For decades, dye-based angiography has been the gold standard clinical imaging modality for evaluating retinal and choroidal vascular pathologies.1-4 Despite their widespread success, fluorescein and indocyanine green angiography are invasive and time-consuming, in addition to having the potential for allergic reactions to the dyes.5 Moreover, FA is only a two-dimensional study focusing on the superficial retinal circulation, without the ability to visualize the deeper capillary structures, and ICGA is mostly useful for imaging the choroid.6,7 These limitations spurred the development of faster, safer imaging tools, capable of effectively imaging both the retinal and choroidal circulations, as represented by optical coherence tomography angiography. OCTA, however, still has several limitations of its own. Therefore, the important question of whether OCTA can completely replace conventional dye-based angiography in modern day clinical practice remains unanswered. Here, we&#;ll look at the pros and cons of both approaches.
weiqing Product Page
Figure 1. A) Fluorescein angiogram of a patient with diabetic retinopathy during the late phase shows an enlarged foveal avascular zone (yellow circle). There are also areas of hyperfluorescence caused by leaking microaneurysms, as well as fluorescence blocked by intraretinal hemorrhage. Notice the obscuration of the edges of the FAZ by the leakage. B) En face optical coherence tomography angiogram of the superficial capillary plexus (SCP), highlights the extent of the FAZ enlargement, as well as the areas of capillary nonperfusion. C) En face OCTA of the deep capillary plexus (DCP), shows the extension of the capillary closure in the deep plexus, which can&#;t be appreciated on the FA. D) FA of another patient with diabetic retinopathy during the late phase also shows an enlarged FAZ (yellow circle), as well as large areas of nonperfusion. There are widespread leaking microaneurysms. E) En face OCTA of the SCP centered on the macula, shows extensive capillary nonperfusion that&#;s better appreciated here than on the FA. F) En face OCTA of the DCP of the same patient, depicting even more widespread capillary dropout at the DCP, largely unappreciated on FA.
Weighing the Options
Using FA, the size and shape of the foveal avascular zone have long been considered important markers of foveal perfusion, with serious implications for photoreceptor integrity and central visual function.8-12 Unfortunately, FA only visualizes the boundaries of the superficial retinal capillary vasculature, and is easily obscured by leakage from surrounding hyperpermeable capillaries, further complicating the quantitative analysis of the FAZ.7,13 In contrast, OCTA provides a highly-detailed, depth-resolved, cross-sectioned, angiographic representation of the individual retinal capillary plexuses, facilitating qualitative and quantitative assessments of the perfusion state of the superficial, middle and deep capillary plexuses of the fovea, unobscured by leakage (Figure 1).14-18 This technology therefore yields an in-depth understanding of the three-dimensional consequences of retinal vascular pathologies, such as disorganization of the retinal inner layers in diabetic retinopathy, retinal vein and artery occlusions, sickle-cell retinopathy, acute macular neuroretinopathy and paracentral acute middle maculopathy.6,16,19-21
Dye-based angiography remains the gold standard for diagnosis, and occasionally for follow-up, of neovascular age-related macular degeneration.22,23 Despite their high sensitivity rates in detecting neovascular fronds, FA and ICGA still face a number of challenges in the clinic. Most relevant, nAMD is a complex pathology that requires long-term treatment and extended follow-up.24 The invasive, time-consuming nature of FA and ICGA impedes their practical use for the routine following of treatment responses. Moreover, fluorescence from subclinical choroidal neovascular lesions may be blocked by overlying pigment epithelial cells, impeding their early detection.25-27 Dye-based technology also doesn&#;t reveal the anatomical and structural effect of nAMD on the photoreceptor and RPE layers, which may, therefore, favor the use of OCTA for improved structural imaging of nAMD during therapy and follow up, as it may additionally reveal subtle changes that may affect vision, such as coexisting geographic atrophy.28-31
