Current Trends in Ophthalmology Simultaneous Angiography for the Anterior Segment and Posterior Fundus of Eyes with Anterior Segment Neovascularization using Heidelberg Retina Angiograph 2

Objective: To present a method of indocyanine green angiography (IA) and fluorescein sodium angiography (FA) for simultaneously evaluating anterior segment neovascularization and fundus abnormality. Participants: We examined 19 eyes of 19 patients suspected of having neovascularization in the anterior segment of the eye. Seventeen eyes of 17 patients suffered from proliferative diabetic retinopathy, and two eyes of 2 patients had central retinal vein occlusion. Methods: Using Heidelberg Retina Angiograph 2 (HRA2), we performed angiography of the anterior and posterior segment of the eye. Results: Of the 19 cases, anterior segment neovascularization was clearly observed with slit-lamp examination and gonioscopy in 12 eyes (63.1%). However, anterior segment neovascularization was detected by HRA2 angiography in 18 eyes (94.7%). Posterior segment angiography revealed non-perfusion area in 16 eyes (84.2%) and retinal neovascularization in 10 eyes (52.6%). In one case, the posterior segment findings were not obtained due to vitreous hemorrhaging. Conclusion: Simultaneous anterior and posterior segment HRA2 angiography using indocyanine green and fluorescein sodium is a useful technique for detecting neovascularization in the anterior segment of the eye as well as non-perfusion areas and neovascularization of the retina.


Introduction
Neovascular Glaucoma (NVG) is a serious complication associated with retinal ischemic disorders, such as diabetic retinopathy and central retinal vein occlusion.The etiology of intraocular pressure elevation in patients with anterior segment neovascularization is thought to arise from aqueous flow blocking, which may be caused by the development of a fibrovascular membrane covering the anterior surface of the trabecular meshwork or by invasion of newly formed vessels to the intertrabecular spaces [1][2][3].The detection of the fibro vascular membrane in the iris and iridocorneal angle is very important for early diagnosis of NVG.These patients sometimes receive treatments such as pan-retinal photoablation and intravitreal injection of anti-VEGF monoclonal antibody.However, the detection of the newly formed vessels in the anterior segment of the eye can be difficult in these patients when performing a slit lamp examination.Jensen et al. reported on the utility of fluorescein iris imaging for the early detection of newly formed vessels in diabetic patients [3].Since then, anterior segment angiography had been reported to be useful for the early detection of newly formed vessels in the iris and iridocorneal angle [4][5][6][7][8][9][10][11][12][13].Previous studies have reported that FA and IA in the anterior ocular segment are useful for studying the structure and hemodynamic of newly formed vessels [12,14,15].This study was conducted to evaluate the usefulness of the simultaneous anterior and posterior ocular segment angiography using Heidelberg retina angiography 2 (HRA2) with FA and IA.

Study design: Cross sectional study
Nineteen eyes of 19 patients suspected of having neovascularization of the iris or iridocorneal angle associated with ischemic retinal disease were included in the study between July 2014 and July 2015.Thirteen patients were male, and six patients were female.The average age was 58.5 ± 10.9 years old (range: 38 -85 years old).In all patients, blood sampling was performed before the ocular fundus angiographic examination.No particular problems were seen in the kidney or liver function that might prevent performing the examination.The fundamental ischemic retinal diseases included proliferative diabetic retinopathy in 17 eyes and central retinal vein occlusion in 2 eyes.All of the patients underwent a complete ocular examination that evaluated the best-corrected visual acuity and intraocular pressure and included slit lamp biomicroscopy, gonioscopy, and a fundus examination.The mean intraocular pressure before treatment was 32.1 ± 15.3 mmHg (range: 8-63 mmHg).Glaucoma drugs had been used in 15 eyes, and retinal photoablation had been enforced in 17 eyes (Table 1).
Anterior and posterior segment angiography were simultaneously performed using HRA2 (Heidelberg Engineering Company, Heidelberg, Germany).We used a mydriatic agent just before beginning angiography.Anterior segment angiography was first performed using 0.5% indocyanine green and 10% fluorescein sodium.We observed the presence of newly formed vessels on the pupillary region and the front iris through the center lens of the gonioscope, and observed the entire circumference of the iridocorneal angle through the lens of the gonioscope.After confirming mydriasis, the gonioscope was removed, and we observed the pathological changes to the posterior fundus.If necessary, contrast agents were additionally injected.The existence and area of the iris and iridocorneal angle neovascularization are described in table 2, along with the presence or absence of the non-perfusion area and neovascularization of the retina.
The study was approved by the institutional review board of Oita University Hospital, and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.After the nature of the study was explained to the participants, informed consent was obtained from all individual participants included in the study.

