Laser and Anti Vascular Endothelial Growth Factor Agent Treatments for Retinal Arterial Macroaneurysm

Transcription

1 original clinical study Laser and Anti Vascular Endothelial Growth actor Agent Treatments for Retinal Arterial acroaneurysm Yen-Yi Chen,* Lo-Yi Lin,* Pei-Yao Chang,* ang-ting Chen* Elsa L.C. ai,* and Jia-Kang Wang* Purpose: To describe the efficacy of laser and intravitreal injection of anti vascular endothelial growth factor (anti-veg) agents for patients with symptomatic retinal arterial macroaneurysm (RA). Design: rom 2009 to 206, we collected patients with exudative or hemorrhagic RA all treated by focal laser photocoagulation. ethods: Nd:YAG laser was performed in patients with subinternal limiting membrane (sub-il) hemorrhage. Intravitreal anti-veg agents were given in eyes with macular exudation as adjuncts. Changes of visual acuity and central foveal thickness before and after treatment were recorded and compared with Wilcoxon signed-rank test. Results: Thirty-five eyes that underwent a single session of laser photocoagulation for RA resulted in macroaneurysm regression. The hemorrhagic group included 24 eyes having ruptured macroaneurysms without macular exudation. ive eyes with simultaneous sub-il hemorrhage receiving Nd:YAG laser membranotomy had resolution of preretinal hemorrhage. Exudative RA having cystoid macular edema or submacular fluid with or without ruptured macroaneurysms was treated by focal laser photocoagulation alone in, or combined with single intravitreal anti-veg agent in 8 eyes. All patients had significantly improved vision when comparing visual acuity at baseline and final follow-up (P = ). Significant reduction of macular thickness was also observed after laser monotherapy or combined treatment in exudative RA (P = 0.08). Conclusions: ocal laser photocoagulation was helpful for the management of ruptured or leaky RA. Combined focal laser and intravitreal anti-veg agents could better reduce macular exudation caused by RA. Additionally, Nd:YAG laser was a safe and effective method to remove the sub-il hemorrhage caused by RA. Key Words: aflibercept, bevacizumab, argon laser, retinal arterial macroaneurysm (Asia-Pac J Ophthalmol 207;6: ) Retinal arterial macroaneurysm (RA) is acquired saccular or fusiform dilatation of the large arteriole of the retina, usually rom the *Department of Ophthalmology, ar Eastern emorial Hospital, New Taipei City; Department of edicine, Taipei edical University, Taipei City; Department of edicine, National Taiwan University, Taipei City; Department of edicine, National Yang ing University, Taipei City; Departments of Healthcare Administration and Nursing, Oriental Institute of Technology, New Taipei City; and Department of Electrical Engineering, Yuan Ze University, Taoyuan City, Taiwan. Received for publication ebruary 0, 207; accepted July, 207. The authors have no funding or conflicts of interest to declare. Reprints: Jia-Kang Wang, Department of Ophthalmology, ar Eastern emorial Hospital, 2, Sec. 2, Nan-Ya South Road, Pan-Chiao District, New Taipei City, 220, Taiwan. E mail: jiakangw258@gmail.com. Copyright 207 by Asia Pacific Academy of Ophthalmology ISSN: DOI: 608/APO within the first orders of bifurcation. It is more common in elderly women with poorly controlled hypertension. 2 The perfusion pressure is high and the thin stretched arterial sac of RA is relatively easily perforated, resulting in associated hemorrhage or fluid leakage of ruptured macroaneurysms. In terms of the most dominant finding in fundus, RA can be classified into hemorrhagic, exudative, and quiescent types. 