OCTA, on the other hand, is a quick and noninvasive tool that combines angiographic visualization of the exact site, size and extent of neovascular lesions, even those that may be missed by FA, together with cross-sectional representation of the retinal structure and the impact of the lesion on the outer retinal layers, as offered by OCT (Figure 2).25,32-34 It offers the convenience and practicality required for the frequent follow-up of these eyes.35,36 In terms of OCTA&#;s accuracy, one of these studies reported a 90-percent specificity rate when diagnosing different types of CNV,35 while another found that combining OCTA and structural OCT yielded a sensitivity rate of almost 86 percent in detecting type 1 CNV, compared to about 67 percent using FA.34 Another advantage of OCTA is its innate ability to visualize both retinal and choroidal vasculature equally, enhancing its ability to visualize retinal neovascular lesions, such as retinal angiomatous proliferation, subretinal neovascularization and other vascular changes in type 2 macular telangectasias, as well as choroidal lesions like CNV and polypoidal growths.37-40
Figure 2. A & B) Fluorescein angiogram of the right eye of a patient with central serous chorioretinopathy during the early venous (A) and late (B) phases. There is focal hyperfluorescence inferotemporal to the fovea, with equivocal increased fluorescence in the late phase. C & D) En face optical coherence tomography angiography at the level of the choriocapillaris (C) and cross section (D), shows a clear secondary choroidal neovascularization (yellow circles) located between Bruch&#;s membrane and the retinal pigment epithelium, confirming the diagnosis. E) En face OCT shows that the location of the CNV corresponds to the hyperfluorescent area seen on the FA. F) Spectral-domain OCT shows subretinal fluid as well as the elevated RPE, corresponding to the CNV. G & H) FA of the left eye of the same patient also shows two areas of hyperfluorescence that are suspicious for secondary CNV. I & J) En face OCTA at the level of the choriocapillaris (I) and cross sections (J) reveal the absence of CNV. (cyan circle). K) En face OCT shows absence of CNV (or RPE elevation) corresponding to the hyperfluorescence on FA. L) SD-OCT shows a pocket of subretinal fluid, with no signs suggestive of CNV.
Fluorescein angiography, however, has a better sensitivity when detecting vascular lesions with low flow characteristics. OCTA operates by capturing two consecutive B-scans at each sampling location, from which the red blood cell flow information is extracted using various machine-specific algorithms. Vascular lesions with low, turbulent blood flow, such as microaneurysms and some polypoidal lesions, may thus fall below the detection threshold of OCTA.38,41,42 Dye-based techniques, on the other hand, are capable of capturing even small vascular lesions, such as microaneurysms, with very high sensitivity rates, regardless of their flow speeds.41
Another clear advantage of FA and ICGA over OCTA is their ability to capture a much wider area of the retinal and choroidal vasculature. The largest scanning area of commercially available OCTA is 8x8 mm, which covers a field of view of about 30 degrees, with the largest area available in prototype research OCTA machines reaching a FOV of 45 degrees.43 Despite the ability to montage these scans, the quality of the acquired images is negatively affected by increasing the size of the scanning area.44,45 This is an area where dye-based imaging easily outperforms OCTA; the former routinely delivers images with FOVs of 30 to 45 degrees, and has the ability to achieve widefield imaging of 60 to 120 degrees FOV, and most recently, ultra widefields of up to 200 degrees.46 The clinical benefits of these wider FOVs can&#;t be overstated. They provide invaluable information about peripheral changes due to diabetic retinopathy, as well as changes from such conditions as sickle-cell retinopathies and retinal vasculitis.47-50 In diabetic retinopathy, widefield FA is capable of demonstrating retinal ischemia and peripheral retinal neovascularization, with clear implications for the grading of retinopathy severity and management decisions (Figure 3).51-54
Another advantage of dye-based angiography is that its images are less liable to show artifacts than OCTA, and are, arguably, easier to interpret. Unfortunately, the intricate process by which OCTA detects motion of red blood cells to represent flow inherently brings with it an array of motion and projection artifacts.6,55 Various factors, including patient cooperation and the various imaging artifacts&#;especially those related to decorrelation tails (i.e., projection artifacts)&#;complicate the learning curve required to capture and interpret these images on OCTA.31,55,56 FA and ICGA, on the other hand, require much less patient cooperation, and are significantly less affected by artifacts.
