- Email: [email protected]
Intravitreal Bevacizumab for Symptomatic Retinal Arterial Macroaneurysm
Intravitreal Bevacizumab for Symptomatic Retinal Arterial Macroaneurysm HAN JOO CHO, TAEK KWAN RHEE, HYOUNG SEOK KIM, JUNG IL HAN, DONG WON LEE, SUNG WON CHO, AND JONG WOO KIM PURPOSE:
To evaluate the therapeutic effect of intravitreal bevacizumab injection for symptomatic retinal arterial macroaneurysm. DESIGN: Retrospective interventional case series. METHODS: The study included 23 patients (23 eyes) with symptomatic retinal arterial macroaneurysm. They were categorized according to treatment method into 2 groups: an intravitreal bevacizumab–treated group (11 eyes) and an untreated group (12 eyes). Bevacizumab was injected at the initial visit, followed by as-needed monthly reinjection. Best-corrected visual acuity (BCVA) and central macular thickness were documented and analyzed between groups. RESULTS: The mean follow-up period for all subjects was 10.83 ± 4.6 months. The mean number of injections for the treated group was 1.42 ± 0.69. The mean logarithm of the minimal angle of resolution (logMAR) of BCVA improved from baseline at the last follow-up by 0.26 in the bevacizumab-treated group (P [ .02) and by 0.34 in the untreated group (P [ .005). Average central macular thickness decreased from 384.4 ± 150.1 mm to 265 ± 112.5 mm in the bevacizumab-treated group (P [ .0002) and from 413.2 ± 155.2 mm to 236.3 ± 103.5 mm in the untreated group (P [ .008). The BCVA was significantly improved from baseline after 1 month in the bevacizumab-treated group (P [ .02) and after 3 months in the untreated group (P [ .01). However, there was no statistically significant difference in BCVA improvement or central macular thickness improvement achieved at the final visit. CONCLUSIONS: Intravitreal bevacizumab injection likely hastens resolution of macular edema and hemorrhage secondary to retinal arterial macroaneurysm. Intravitreal bevacizumab injection could be an effective treatment option for symptomatic retinal arterial macroaneurysm. (Am J Ophthalmol 2013;155: 898–904. Ó 2013 Published by Elsevier Ltd.)
R
ETINAL
ARTERIAL
MACROANEURYSM
IS
AN
acquired large arteriolar dilation that usually occurs within the first 3 orders of the retinal arterial vasculature bifurcations, typically in the macular or postequato-
Accepted for publication Dec 5, 2012. From the Department of Ophthalmology, Kim’s Eye Hospital, MyungGok Eye Research Institute, Konyang University College of Medicine, Seoul, South Korea. Inquiries to Jong Woo Kim, Kim’s Eye Hospital, 156, 4ga, Yeoungdeungpodong, Yeoungdeungpo-gu, Seoul, Korea; e-mail: [email protected]
898
Ó
2013
rial regions.1,2 Retinal arterial macroaneurysms most commonly develop in hypertensive women aged between 50 and 80.2 This condition may lead to visual loss secondary to macular edema or hemorrhage in 1 or all retinal layers.1,2 The treatment of retinal arterial macroaneurysm with macular edema or hemorrhage is controversial. Some authors have reported a good visual outcome simply with observation.3,4 Even though there is no consensus about the management of retinal arterial macroaneurysm, treatment is advised in cases of exudative manifestations involving the fovea with visual acuity deterioration.5 Therapeutic interventions for eyes with retinal arterial macroaneurysm include direct photocoagulation to the aneurysm itself,2,6 pneumatic displacement with tissue plasminogen activator for submacular hemorrhage secondary to retinal arterial macroaneurysm,7,8 surgical removal of associated hemorrhage with pars plana vitrectomy,9,10 and photodisruption of the internal limiting membrane (ILM) or the posterior hyaloid using neodymium:yttrium-aluminum-garnet (Nd:YAG) or argon laser to release the hemorrhage.11,12 Recently, intravitreal injections of anti–vascular endothelial growth factor (VEGF) drugs have been considered as a treatment option for retinal arterial macroaneurysm. Several case reports have shown encouraging results of intravitreal anti-VEGF agents for retinal macroaneurysms.13,14 However, there have not been sufficient reports about anti-VEGF treatment for retinal arterial macroaneurysm. We hypothesized that intravitreal bevacizumab administration may be effective in treating retinal arterial macroaneurysm with macular edema and/or hemorrhage. The purpose of the current study was to evaluate the efficacy of intravitreal bevacizumab in treating eyes with retinal arterial macroaneurysm.
