Fluorescein angiography allows visualization of blood flow in retinal and choroidal tissues, permitting diagnostic support in many ocular diseases. In particular, fluorescein angiography has become a very important tool in the diagnosis and treatment of chorio-retinal diseases. However, limitations of fluorescein angiography in imaging the choroidal circulation and associated pathologies prompted the use of alternative dyes to improve choroidal angiography.
Indocyanine green angiography is a diagnostic study where indocyanine green, a fluorescent dye, is injected intravenously, and observations of the retina are made at intervals as increasing intensity of retinal and choroidal circulation is displayed. Indocyanine green angiography is used for the imaging of retinal and choroidal vasculatures. It is effective when used as an adjunct to fluorescein angiography in the diagnosis and treatment of ill-defined choroidal neovascularization (i.e., associated with age-related macular degeneration). It is generally used in evaluating retinal neovascularization, serous detachment of retinal pigment epithelium, hemorrhagic detachment of retinal pigment epithelium, and retinal hemorrhage.
Indocyanine green angiography has been under development for the past 30 years as an imaging method for the choroidal vasculature. Although standard fluorescein angiography is widely used to evaluate exudative and proliferative lesions of the retina, its diagnostic ability in imaging the choroid is limited because of dye scatter by the overlying pigmented structures of the fundus, and also due to leakage of fluorescein through the fenestrated capillaries of the choroid. Improvements in indocyanine green angiography, specifically the development of high resolution digital imaging systems, have permitted the technical feasibility and commercialization of the technology.
The most commonly proposed application of indocyanine green angiography is the detection of choroidal neovascularization, a common component of age related macular degeneration. A series of randomized studies in the 1980s (called the Macular Photocoagulation Study) showed that patients with "classic" choroidal neovascularization could benefit from photocoagulation treatment. Those with diffuse or poorly defined disease or disease involving the foveal avascular zone were considered poor candidates for photocoagulation. With these criteria, it has been estimated that only about about half of patients would be candidates for treatment. In as much as the key to the success of photocoagulation was accurate delineation of choroidal neovascularization, it was hoped that the improved diagnostic capabilities of indocyanine green angiography would lead to the identification of more patients who would be appropriate candidates for treatment.
Given the above discussion, an appropriate outcome for indocyanine green angiography would be its diagnostic capabilities compared to fluorescein angiography in the evaluation of patients with choroidal neovascularization. Yannuzzi and colleagues (1992) performed indocyanine green angiography on 129 patients with age related macular degeneration and ill defined or occult neovascularization as identified by a previous fluorescein angiography. In 50 (39 %) of the patients, indocyanine green angiography provided additional information such that occult choroidal neovascularization could be reclassified as a classic pattern. A total of 12 patients underwent laser photocoagulation based on the indocyanine green videoangiography (ICGA) findings. Although the exact techniques may vary from study to study, several subsequent reports have also documented improved diagnostic capabilities of indocyanine green angiography compared to fluorescein angiography.
As discussed in the studies above, indocyanine green angiography is used as a second level diagnostic test to further evaluate patients with choroidal neovascularization. Typically all patients will first undergo a fluorescein angiography which will simultaneously evaluate the retinal vasculature, and give initial information regarding the choroidal vasculature. Fluorescein angiography can definitively identify some patients who are not candidates for photocoagulation (i.e. those with neovascularization involving the fovea) and also those who do not have neovascularization. Indocyanine green angiography is then appropriate in those patients with equivocal results with fluorescein angiography, or who require more accurate definition of the neovascularization before proceeding to photocoagulation therapy. Therefore the appropriateness of indocyanine green angiography is contingent upon the results of fluorescein angiography.
In an evidence review on the use of indocyanine green angiography in chorio-retinal diseases, Stanga et al (2003) stated that they do not recommend ICGA for scleritis and posterior scleritis, drusen differentiation, Behcet's disease (Behcet's syndrome), or sarcoidosis, because it has not been demonstrated to add useful clinical information.
Surgical management of macular holes consists of pars plana vitrectomy, removal of the posterior hyaloid facia, and peeling of the epi-retinal membranes (ERM). Additionally, removal of the internal limiting membrane (ILM) may enable an increase in the anatomical and functional success rates. However, recognition of fine ILM is difficult; thus increasing the time that the macula is exposed to intra-operative light. Staining the ILM with indocyanine green (ICG) dye during vitrectomy has been reported to facilitate recognition of the ILM and assures that all adjacent ERM are removed. Therefore, ICG-assisted ILM peeling has gained popularity among vitreo-retinal surgeons. However, there are some concerns about the intra-vitreal ICG application. Reports in the literature described a variety of application techniques using different concentrations. The post-operative outcomes were controversial reporting heterogeneous anatomical and functional outcomes after ICG application, as well as descriptions of adverse effects related to the dye.
