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1.  A comparison of outcomes after indocyanine green and trypan blue assisted internal limiting membrane peeling during macular hole surgery 
Aims: To compare the anatomical and visual outcomes of macular hole repair surgery using indocyanine green (ICG) or trypan blue (TB) staining of the internal limiting membrane (ILM).
Method: Retrospective analysis of 37 eyes from 37 consecutive patients with stage 2, 3, and 4 idiopathic macular holes who underwent macular hole repair by one surgeon using the same technique but utilising different dyes for ILM peeling. In 19 patients ICG was used while 18 patients had TB. The anatomical and visual results in these two groups were compared.
Results: There were no significant differences in the demographic and macular hole characteristics of the ICG and TB groups. Macular hole closure was achieved in 91.9% of all patients of which the ICG group had an 89.5% hole closure rate and the TB group had a 94.4% hole closure rate. After excluding cases with failed hole closure and other vision affecting complications, there was no significant difference between the preoperative visual acuities in the TB and ICG groups but the postoperative visual acuities were better in the TB than the ICG group (p = 0.036). The TB group also had more Snellen lines of improvement than the ICG group (2.94 v 1.79 lines; p = 0.046).
Conclusion: TB appears to be less toxic than ICG when used in dye assisted peeling of ILM during macular hole repair as reflected by the better visual results in the TB group of patients.
PMCID: PMC1772609  PMID: 15774917
macular hole; indocyanine green; trypan blue
2.  Residual indocyanine green fluorescence pattern after vitrectomy for idiopathic macular hole with internal limiting membrane peeling 
Internal limiting membrane (ILM) peeling with indocyanine green (ICG) staining is a commonly used procedure to treat idiopathic macular holes (MH).
To report changes in the patterns of residual ICG fluorescence over time after vitrectomy using the Heidelberg Retina Angiograph 2 (HRA2, Heidelberg Engineering, Heidelberg, Germany).
10 patients (10 eyes) who had undergone vitrectomy for MH with ILM peeling were included. 9 (90%) patients underwent ILM peeling with ICG, and 1 (10%) patient had it with triamcinolone acetonide (TA). We observed residual ICG using HRA2, postoperatively. Autofluorescence, optical coherence tomography images and best‐corrected visual acuity (BCVA) measurements were also obtained. The minimal follow‐up was 3 months.
The MHs were closed postoperatively in all patients (100%). In eyes that underwent ILM peeling with ICG, the BCVA improved significantly (p<0.001) in 8 (89%) eyes and was unchanged in 1 (11%) eye. HRA2 showed the ICG fluorescence patterns but not TA postoperatively. The ICG hyperfluorescent signal was typically diffuse at the posterior retina and was hypofluorescent around the fovea. The hyperfluorescence then migrated towards the optic nerve disc presumably along the nerve fibre, and the area of ILM peeling was clearly identified. A large number of hyperfluorescent dots were observed instead of diffuse hyperfluorescence that was observed just after surgery.
Patterns of residual ICG fluorescence were sequentially observed with HRA2 after vitrectomy for MH with ICG‐assisted ILM peeling.
PMCID: PMC1955671  PMID: 17215268
3.  Internal limiting membrane removal in macular hole surgery for severely myopic eyes: a case-control study 
Aims: To determine the surgical outcome of indocyanine green (ICG) assisted retinal internal limiting membrane (ILM) peeling in macular hole surgery for severely myopic eyes and compare the visual and anatomical outcomes with an emmetropic control group.
Methods: 10 severely myopic eyes (−6.0 D or greater) of 10 patients with macular holes without retinal detachment were recruited prospectively. All eyes received ICG assisted ILM removal of 3–4 disc diameters around the macular holes. Cases were matched with a prospective control group of 10 emmetropic macular hole patients who underwent identical ICG assisted ILM peeling surgery in the same period.
Results: The mean refractive error in the myopic and control group was −11.8 D and +0.3 D, respectively (two tailed t test, p < 0.001). The mean follow up duration for the myopic and control group was 12.1 and 13.3 months, respectively (two tailed t test, p = 0.63). The primary anatomical closure rate in both groups was 90% (Fisher’s exact test, p = 1.0). For both the myopic and control groups, there were significant improvement in the mean log MAR visual acuity after the surgery with improvements from 0.86 to 0.57 for the myopic group (two tailed t test, p = 0.015) and 0.89 to 0.44 for the control group (two tailed t test, p = 0.002). The mean preoperative and postoperative visual acuity, rates of final visual acuity of 20/50 or better, and improvement of two or more lines were not statistically different between the two groups.
Conclusion: ICG assisted ILM peeling in macular hole surgery for severely myopic eyes without retinal detachment gives promising anatomical and visual outcomes, which are comparable to that of non-severely myopic eyes.
PMCID: PMC1771733  PMID: 12812892
severe myopia; indocyanine green; internal limiting membrane; macular hole
4.  Clinical Outcomes of Double Staining and Additional ILM Peeling during ERM Surgery 
To assess the clinical outcomes in idiopathic epiretinal membrane (ERM) patients after vitrectomy and ERM removal with or without additional indocyanine green (ICG)-assisted internal limiting membrane (ILM) peeling.
The medical records of 43 patients with an idiopathic ERM that underwent vitrectomy and ERM removal between July 2007 and April 2010 were reviewed. The patients were divided into two groups: triamcinolone-assisted simple ERM peeling only (group A, n = 23) and triamcinolone-assisted ERM peeling followed by ICG staining and peeling of the remaining internal ILM (group B, n = 20).