2 Exudative RA leads to hard exudates or macular edema. Hemorrhagic RA is responsible for subretinal, intraretinal, preretinal (subhyaloidal or subinternal limiting membrane) hemorrhage, or intravitreal hemorrhages. Both hemorrhagic and exudative types of RA can cause remarkable visual decrease if edema or hemorrhage affects the macular region. Quiescent RA is typically asymptomatic, but it can rupture or leak to develop into either hemorrhagic or exudative form. There are no standard treatment guidelines for symptomatic RA. The proposed treatment strategies include observation,,2 intravitreal injection of anti vascular endothelial growth factor (anti-veg) agents, 8 and laser photocoagulation of RA. 9 9 Complications caused by RA consist of dense premacular hemorrhage, which can be drained by YAG laser membranotomy or hyaloidotomy,4 ; dispersed vitreous hemorrhage, which can be removed by vitrectomy 9 ; submacular hemorrhage, which can be displaced by intravitreal injection of both tissue plasminogen activator and long-acting gas or removed by submacular surgery. 2,0 In this study, we used various treatment strategies for different types and complications of RA. The clinical anatomical and functional outcomes were analyzed retrospectively. aterials and ethods The protocol of the study, which followed the Declaration of Helsinki, was approved by the institutional review board of ar Eastern emorial Hospital. rom September 2009 to October 206, we retrospectively reviewed consecutive patients with exudative or hemorrhagic RA. Ruptured RA associated with vitreous, preretinal, retinal, and/or subretinal hemorrhage without simultaneous macular edema was regarded as hemorrhagic type. The patients with submacular fluid and/or cystoid macular edema caused by ruptured or nonruptured macroaneurysms were categorized as exudative type. All the patients were examined with bestcorrected visual acuity (BCVA) measurement, color fundus photography, fundus fluorescein angiography, and spectral-domain optical coherence tomography (SD-OCT; RTVue-00, Optovue Inc, CA). ocal green laser photocoagulation of 52 nm (C-500, Nidek Inc, Tokyo, Japan) was applied on macroaneurysms in all patients, according to prior study. 9,9 Threshold laser was performed around the macroaneurysm with confluent pattern and the following settings: spot size of 200 μm, laser duration of 0.2 seconds, Asia-Pacific Journal of Ophthalmology Volume 6, Number 5, September/October 207

2 Asia-Pacific Journal of Ophthalmology Volume 6, Number 5, September/October 207 Laser, Anti-VEG, and RA figure. Optical coherence tomography showing subinternal limiting figure 2. Optical coherence tomography showing empty space beneath membrane hemorrhage (solid arrow) and posterior hyaloid surface (hollow arrow). internal limiting membrane (solid arrow) and residual subhyaloid hemorrhage (hollow arrow) after YAG laser membranectomy. and 200 to 600 mw of power until retinal whitening. Subthreshold laser was applied to the macroaneurysm to facilitate thrombosis and stop active bleeding until the laser spot was barely visible. In patients with hemorrhagic type associated with premacular hemorrhage, subinternal limiting membrane (sub-il) hemorrhage was confirmed with SD-OCT as previously described, showing separation of the hyporeflective plane of posterior hyaloid and hyperreflective plane of IL, and the blood noted beneath IL (igs., 2).20 Nd:YAG laser (000LE, Alcon Inc, Texas) was used to break the IL with power settings of 6 to 0 mj on the lowest part of the sub-il hemorrhage until the blood was successfully drained. Subsequent green laser photocoagulation was done for ruptured macroaneurysms week after Nd:YAG membranotomy. If severe vitreous hemorrhage obstructing the visual axis persisted for month, patients underwent 2-gauge vitrectomy (Constellation, Alcon Inc, Texas) to remove bloody vitreous and simultaneous focal diode endolaser (OcuLight, Iridex Inc, CA) around the macroaneurysm at threshold power and on the macroaneurysm at subthreshold power. ocal laser monotherapy on the macroaneurysm was performed in patients with exudative RA from 2009 to 200. Laser photocoagulation combined with single intravitreal anti-veg agents including bevacizumab.25 mg from 20 to 20, ranibizumab 0.5 mg in 204, and aflibercept 2 mg from 205 to 206 was done in eyes with macular exudation within week after laser therapy. All the patients were followed for at least months. Those with follow-up periods of less than months were excluded, along with those with vision-threatening disorders other than RA, such as glaucoma, uveitis, proliferative diabetic retinopathy, macular edema associated with diabetes