Nakamura et al (2005) examined the duration of post-operative persistence of ICG dye used during vitreous surgery. They found that ICG dye used during macular surgery can persist in the macular region for up to 7 months following surgery, and seems to remain for a longer period of time in cases with macular hole than in cases with other diseases. Caution is needed regarding light exposure by post-operative fundus examinations, daylight, and other natural light. Cheng et al (2005) report 6 cases of ICG-related ocular toxicity after intra-vitreal ICG usage. Five cases had pre-operative diagnosis of macular hole, 1 case had pre-operative rhegmatogenous retinal detachment complicated with proliferative vitreo-retinopathy. All cases received vitrectomy, ICG-assisted ILM peeling and air-fluid exchange. All eyes had residual ICG left at the end of surgery. The authors noted that ocular toxicity caused by ICG may present as pigment epithelial atrophy, which is characteristically larger than the previous area of macular hole and surrounding cuff. Disc atrophy, retinal toxicity, and ocular hypotony were also observed in some cases. In addition, Tognetto et al (2005) reported a case of massive macular edema and visual loss following ICG-assisted macular pucker surgery.
An American Academy of Ophthalmology Preferred Practice Pattern on idiopathic macular hole (AAO, 2003) states that "there are no randomized controlled studies to prove the benefit of ILM peeling and there are many reports of similar results without peeling; current evidence is inconclusive." Regarding the use of ICG, the AAO Preferred Practice Pattern (2003) states: "Some surgeons recommend visualizing the ILM with indocyanine green (ICG) dye staining to aid peeling. There have been reports of damage to the retinal pigment epithelium with the use of ICG dye. The current evidence is inconclusive to recommend for or against the use of ICG during surgery."
In an observational case series (n = 31), Uemoto et al (2005) ascertained the changes in the retinal pigment epithelium (retinal pigment epithelium) and secondary changes in the choroid and fovea following ICG staining of the internal limiting lamina during surgery for an idiopathic macular hole (MH). The authors concluded that the use of ICG dye with illumination may increase the risk of retinal pigment epithelium damage and secondary choroidal and foveal morphological changes.
In a retrospective review, Husson-Danan et al (2006) examined the role of ICG in macular hole surgery. This study included a total of 38 consecutive eyes with macular hole, operated on with ILM, using or not using ICG, diluted in glucose 5 % and filtered. Anatomical and functional results were analyzed in each group, using visual field testing, fluorescein fundus angiography and particularly blue filter fundus photographs for the detection of retinal pigment epithelial changes and lesions of optic nerve fibers layer. Fifteen eyes underwent surgery without ICG and 23 eyes with ICG. The mean period of follow-up was 10 months. The duration of surgery was significantly lower in the group with ICG than without (p < 0.001). Overall, 84 % of the holes closed without difference between both groups. The improvement in vision at 1, 6 and 12 months was similar in both groups. Fewer defects in the optic nerve fibers layer were observed in the group with ICG than without (p = 0.02). Staining with ICG revealed the presence of an associated ERM in 61 % of eyes, whereas it was clinically visible in only 17.5 % before surgery. These researchers concluded that using ICG for ILM peeling produced similar visual results to those obtained without ICG. It reduced significantly the duration of surgery and the trauma to the optic nerve fibers layer, without increasing the risk of retinal pigment epithelial damage. However, in light of recent reports concerning the possible toxicity of ICG, its use should be limited in clinical practice to difficult cases.
In a non-randomized comparative study (n = 32), Oie et al (2007) examined the effect of using ICG to stain the ILM during vitrectomy in eyes with retinal detachment resulting from macular hole (MHRD). The medical records of the cases were reviewed retrospectively. During the initial vitrectomy, the ILM was peeled in 22 eyes with ICG (group A) and in 10 eyes without ICG (group B). Main outcome measures included anatomical re-attachment, visual acuity, and optical coherence tomography-determined closure of macular hole. The initial re-attachment rate in group A (86 %) was significantly higher than in group B (40 %; p = 0.013, Fisher exact test). The post-operative visual acuity at 6 months and the visual improvements at 6 and 12 months in eyes with an initial re-attachment were not significantly different between the 2 groups (p = 0.123, Mann-Whitney rank-sum test; p = 0.17, t test; p = 0.237, t test). The post-operative visual acuity at 12 months with an initial re-attachment in group A was significantly better than in group B (p = 0.039, t test). The macular hole closure rate with an initial re-attachment was 6 of 17 eyes (35 %) in group A and 0 of 4 eyes (0 %) in group B, and this difference was not significant (p = 0.281, Fisher exact test). The authors concluded that these results show that ICG staining improves the initial reattachment rate and is associated with better post-operative visual acuity at 12 months. Thus, ICG staining should be used during vitrectomy for MHRD because the complete removal of the ILM with ICG ensures the removal of the tangential traction by an ERM and the inverse traction by the retina that cannot follow the posterior enlargement of a staphyloma. Moreover, these researchers noted that the number of patients in this study was small, and a further prospective, randomized controlled trial is needed to ascertain the effect of ICG. Confirmation of the present findings with a randomized study using a larger sample size and a longer follow-up would be ideal.