PUBLISHED
METHODS WE RETROSPECTIVELY REVIEWED THE MEDICAL RECORDS OF
58 consecutive patients with retinal arterial macroaneurysm who were treated at the Retina Center of Kim’s Eye Hospital in Konyang University College of Medicine from June 2008 through February 2012. This study was approved by the Institutional Review Board of Kim’s Eye Hospital, Konyang University College of Medicine. BY
ELSEVIER LTD.
0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2012.12.003
Clinical research in this study followed the tenets of the Declaration of Helsinki. INCLUSION AND EXCLUSION CRITERIA: Records for patients who met the following criteria were included in this study: (1) diagnosis of symptomatic retinal arterial macroaneurysm (defined as retinal arterial macroaneurysm with exudative foveal manifestations [including subretinal/ intraretinal fluid, hard exudates, and/or hemorrhages]); (2) vision loss attributable to macular exudates or hemorrhage; (3) retinal arterial macroaneurysm confirmed by fluorescein angiography (FA) and indocyanine green angiography (ICGA), performed using a confocal laser scanning system (HRA-2; Heidelberg Engineering, Dossenheim, Germany) at the first visit; (4) treatment naivete´; and (5) a minimum follow-up period of 6 months. No limits on visual acuity were set for either inclusion or exclusion criteria. Exclusion criteria included the following: (1) no edema or hemorrhage involving the macula despite definite retinal arterial macroaneurysm; (2) any other treatment except intravitreal bevacizumab injection; (3) cases complicated by thick vitreous hemorrhage requiring vitrectomy; (4) other ocular diseases that could affect visual acuity; and (5) previous vitreoretinal surgery. Patients were divided into 2 groups according to the treatment method: (1) the bevacizumab-treated group, in which intravitreal bevacizumab injection was performed; and (2) the untreated group, in which patients were observed but not treated. OUTCOME MEASURES: The primary outcome was the mean change from baseline in best-corrected visual acuity (BCVA) at 1, 3, and 6 months and at the final visit. The secondary outcome was the mean change from baseline for central macular thickness (as measured by spectral-domain optical coherence tomography [SD-OCT, Spectral OCT/ SLO; OTI Ophthalmic Technologies Inc, Miami, Florida, USA]) at 1, 3, and 6 months and at the final visit. The percentage of patients gaining or losing more than 3 lines of vision, as measured from baseline, was also examined. BCVA was assessed using the Snellen chart at baseline and at each monthly follow-up visit after intravitreal bevacizumab injection treatment. For statistical analysis, the Snellen BCVA was converted to logarithm of the minimal angle of resolution (logMAR) values. Central macular thickness was assessed by measurement of retinal thickness of the 1-mm central retina, which was obtained by a macular scan. Only well-centered scans without overt algorithm failure messages were selected for analysis. INTRAVITREAL BEVACIZUMAB INJECTION TREATMENT: The off-label nature of the treatment and its poten-
tial risks and benefits were discussed in detail with patients. Informed consent was obtained from all patients before intravitreal injection of bevacizumab. Patients were chosen VOL. 155, NO. 5
for intravitreal bevacizumab injection if they declined other treatment methods such as laser photocoagulation or vitrectomy. Cases were also included if it was not possible to perform direct laser photocoagulation to the aneurysm because of thick preretinal hemorrhage or if patients were unable to keep the required face-down position after expansive gas injection for submacular hemorrhage. Intravitreal bevacizumab (1.25 mg/0.05 mL; Avastin; Genentech Inc, South San Francisco, California, USA) injections were performed for all patients with the same treatment and retreatment protocols. After the first injection, patients were retreated if any of the following were observed: (1) evidence of persistent fluid or hemorrhage involving the macula on OCT at least 1 month after the previous injection; (2) visual deterioration of more than 2 lines; or (3) evidence of an active retinal arterial macroaneurysm lesion, as found on fundus examination, FA, ICGA, or OCT. STATISTICAL ANALYSIS:
SPSS software version 13.0 (SPSS Inc, Chicago, Illinois, USA) was used for all analyses. Frequencies were compared between treatment groups using Fisher exact test. Comparative statistics were determined using unpaired 2-sided t tests. For the nonparametric data, the Mann-Whitney U test and the Kruskal-Wallis test were used. A P value of less than .05 was considered statistically significant.