Figure 3. A) Widefield fundus photograph of the left eye of a patient with an old ischemic central retinal vein occlusion, shows evidence of thin sclerotic vessels extending towards the periphery (White arrows). B) Widefield fluorescein angiography of the same eye during the late phase, shows markedly tortuous veins, with areas of leakage surrounding the fovea, and an area of nonperfusion temporal to the fovea. The widefield image allows the visualization of extensive capillary drop-out extending along the temporal periphery of the retina, denoting marked ischemia (yellow arrows).
OCTA Innovations
Swept-source OCTA approaches may offer several advantages over spectral-domain OCTA in terms of the depth and resolution of the imaging.57-59 Compared to SD-OCTA, which uses a near-infrared diode light source with a central wavelength of about 840 nm, SS-OCTA uses a frequency-swept laser light source operating at a wavelength of nm.60 The longer wavelength reduces the scattering and absorption of the light waves by the RPE, and enhances its penetration into the deeper layers of the choroid.57,61 Furthermore, while SD-OCTA device speeds are about 70,000 A-scans/second, SS-OCTA can do 100,000 scans/second&#;and up to 400,000 scans/second in some research prototypes.33 The longer wavelength in SS-OCTA allows deeper imaging into the choroid, while the higher speeds have allowed widefield images with much greater resolution, further narrowing the gap between OCTA and dye-based imaging modalities.62-65
In conclusion, OCTA provides a convenient and noninvasive tool for documenting and following retinal and choroidal vascular pathologies, with valuable cross-sectional and three-dimensional displays. Despite these advantages, there&#;s still a lot more work to be done before the technology can be used in routine practice in all patients. OCTA&#;s limited FOV which precludes imaging of the retinal periphery, its potential for projection artifacts, its inability to visualize low-flow lesions, and its steep learning curve are areas that could be enhanced. These issues are the focus of active and diligent research, as well as software and hardware upgrades that are being developed by instrument companies. REVIEW
Dr. Fawzi is a professor of ophthalmology at Northwestern University&#;s Feinberg School of Medicine. Dr. Fayed is a visiting scholar and retina research fellow at Northwestern and assistant lecturer at the Department of Ophthalmology, Kasr Al-Ainy School of Medicine, Cairo University, Egypt. Dr. Fawzi can be reached at or (312) 908 ; Fax: 312-503-.
This work was funded in part by NIH grant DP3DK (A.A.F.), and research instrument support was provided by Optovue (Fremont, California). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
1. Kikai K. Über die Vitalfärbung des hinteren Bulbusabschnittes. Arch Augenheilkd ;103:541-53.
2. Flocks M, Miller J, Chao P. Retinal circulation time with the aid of fundus cinephotography. American Journal of Ophthalmology ;48:3-6.
3. MacLean AL, Maumenee AE. Hemangioma of the choroid. Transactions of the American Ophthalmological Society ;57:171.
4. Novotny HR, Alvis DL. A method of photographing fluorescence in circulating blood in the human retina. Circulation ;24:82-6.
5. Yannuzzi LA, Rohrer KT, Tindel LJ, et al. Fluorescein angiography complication survey. Ophthalmology ;93:611-7.
6. De Carlo TE, Romano A, Waheed NK, Duker JS. A review of optical coherence tomography angiography (OCTA). International Journal of Retina and Vitreous ;1:5.
7. Weinhaus RS, Burke JM, Delori FC, Snodderly DM. Comparison of fluorescein angiography with microvascular anatomy of macaque retinas. Experimental eye research ;61:1-16.
8. Bresnick GH, Condit R, Syrjala S, Palta M, Groo A, Korth K. Abnormalities of the foveal avascular zone in diabetic retinopathy. Archives of Ophthalmology ;102:-93.
9. Mansour A, Schachat A, Bodiford G, Haymond R. Foveal avascular zone in diabetes mellitus. Retina ;13:125-8.
10. Lee CM, Charles HC, Smith RT, Peachey NS, Cunha-Vaz JG, Goldberg MF. Quantification of macular ischaemia in sickle cell retinopathy. British Journal of Ophthalmology ;71:540-5.
11. Gass JDM. A fluorescein angiographic study of macular dysfunction secondary to retinal vascular disease: II. Retinal vein obstruction. Archives of Ophthalmology ;80:550-68.