No difference was found between the two groups in terms of visual acuity, macular thickness, P1 amplitude or implicit time on multifocal-electroretinogram (mfERG) at six and 12 months postoperatively. In group B, ICG staining after ERM peeling demonstrated that the ILM had been removed together with the ERM in 12 eyes (60%), and all 12 eyes showed punctate retinal hemorrhages during ERM peeling. There was no recurrence of an ERM in either group.
Additional procedures involving ICG staining and ILM peeling during ERM surgery do not appear to have an additive effect on the clinical outcomes in terms of visual acuity, retinal function based on mfERG, or recurrence rate.
PMCID: PMC3730067  PMID: 23908571
Double staining; Epiretinal membrane; Internal limiting membrane
5.  Indocyanine green assisted retinal internal limiting membrane removal in stage 3 or 4 macular hole surgery 
Aims: To determine surgical outcome in primary idiopathic stage 3 or 4 macular holes with indocyanine green (ICG) assisted retinal internal limiting membrane (ILM) peeling.
Methods: A prospective, consecutive, interventional case series with 41 eyes of 40 patients was included. No patient defaulted follow up. Besides a standard macular hole surgery, all eyes received ICG assisted ILM removal of 3–4 disc diameters around macular holes. At the end of the surgery, 12% perfluoropropane gas was used. A face down posture for 2 weeks was required postoperatively.
Results: The mean follow up period was 15.1 months (range 6–24 months). Twenty (48.8%) eyes had stage 3 macular holes and 21 (51.2%) had stage 4 macular holes. The overall median duration of holes was 11 months. 19 (46.3%) were chronic macular holes of more than 12 months’ duration. The anatomical success rates after one surgery was 87.8% (36 eyes), while that of chronic and non-chronic ones was 78.9% and 95.5%, respectively. The median preoperative and postoperative visual acuity was 20/200 (range 20/60 to counting fingers) and 20/100 (range 20/20 to 20/400), respectively. 24 (58.5%) eyes had improvement of two or more Snellen lines. The mean was 3.2 lines (range two to nine lines), with 3.6 lines and 2.7 lines for non-chronic and chronic holes, respectively. For all the 41 eyes, 16 (39%) eyes had a final visual acuity of 20/50 or better.
Conclusion: ICG assisted retinal ILM removal, in idiopathic primary chronic and non-chronic stage 3 or 4 macular hole surgery, appears to give a promising anatomical closure rate without compromising the visual result.
PMCID: PMC1771454  PMID: 12488266
indocyanine green; internal limiting membrane; macular hole
To compare the anatomic and functional results of 3 different epimacular dissection techniques on macular hole surgery.
Vitrectomy was performed in 123 eyes for macular hole in a retrospective, consecutive case series by one surgeon. The surgical technique was identical except for the method of epimacular dissection, which was performed using 1 of 3 techniques sequentially. The first group of 29 eyes had abrasion of the macula with a sharp pick (epiretinal dissection [ERD]), the second group of 32 eyes had partial or complete removal of the internal limiting membrane (ILM), without ILM staining. The third group of 62 eyes had complete removal of the ILM using indocyanine green (ICG) to stain the ILM.
The mean preoperative visual acuity was 20/125 -2 in the ERD and ILM groups and 20/160 -2 in the ICG groups (P = .167). Long-term successful closure of the macular hole was achieved with one operation in 22 of 29 ERD eyes (75.9%), 31 of 32 ILM eyes (96.7%), and 62 of 62 ICG eyes (100%). The mean visual acuity at 3 months was 20/63 +2 (ERD), 20/80 (ILM), and 20/125 (ICG) (P < .001), with significantly poorer visual acuity in the ICG group. The final visual acuity (mean, 2.27 years) was 20/63 +1 (ERD), 20/50 -2 (ILM), and 20/80 -1 (ICG, P = .073), with no significant differences in mean visual acuity, visual acuity gain, gain of ≥3 lines, or percentage ≥20/40.
Removal of the ILM decreases persistent and recurrent macular holes. ICG staining and complete removal of the ILM slows the rate of visual recovery but does not appear to have any long-term deleterious effect on the results of macular hole surgery.
PMCID: PMC2258112  PMID: 18427610
7.  Removal of sodium from the solvent reduces retinal pigment epithelium toxicity caused by indocyanine green: implications for macular hole surgery 
Backgrounds/aims: Staining of internal limiting membrane with indocyanine green (ICG) has been reported to be associated with postoperative atrophic retinal pigment epithelium (RPE) change. Here the authors examined whether removing sodium from the solvent reduces ICG induced RPE cytotoxicity.
Methods: Human RPE cells were exposed to ICG (0.25 and 0.025 mg/ml) reconstituted with balanced salt solution (BSS) or Na+ free BSS. Light microscopy, trypan blue dye exclusion, acridine orange/ethidium bromide staining, and DNA electrophoresis were used to evaluate the cytotoxic effects of ICG. ICG uptake was measured by optical absorption at 790 nm.
Results: Sodium removal reduced the ICG induced changes in cell morphology and improved the RPE cell viability. When RPE cells were incubated for 4 hours in 0.25 mg/ml ICG dissolved in BSS and sodium free BSS, 86.3% (SD 6.7%) and 2.4% (1.1%) of the cells were stained with trypan blue, respectively. After ICG treatment, RPE dies mainly through a necrotic mechanism. ICG uptake by RPE was also reduced with sodium removal.