Beutel et al (2007) reported on anatomical and visual outcomes after vitrectomy and ILM peeling for idiopathic macular hole repair. A total of 40 patients with stage II to IV idiopathic macular holes were randomly assigned (1:1) in a 2-arm, single-center, randomized controlled. Internal limiting membrane delamination was performed using ICG solution (n = 20) or trypan blue (TB) (n = 20). Two patients did not complete the study, for a total of 19 in each group. Follow-up examinations included Early Treatment of Diabetic Retinopathy Study visual acuity, scanning laser ophthalmoscope micro-perimetry, optical coherence tomography, and fluorescein angiography. Main outcome measure was visual acuity 3 months after surgery. Visual acuity did not show a significant difference between study groups (95 % confidence interval [CI]: -2 to 1 lines). The rate of macular hole closures was identical (84 %; 95 % CI: 60 % to 97 %). Within-group visual recovery was significant only in the TB group. Central scotomata despite hole closure persisted in 8 patients (42 %) in the ICG group and in 5 (26 %) in the TB group. The authors concluded that although no statistically significant difference was detected for the primary end point, the better visual recovery in the TB group and the higher rate of persistent central scotomata in the ICG group justify a larger clinical trial.
In a prospective, non-comparative, interventional case series, Kimura et al (2005) assessed the effectiveness of surgical removal of the ILM in diabetic cystoid macular edema (CME). A total of 21 eyes of 18 consecutive patients with diabetic CME were included in this study. Vitrectomy with separation of the posterior hyaloid and induction of posterior vitreous detachment had been performed previously on 9 eyes. Pars plana vitrectomy for removal of the ILM was performed. CME resolved in eyes that underwent initial vitrectomy and in those with long-standing (greater than 1 year) CME after previous vitrectomy. Post-operative best-corrected visual acuity improved by greater than or equal to 2 lines of a Snellen equivalent in 14 eyes (67 %) (p < 0.01). The mean foveal thickness (distance between the inner retinal surface and the retinal pigment epithelium) decreased from 553 microm to 221 microm at 4 weeks (p < 0.001). No recurrences or deterioration of CME was observed during the entire follow-up period (mean, 17.8 months; range of 8 to 34 months). These investigators concluded that surgical removal of the ILM might be an effective procedure for reducing CME in patients with diabetes. They noted that a prospective, randomized, controlled study is needed to further evaluate the effectiveness of the procedure.
Kwok et al (2005) evaluated the visual outcome and recurrence rate of ERM formation following vitreo-retinal surgery with and without ILM peel. The medical records of 42 consecutive patients who underwent surgery for macular ERM by a single surgeon were reviewed. All patients underwent pars plana vitrectomy and ERM removal with a subset undergoing ILM peel. Recurrence of macular ERM within 18 months and the final visual outcome after surgery were compared between patients with and without ILM removal. Twenty-five patients (59.5 %) underwent ERM surgery with ILM peeling and 17 patients (40.5 %) underwent ERM surgery without ILM peeling. The mean pre-operative logMAR visual acuity was 0.77 and 0.96 for the ILM peeling and non-ILM peeling groups, respectively. Visual acuity improved significantly in both the ILM and non-ILM peeling groups after ERM surgery (p < 0.001 and p = 0.003, respectively). Eighteen months after surgery, 3/17 eyes without ILM peeling (17.6 %) developed recurrent macular ERM, compared with none of the 25 eyes with ILM peeling (log-rank test, p = 0.030). These investigators concluded that ILM removal during macular ERM surgery may minimize the recurrence of ERM, without adverse visual outcome. Moreover, they noted that further controlled prospective studies are needed to determine the role of ILM peeling in ERM surgery.
In a randomized controlled clinical trial, Hillenkamp and colleagues (2007) performed a prospective investigation of the functional and morphological outcome of idiopathic epiretinal membrane (IEM) surgery with or without the assistance of ICG. A total of 60 patients who underwent vitrectomy with removal of IEM combined with cataract surgery were randomly allocated to two groups: (i) 27 patients were operated on with ICG 0.1 % in glucose 5 %, and (ii) 33 patients without ICG. Functional outcome was assessed 3 to 4 months post-operatively with improvement of best-corrected visual acuity (BCVA), Amsler grid test, and automated and kinetic perimetry. Post-operative residual or recurrent IEM was assessed with bio-microscopy, and macular edema with optical coherence tomography (OCT). Improvement in BCVA was the main outcome measure. BCVA improved in 49 patients, remained unchanged in 5 and decreased in 5. Improvement in BCVA and reduction of macular edema were statistically significant within both groups (p < 0.01). Improvement in BCVA was not statistically significantly different whether ICG was used or not [0.17 (logarithm of minimum angle of resolution; logMAR) with ICG and 0.24 (logMAR) without ICG] (p = 0.59). There was no statistically significant difference in pre-operative or post-operative BCVA, reduction of macular edema, post-operative Amsler grid test, or incidence of residual or recurrent IEM between the two groups. Visual field defects were detected in 2 patients operated on with ICG. The authors concluded that removal of IEM with or without the assistance of ICG equally improved visual function and macular morphology.