12. Balaratnasingam C, Inoue M, Ahn S, et al. Visual acuity is correlated with the area of the foveal avascular zone in diabetic retinopathy and retinal vein occlusion. Ophthalmology ;123:-67.
13. Hwang TS, Jia Y, Gao SS, et al. Optical coherence tomography angiography features of diabetic retinopathy. Retina ;35:.
14. Hwang TS, Gao SS, Liu L, et al. Automated quantification of capillary nonperfusion using optical coherence tomography angiography in diabetic retinopathy. JAMA Ophthalmology ;134:367-73.
15. Di G, Weihong Y, Xiao Z, et al. A morphological study of the foveal avascular zone in patients with diabetes mellitus using optical coherence tomography angiography. Graefe&#;s Archive for Clinical and Experimental Ophthalmology ;254:873-9.
16. Scarinci F, Nesper PL, Fawzi AA. Deep retinal capillary nonperfusion is associated with photoreceptor disruption in diabetic macular ischemia. American Journal of Ophthalmology ;168:129-38.
17. Nesper PL, Roberts PK, Onishi AC, et al. Quantifying microvascular abnormalities with increasing severity of diabetic retinopathy using optical coherence tomography angiography. Investigative Ophthalmology & Visual Science ;58:BIO307-BIO15.
18. Takase N, Nozaki M, Kato A, Ozeki H, Yoshida M, Ogura Y. Enlargement of foveal avascular zone in diabetic eyes evaluated by en face optical coherence tomography angiography. Retina ;35:-83.
19. Minvielle W, Caillaux V, Cohen SY, et al. Macular microangiopathy in sickle cell disease using optical coherence tomography angiography. American Journal of Ophthalmology ;164:137-44.
20. Chu S, Nesper PL, Soetikno BT, Bakri SJ, Fawzi AA. Projection-resolved OCT angiography of microvascular changes in paracentral acute middle maculopathy and acute macular neuroretinopathy. Investigative Ophthalmology & Visual science ;59:-22.
21. Onishi AC, Ashraf M, Soetikno BT, Fawzi AA. Multilevel ischemia in disorganization of the retinal inner layers on projection-resolved optical coherence tomography angiography. Retina. April 10, [epub ahead of print].
22. Bird A, Bressler N, Bressler S, et al. An international classification and grading system for age-related maculopathy and age-related macular degeneration. Survey of Ophthalmology ;39:367-74.
23. Cohen SY, Creuzot-Garcher C, Darmon J, et al. Types of choroidal neovascularization (CNV) in newly diagnosed exudative age-related macular degeneration (AMD). British Journal of Ophthalmology ;91:9:-6
24. Rofagha S, Bhisitkul RB, Boyer DS, Sadda SR, Zhang K, Group S-US. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: A multicenter cohort study (SEVEN-UP). Ophthalmology ;120:-9.
25. Malihi M, Jia Y, Gao SS, et al. Optical coherence tomographic angiography of choroidal neovascularization ill-defined with fluorescein angiography. British Journal of Ophthalmology ;101:1:45-50.
26. de Oliveira Dias JR, Zhang Q, Garcia JMB, et al. Natural history of subclinical neovascularization in nonexudative age-related macular degeneration using swept-source OCT angiography. Ophthalmology ;125:255-66.
27. Roisman L, Zhang Q, Wang RK, et al. Optical coherence tomography angiography of asymptomatic neovascularization in intermediate age-related macular degeneration. Ophthalmology ;123:-19.
28. Leibowitz HM, Krueger D, Maunder L, et al. The Framingham Eye Study monograph: An ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of adults, -. Survey of Ophthalmology ;24:335-610.
29. Lanchoney DM, Maguire MG, Fine SL. A model of the incidence and consequences of choroidal neovascularization secondary to age-related macular degeneration: Comparative effects of current treatment and potential prophylaxis on visual outcomes in high-risk patients. Archives of Ophthalmology ;116:-52.
30. Chhablani J, Kim JS, Freeman WR, Kozak I, Wang H-Y, Cheng L. Predictors of visual outcome in eyes with choroidal neovascularization secondary to age related macular degeneration treated with intravitreal bevacizumab monotherapy. International Journal of Ophthalmology ;6:62.