Conclusions: ICG induced cytotoxicity in cultured human RPE was reduced with removal of sodium from the solvent. This reconstitution method may provide a safer intravitreal use of ICG in macular hole surgery.
PMCID: PMC1772071  PMID: 15031176
indocyanine green; retinal pigment epithelium; cytotoxicity; macular hole surgery
8.  Macular function and morphology after peeling of idiopathic epiretinal membrane with and without the assistance of indocyanine green 
Aim: To investigate macular function and morphology after surgical removal of idiopathic epiretinal membrane (IEM) with and without assistance of indocyanine green (ICG).
Methods: A retrospective study as a consecutive case series, of 39 patients with IEM. 39 patients, 23 female, 16 male, mean age 67 years, underwent standard three port pars plana vitrectomy with removal of epiretinal membrane. Two groups of patients were consecutively operated: in 20 patients ICG 0.1% in glucose 5% was used to stain the epiretinal membrane. 19 patients underwent the identical procedure but without use of ICG. Postoperative follow up was 1–92 months (mean 15.5 months). Functional outcome was assessed with subjective improvement, best corrected visual acuity (BCVA), Amsler grid test, 10° and 30° automated perimetry (Heidelberg visual field analyser) (HFA), and Goldmann kinetic perimetry. Macular morphology was assessed with stereoscopic biomicroscopy and optical coherence tomography (OCT). The main outcome measures were macular function as determined by BCVA, presence of visual field defects, and metamorphopsia as determined by Amsler grid test, macular morphology as determined by slit lamp biomicroscopy, and OCT.
Results: BCVA improved in 28 patients, remained unchanged in eight patients, and decreased in three patients. Improvement of BCVA was statistically significant in both groups (p = 0.003). Mean BCVA in patients operated with ICG improved from 0.33 preoperatively to 0.53 postoperatively. Mean BCVA in patients operated without ICG improved from 0.32 preoperatively to 0.54 postoperatively. Reduction of macular oedema as measured by OCT was statistically significant in both groups (p<0.01). There was no statistically significant difference in postoperative BCVA, macular oedema as measured by OCT, postoperative Amsler grid test, and subjective improvement between the two groups. The incidence of residual or recurrent epiretinal membrane was greater in the group operated without ICG (p = 0.014). Visual field defects were detected in one patient operated with ICG and in three patients operated without ICG.
Conclusions: Removal of epiretinal tissue with or without assistance of ICG improved visual function and reduced macular oedema in most patients. Adverse effects clearly attributable to the use of ICG were not observed but further investigation is warranted.
PMCID: PMC1772583  PMID: 15774920
indocyanine green; toxicity; epiretinal membrane; visual field
9.  Histopathologic and Electron Microscopic Features of Internal Limiting Membranes in Maculopathies of Various Etiologies 
To report micro- and ultrastructural features of internal limiting membranes (ILMs) in various maculopathies and to evaluate the effects of indocyanine green (ICG) and triamcinolone acetonide (TA) on epiretinal proliferations associated with ILM and on retinal cleavage plane.
ILMs from various maculopathies were evaluated regarding presence or absence of membrane-associated cells, type of cells and ILM thickness based on routine histopathology, immunohistochemistry and transmission electron microscopy (TEM).
Thirty ILM specimens were enrolled; 25 of which were evaluated by histopathology and immunohistochemistry and 5 by TEM. ICG only had been used in 17 specimens, TA in 4, and both agents in one specimen. The majority of specimens were immunoreactive for glial fibrillary acidic protein and neuron specific enolase. No significant difference in specimen cellularity and alteration of cleavage plane was noted between ICG-stained and non-ICG-stained ILMs or between TA-assisted and non-TA-assisted ones. Excluding central retinal vein occlusion (CRVO) cases, acellularity was not observed in any of ILMs from diabetic macular edema (DME), cystoid macular edema (CME), and traumatic macular hole (TMH) eyes. TEM disclosed ILM thickening and cellularity in DME as compared to CRVO.
Acellular membranes from CRVO maculopathy may be a sequel of acute retinal ischemia. Thickened diabetic ILMs with high cellularity may be related to chronic activation of Muller cells. No obvious influence of ICG or TA on epiretinal cellularity was detected and the dyes seem to have no significant effect on cleavage plane.
PMCID: PMC4181205  PMID: 25279124
Interanl Limiting Membrane; Maculopathy; Central Retinal Vein Occlusion: Transmission Electron Microscopy
10.  Comparisons of Retinal Nerve Fiber Layer Thickness after Indocyanine Green, Brilliant Blue G, or Triamcinolone Acetonide-Assisted Macular Hole Surgery 
Journal of Ophthalmology  2014;2014:187308.
Purpose. To compare the postoperative changes of the retinal nerve fiber layer (RNFL) thickness in patients with macular holes (MHs) treated with vitrectomy with indocyanine green- (ICG-), brilliant blue G- (BBG-), or triamcinolone acetonide- (TA-)assisted internal limiting membrane (ILM) peeling. Methods. Sixty-one eyes of 61 consecutive patients with MHs were studied. Each eye was randomly selected to undergo either ICG- (n = 18), BBG- (n = 21), or TA-assisted (n = 22) ILM peeling. The circumferential retinal nerve fiber layer (RNFL) thickness was determined by spectral-domain optical coherence tomography (SD-OCT) before and 1, 3, 6, 9, and 12 months postoperatively. The mean overall and the sectoral thicknesses of the RNFL were obtained for each group. Results. A transient increase of the RNFL thickness was seen in the mean overall and sectoral thicknesses except for the nasal/inferior sector at 1 month after surgery for the three groups. Then, the thickness gradually decreased and returned to the baseline level in all sectors except for the nasal/inferior sector. The differences in the RNFL thickness among the groups were not significant for at least 12 months postoperatively. Conclusions. The degree of change of the RNFL thickness was not significantly related to the type of vital stain used during MH surgery.