mellitus or retinal vein occlusion, or high myopia. Patients demographics, laterality, initial fundus presentation, treatment modalities, follow-up periods, and BCVA were recorded before, after treatment at month, and at last follow-up. Central foveal thickness (CT) was documented at baseline, month, and last follow-up in exudative type. Changes of BCVA and CT before and after treatment were compared with Wilcoxon signed-rank test. Results Thirty-five eyes of 4 patients with symptomatic RA were reviewed, including 25 women and 9 men. The mean age at diagnosis was 72 ± years (range, 44 9 years). The mean followup duration was.2 ± months (range, 8 months). Baseline mean BCVA was 0.9 ± 7 logarithm of the minimum angle of resolution (logar). All the patients had systemic hypertension under medical control. Diabetes mellitus was not found in this study. After treatment, mean BCVA significantly improved to 8 ± 0.05 logar at month (P = 0.000) and 0.24 ± 0.0 (P = ) at the final visit (ig. ). Of all patients, 24 eyes of 2 patients were categorized as hemorrhagic RA, including 7 women and 6 men (Table ). The mean age was 7.5 ± years (range, years). The mean follow-up duration was 9. ± months (range, 8 months). Seven eyes (cases to 7) underwent focal laser therapy for ruptured RA with perianeurysmal retinal and subretinal figure. Changes of baseline, month after treatment, and final mean BCVA in all patients (solid line), patients with hemorrhagic retinal arterial macroaneurysm (dotted line), and patients with exudative retinal arterial macroaneurysm (dashed line). 207 Asia-Pacific Academy of Ophthalmology 445

3 Chen et al Asia-Pacific Journal of Ophthalmology Volume 6, Number 5, September/October 207 Table. Clinical Data of Hemorrhagic Retinal Arterial acroaneurysm Before and After Treatment Visual Acuity (logar) Patient Age (y) Sex Eye Presentation Treatment Initial -o ollow-up inal ollow-up Period (mo) RRA RRA RRA RRA RRA RRA RRA Sub-IL hemorrhage + RRA Sub-IL hemorrhage + RRA Sub-IL hemorrhage + RRA Sub-IL hemorrhage + RRA Sub-IL hemorrhage + RRA + vitreous hemorrhage + macular edema Vitrectomy + diode laser Vitrectomy + diode laser YAG laser + vitrectomy + diode laser + IVA IVA indicates intravitreal aflibercept;, oculus dexter (right eye);, oculus sinister (left eye); RRA, ruptured retinal arterial macroaneurysm. hemorrhage in the extrafoveal area. Ten eyes (cases 7 to 6) had aneurysmal rupture complicated with vitreous hemorrhage that still allowed laser photocoagulation on RA. Two eyes (cases 7 and 8) presented as nonclearing vitreous hemorrhage for month. During vitrectomy, ruptured RA was found and diode endolaser photocoagulation performed for RA. ive eyes (cases 9 to 2) presenting as premacular sub-il hemorrhage underwent Nd:YAG membranotomy and successfully drained premacular blood, complicated with dispersed vitreous hemorrhage. our eyes (cases 9 to 22) received focal green laser treatment for RA week after Nd:YAG laser membranotomy until vitreous hemorrhage cleared. One eye (case 2) suffered from persistent massive vitreous hemorrhage for month after Nd:YAG laser, impeding focal green laser for RA. Subsequent vitrectomy and diode endolaser were performed on ruptured macroaneurysms. One month after vitrectomy, a single dose of intravitreal aflibercept was injected due to cystoid macular edema. acular edema subsided thereafter. The patients with hemorrhagic RA all underwent a single session of laser photocoagulation with or without membranotomy and/or vitrectomy, causing disappearance of retinal, subretinal, premacular, and vitreous hemorrhage without recurrence. The macroaneurysms were all regressed without recurrence of hemorrhage observed by fundus examination during follow-up. There was no case having submacular hemorrhage. Baseline mean BCVA of hemorrhagic RA was.0 ± 0.2 logar. After treatment, mean BCVA significantly improved to ± 0.08 logar at month (P = 0.05) and 0.27 ± 0.04 (P = ) at the final visit (ig. ). Eleven eyes of patients were categorized as exudative RA, including 8 women and men (Table 2). The mean age was 75.4 ± 8.8 years (range, 62 9 years). The mean follow-up duration