Indocyanine green angiography has been used intra-operatively in the management of intracranial aneurysms. Raabe et al (2005) described the technical integration of ICG near-infrared technology into the optical path of the surgical microscope and reported on the image quality achieved by this method. These researchers hypothesized that ICG angiography permits a simple and quick intra-operative assessment of vessel patency and aneurysm occlusion after clip placement. A special arrangement of filters was designed to allow the passage of near-infrared light required for the excitation of ICG fluorescence (700 to 850 nm) from a modified microscope light source into the surgical field and the passage of ICG fluorescence (780 to 950 nm) from the surgical field back into the optical path of the surgical microscope. Thus, ICG angiography could be completely performed with a surgical microscope. A total of 20 patients with intracranial aneurysms were included in the technical evaluation of the new method. Image quality and spatial resolution were excellent and permitted a real-time assessment of vessel patency and aneurysm occlusion if the structures of interest were visible to the surgeon's eye under the microscope, including perforating arteries with a diameter of less than 1 millimeter. In 1 patient, vessel occlusion by the clip was found and in 1 case residual filling of the aneurysm was diagnosed. Both cases could be treated by clip correction within 2 mins after primary placement of the clip. In all cases, the intra-operative findings correlated with the post-operative digital subtraction angiography. The authors concluded that ICG angiography using a surgical microscope is valuable for the intra-operative imaging of arterial and venous flow in all visible vessels including small perforating arteries. The simplicity of the method and the speed with which the investigation can be performed indicate that this technique may help to improve the quality and outcome of surgical procedures and reduce the need for intra- or post-operative angiography in selected cases.
de Oliveira et al (2007) described the usefulness of near-infrared ICGA for the intra-operative assessment of blood flow in perforating arteries that are visible in the surgical field during clipping of intracranial aneurysms. In addition, these researchers analyzed the incidence of perforating vessels involved during the aneurysm surgery and the incidence of ischemic infarct caused by compromised small arteries. A total of 60 patients with 64 aneurysms were surgically treated and prospectively included in this study. Intra-operative ICGA was performed using a surgical microscope with integrated ICGA technology. The presence and involvement of perforating arteries were analyzed in the microsurgical field during surgical dissection and clip application. Assessment of vascular patency after clipping was also investigated. Only those small arteries that were not visible on pre-operative digital subtraction angiography were considered for analysis. The ICGA was able to visualize flow in all patients in whom perforating vessels were found in the microscope field. Among 36 patients whose perforating vessels were visible on ICGA, 11 (30 %) presented a close relation between the aneurysm and perforating arteries. In 1 (9 %) of these 11 patients, ICGA showed occlusion of a P1 perforating artery after clip application, which led to immediate correction of the clip confirmed by immediate re-establishment of flow visible with ICGA without clinical consequences. Four patients (6.7 %) presented with post-operative perforating artery infarct, 3 of whom had perforating arteries that were not visible or distant from the aneurysm. The authors concluded that the involvement of perforating arteries during clip application for aneurysm occlusion is a usual finding. Intra-operative ICGA may provide visual information with regard to the patency of these small vessels.
Imizu et al (2008) evaluated the clinical use and the completeness of clipping with total occlusion of the aneurysmal lumen, real-time assessment of vascular patency in the parent, branching and perforating vessels, intra-operative assessment of blood flow, image quality, spatial resolution and clinical value in difficult aneurysms using near infrared ICGA integrated on to an operative Pentero neurosurgical microscope. A total of 13 patients with aneurysms were operated upon. An infrared camera with near infrared technology was adapted on to the OPMI Pentero microscope with a special filter and infrared excitation light to illuminate the operating field which was designed to allow passage of the near infrared light required for excitation of ICG, which was used as the intravascular marker. The intravascular fluorescence was imaged with a video camera attached to the microscope. ICG fluorescence (700 to 850 nm) from a modified microscope light source on to the surgical field and passage of ICG fluorescence (780 to 950 nm) from the surgical field, back into the optical path of the microscope was used to detect the completeness of aneurysmal clipping. Incomplete clipping in 3 patients (1 female and 2 males) with unruptured complicated aneurysms was detected using ICGA. There were no adverse effects after injection of ICG. The completeness of clipping was inadequately detected by Doppler ultrasound mini-probe and rigid endoscopy and was thus complemented by ICGA. The authors concluded that the operative microscope-integrated ICGA as a new intra-operative method for detecting vascular flow, was found to be quick, reliable, cost-effective and possibly a substitute or adjunct for Doppler ultrasonography or intra-operative digital subtraction angiography (DSA), which is presently the gold standard. The simplicity of the method, the speed with which the investigation can be performed, the quality of the images, and the outcome of surgical procedures have all reduced the need for angiography. This technique may be useful during routine aneurysm surgery as an independent form of angiography and/or as an adjunct to intra-operative or post-operative DSA.