31. Nesper PL, Lutty GA, Fawzi AA. Residual choroidal vessels in atrophy can masquerade as choroidal neovascularization on optical coherence tomography angiography: introducing a clinical and software approach. Retina ;38:-300.
32. Moult E, Choi W, Waheed NK, et al. Ultrahigh-speed swept-source OCT angiography in exudative AMD. Ophthalmic Surgery, Lasers and Imaging Retina ;45:496-505.
33. Novais EA, Adhi M, Moult EM, et al. Choroidal neovascularization analyzed on ultrahigh-speed swept-source optical coherence tomography angiography compared to spectral-domain optical coherence tomography angiography. American Journal of Ophthalmology ;164:80-8.
34. Inoue M, Jung JJ, Balaratnasingam C, et al. A comparison between optical coherence tomography angiography and fluorescein angiography for the imaging of type 1 neovascularization. Investigative Ophthalmology & Visual Science ;57:OCT314-OCT23.
35. Nikolopoulou E, Lorusso M, Micelli Ferrari L, et al. Optical coherence tomography angiography versus dye angiography in age-related macular degeneration: Sensitivity and specificity analysis. BioMed Research International Mar 7;: [online publication].
36. Costanzo E, Miere A, Querques G, Capuano V, Jung C, Souied EH. Type 1 choroidal neovascularization lesion size: Indocyanine green angiography versus optical coherence tomography angiography. Investigative Ophthalmology & Visual Science ;57:OCT307-OCT13.
37. Miere A, Querques G, Semoun O, et al. Optical coherence tomography angiography changes in early type 3 neovascularization after anti-vascular endothelial growth factor treatment. Retina ;37:-9.
38. Inoue M, Balaratnasingam C, Freund KB. Optical coherence tomography angiography of polypoidal choroidal vasculopathy and polypoidal choroidal neovascularization. Retina ;35:-74.
39. Gaudric A, Krivosic V, Tadayoni R. Outer retina capillary invasion and ellipsoid zone loss in macular telangiectasia type 2 imaged by optical coherence tomography angiography. Retina ;35:-6.
40. Toto L, Di Antonio L, Mastropasqua R, et al. Multimodal imaging of macular telangiectasia type 2: Focus on vascular changes using optical coherence tomography angiography. Investigative Ophthalmology & Visual Science ;57:OCT268-OCT76.
41. La AM, Kurt RA, Mejor S, et al. Comparing fundus fluorescein angiography and swept-source optical coherence tomography angiography in the evaluation of diabetic macular perfusion. Retina. Jan 16, [epub ahead of print].
42. Rebhun CB, Moult EM, Novais EA, et al. Polypoidal choroidal vasculopathy on swept-source optical coherence tomography angiography with variable interscan time analysis. Translational Vision Science & Technology ;6:6:4.
43. Salas M, Augustin M, Felberer F, et al. Compact akinetic swept source optical coherence tomography angiography at nm supporting a wide field of view and adaptive optics imaging modes of the posterior eye. Biomedical Optics Express ;9:-92.
44. Poddar R, Migacz JV, Schwartz DM, Werner JS, Gorczynska I. Challenges and advantages in wide-field optical coherence tomography angiography imaging of the human retinal and choroidal vasculature at 1.7-MHz A-scan rate. Journal of biomedical optics ;22:.
45. Wang L, Murphy O, Caldito NG, Calabresi PA, Saidha S. Emerging Applications of Optical Coherence Tomography Angiography (OCTA) in neurological research. Eye and Vision ;5:11.
46. Manivannan A, Plskova J, Farrow A, Mckay S, Sharp PF, Forrester JV. Ultra-wide-field fluorescein angiography of the ocular fundus. American journal of ophthalmology ;140:525-7.
47. Abucham-Neto JZ, Torricelli AAM, Lui ACF, Guimarães SN, Nascimento H, Regatieri CV. Comparison between optical coherence tomography angiography and fluorescein angiography findings in retinal vasculitis. International Journal of Retina and Vitreous ;4:15.