was 9.9 ± 7.8 months (range, 0 months). Cases 24, 26, 28, and having ruptured macroaneurysms were categorized into the exudative group because the main reason for impaired vision in these patients was macular exudation rather than focal retinal hemorrhage. These cases with or without macroaneurysm rupture were all treated by a single session of green laser photocoagulation. The first cases (cases 24 to 26) received laser treatment without adjuncts, resulting in visual improvement at month and the final visit. Although dry macula was found at the end of follow-up in these cases, residual intraretinal or subretinal fluid persisted month after laser therapy with CT more than 00 μm. A single dose of intravitreal bevacizuamb in 4 eyes (cases 27 to 0), ranibizumab in 2 eyes (cases and 2), and aflibercept in 2 eyes (cases and 4) was injected. Visual gains and dry macula were demonstrated in these cases receiving combination therapy at month and final follow-up. Baseline mean BCVA of exudative RA was 0.64 ± logar. After treatment, mean Asia-Pacific Academy of Ophthalmology

4 Asia-Pacific Journal of Ophthalmology Volume 6, Number 5, September/October 207 Laser, Anti-VEG, and RA Table 2. Clinical Data of Exudative Retinal Arterial acroaneurysm Before and After Treatment Visual Acuity (logar) Central oveal Thickness (μm) Patient Age (y) Sex Eye Presentation Treatment Initial -o ollow-up inal Initial -o ollow-up inal ollow-up Period (mo) CE + RRA CE SD + RRA CE + SD CE + RRA SD CE CE + RRA SD SD SD + IVB + IVB + IVB + IVB + IVR + IVR + IVA + IVA CE indicates cystoid macular edema; IVB, intravitreal bevacizumab; IVR, intravitreal ranibizumab; SD, serous macular detachment. BCVA significantly improved to 0.2 ± 0.07 logar at month (P = 0.007) and 8 ± 0.04 (P = ) at the final visit (ig. ). The mean CT decreased from ± 8. μm to 25 ± 8.6 μm at month (P = 0.0) and 26. ± 6.9 μm (P = 0.08) at the final visit (ig. 4). Discussion There are no treatment guidelines for symptomatic RA. Some prior studies recommended observation for spontaneous thrombosis and involution of RA.,2 Laser photocoagulation of macroaneurysm is controversial because the visual outcome after laser therapy is variable. Brown et al 5 concluded visual results were comparable between groups of observation and direct laser treatment for RA over a mean 6-month follow-up. However, they used xenon laser for RA photocoagulation, which was more destructive than modern green or yellow laser. Koinzer et al 9 found that the mean visual acuity of the observation or laser group for RA did not improve significantly from baseline to the end of long-term follow-up (mean, 6.6 months). However, there were some patients with submacular hemorrhage in the figure 4. Changes of baseline, month after treatment, and final mean CT in patients with exudative retinal arterial macroaneurysm. laser group, who may have poor visual results because of profound photoreceptor damage and disorganization of retinal layer integrity. Although a few studies showed no difference in clinical outcome between observation and laser therapy for RA, most researchers favored laser treatment due to high efficacy and few complications. Previous reports noted that visual gains were significant after threshold or subthreshold laser photocoagulation for patients with RA.,6 9 Parodi et al 6 performed a randomized study, which concluded subthreshold laser had similar efficacy to treat ruptured RA as threshold laser to cause significant visual gain. Reported complications included vitreous hemorrhage, branch retinal vein occlusion, secondary choroidal neovascularization, and RA recurrence. 8 In this study, we used both indirect and direct laser photocoagulation to treat ruptured RA. Indirect threshold laser surrounded the macroaneurysms to prevent perivascular leakage and further extension of hemorrhage, and to lower oxygen demand. The laser also avoided the macular branch of the retinal artery to shun macular infarct. Direct subthreshold laser on the aneurysm can facilitate thrombosis and regression of RA and prevent retinal or macular ischemia caused by distal circulation obstruction. Additionally, we did not have cases with subfoveal hemorrhage, which may predispose to poor visual outcome. Significant visual gains were found in 24 eyes with ruptured RA and associated hemorrhage after a mean 9.