Dashti et al (2009) evaluated the reliability of ICGA in the evaluation of neck residuals and patency of branches after micro-neurosurgical clipping of intra-cranial aneurysms (IAs). During a period of 14 months, 289 patients with intra-cranial aneurysms were operated on in the authors' institution. Intra-operative ICGA was performed during micro-neurosurgical clipping of 239 IAs in 190 patients. Post-operative computed tomography and computed tomography angiography (CTA) were performed for all patients. Intra-operative interpretation of ICGA in assessing the neck residual or the patency of vessels after clipping of each single aneurysm were recorded and correlated with post-operative CTA and/or DSA. Post-operative imaging studies revealed no incomplete occlusions of aneurysm domes. Unexpected neck residuals were observed in 14 aneurysms (6 %). There were no parent artery occlusions. Unexpected branch occlusions including both major and minor branching arteries were observed in 15 aneurysms (6 %). The authors concluded that ICGA is a simple and fast method of blood flow assessment with acceptable reliability. Indocyanine green videoangiography can provide real-time information to assess blood flow in vessels of different size as well as the occlusion of the aneurysm. Intra-operative assessment of blood flow in the perforating branches is one of the most important advantages. In selected cases such as giant, complex, and deep-sited aneurysms or when the quality of image in ICGA is not adequate, other methods of intra-operative blood flow assessment should be considered.
Wang et al (2009) assessed the effects of surgical microscope-based ICGA in aneurysm surgery and compared the values of ICGA and post-operative DSA. A total of 101 patients with intracranial aneurysm underwent clipping of 113 aneurysms. A microscope-integrated light source containing infrared excitation light illuminated the operating field. The dye ICG was injected intravenously, and the intravascular fluorescence was recorded by a video camera attached to the microscope with optical filtering to block ambient and laser light for collection of only ICG-induced fluorescence. All patients underwent DSA 6-13 days post-operatively. The results of patency of parent, branching, and perforating arteries and documentation of aneurysm obliteration shown by ICGA and DSA were compared. A total of 219 times of ICGA was performed in these 101 patients with excellent image quality and resolution, allowing intra-operative real-time assessment of the cerebral circulation. The ICG angiographic results could be divided into arterial, capillary, and venous phases, comparable to those observed with DSA. In all cases, the post-operative angiographic results corresponded to the intra-operative ICG video angiographic findings. In 3 cases, the information provided by intra-operative ICGA significantly changed the surgical procedure. The authors concluded that simple and repeatable, microscope-based ICGA provides real-time information about vessels and aneurysm sac. This technique may be useful during routine aneurysm surgery as an adjunct to intra-operative microvascular Doppler ultrasonography and DSA.
Li et al (2009) assessed the clinical value of ICG in intracranial aneurysm surgery by comparing the findings with post-operative angiographic results. A total of 120 patients with 148 intracranial aneurysms were included. Indocyanine green angiography was performed before and/or after the aneurysm clipping. A near-infrared excitation light illuminated the operation field, ICG was injected intravenously. The intravenous fluorescence was imaged with a video camera integrated into the microscope. A total of 208 investigations of ICGA were performed. Aneurysm clipping was applied in 120 patients. Incomplete clipping was detected in 4 patients. Parent and/or branching artery stenosis was found in 5 patients. Delayed perfusion of ICG was detected in 1 patient. Post-operative DSA was performed in 108 patients. The post-operative angiographic results were consistent with findings on intra-operative ICG angiograms in 100 patients (92.6 %). In 3 cases, a mild stenosis was seen on DSA, which was not detected intra-operatively using ICG angiogram. In 1 patient, middle cerebral artery stenosis was found. Three patients had small residual aneurysms found by post-operative DSA. The remaining 1 developed a severe cerebral vasospasm. The authors concluded that ICGA is a simple, reliable and cost-effective method. It provides real-time information in detecting the patency of parent, branching, perforating arteries and residual aneurysm. This technique may be a useful adjunct to improve the quality of intracranial aneurysm surgery.
Ma et al (2009) illustrated the use of intra-operative ICGA in the surgical management of intracranial aneurysms, including microsurgical clipping and re-vascularization. This study included a series of 45 patients who were surgically treated between June 2007 and May 2008 for intracranial aneurysms; 43 had anterior circulation aneurysms, and 2 had posterior circulation aneurysms. Forty-one patients were treated with microsurgical clipping; and 4 patients underwent re-vascularization combined with aneurysm dissection or trapping. Intra-operative ICGA was used to visualize the aneurysm clipping, patency of parent artery or graft. The ICGA technique was described, with particular reference to evaluation of the aneurysm clipping and re-vascularization. A total of 89 ICGA procedures were performed in 45 patients with intracranial aneurysms. The aneurysms were completely obliterated for all patients, and the grafts were patented for all except 1 patient. Pre-clipping ICGA showed the relationship of aneurysm and its parent artery clearly. After aneurysms being clipped, intra-operative ICGA found remnant of aneurysms, stenosis or occlusion of parent arteries and grafts in 8 cases, which were revised in the same surgical procedure. The results of ICGA correlated well with post-operative DSA in 97 % patients. The authors concluded that ICGA can provide real-time information and guide revision in the same surgical procedure for the management of intracranial aneurysms.