PMCID: PMC4055247  PMID: 24967097
11.  Vitrectomy with internal limiting membrane peeling vs no peeling for Macular Hole-induced Retinal Detachment (MHRD): a meta-analysis 
BMC Ophthalmology  2015;15:62.
we conducted our meta-analysis of published studies to assess existing evidence about the efficacy and safety of vitrectomy with ILM peeling vs. that of vitrectomy with no ILM peeling for Macular hole-induced retinal detachment.
Databases, including Pubmed, Cochrane Library, Ovid, Web of Science, Wanfang and CNKI, were searched to identify studies comparing outcomes following vitrectomy with ILM peeling and that with no ILM peeling for macular hole-induced retinal detachment. The meta-analysis was performed by RevMan 5.1.
Six comparative studies comprising 180 eyes were identified. It was indicated that the rate of retinal reattachment (Odds ratio (OR) = 3.03, 95 % Confidence interval (CI):1.35 to 6.78; P = 0.007) and macular hole closure (OR = 6.74, 95 % CI:3.26 to 13.93; P < 0.001) after initial surgery was higher and the rate of recurrent retinal detachment (OR = 0.08, 95 % CI:0.02 to 0.30; P = 0.0002) was lower in the group of vitrectomy with ILM peeling than that in the group of vitrectomy with no ILM peeling. However, the improved BCVA (Weighted mean difference (WMD) = 0.14, 95 % CI: −0.20 to 0.47; P = 0.42) and the rate of postoperative complications were similar between the two groups.
Vitrectomy with internal limiting membrane peeling is an efficient and safe procedure for macular hole-induced retinal detachment.
PMCID: PMC4475314  PMID: 26091910
Macular hole-induced retinal detachment; Vitrectomy; Internal limiting membrane peeling; Meta-analysis
12.  Macular configuration determined by optical coherence tomography after idiopathic macular hole surgery with or without internal limiting membrane peeling 
The British Journal of Ophthalmology  2002;86(11):1240-1242.
Aims: To evaluate the effect of pars plana vitrectomy (PPV) with or without internal limiting membrane (ILM) peeling on the closure and configuration of idiopathic macular holes (IMH).
Methods: PPV was performed for IMH on 44 eyes with ILM peeling (ILM peeled group) and on 42 eyes without ILM removal (ILM preserved group). Optical coherence tomography (OCT) was performed on 34 ILM peeled eyes and 14 ILM preserved eyes after successful surgery. The repaired macular holes were classified by the OCT images as being of “good shape” (nearly normal foveal contour) or “poor shape” (abnormal foveal contour with flat fovea and steep edge, or with a thick retina without a foveal pit).
Results: The anatomical closure rate was significantly higher in the ILM peeled group (93.2%) than in the ILM preserved group (76.2%) (p = 0.028). In the ILM peeled group, 31 eyes had a fovea of good shape and three eyes had a fovea with a poor shape, while in the ILM preserved group, six eyes had a fovea of good shape and eight eyes had a fovea of poor shape. The percentage of eyes with good macular configuration in the ILM peeled group was significantly higher than in the ILM preserved group (p = 0.0003). No significant difference was found in the postoperative visual acuity and the increase of visual acuity between the ILM peeled group and the ILM preserved group (p = 0.26, and p = 0.91 respectively). There was also no significant difference in the postoperative visual acuity and improvement in visual acuity between eyes with a fovea of good shape and those with fovea of poor shape fovea (p = 0.99 and p = 0.66, respectively).
Conclusions: ILM peeling may provide better anatomical success and recovery of the macular shape, but the postoperative visual acuity and improvement of visual acuity were not related to the morphological results.
PMCID: PMC1771338  PMID: 12386079
optical coherence tomography; macular hole surgery; internal limiting membrane
13.  Randomized Comparison of Near-Infrared Fluorescence Lymphatic Tracers for Sentinel Lymph Node Mapping of Cervical Cancer 
Gynecologic oncology  2012;127(1):126-130.
Near-infrared fluorescence imaging using indocyanine green (ICG) has recently been introduced as a novel technique for sentinel lymph node (SLN) mapping in early-stage cervical cancer. Although preclinical research has shown that ICG adsorbed to human serum albumin (ICG:HSA) improves its performance, the need for HSA has not yet been confirmed in cervical cancer patients. The current randomized study aims to determine whether ICG:HSA offers advantages over using ICG alone.
Eighteen consecutive early-stage cervical cancer patients scheduled to undergo pelvic lymphadenectomy were included. Prior to surgery, 1.6 mL of 500 μM ICG:HSA or 500 μM ICG alone was injected transvaginally in 4 quadrants around the tumor. The Mini-FLARE imaging system was used for intraoperative NIR fluorescence detection and quantitation.
SLNs were identified intraoperatively in 78% of the patients. Patient and tumor characteristics were equally distributed over both treatment groups. No significant difference in signal-to-background ratio (9.3 vs. 10.1, P = .72) or average number of detected SLNs (2.9 vs 2.7, P = .84) was found between the ICG:HSA group and the ICG alone group, respectively.