RESULTS OUT OF THE 58 PATIENT RECORDS EXAMINED, 23 EYES (23
patients) were included in analysis and 35 eyes (35 patients) were excluded from analysis. Eleven eyes had no macular hemorrhage or exudates, 12 required vitrectomy because of a thick vitreous hemorrhage, and 12 were treated using laser photocoagulation or a combination of intravitreal anti-VEGF and laser photocoagulation. Table 1 summarizes patient characteristics and their treatment results. The mean age of the subjects was 70.3 6 9.5 years (range, 59-83 years). The mean BCVA of all the subjects at baseline was 0.85 6 0.32 logMAR units and the mean central macular thickness at baseline was 398.8 6 144.2. The mean follow-up period was 10.83 6 4.6 months (range, 6-23 months). The bevacizumab-treated group contained 11 eyes of 11 patients, and the untreated group contained 12 eyes of 12 patients. Both groups had similar baseline characteristics for age, sex, duration of symptoms, baseline BCVA, baseline central macular thickness, and complication type (Table 2). At baseline, the mean logMAR of BCVA in the bevacizumab-treated group and the untreated group was 0.76 6 0.38 (Snellen equivalent: 20/115) and 0.93 6 0.42 (Snellen equivalent: 20/170), respectively. With
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TABLE 1. Clinical Characteristics of Patients With Retinal Arterial Macroaneurysm Age/ Sex
Complication Type
Duration of Symptoms (d)
1 2
77/F 73/F
Hemorrhagic Hemorrhagic
14 4
3 4 5 6
81/F 62/F 73/F 64/F
Hemorrhagic Hemorrhagic Hemorrhagic Hemorrhagic
15 10 14 1
7 8 9 10 11
63/M 70/F 73/F 82/F 76/F
Exudative Exudative Exudative Hemorrhagic Hemorrhagic
30 20 28 21 2
12 13 14 15
59/F 60/F 74/F 75/M
Hemorrhagic Exudative Hemorrhagic Hemorrhagic
3 2 7 2
16
64/F
Hemorrhagic
2
17
78/M
Hemorrhagic
5
18 19 20 21
83/F 68/F 62/M 79/F
Exudative Hemorrhagic Hemorrhagic Hemorrhagic
3 1 4 2
22
72/F
Hemorrhagic
10
23
64/F
Exudative
Patient
1
Foveal Condition at Presentation
Treatment
Initial BCVA
Final BCVA
Initial CMT (mm)
Final CMT (mm)
Follow-up Period (mo)
SRD, intraretinal edema Sub-ILM hemorrhage, preretinal hemorrhage SRD, intraretinal edema SRD, intraretinal edema SRD Sub-ILM hemorrhage, preretinal hemorrhage SRD Intraretinal edema SRD SMH Sub-ILM hemorrhage, preretinal hemorrhage SMH SRD, intraretinal edema SMH, preretinal hemorrhage Sub-ILM hemorrhage, preretinal hemorrhage Sub-IL M hemorrhage, preretinal hemorrhage Sub-ILM hemorrhage, preretinal hemorrhage Intraretinal edema SMH, sub-ILM hemorrhage SRD Sub-ILM hemorrhage, preretinal hemorrhage Sub-ILM hemorrhage, preretinal hemorrhage SRD, intraretinal edema
IVB #1 IVB #1
20/50 10/200
20/25 20/100
437 411
252 207
23 10
IVB #1 None None None
10/200 20/30 20/30 10/200
20/50 20/30 20/25 20/100
661 256 247 482
302 197 212 286
10 12 18 8
IVB #1 None IVB #1 None None
20/100 20/70 20/70 20/200 HM
20/25 20/40 20/40 10/200 20/25
284 256 448 321 586
184 221 273 225 311
8 20 12 6 10
IVB #3 IVB #2 None None
20/70 20/25 CF CF
CF 20/20 10/200 20/100
642 445 288 467
146 176 224 237
7 17 9 7
None
CF
20/30
334
205
6
IVB #2
CF
20/50
552
206
9
None IVB #1 IVB #2 None
CF 20/100 20/50 CF
20/40 20/40 20/30 20/200
356 552 256 412
188 221 195 224
7 10 6 10
None
5/200
20/50
399
212
13
IVB #1
5/200
20/50
446
233
11
BCVA ¼ best-corrected visual acuity; CF ¼ counting fingers; CME ¼ cystoid macular edema; CMT ¼ central macular thickness; HM ¼ hand movement; ILM ¼ inner limiting membrane; IVB ¼ intravitreal bevacizumab injection; SMH = submacular hemorrhage; SRD = serous retinal detachment.