Hanel and colleagues (2010) stated that identification and complete interruption of fistulae are essential but not always obvious during the surgical treatment of spinal dural arteriov-enous fistulae (dAVFs). These researchers examined cases in which they identified and confirmed surgical obliteration of a spinal dAVF with the aid of microscope-integrated near-infrared ICGA, which was performed during 6 surgical interventions in which 6 intra-dural dorsal AVFs (type I) were interrupted. An operating microscope-integrated light source containing infrared excitation light illuminated the operating field and was used to visualize an intravenous bolus of ICG. The locations of fistulae, feeding arteries, and draining veins and documentation of occlusion of the fistulae were compared with findings on pre-operative and post-operative digital subtraction angiography. Indocyanine green videoangiography identified the fistulous point(s), feeding arteries, and draining veins in all 6 cases, as confirmed by immediate post-operative selective spinal angiography. In 1 case, intra-operative ICG ruled out an additional questionable fistula at a contiguous level suspected on the pre-operative angiography. The authors concluded that microscope-based ICGA is simple and provides real-time information about the precise location of spinal dAVFs. During spinal dAVF surgery, this technique can be useful as an independent form of angiography or as an adjunct to intra- or post-operative digital subtraction angiography. They stated that larger series are needed to determine whether use of this modality could reduce the need for immediate post-operative spinal angiography after obliteration of intra-dural dorsal AVFs.
Polom et al (2011) stated that ever since Kitai first performed fluorescent navigation of sentinel lymph nodes (SLNs) using ICG dye with a charge-couple device and light emitting diodes, the intra-operative use of near infrared fluorescence has served a critical role in increasing the understanding in various fields of surgical oncology. These investigators reviewed the emerging role of the ICG fluorophore and its use in SLN mapping and biopsy in various cancers. In addition, they introduced the novel role of ICG-guided video angiography as a new intra-operative method of assessing microvascular circulation. The authors discussed the promising potential in addition to assessing several challenges and limitations in the context of specific surgical procedures and ICG as a whole. PubMed and Medline literature databases were searched for ICG use in clinical surgical settings. Despite ICG's significant impact in various fields of surgical oncology, ICG is still in its nascent stages, and more in-depth studies need to be carried out to fully evaluate its potential and limitations.
Vogt-Koyanagi-Harada (VKH) disease is a multi-systemic autoimmune disorder characterized by granulomatous panuveitis with exudative retinal detachments that is frequently associated with neurological and cutaneous manifestations. Bouchenaki and Herbort (2011) reported the management of VKH disease based on ICGA. Subjects with acute episodes of inflammation (inaugural or recurrent) who had received standard ICGA-guided care were studied retrospectively. Standard of care included high-dose systemic corticosteroids at presentation and close ICGA follow-up with addition of immunosuppressive agents and/or intensification of ongoing therapy when recurrent choroidal lesions were detected by ICGA. Visual acuity, number of sub-clinical recurrences, type and duration of therapy, proportion of quiescent patients after therapy, and ICGA findings were recorded. A total of 9 patients (8 females and 1 male) were studied; 5 had inaugural disease and 4 presented with recurrent acute episodes. Visual acuity increased from 0.86 +/- 0.36 to 1.14 +/- 0.34 in the right eyes, and from 0.77 +/- 0.34 to 1.05 +/- 0.33 in the left eyes. The number of ICGA-detected occult choroidal recurrences amounted to 13. Mean duration of treatment was 30.1 +/- 34.6 months leading to recurrence-free status after discontinuation of therapy in 6 cases with mean duration of 29.5 months. The authors concluded that continuous monitoring and aggressive therapy guided by ICGA in VKH disease prolonged treatment as compared to textbook guidelines but offered the prospect of reaching inflammation-free status after discontinuation of therapy.
Chee and Jap (2013) compared outcomes of ICGA versus clinically monitored immunotherapy in VKH disease. Consecutive patients of Singapore National Eye Centre with VKH receiving high-dose corticosteroids within 4 weeks of onset of symptoms had therapy titrated to clinical signs of activity (controls) or ICGA findings (ICGA). Charts were reviewed for demographics, interval to treatment, duration of therapy and number of systemic immunosuppressants required. Outcome measures were BCVA, disease activity, presence of sun-set glow (SSG) fundus and peri-papillary atrophy (PPA) at 2 years. A total of 52 patients were included (38 controls, 14 ICGA). Duration of treatment was shorter in the control group (17 versus 42 months, p < 0.001) and they required fewer systemic immunosuppressants than the ICGA group (16 % versus 96 %, p < 0.001). The majority (49 eyes, 96.1 %) had 6/12 or better vision and were clinically quiet (43 eyes, 84.3 %) in both groups. Sun-set glow fundus and PPA were similar in both groups. Treatment within 2 weeks of onset was the main factor affecting their occurrence on multi-variate analysis (OR 0.18, 95 % CI: 0.03 to 0.9, p = 0.047; OR 0.08, 95 % CI: 0.01 to 0.51, p = 0.007, respectively). The authors concludedthat ICGA-guided immunotherapy did not result in significantly better outcomes with respect to visual acuity and disease activity in VKH eyes treated within 1 month of onset.