In conclusion, this double-blind, randomized trial showed no advantage of ICG:HSA over ICG alone for the SLN procedure in early-stage cervical cancer. Further optimization is required to improve the intraoperative detection rate.
PMCID: PMC3432653  PMID: 22796548
Near-Infrared Fluorescence Imaging; Image-Guided Surgery; Cervical Cancer; Sentinel Lymph Node Mapping; Indocyanine Green; Albumin
14.  The application of intraoperative near-infrared indocyanine green videoangiography and analysis of fluorescence intensity in cerebrovascular surgery 
To evaluate the usefulness and limitations of the intraoperative near-infrared (NIR) indocyanine green videoangiography (ICG-VA) and analysis of fluorescence intensity in cerebrovascular surgery.
Forty-eight patients received ICG-VA during various surgical procedures from May 2010 to August 2010. Included among them were 45 cases of cerebral aneurysms and 3 cases of cerebral arteriovenous malformations (AVMs). The infrared fluorescence module integrated into the surgical microscope was used to visualize fluorescent areas in the surgical field. An integrated analytical visualization tool constantly analyzed the fluorescence video sequence and generated it in the form of an intensity diagram for objective interpretation.
Overall, the procedure of ICG VA was done 158 times in 48 patients. There was no adverse effect of ICG dye. In cerebral aneurysm cases, the images obtained were of high resolution. In 4 cases, incomplete clipping was detected by ICG-VA and allowed suitable adjustment to completely obliterate the aneurysm. In 3 aneurysm cases, the intensity diagram of ICG VA provided valuable information. ICG-VA identified the feeding arteries, the draining veins, and nidus in all 3 AVM cases, which was confirmed by an immediate analysis of fluorescence intensity.
ICG-VA provides high resolution images allowing real-time assessment of the blood flow in surgical field. The intensity analysis function, in addition, is a useful adjunct to improve the accuracy of the clipping and decrease the complication rates in cerebral aneurysm cases. In cerebral AVM cases, with the help of color map and intensity diagram function, the superficial feeders, drainers, and nidus can be identified easily.
PMCID: PMC3075608  PMID: 21541008
Cerebral aneurysm; cerebral arteriovenous malformation; indocyanine green videoangiography
15.  Indocyanine green-assisted epiretinal membrane peeling evaluated by optical coherence tomography and multifocal electroretinography 
To evaluate the anatomical and functional outcome in eyes with indocyanine green (ICG)-assisted idiopathic epiretinal membrane (ERM) peeling by optical coherence tomography (OCT) and multifocal electroretinogram (MFERG).
Prospective, interventional, noncomparative case series.
Twenty eyes of 20 patients with idiopathic ERM underwent pars plana vitrectomy and ICG-assisted ERM and internal limiting membrane (ILM) removal. Visual acuity (VA), OCT, and MFERG measurements were performed preoperatively and postoperatively at 1, 3, 6, and 12 months.
Best-corrected VA (BCVA) improved ≥2 Snellen lines in 70% of our patients at the 12th postoperative month. Mean VA increased from 20/100 preoperatively to 20/40 at 12 months. VA increased significantly at all postoperative examinations, compared to preoperative VA. Foveal thickness measured by OCT decreased significantly at all postoperative examinations. OCT mean values dropped from 472.3 μm preoperatively, to 249.2 μm at 12 months. Preoperative MFERG values significantly improved only at 12 months. OCT measurements and MFERG values did not correlate at any time. OCT values correlated with VA values only preoperatively while MFERG measurements correlated with VA at 12 months.
In our series of eyes with ERM surgery, OCT measurements and VA improved gradually throughout the first postoperative year, while MFERG values showed significant improvement at 12 months.
PMCID: PMC2704540  PMID: 19668533
16.  Randomized, double-blind comparison of indocyanine green with or without albumin premixing for near-infrared fluorescence imaging of sentinel lymph nodes in breast cancer patients 
Near-infrared (NIR) fluorescence imaging has the potential to improve sentinel lymph node (SLN) mapping in breast cancer. Indocyanine green (ICG) is currently the only clinically available fluorophore that can be used for SLN mapping. Preclinically, ICG adsorbed to human serum albumin (ICG:HSA) improves its performance as a lymphatic tracer in some anatomical sites. The benefit of ICG:HSA for SLN mapping of breast cancer has not yet been assessed in a clinical trial. We performed a double-blind, randomized study to determine if ICG:HSA has advantages over ICG alone. The primary endpoint was the fluorescence brightness, defined as the signal-to-background ratio (SBR), of identified SLNs. Clinical trial subjects were 18 consecutive breast cancer patients scheduled to undergo SLN biopsy. All patients received standard of care using 99mTechnetium-nanocolloid and patent blue. Patients were randomly assigned to receive 1.6 mL of 500 μM ICG:HSA or ICG that was injected periareolarly directly after patent blue. The Mini-Fluorescence-Assisted Resection and Exploration (Mini-FLARE) imaging system was used for NIR fluorescence detection and quantitation. SLN mapping was successful in all patients. Patient, tumor and treatment characteristics were equally distributed over the treatment groups. No significant difference was found in SBR between the ICG:HSA group and the ICG alone group (8.4 vs. 11.3, respectively, P = 0.18). In both groups, the average number of detected SLNs was 1.4 ± 0.5 SLNs per patient (P = 0.74). This study shows that there is no direct benefit of premixing ICG with HSA prior to injection for SLN mapping in breast cancer patients, thereby reducing the cost and complexity of the procedure. With these optimized parameters that eliminate the necessity of HSA, larger trials can now be performed to determine patient benefit.