-month follow-up of treatment with a single session of laser photocoagulation. We did not observe any adverse effects after laser therapy for RA. Premacular subhyaloid or sub-il hemorrhage may occur in ruptured RA. undus examination reveals a circumscribed, round, dumbbell- or boat-shaped bright red mound of blood, which may obstruct visualization of fovea and severely impair vision. It is hard to differentiate between sub-il hemorrhage or subhyaloid hemorrhage using only fundoscopic examination. With the help of SD-OCT, the highly reflective IL and an overlying patchy membrane with low optical reflectivity can be visualized, which was consistent with the posterior hyaloid. Though spontaneous resolution of premacular hemorrhage may occur, this process takes several weeks or months depending on 207 Asia-Pacific Academy of Ophthalmology 447

5 Chen et al Asia-Pacific Journal of Ophthalmology Volume 6, Number 5, September/October 207 the thickness and total amount of blood present. The temporarily impaired vision can cause inconvenience to patients. oreover, it may result in permanent visual impairment due to pigmentary macular changes or formation of epiretinal membranes and toxic damage to the retina due to prolonged contact with hemoglobin and iron. 2 Drainage of premacular hemorrhage by Nd:YAG laser is a noninvasive, effective, and relatively safe treatment compared with vitrectomy.,4 The laser facilitates absorption of blood cells within days by clearance of the obstructed macular area, which allows rapid restoration of vision and access for laser photocoagulation of RA. Several prior reports demonstrated significant visual improvement after Nd:YAG membranotomy or hyaloidotomy for premacular hemorrhage associated with RA.,4,2,22 A total of 9.% of the patients with subhyaloid hemorrhage treated by Nd:YAG laser developed persistent, dense, and nonclearing vitreous hemorrhage or opacity for at least months and finally required vitrectomy. 2 Tractional or rhegmatogenous retinal detachment and epiretinal membrane may happen after Nd:YAG laser for premacular hemorrhage. 22 We found 5 eyes with ruptured RA having sub-il hemorrhage all with associated subhyaloid hemorrhage after SD-OCT examination in the study. The patients were treated successfully by Nd:YAG membranotomy and subsequent green laser photocoagulation in 4 eyes. One patient had dispersed dense vitreous hemorrhage after Nd:YAG laser treatment requiring additional vitrectomy to clear the ocular media, which was similar to a previous study. 2 However, 5 patients all had improved BCVA at the final visit without serious ocular adverse effects observed. Koinzer et al 9 performed vitrectomy in 8 patients with RA and associated vitreous or macular hemorrhage. Some patients with vitreous hemorrhage were adequately treated by vitrectomy alone. Patients with subretinal blood received tissue plasminogen activator intravitreally or subretinally and gas endotamponade. Cases with subhyaloidal bleeding received IL peeling. Visual performance significantly improved in these patients. oosavi et al recommended vitreous hemorrhage associated with RA should be observed for 4 months and should be removed by vitrectomy if it does not resolve. In our study, patients underwent vitrectomy owing to nonclearing vitreous hemorrhage for month. Two eyes presented as vitreous hemorrhage with ruptured RA without associated sub-il or submacular bleeding. One case had persistent dispersed vitreous hemorrhage as a complication after Nd:YAG membranotomy for premacular sub-il hemorrhage. Because the baseline vision was poor in these eyes, the patients actively requested surgical intervention after waiting month for the hemorrhage to spontaneously resolve. Three patients had an increase of more than 9 lines of BCVA after surgical treatment. Prolonged subretinal or intraretinal exudates in the fovea may cause irreversible photoreceptor damage and morphological changes in the macula. 