Braun et al (2013) noted that patients requiring lower extremity re-vascularization are increasingly complex. Traditional means of evaluating perfusion before and after re-vascularization are often limited by the presence of medial calcinosis, open wounds, prior toe or fore-foot amputations, and infection. These researchers evaluated the initial application of ICGA to patients with severe lower extremity ischemia to develop quantitative, reproducible parameters to assess perfusion. Indocyanine green angiography uses a charge-coupled device camera, a laser, and intravenous contrast to visually assess skin surface perfusion. From January 2011 to April 2012, they performed ICGA within 5 days of 31 re-vascularization procedures in patients with Rutherford class 5 and 6 ischemia. They also compared ICGA before and after re-vascularization in a subset of 13 patients. These researchers evaluated multiple, quantitative parameters to assess perfusion. A total of 24 patients underwent ICGA associated with 31 re-vascularization procedures (26 endovascular, 4 open, 1 hybrid) for 26 lower limb wounds; 92 % were diabetic and 20 % were dialysis-dependent. In 50 % of these patients, it was not possible to measure ankle-brachial indexes due to medial calcinosis. Paired analysis of ingress (increase in pixel strength [PxS]), ingress rate (slope of increase in PxS), curve integral (area under the curve in PxS over time), end intensity (PxS at end of study), egress (decrease in PxS from maximum), and egress rate (slope of decrease in PxS) increased significantly (p < 0.05) after re-vascularization. The authors concluded that ICGA provides rapid visual and quantitative information about regional foot perfusion. They believed this is the first report describing quantification of foot perfusion before and after lower extremity re-vascularization for severe limb ischemia. Moreover, they stated that further study is needed to help define the utility of this intriguing new technology to assess perfusion, response to re-vascularization, and potentially, to predict likelihood of wound healing.
The Spy Elite System (LifeCell Corp., Branchburg, NJ) is designed to aid surgeons in identifying and attaching viable tissue during breast reconstruction surgery. The Spy Elite System (using near-infrared light technology) enables surgeons performing breast reconstruction to capture images while in the operating room and allow them to objectively evaluate the quality of blood flow in vessels and tissue. In this regard, the Spy Elite System gives the surgeon real-time confirmation that perfusion of blood to the flap is adequate. Inadequate blood flow into or out of the flap could potentially result in partial or total loss of the flap. The blood flow pattern to the breast skin will be monitored by means of ICGA; the dye highlights areas of tissue with a healthy blood supply, while those areas where circulation is less robust remain darker. Seeing these differences enables surgeons to ascertain which tissue is healthiest and also to evaluate circulation following the procedure.
Newman and associates (2010) stated that skin-sparing mastectomy has been associated with flap ischemia and necrosis. Current clinical methods for assessment of flap viability following mastectomy are largely subjective and lack objective data to guide intra-operative decisions. Intra-operative laser-assisted ICGA (LA-ICGA) was performed on 20 skin sparing mastectomy flaps; L A-ICGA data were retrospectively compared with clinical outcome. Pre-operative, intra-operative, and post-operative digital photographs along with clinical course were evaluated in an effort to identify potential complications. Laser-assisted-ICGA was performed on 20 breasts in 12 patients. Eleven breasts (55 %) demonstrated no wound-healing issues. Nine breasts (45 %) experienced wound-healing issues, which were stratified as follows: 1 (5 %) mild, 1 (5 %) moderate, and 7 (35 %) severe. Of these 7 severe wound-healing issues, 5 (25 %) required debridement and 2 (10 %) required complete removal of the prosthetic device. Retrospective analysis demonstrated a 95 % correlation between intra-operative imaging and clinical course with 100 % sensitivity and 91 % specificity. There was a false-positive rate of 9 %. This series suggested LA-ICGA is a useful adjunct to determine mastectomy flap viability. The authors stated that further quantitative advances in this technology may provide objective numerical thresholds to guide intra-operative mastectomy flap debridement when indicated.
Liu et al (2011) noted that in flap reconstruction of complex defects the perfusion of the reconstructive flap is critical to the ultimate success of the reconstruction. This is especially true in perforator-based flaps where it can be difficult to assess the adequacy of perfusion in the operating room. However, the ability to definitively determine the degree of flap perfusion is imperative to clinical decision-making. The authors stated that an emerging technology using near-infrared angiography with ICG dye may significantly improve the immediacy and accuracy of the assessment of flap perfusion.