PMCID: PMC3667709  PMID: 21360075
Near-Infrared Fluorescence Imaging; Image-Guided Surgery; Breast Cancer; Sentinel Lymph Node Mapping; Indocyanine Green; Albumin
17.  Endoilluminator phototoxic maculopathy associated with combined ICG-assisted epiretinal membrane and internal limiting membrane peeling 
Phototoxic maculopathy caused by endoillumination during macular surgery is uncommon. Previously identified risk factors have included intensity of the light source, proximity to the retinal surface, and length of exposure. In the era of indocyanine green (ICG)-assisted internal limiting membrane (ILM) peeling, the use of ICG, and the technique of ILM peeling may both contribute to subsequent phototoxic maculopathy. We present cases of routine chromovitrectomy who developed phototoxic maculopathy in the precise discrete distribution of the ILM rhexes, and discuss potential mechanisms and implications.
PMCID: PMC4266418  PMID: 25525328
ILM peeling; indocyanine green; vitrectomy; ERM
18.  Perioperative indocyanine green clearance is predictive for prolonged intensive care unit stay after coronary artery bypass grafting - an observational study 
Critical Care  2009;13(5):R149.
During cardiac surgery with cardiopulmonary bypass (CPB) haemodilution occurs. Hepatic dysfunction after CPB is a rare, but serious, complication. Clinical data have validated the plasma-disappearance rate of indocyanine green (PDR ICG) as a marker of hepatic function and perfusion. Primary objective of this analysis was to investigate the impact of haemodilutional anaemia on hepatic function and perfusion by the time course of PDR ICG and liver enzymes in elective CABG surgery. Secondary objective was to define predictors of prolonged ICU treatment like decreased PDR ICG after surgery.
60 Patients were subjected to normothermic CPB with predefined levels of haemodilution anaemia (haemotacrit (Hct) of 25% versus 20% during CPB). Hepatic function and perfusion was assessed by PDR ICG, plasma levels of aspartate aminotransferase (ASAT) and α-GST. Prolonged ICU treatment was defined as treatment ≥ 48 hours.
Logistic regression analysis showed that all postoperative measurements of PDR ICG (P < 0.01), and the late postoperative ASAT (P < 0.01) measurement were independent risk factors for prolonged ICU treatment. The predictive capacity for prolonged ICU treatment was best of the PDR ICG one hour after admission to the ICU. Furthermore, the time course of PDR ICG as well as ASAT and α-GST did not differ between groups of haemodilutional anaemia.
Our study provides evidence that impaired PDR ICG as a marker of hepatic dysfunction and hypoperfusion may be a valid marker of prolonged ICU treatment. Additionally this study provides evidence that haemodilutional anaemia to a Hct of 20% does not impair hepatic function and perfusion.
Trial registration
PMCID: PMC2784368  PMID: 19747406
19.  Retinal pigment epithelial atrophy following indocyanine green dye- assisted surgery for serous macular detachment 
Indian Journal of Ophthalmology  2008;56(5):423-425.
To report subretinal migration of indocyanine green dye (ICG) and subsequent retinal pigment epithelial (RPE) atrophy during macular surgery for serous macular detachment. A 65-year-old woman presented with residual epiretinal membrane and serous detachment of the macula following vitreoretinal surgery for epiretinal membrane. She underwent resurgery with ICG- assisted internal limiting membrane peeling and intraocular tamponade. Intraoperatively a large area of subretinal ICG was seen with subsequent RPE mottling and atrophy of the macula in the area involved during follow-up. This case demonstrates that subretinal migration of ICG is possible and can be toxic to RPE.
PMCID: PMC2636149  PMID: 18711276
Indocyanine green; macular hole; retinal pigment epithelial atrophy; serous macular detachment
20.  The Expansion of RPE Atrophy after the Inverted ILM Flap Technique for a Chronic Large Macular Hole 
Case Reports in Ophthalmology  2014;5(1):83-86.
To report a case of the expansion of submacular retinal pigment epithelium (RPE) atrophy after using the inverted internal limiting membrane (ILM) flap technique for a persisting, large, stage IV macular hole (MH).
Case Report
A 79-year-old woman presented with a chronic large MH that remained open despite pars plana vitrectomy (PPV). The surgery was performed twice for the MH closure 14 years earlier. ILM peeling was not performed during the previous surgeries. The best-corrected visual acuity (BCVA) with the Landolt ring chart was 0.08 at her visit. The minimum MH diameter was 1,240 μm. Inverted ILM flap technique with 20% SF6 gas tamponade was performed for the MH closure. For the inverted ILM flap technique, 25-gauge PPV and ILM staining with indocyanine green were used. The ILM was peeled off for 2 disc diameters around the MH, but the ILM was not removed completely. The ILM was then inverted and covered the MH.
One month after surgery, the MH was closed, accompanied by glial cell proliferation spreading from the inverted ILM flap (as reported before). On the other hand, the area of the submacular RPE atrophy, which was already observed 1 week after surgery, gradually increased in size. BCVA improved to 0.3 six months after the surgery.
The inverted ILM flap technique may be promising even for persisting large MH which were not closed in previous surgeries, but long-term observation is needed because the detailed behavior of the inverted ILM and the Müller cells after surgery is not yet known.
PMCID: PMC3975172  PMID: 24707278
Macular hole; Inverted internal limiting membrane flap technique; Chronic macular hole; Indocyanine green; Retinal pigment epithelium atrophy
21.  Treatment of idiopathic macular hole with silicone oil tamponade 
We analyzed the anatomical and visual outcomes after surgical treatment of idiopathic macular holes with pars plana vitrectomy, internal limiting membrane (ILM) peeling using Brilliant Blue dye, and silicone oil tamponade without postoperative posturing.