48. Penman AD, Talbot JF, Chuang EL, Thomas P, Serjeant GR, Bird AC. New classification of peripheral retinal vascular changes in sickle cell disease. British Journal of Ophthalmology ;78:681-9.
49. Vine AK. Severe periphlebitis, peripheral retinal ischemia, and preretinal neovascularization in patients with multiple sclerosis. American Journal of Ophthalmology ;113:28-32.
50. Magargal LE, Donoso LA, Sanborn GE. Retinal ischemia and risk of neovascularization following central retinal vein obstruction. Ophthalmology ;89:-5.
51. Patel RD, Messner LV, Teitelbaum B, Michel KA, Hariprasad SM. Characterization of ischemic index using ultra-widefield fluorescein angiography in patients with focal and diffuse recalcitrant diabetic macular edema. American Journal of Ophthalmology ;155:-44.
52. Sim DA, Keane PA, Rajendram R, et al. Patterns of peripheral retinal and central macula ischemia in diabetic retinopathy as evaluated by ultra-widefield fluorescein angiography. American Journal of Ophthalmology ;158:144-53.
Want more information on Indocyanine Green Angiography? Feel free to contact us.
53. Wessel MM, Nair N, Aaker GD, Ehrlich JR, D&#;amico DJ, Kiss S. Peripheral retinal ischaemia, as evaluated by ultra-widefield fluorescein angiography, is associated with diabetic macular oedema. British Journal of Ophthalmology ;96:694-8.
54. Hamanaka T, Akabane N, Yajima T, Takahashi T, Tanabe A. Retinal ischemia and angle neovascularization in proliferative diabetic retinopathy. American Journal of Ophthalmology ;132:648-58.
55. Gao SS, Jia Y, Zhang M, et al. Optical coherence tomography angiography. Investigative ophthalmology & visual science ;57:OCT27-OCT36.
56. Louzada RN, Talisa E, Adhi M, et al. Optical coherence tomography angiography artifacts in retinal pigment epithelial detachment. Canadian Journal of Ophthalmology ;52:419-24.
57. Potsaid B, Baumann B, Huang D, et al. Ultrahigh speed nm swept source/Fourier domain OCT retinal and anterior segment imaging at 100,000 to 400,000 axial scans per second. Optics express ;18:-48.
58. Chinn S, Swanson E, Fujimoto J. Optical coherence tomography using a frequency-tunable optical source. Optics letters ;22:340-2.
59. Unterhuber A, Považay B, Hermann B, Sattmann H, Chavez-Pirson A, Drexler W. In vivo retinal optical coherence tomography at nm-enhanced penetration into the choroid. Optics express ;13:-8.
60. Wang RK, An L. Multifunctional imaging of human retina and choroid with -nm spectral domain optical coherence tomography at 92-kHz line scan rate. Journal of biomedical optics ;16:.
61. Barteselli G, Bartsch D-U, Weinreb RN, et al. Real-time full-depth visualization of posterior ocular structures: comparison between Full Depth Imaging Spectral Domain OCT and Swept Source OCT. Retina (Philadelphia, Pa) ;36:.
62. Miller AR, Roisman L, Zhang Q, et al. Comparison between spectral-domain and swept-source optical coherence tomography angiographic imaging of residual choroidal vessels in atrophy can masquerade as choroidal neovascularization. Investigative ophthalmology & visual science ;58:-505.
63. Jung JJ, Chen MH, Chung PY, Lee SS. Swept-source on optical coherence tomography angiography for choroidal neovascularization after bevacizumab and photodynamic therapy. American Journal of Ophthalmology Case Reports ;1:1-4.
64. Tan CS, Ngo WK, Cheong KX. Comparison of choroidal thicknesses using swept source and spectral domain optical coherence tomography in diseased and normal eyes. British Journal of Ophthalmology :bjophthalmol--.
65. Ting DS, Cheung GC, Lim LS, Yeo IY. Comparison of swept source optical coherence tomography and spectral domain optical coherence tomography in polypoidal choroidal vasculopathy. Clinical & experimental ophthalmology ;43:815-9.