follow-up, the mean logMAR BCVA significantly decreased over time in both groups (Figure 1). At the final visit, the mean logMAR BCVA in both groups had significantly decreased to 0.50 6 0.32 (Snellen equivalent: 20/ 63) (P ¼ .002) and 0.59 6 0.38 (Snellen equivalent: 20/ 77) (P ¼ .0005), respectively. The mean central macular thickness at baseline in the bevacizumab-treated group and untreated group was 384.4 6 150.1 mm and 413.2 6 155.2 mm, respectively. With follow-up, the mean central macular thickness significantly decreased over time in both groups (Figure 2). At the final visit, the central macular thickness of both the bevacizumab-treated group and the untreated group had significantly decreased to 265.6 6 112.5 mm (P ¼ .0002) and 236.3 6 103.5 mm (P ¼ .008), respectively. Both groups showed improvement in central macular thickness from baseline with follow-up. 900
Both groups showed significant improvement from baseline and stability of BCVA and central macular thickness over time. However, there was no statistically significant difference in BCVA improvement achieved with these 2 groups. Seven out of 11 eyes (63.6%) in the bevacizumab-treated group and 8 out of 12 eyes (66.7%) in the untreated group showed a gain of 3 or more lines of visual acuity at the final visit. No significant difference in the proportion of patients with more than 3 lines gain of visual acuity was observed in either group (P ¼ .85) (Table 3). One out of 11 eyes (9.1%) in the bevacizumab-treated group and 1 out of 12 eyes (8.3%) in the untreated group showed a loss of 3 or more lines of visual acuity. There was also no significant difference in the proportion of patients with 3 or more lines loss in visual acuity in either group (P ¼ .71) (Table 3). The mean logMAR change from baseline was 0.26 in the
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TABLE 2. Comparison of Baseline Characteristics Between the Bevacizumab-Treated Group and Untreated Group With Symptomatic Retinal Arterial Macroaneurysm Untreated Group (12 Eyes of 12 Patients)
P
62.6 6 10.42
72.8 6 6.88
.24a
2 (18.2%) 9 (81.8%) 10.3 6 9.5 0.76 6 0.38 384.4 6 150.1
2 (16.7%) 10 (83.3%) 8.7 6 7.5 0.93 6 0.42 413.2 6 155.2
.73b .53a .28a .22a
7 (63.6%) 4 (36.4%)
9 (75.0%) 3 (25.0%)
.66b
Bevacizumab-Treated Group (11 Eyes of 11 Patients)
Age (y) Sex Male Female Duration of symptoms (d 6 SD) Baseline BCVA (logMAR) Baseline CMT 6 SD (mm) Complication type Hemorrhagic Exudative
BCVA ¼ best-corrected visual acuity; CMT ¼ central macular thickness; logMAR ¼ logarithm of the minimal angle of resolution; SD ¼ standard deviation. a P value by t test. b P value by Fisher exact test.