This was a retrospective interventional study of 10 eyes in eight patients who underwent surgical treatment of idiopathic macular holes using pars plana vitrectomy, ILM peeling using Brilliant Blue dye, and silicone oil tamponade without postoperative posturing. The preoperative staging of macular holes and postoperative anatomic outcomes were assessed using spectral-domain optical coherence tomography.
All patients were women with a mean age of 66.86 ± 4.8 years. In two patients, bilateral macular holes were present and both eyes were operated on. Stage 2 macular hole was diagnosed in three eyes, three eyes had stage 3, and four eyes had stage 4 macular holes. Anatomical success and closure of the macular hole was achieved in nine eyes (90%) after one operation. In one eye, the macular hole was closed after reoperation. The preoperative mean best-corrected visual acuity (BCVA) was 0.15 decimal units (0.8 logMAR units). Until the end of the follow-up period, BCVA was 0.25 decimal units (0.6 logMAR units). Visual acuity was improved in seven patients (70%). In two patients (20%), visual acuity remained at the same level, and in one eye (10%), visual acuity decreased. Postoperatively, all patients reported a significant reduction of metamorphopsia.
Initial results after 20G pars plana vitrectomy with peeling of the ILM, use of dye (Brilliant Blue), and tamponade with silicone oil without postoperative posturing gave good anatomical and functional outcome in terms of visual acuity and reduction of metamorphopsia. Taking into account the age of the patients, this method, which does not require prolonged postoperative face-down posturing, was well tolerated by the patients. Because the anatomical and visual outcome as well as the rate of postoperative complications are comparable to those when gas is used as a tamponading agent, silicone oil tamponade can also be safely used as a first option in surgery of macular holes. However, a longer period of follow-up of the operated eyes, as well as a larger group of operated eyes, will be required to identify long-term outcomes of this surgical treatment.
PMCID: PMC3460698  PMID: 23055662
macular hole; silicone oil; ILM peeling; pars plana vitrectomy
22.  Short PEG-Linkers Improve the Performance of Targeted, Activatable Monoclonal Antibody-Indocyanine Green Optical Imaging Probes 
Bioconjugate chemistry  2013;24(5):811-816.
The ability to switch optical imaging probes from the quenched (off) to the active state (on) has greatly improved target to background ratios. The optimal activation efficiency of an optical probe depends on complete quenching before activation and complete de-quenching after activation. For instance, monoclonal antibody-indocyanine green (mAb-ICG) conjugates, which are promising agents for clinical translation, are normally quenched but can be activated, when bound to a cell surface receptor and internalized. However, the small fraction of commonly used ICG derivative (ICG-Sulfo-OSu) can bind noncovalently to its mAb and is thus, gradually released from the mAb leading to relatively high background signal especially in the liver and the abdomen. In this study, we re-engineered a mAb-ICG conjugate, (Panitumumab-ICG) using bifunctional ICG derivatives (ICG-PEG4-Sulfo-OSu and ICG-PEG8-Sulfo-OSu) with short polyethylene glycol (PEG) linkers. Higher covalent binding (70–86%) was observed using the bifunctional ICG with short PEG linkers resulting in less in vivo non-covalent dissociation. Panitumumab-ICG conjugates with short PEG linkers were able to detect human epidermal growth factor receptor 1 (EGFR)-positive tumors with high tumor-to-background ratios (15.8 and 6.9 for EGFR positive tumor-to-negative tumor and tumor-to-liver ratios, respectively, at 3 d postinjection).
PMCID: PMC3674550  PMID: 23600922
indocyanine green; PEG linker; fluorescence imaging; activatable; monoclonal antibody
23.  The dilution effect and the importance of selecting the right internal control genes for RT-qPCR: a paradigmatic approach in fetal sheep 
BMC Research Notes  2015;8:58.
The key to understanding changes in gene expression levels using reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR) relies on the ability to rationalize the technique using internal control genes (ICGs). However, the use of ICGs has become increasingly problematic given that any genes, including housekeeping genes, thought to be stable across different tissue types, ages and treatment protocols, can be regulated at transcriptomic level. Our interest in prenatal glucocorticoid (GC) effects on fetal growth has resulted in our investigation of suitable ICGs relevant in this model. The usefulness of RNA18S, ACTB, HPRT1, RPLP0, PPIA and TUBB as ICGs was analyzed according to effects of early dexamethasone (DEX) treatment, gender, and gestational age by two approaches: (1) the classical approach where raw (i.e., not normalized) RT-qPCR data of tested ICGs were statistically analyzed and the best ICG selected based on absence of any significant effect; (2) used of published algorithms. For the latter the geNorm Visual Basic application was mainly used, but data were also analyzed by Normfinder and Bestkeeper. In order to account for confounding effects on the geNorm analysis due to co-regulation among ICGs tested, network analysis was performed using Ingenuity Pathway Analysis software. The expression of RNA18S, the most abundant transcript, and correlation of ICGs with RNA18S, total RNA, and liver-specific genes were also performed to assess potential dilution effect of raw RT-qPCR data. The effect of the two approaches used to select the best ICG(s) was compared by normalization of NR3C1 (glucocorticoid receptor) mRNA expression, as an example for a target gene.