Not to be confused with Infracyanine green
Indocyanine green (ICG) is a cyanine dye used in medical diagnostics. It is used for determining cardiac output, hepatic function, liver and gastric blood flow, and for ophthalmic and cerebral angiography.[4] It has a peak spectral absorption at about 800 nm.[5] These infrared frequencies penetrate retinal layers, allowing ICG angiography to image deeper patterns of circulation than fluorescein angiography.[6] ICG binds tightly to plasma proteins and becomes confined to the vascular system.[4] ICG has a half-life of 150 to 180 seconds and is removed from circulation exclusively by the liver to bile.[4]
ICG is a fluorescent dye which is used in medicine as an indicator substance (e.g. for photometric hepatic function diagnostics and fluorescence angiography) in cardiac, circulatory, hepatic and ophthalmic conditions.[7] It is administered intravenously and, depending on liver performance, is eliminated from the body with a half life of about 3 to 4 minutes.[8] ICG sodium salt is normally available in powder form and can be dissolved in various solvents; 5% (< 5% depending on batch) sodium iodide is usually added to ensure better solubility.[9] The sterile lyophilisate of a water-ICG solution is approved in many European countries and the United States under the names ICG-Pulsion and IC-Green as a diagnostic for intravenous use.
[
edit
]
ICG was developed in the Second World War as a dye in photography and tested in at the Mayo Clinic for use in human medicine by I.J. Fox. After being granted FDA approval in , ICG was initially used primarily in hepatic function diagnostics and later in cardiology. In , S. Schilling was able to determine renal blood flow using ICG. From , ICG was also used in the research and diagnosis of subretinal processes in the eye (in the choroid). In the years since , the development of new types of cameras and better film material or new photometric measuring devices has cleared away many technical difficulties. In the meantime, the use of ICG in medicine (and especially in fluorescent angiography in ophthalmology) has become established as standard. A distinction is therefore also made, when describing fluorescent angiography, between NA fluorescent angiography and ICGA / ICG fluorescent angiography. Around 3,000 scientific papers on ICG have now been published worldwide.[10]
[
edit
]
The absorption and fluorescence spectrum of ICG is in the near infrared region. Both depend largely on the solvent used and the concentration.[11] ICG absorbs mainly between 600 nm and 900 nm and emits fluorescence between 750 nm and 950 nm. The large overlapping of the absorption and fluorescence spectra leads to a marked reabsorption of the fluorescence by ICG itself. The fluorescence spectrum is very wide. Its maximum values are approx. 810 nm in water and approx. 830 nm in blood. For medical applications based on absorption, the maximum absorption at approx. 800 nm (in blood plasma at low concentrations) is important. In combination with fluorescence detection, lasers with a wavelength of around 780 nm are used. At this wavelength, it is still possible to detect the fluorescence of ICG by filtering out scattered light from the excitation beam.[12]
[
edit
]
ICG is metabolized microsomally in the liver and only excreted via the liver and bile ducts; since it is not absorbed by the intestinal mucous membrane, the toxicity can be classified as low. Administration is not without risks during pregnancy. It has been known since September that ICG decomposes into toxic waste materials under the influence of UV light, creating a number of still unknown substances. A study published in February , however, shows that ICG (the substance without UV effect) is basically, as such, of only minor toxicity. The intravenous LD50 values measured in animals are 60 mg/kg in mice[13] and 87 mg/kg in rats. Occasionally &#; in one out of 42,000 cases &#; slight side-effects occur in humans such as sore throats and hot flushes. Effects such as anaphylactic shock, hypotension, tachycardia, dyspnea and urticaria only occurred in individual cases; the risk of severe side-effects rises in patients with chronic kidney impairment.[14] The frequencies of mild, moderate and severe side-effects were only 0.15%, 0.2% and 0.05%; the rate of deaths is 1:333,333. For the competitor substance fluorescein, the proportion of people with side-effects is 4.8% and the death rate is 1:222,222.