Results
Table 1 shows the age, gender, right or left eye, causative disease, best-corrected visual acuity, intraocular pressure before therapy, treatment history, surgical procedure, and preoperative and postoperative use of glaucoma drugs for all 19 cases.We present a representative case in the figure 1 (case 18, 58 years old, female, PDR, right eye).The patient had been treated with pan-retinal photoablation because of proliferative diabetic retinopathy.She was referred to us because of elevated intraocular pressure.The findings of the slitlamp examination showed unclear neovascularization of the iris and iridocorneal angle (Figure 1A and B).However, anterior segment angiography clearly revealed neovascularization in both (Figure 2).The retinal nonperfusion area and retinal neovascularization were not observed in either eye (Figure 3).
The findings of the iris and iridocorneal neovascularization of all cases are summarized in table 2. Using a slit-lamp examination, the new formation of vessels in the iris in the range of 1 quadrant or more was observed in 8 eyes (42.1%).Using gonioscopy, the new formation of vessels in the iridocorneal angle in the range of 1 quadrant or more was observed in 8 eyes (42.1%).Peripheral anterior synechia was observed in 6 eyes (31.5%).However, anterior segment angiography revealed neovascularization in 18 eyes (94.7%).Posterior segment angiography revealed retinal non-perfusion area in 16 eyes (84.2%) and retinal neovascularization in 10 eyes (52.6%).In one eye (Case 2), it was impossible to observe the posterior fundus due to vitreous hemorrhaging.We diagnosed neovascular glaucoma in 18 eyes and secondary angle-closure glaucoma accompanied with iridocyclitis in one eye (Case 10).Among the 18 cases, iris and/or iridocorneal angle neovascularization was observed in 12 cases on an ophthalmoscopic examination, resulting in a sensitivity of 66.7% and specificity of 100%.Neovascularization was observed in 12 cases by ophthalmoscope and was detected in all 12 cases by anterior segment angiography.The positive predictive value was 100%.Neovascularization was not observed in 7 cases by ophthalmoscope and in 1 case (Case 10) by anterior segment angiography.The negative predictive value was 14.3%.

Discussion
Many previous reports had been published regarding the usefulness of early rubeosis detection by fluorescence anterior segment angiography [3][4][5][6][7][8][9][10][11][12][13].Azad et al. [13] reported Retcam fluorescein gonioangiography to be a novel technique for the early detection of angle neovascularization in patients with diabetic retinopathy.They concluded that the technique helped to prevent the progression to neovascular glaucoma.Ishibashi et al. evaluated the effects of the intravitreal injection of bevacizumab on anterior segment neovascularization using anterior segment angiography with HRA2 [12].They observed anterior segment neovascularization with fluorescein and indocyanine green angiograpy.
The eyes with anterior segment neovascularization exhibited vascular structure with IA and marked leakage with FA.Fluorescein passes through the fenestration of newly formed vessels, but indocyanine green does not, due to the molecule size [14].The vascular structures showing leakage with FA in the anterior segment are believed to represent newly formed vessels.Indocyanine green angiography is suitable for evaluating the detailed structure of newly formed vessels because of the absence of extravasation of indocyanine green.
We performed simultaneous anterior and posterior ocular segment angiography using HRA2 with FA and IA to detect anterior segment neovascularization and fundus abnormalities in eyes suspected of having newly formed vessels in the iris and iridocorneal angle.In this procedure, a mydriatic agent was used just before beginning anterior segment angiography.Anterior segment angiography requires a gonioscope and has a disadvantage, due to the difficulty to evaluation under mydriasis.Sufficient mydriasis is obtained when anterior segment angiography is finished in the present procedure.Therefore, we can easily continue fluorescence fundus angiography and observe retinal pathological changes, including retinal non-perfusion area and neovascularization, using HRA2.
The present study confirmed the results of previous that the anterior segment angiography is more sensitive for early detection of the newly formed vessels in both the iris and iridocorneal angle than biomicroscopy [2][3][4][5][6][7][8][9][10][11][12].Anterior segment angiography showed that neovascularization had a good correlation with posterior fundus abnormalities (Table 2).The subjects were patients with retinal ischemic disorders suspected of having anterior segment neovascularization.Newly formed vessels in the anterior segment were detected in all patients except for one with secondary angle closure glaucoma accompanied by iridocyclitis.In the present study, many patients had undergone previous treatment, including pan-retinal photoablation, anti-VEGF intravitreal injection, and vitrectomy.The patients with newly formed vessels in the anterior segment had compatible retinal abnormalities in the present study.Biomicroscopic detection of these newly formed vessels is not easy in patients with a history of retinal treatments.Therefore, we highly recommend this method using HRA2 be used for the early diagnosis of neovascular glaucoma in patients with retinal ischemic disorders.

Figure 1 :
Figure 1: Case 18, 58 years old, anterior segment neovascularization associated with proliferative diabetic retinopathy.A: Iris rubeosis is unclear under a slit lamp examination in the right eye.B: Iridocorneal rubeosis is unclear with gonioscopy in the right eye.

Figure 2 :
Figure 2: Anterior segment angiography in the right eye In IA (right), the entire blood vessel construction, including the healthy blood vessels are visualized.In FA (left), leakage from neovascularization can be clearly seen.

Figure 3 :
Figure 3: Neither the retinal non-perfusion area nor retinal neovascularization are seen in either eye.

Table 1 :
Clinical characteristics of patients with suspected anterior segment neovascularization.
Sup: superior, neovascularization was observed in the superior quadrant area; inf: inferior; tem: temporal; nas: nasal; all: all quadrants; neovascularization was observed in all quadrants.