Raw RT-qPCR data of all the tested ICGs was significantly reduced across gestation. TUBB was the only ICG that was affected by DEX treatment. Using approach (1) all tested ICGs would have been rejected because they would initially appear as not reliable for normalization. However, geNorm analysis (approach 2) of the ICGs indicated that the geometrical mean of PPIA, HPRT1, RNA18S and RPLPO can be considered a reliable approach for normalization of target genes in both control and DEX treated groups. Different subset of ICGs were tested for normalization of NR3C1 expression and, despite the overall pattern of the mean was not extremely different, the statistical analysis uncovered a significant influence of the use of different normalization approaches on the expression of the target gene. We observed a decrease of total RNA through gestation, a lower decrease in raw RT-qPCR data of the two rRNA measured compared to ICGs, and a positive correlation between raw RT-qPCR data of ICGs and total RNA. Based on the same amount of total RNA to performed RT-qPCR analysis, those data indicated that other mRNA might have had a large increase in expression and, as consequence, had artificially diluted the stably expressed genes, such as ICGs. This point was demonstrated by a significant negative correlation of raw RT-qPCR data between ICGs and liver-specific genes.
The study confirmed the necessity of assessing multiple ICGs using algorithms in order to obtain a reliable normalization of RT-qPCR data. Our data indicated that the use of the geometrical mean of PPIA, HPRT1, RNA18S and RPLPO can provide a reliable normalization for the proposed study. Furthermore, the dilution effect observed support the unreliability of the classical approach to test ICGs. Finally, the observed change in the composition of RNA species through time reveals the limitation of the use of ICGs to normalize RT-qPCR data, especially if absolute quantification is required.
Electronic supplementary material
The online version of this article (doi:10.1186/s13104-015-0973-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4352295  PMID: 25881111
Dexamethasone; Sheep; Fetal liver; geNorm; Co-regulation; Internal control gene; RNA18S; RPLP0; HPRT1; PPIA; TUBB; ACTB; RNA28S
24.  Clinical and cost-effectiveness of internal limiting membrane peeling for patients with idiopathic full thickness macular hole. Protocol for a Randomised Controlled Trial: FILMS (Full-thickness macular hole and Internal Limiting Membrane peeling Study) 
Trials  2008;9:61.
A full-thickness macular hole (FTMH) is a common retinal condition associated with impaired vision. Randomised controlled trials (RCTs) have demonstrated that surgery, by means of pars plana vitrectomy and post-operative intraocular tamponade with gas, is effective for stage 2, 3 and 4 FTMH. Internal limiting membrane (ILM) peeling has been introduced as an additional surgical manoeuvre to increase the success of the surgery; i.e. increase rates of hole closure and visual improvement. However, little robust evidence exists supporting the superiority of ILM peeling compared with no-peeling techniques. The purpose of FILMS (Full-thickness macular hole and Internal Limiting Membrane peeling Study) is to determine whether ILM peeling improves the visual function, the anatomical closure of FTMH, and the quality of life of patients affected by this disorder, and the cost-effectiveness of the surgery.
Patients with stage 2–3 idiopathic FTMH of less or equal than 18 months duration (based on symptoms reported by the participant) and with a visual acuity ≤ 20/40 in the study eye will be enrolled in this FILMS from eight sites across the UK and Ireland. Participants will be randomised to receive combined cataract surgery (phacoemulsification and intraocular lens implantation) and pars plana vitrectomy with postoperative intraocular tamponade with gas, with or without ILM peeling. The primary outcome is distance visual acuity at 6 months. Secondary outcomes include distance visual acuity at 3 and 24 months, near visual acuity at 3, 6, and 24 months, contrast sensitivity at 6 months, reading speed at 6 months, anatomical closure of the macular hole at each time point (1, 3, 6, and 24 months), health related quality of life (HRQOL) at six months, costs to the health service and the participant, incremental costs per quality adjusted life year (QALY) and adverse events.
FILMS will provide high quality evidence on the role of ILM peeling in FTMH surgery.
Trial registration
This trial is registered with Current Controlled Trials ISRCTN number 33175422 and Clinical identifier NCT00286507.
PMCID: PMC2607251  PMID: 18980675
25.  Retinal ganglion cells toxicity caused by photosensitising effects of intravitreal indocyanine green with illumination in rat eyes 
To investigate the effects of indocyanine green (ICG) with or without illumination on rat retinal ganglion cells (RGC) and retinal morphology.
Intravitreal injections of 1.0 mg/ml ICG solution were performed in rat eyes with or without subsequent illumination for 5 minutes. Eyes in the control group had intravitreal injections of balanced salt solution with illumination. Retrograde labelling of RGC with 6% Fluoro‐Gold was performed 1 month later and RGC densities were compared between the three groups. Light microscopy with measurements of outer nuclear layer (ONL) and inner nuclear layer (INL) thicknesses were also performed and compared.
Eyes with ICG without illumination showed insignificant reduction in RGC density compared with the control group (p = 0.28), whereas a significant decrease in RGC density was found in eyes that had ICG injection with illumination (p = 0.036). A significant increase in ONL thickness was also observed in the ICG with illumination treated eyes compared with the ICG without illumination and the control groups (p<0.001). No significant difference in INL thickness was observed between the three groups.
Intravitreal injection of 0.1 mg/ml ICG in rat eyes followed by illumination resulted in photosensitising toxicity to RGC. Lower ICG concentration or illumination level should be considered when performing ICG assisted macular surgery.
PMCID: PMC1856904  PMID: 16361677
indocyanine green; retinal ganglion cell; photosensitising toxicity; rat

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