[
edit
]
[
edit
]
[
edit
]
Because the preparation contains sodium iodide, a test must be carried out for iodine intolerance. Because around 5% of iodide is added, the iodine content of a 25 mg ampoule is 0.93 mg. In comparison, preparations for a bone marrow CT (140 ml) contain 300 mg/ml and for a corona angiography (200 ml) 350 mg/ml of iodine. ICG has the ability to bind 98% to plasma proteins &#; 80% to globulins and 20% to alpha-lipoprotein and albumin[8] &#; and thus, in comparison with fluorescein as a marker, has a lower leakage (slower emergence of dye from the vessels, extravasally).[15] Because of the plasma protein binding, ICG stays for up to 20 to 30 minutes in the vessels (intravasally). When the eye is examined, it thus stays for a long time in tissues with a higher blood flow, such as the choroid and the blood vessels of the retina.[8]
[
edit
]
Capsulorhexis is a technique used to remove the lens capsule during cataract surgery. Various dyes are used to stain lens capsule during cataract surgery. In , Horiguchi et al. first described the use of indocyanine green dye (0.5%) for capsular staining to assist cataract surgery.[16] ICG-enhanced anterior and posterior capsulorhexis is useful in childhood cataract surgery.[17] It may also use in adult cataract with no fundus glow.[17] Although ICG is approved by US FDA, still there is no approval for intraocular use of the dye.[18]
[
edit
]
ICG is used as a marker in the assessment of the perfusion of tissues and organs in many areas of medicine. The light needed for the excitation of the fluorescence is generated by a near infrared light source which is attached directly to a camera. A digital video camera allows the absorption of the ICG fluorescence to be recorded in real time, which means that perfusion can be assessed and documented. [citation needed]
In addition, ICG can also be used as a tracer in cerebral perfusion diagnostics. In the case of stroke patients, monitoring in the recovery phase seems to be achievable by measurement of both the ICG absorption and the fluorescence in everyday clinical conditions.[19][20][21]
[
edit
]
Sentinel lymph node biopsy (SLB or SLN biopsy) allows selective, minimally invasive access for assessment of the regional lymph node status with malignant tumours. The first draining lymph note, the "sentinel", represents an existing or non-existing tumour of an entire lymph node region. The method has been validated using radionuclides and/or blue dye for breast cancer, malignant melanoma and also gastrointestinal tumours and gives a good detection rate and sensitivity. For the SLB, a reduced mortality has been observed in comparison with complete lymph node dissection, but the methods have disadvantages with regard to availability, application and disposal of the radionuclide and the risk of anaphylaxis (up to 1%) for the blue dye. ICG, because of its near-infrared fluorescence and previous toxicity investigations, was evaluated in this investigation as a new, alternative method for SLB with regard to the clinical application of the transcutaneous navigation and lymph vessel visualisation and SLN detection. This technique is sometimes referred as fluorescence image-guided surgery (FIGS). ICG fluorescence navigation achieves high rates of detection and sensitivity in comparison with the conventional methods. Taking into account the learning curve required, the new, alternative method offers a combination of lymphography and SLB and the possibility of carrying out an SLB without the need for radioactive substances for solitary tumours[22][23][24]
Selectively over-heating cells (especially cancer)[
edit
]
ICG absorbs near infra-red, especially light with a wavelength of about 805 nanometers. A laser of that wavelength can penetrate tissue.[25] That means, dying tissue with injected ICG allows an 800 nm to 810 nm laser to heat or overheat the dyed tissue without harming the surrounding tissue.[26][27] Although overheating is the main mechanism for it to kill cells, a small amount of the laser energy absorbed by the ICG releases free radicals such as singlet oxygen that also damage target cells.
That works particularly well on cancer tumors, because tumors naturally absorb more ICG than other tissue. When ICG is injected near tumors, tumors react to the laser 2.5 times as much as the surrounding tissue does.[28] It is also possible to target specific cells by conjugating the ICG to antibodies such as daclizumab (Dac), trastuzumab (Tra), or panitumumab (Pan).[29]
ICG and laser therapy has been shown to kill human pancreatic cancer cells (MIA PaCa-2, PANC-1, and BxPC-3) in vitro.[30]
ICG and an infrared laser have also been used the same way to treat acne vulgaris.[31][32]
[
edit
]
ICG is being studied as a possible antidote for the death cap mushroom toxin alpha-amanitin by inhibiting the enzyme STT3B.[33]
[
edit
]
If you want to learn more, please visit our website Laser Retinal Imaging.