2 Treatment for exudative RA was essential for visual recovery or preservation. Laser treatment could be considered to seal the aneurysm and leaky perianeurysmal vessels for exudative RA.,4,6,7 Parodi et al 8 found improved visual acuity and macular thickness 4 months after focal laser treatment of exudative RA. Inhibitors of VEG can prevent the formation of neovascularization and counteract VEG-induced vascular permeability, which might actively close the involved pathological retinal artery and decrease macular exudation in cases with RA. 5 Bevacizumab (Avastin; Genentech Inc, South San rancisco, CA) is a recombinant humanized monoclonal antibody directed against VEG-A. Pichi et al 5 considered 7 patients with RA associated with foveal complications treated with monthly doses of intravitreal bevacizumab. our weeks after the third injection, macular edema had completely resolved. Visual acuity improved significantly and CT decreased significantly after -year follow-up. Ranibizumab (Lucentis; Genentech Inc, South San rancisco, CA) is a ab portion of VEG-A antibody. Erol et al 6 applied intravitreal ranibizumab to 7 patients with symptomatic exudative or hemorrhagic RA. ean BCVA improved by nearly 9 lines and the mean CT became significantly thinner after a mean -month follow-up. Aflibercept (Eylea; Regeneron Pharmaceuticals, Inc and Bayer Pharma AG, Berlin, Germany) is a decoy receptor fusion protein composed of the second domain of human VEG receptor and the third domain of VEG receptor 2, which are fused to the c domain of human IgG. Intravitreal aflibercept, the most recently approved anti-veg agent, can effectively manage macular edema secondary to diabetes mellitus or retinal vein occlusion. 7,8 There is no previous study applying aflibercept to RA. In our study, patients with exudative RA benefited from laser photocoagulation, causing a mean of nearly 4 lines of visual improvement along with significant macular thickness decrease after a mean 9.9-month follow-up. Although laser therapy had long-term effects to stop macular exudation from leaky RA, the onset of submacular or intramacular fluid resorption was slow. The first cases had CT more than 00 μm month after laser monotherapy. The other 8 eyes all had CT less than 00 μm month after combined laser and intravitreal anti-veg agents. The facts implied anti-veg agents, including bevacizumab, ranibizumab, and aflibercept, were useful to induce rapid disappearance of macular exudation. A prior study also had similar findings of rapid onset of action of anti-veg agents. Cho et al 4 compared symptomatic RA eyes that were treated with bevacizumab with 2 untreated symptomatic cases. It took 4 weeks for the resolution of macular edema and retinal hemorrhage in 6.% of eyes in the bevacizumab-treated group after only bevacizumab injection, resulting in significantly better visual acuity and macular thickness than those in the observation group. They concluded that bevacizumab treatment hastened visual recovery. Additionally, we found that intravitreal aflibercept may have a similar effect as other anti-veg agents on decreasing macular thickness and improving BCVA in patients with exudative RA. Our study had several limitations, including its retrospective nature and small sample size. However, it was difficult to find large numbers of patients for a higher statistical power in symptomatic RA owing to its infrequent occurrence. In summary, Nd:YAG laser was a safe and effective method to remove sub-il hemorrhage in patients with RA. ocal laser photocoagulation was helpful for managing ruptured or leaky RA. Combined focal laser and bevacizuamb, ranibizumab, or aflibercept injection may quickly reduce macular exudation caused by RA. Vitrectomy was useful for restoring vision in patients with severe nonclearing vitreous hemorrhage associated with RA.. 2. References Speilburg A, Klemencic SA. Ruptured retinal arterial macroaneurysm: diagnosis and management. J Optom. 204;7: 7. Pitkänen L, Tommila P, Kaarniranta K, et al. Retinal arterial Asia-Pacific Academy of Ophthalmology

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