Phillips et al (2012) noted that intra-operative vascular imaging can assist assessment of mastectomy skin flap perfusion to predict areas of necrosis. No head-to-head study has compared modalities such as LA-ICGA and fluorescein dye angiography with clinical assessment. The authors conducted a prospective clinical trial of tissue expander-implant breast reconstruction with intra-operative evaluation of mastectomy skin flaps by clinical assessment, LA-ICGA, and fluorescein dye angiography. Intra-operatively predicted regions of necrosis were photographically documented, and clinical assessment guided excision. Post-operative necrosis was directly compared with each prediction. The primary outcome was all-inclusive skin necrosis. A total of 51 tissue expander-implant breast reconstructions (32 patients) were completed, with 21 cases of all-inclusive necrosis (41.2 %). Laser-assisted ICGA and fluorescein dye angiography correctly predicted necrosis in 19 of 21 of cases where clinical judgment had failed. Only 6 of 21 cases were full-thickness necrosis, and 5 of 21 required an intervention (9.8 %). Risk factors such as smoking, obesity, and breast weight greater than 1,000 g were statistically significant. Laser-assisted ICGA and fluorescein dye angiography over-predicted areas of necrosis by 72 % and 88 % (p = 0.002). Quantitative analysis for LA-ICGA in necrotic regions showed absolute perfusion units less than 3.7, with 90 % sensitivity and 100 % specificity. The authors concluded that LA-ICGA is a better predictor of mastectomy skin flap necrosis than fluorescein dye angiography and clinical judgment. They stated that both methods over-predict without quantitative analysis; LA-ICGA is more specific and correlates better with the criterion standard diagnosis of necrosis.
Sood and Glat (2013) evaluated the use of intra-operative laser angiography using the Spy Elite System for the assessment of perfusion in mastectomy flaps for immediate breast reconstruction. The Spy Elite System uses the contrast ICG, which has an excellent safety profile and pharmacokinetics that allow for repeat evaluations during the same surgical procedure. In recent work, the Spy Elite System has demonstrated high sensitivity and specificity for detection of tissues at risk for ischemia and necrosis during reconstructive surgery. Using a retrospective, chart-review design, the authors compared consecutive cases of immediate breast reconstruction using a prosthesis, before and after implementation of the Spy Elite System. A total of 91 subjects were included in the analysis: 52 prior to Spy (Pre-Spy) and 39 after implementation of Spy (Post-Spy). Baseline characteristics were similar between the groups. Both groups had high rates of co-morbidities, chemotherapy, and radiation therapy. The rate of post-operative complications was 2-fold higher in the Pre-Spy group compared to the Post-Spy group (36.5 % versus 17.9 %); this difference was of borderline significance (p = 0.0631). However, mean number of repeat visits to the OR per patient was significantly higher in the Pre-Spy group (1.21 ± 1.47 versus 0.41 ± 0.71; p = 0.0023). Of the 7 patients with complications in the Post-Spy group, 5 were identified by the Spy Elite System as having poor flap perfusion; none was identified by clinical judgment alone. The authors concluded that the findings of this study suggested that the Spy Elite System can contribute to reduced ischemia-related complications in a population of women undergoing immediate breast reconstruction following mastectomy for breast cancer.
Wu and colleagues (2013) stated that LA-ICGA has been promoted to assess perfusion of random skin, pedicled, and free flaps. Few studies address its potential limitations. In this study, a total of 37 patients who underwent reconstructive procedures with LA-ICGA were studied retrospectively to determine the correlation between clinical findings and LA-ICGA. Indocyanine green angiography under-estimated perfusion when areas of less than or equal to 25 % uptake were not debrided and remained perfused. Indocyanine green angiography over-estimated perfusion when areas with greater than 25 % uptake developed necrosis. Of 14 random skin flaps, LA-ICGA under-estimated perfusion in 14 % and over-estimated in 14 %. In 16 patients undergoing perforator flap breast reconstruction, LA-ICGA correlated with computed tomographic angiogram (CTA) in 85 %. Indocyanine green angiography under-estimated perfusion in 7 % and over-estimated in 7 %. In 8/11 patients undergoing fasciocutaneous flaps, LA-ICGA aided in donor site selection. In 3/6 ALT flaps, a better unilateral blush was found that correlated with Doppler. In all 3, a dominant perforator was found. In 11 patients, there was a 9 % under-estimation of flap perfusion. In 3 pedicled flaps, there was a 66 % under-estimation and 33 % over-estimation of perfusion. The authors concluded that ICGA often confirmed the clinical/radiologic findings in abdominal perforator and fasciocutaneous flaps. It tended to under-estimate perfusion in pedicle and skin flaps. When clinical examination was obvious, LA-ICGA rendered clear-cut findings. When clinical examination was equivocal, LA-ICGA tended to provide ambiguous findings, demonstrating that a distinct cut-off point does not exists for every patient or flap. They stated that ICGA is a promising but expensive technology that would benefit from standardization. They noted that further research is needed before LA-ICGA can become a reliable tool for surgeons.
An UpToDate review on “Breast reconstruction in women with breast cancer” (Nahabedian, 2013) does not mention the use of ICGA/Spy Elite System.