerebrovascular Neurosurgery

Surgical Microscopy

The availability of the apochromatic optic, the zoom, the varioscopic focus, and direct surgical field illumination allows the surgeon to work with high-contrast and sharp images. The smooth device handling via touchscreen, handgrips, mouth switch, and wireless foot control panel help the surgeon to obtain a sharp focus on cerebrovascular structures and the surrounding brain. In specific circumstances, the surgeon can detect arterial blood turbulence and flow. However, this information alone is not sufficient to judge on correct vessel patency or complete aneurysm occlusion by clipping. Moreover, some compression maneuvers can be performed using bipolar forceps to stretch an arterial segment to empty it of blood and observe refilling.

Intraoperative Digital Subtraction Angiography

Due to its high-quality image definition, the multiple angles of view, and the three-dimensional vascular reconstruction modalities, rotational digital subtraction angiography (DSA) has been considered the gold standard diagnostic modality for cerebrovascular pathologies. Assessment is not limited to exposed vessels and the absence of subtraction artifacts from surgical metallic clips allows detailed vascular assessment.

Various authors have reported correction of an imperfectly positioned clip leading to improvement of the surgical procedure in 7 to 34% of selected cases.28 However, several drawbacks are associated with intraoperative DSA. These include the reduced image quality in the operating theater, the limited ability to visualize small perforating arteries, the rather long setup times (15–60 minutes), the possibility of brain ischemia in the case of artery occlusion, the invasiveness (direct puncture, exposure to ionizing radiation, dye injection), the required continuing use, experience, and resource consumption, and the high financial costs. Its rate of severe complications, which include stroke, arterial dissection, and retroperitoneal hemorrhage, has been reported to be up to 3.5%.^{29,30,31,32,33} Therefore, although intraoperative DSA may be considered the gold standard, its drawbacks have kept it from becoming a “standard of care.” In most sites, its application is limited to selected cases and only a few centers around the world have the capability to use it as a routine intraoperative tool.

Microvascular Doppler

The microvascular Doppler (MVD) system has become a standard piece of equipment that is routinely used during aneurysm clipping, available on the operating table and ready for use. It is inexpensive, easy to use, fast, and noninvasive.^34,35 The MVD easily diagnoses occlusion of parent or branching arteries and incomplete clipping provided that there is high flow filling of the aneurysm dome.³⁶ However, MVD requires direct vessel contact and mostly fails in perforating arteries.³⁶ Observing the signal curve or judging the change in noise is always subjective, and a hemodynamically critical stenosis can rarely be reliably identified. Low flow filling of the aneurysm sac after incomplete clipping and small caliber vessel flow can also often be missed.^35,36 The newly developed Charbel–Doppler flow probe measures blood flow quantitatively.³⁷ Although this new flow probe improves the diagnostic accuracy of the Doppler, especially in assessing vessel stenosis, it has the disadvantage of being somewhat bulky in some situations and, like MVD, fails in perforating arteries. However, it is a technological innovation that has overcome some of the limitations of MVD.

18.2 Indocyanine Green Angiography

18.2.1 Principles of Indocyanine Green Videoangiography

ICG is a near-infrared (NIR) fluorescent tricarbocyanine dye that was approved by the U.S. Food and Drug Administration in 1956 for diagnostic use in disorders of cardiocirculatory and liver function. Supplemental U.S. FDA approval for ophthalmic angiography was granted in 1975. After intravenous bolus injection, ICG is bound within 1 to 2 seconds, mainly to globulins (α1-lipoproteins), and remains intravascular with normal vascular permeability. ICG is not metabolized in the body and is excreted exclusively by the liver, with a plasma half-life of 3 to 4 minutes. It is not reabsorbed from the intestine and does not undergo enterohepatic recirculation. The recommended dose for ICG videoangiography is 0.2 to 0.5 mg/kg; the maximal daily dose should not exceed 5 mg/kg.

ICG absorption and emission peaks lie within the “optical window” of tissue, where absorption attributable to endogenous chromophores is low. NIR light can therefore penetrate tissue to depths from several millimeters to a few centimeters. The operative field is illuminated by a light source with a wavelength covering part of the ICG absorption band (range 700–850 nm, maximum 805 nm). Once the dye solution reaches the vessels of the NIR light–illuminated field of interest, ICG fluorescence is induced. The fluorescence (range 780–950 nm, maximum 835 nm) is recorded by a nonintensified video camera. An optical filter blocks both ambient and excitation light so that only ICG-induced fluorescence is visualized. Thus, arterial, capillary, and venous angiographic images can be observed on the video screen in real time. The latest generations of microscopes integrate ICG videoangiography technology, enabling high-resolution and high-contrast NIR images to be obtained. The setup allows high-resolution NIR images based on ICG fluorescence to be visualized and stored without eliminating visible light during the investigation (i.e., without moving the microscope from the surgical field or needing to interrupt the operation).

18.2.2 ICG Videoangiography and Aneurysm Surgery

ICG videoangiography was first introduced in neurosurgery in 2003³⁸ as a new method to visualize flow in vessels exposed in the surgical field. The clinical benefit of ICG in cerebrovascular neurosurgery was reported in 2005,²⁸ after adding NIR imaging to surgical microscopes and comparing it with intraoperative or postoperative DSA. ICG videoangiography was able to identify a suboptimal or wrong clip position in 8% of a total of 10%, and the 9% rate of relevant information provided by ICG angiography for the surgical procedure was compatible with the reported rates associated with intraoperative DSA.²⁸ Its value in influencing the intraoperative decision to correct the aneurysm clip has since been reported as being in the range of 1.8 to 38%^{28,35,36,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55} ( Table 18.1).

The strength of ICG videoangiography is its high image quality, especially in small vessels, and the ease of clinical use in routine situations. The procedure can be performed at any time during surgery, and repeated administration is possible after a time interval of 5 to 15 minutes to allow some clearance of the dye. ICG videoangiography allows the surgeon to examine and manipulate the cerebrovascular anatomy, for instance the clipped aneurysm, in a manner that is not possible with intraoperative DSA.

ICG videoangiography has been validated as a reliable technique for the distinct visualization and flow assessment of perforating arteries and inframillimetric vessels exposed during surgery. This is otherwise rarely achievable with other intraoperative techniques, including intraoperative DSA.^36,39 This is relevant given the rate of perforating vessel occlusion of up to 8% of all postclipping cases.⁵⁶

The incidence of adverse reactions to the ICG dye is similar to that for other types of contrast media: ranging from 0.05% for severe side effects (hypotension, arrhythmia, or, more rarely, anaphylactic shock) to 0.2% for moderate or mild side effects (nausea, pruritus, syncope, or skin eruption),38 and it can therefore be considered a safe intraoperative tool.