bevacizumab-treated group and 0.34 in the untreated group, and there was no significant difference (P ¼ .39) (Table 3). There was no statistically significant difference in BCVA improvement achieved and central macular thickness improvement achieved between the groups at the final visit; however, there was a significant rapid improvement of BCVA in the bevacizumab-treated group. The mean BCVA was significantly improved from baseline after 1 month in the bevacizumab-treated group, whereas the mean BCVA was significantly improved 3 months after the initial visit in the untreated group (Figure 1). At 1 month after the initial visit, there was a significant difference between the 2 groups in mean BCVA improvement and central macular thickness improvement (P ¼ .02; Figures 1 and 2). In the bevacizumab-treated group, the mean number of injections was 1.42 6 0.69. In 7 eyes (63.6%), macular edema, preretinal hemorrhage, or subretinal hemorrhage around the macula was resolved with 1 bevacizumab injection without additional injections (Figure 3). Total resolution of the associated preretinal, intraretinal, and subretinal hemorrhages and improved visual acuity occurred in all patients in the treated group within 3 injections of bevacizumab at 4-week intervals. No complications, such as endophthalmitis, traumatic lens injury, and retinal detachment, were associated with intravitreal injection. Also, no systemic adverse events were recorded for patients treated with intravitreal injection. Two patients (Patients 10 and 12) whose cases were complicated by submacular hemorrhage showed diffuse submacular retinal pigment epithelium (RPE) atrophy and degenerative changes in the photoreceptor layer after treatment, along with a decreased visual acuity that exceeded 0.3 logMAR units, despite complete macroaneurysm obliteration and resolution of subretinal hemorrhage. VOL. 155, NO. 5
DISCUSSION THE BEST APPROACH TO THE MANAGEMENT OF RETINAL
arterial macroaneurysm is still a matter of controversy. Spontaneous obliteration of aneurysm with functional recovery is well known.1–4 However, the long-term persistence of exudative manifestations or hemorrhages leads to a progressive photoreceptor deterioration with functional impairment.5 Thus, in cases of symptomatic retinal arterial macroaneurysm with exudative or hemorrhagic changes involving the fovea together with visual acuity deterioration, early treatment may be desirable in attempting to avoid irreversible anatomic and visual damage. Currently, conventional laser photocoagulation of the aneurysm is the most commonly employed treatment for symptomatic retinal arterial macroaneurysm.15 However, this technique has many complications, including enlargement of the laser scar, choroidal neovascularization, and subretinal fibrosis.16–18 In addition, branch retinal artery occlusion, increased retinal exudation, and scarring, with possible retinal traction, have also been reported in cases of retinal arterial macroaneurysm treated with laser photocoagulation.19–21 Moreover, in cases of thick preretinal hemorrhage located around the aneurysm or cases with a large macroaneurysm located in proximity to the retinal artery, direct laser photocoagulation still has limitations. Recently, several case reports have shown encouraging results of intravitreal anti-VEGF agents for retinal arterial macroaneurysms.13,14 In the current study, even though the bevacizumab-treated group showed significant improvement of BCVA and central macular thickness at the final visit, it did not show superiority in BCVA and central macular thickness improvement compared with the untreated group (Table 3). However, BCVA and central macular thickness in the bevacizumab-treated group showed
INTRAVITREAL BEVACIZUMAB FOR RETINAL ARTERIAL MACROANEURYSM
901
FIGURE 1. Changes in the mean logarithm of minimal angle of resolution (logMAR) of the best-corrected visual acuity (BCVA) of both groups of patients with retinal arterial macroaneurysm between baseline and final visit (*P < .05, P < .05).
rapid improvement compared with the untreated group. One month after the baseline assessment, there was significant BCVA and central macular thickness improvement in the bevacizumab-treated group, whereas significant BCVA and central macular thickness change was not found until 3 months after the baseline assessment in the untreated group. Moreover, the BCVA of the bevacizumab-treated group was significantly more improved than that of the untreated group at 1 month after baseline assessment (Figure 1). The resolution of retinal hemorrhage and visual recovery in the natural course of retinal arterial macroaneurysm takes approximately 8-10 weeks.2 In the current study, it took 4 weeks for the resolution of macular edema and retinal hemorrhage in 63.3% of eyes in the bevacizumab-treated group after only 1 bevacizumab injection. The number of eyes included was too small for statistical analysis; however, more rapid visual acuity improvement and resolution of macular edema was found in the bevacizumab-treated group than in the group that took a natural course. There have not been sufficient reports about the association between VEGF and the pathogenesis of retinal arterial macroaneurysm. However, the rapid resolution of macular edema and retinal hemorrhage secondary to retinal arterial macroaneurysm after intravitreal bevacizumab injection might be explained by 2 possible mechanisms. First, intravitreal anti-VEGF drugs block the angiogenic and vasopermeability effects of VEGF.22 VEGF stimulates endothelial production of nitric oxide, a vasodilator. Anti-VEGF drugs thus theoretically reduce nitric oxide, leading to vasoconstriction. It has been reported that vasoconstriction reduces macular edema independent of the effect on vascular permeability.23,24 902
FIGURE 2. Changes in mean central macular thickness of both groups of patients with retinal arterial macroaneurysm between baseline and final visit (*P < .05, P < .05).
Second, bevacizumab may exert an effect on coagulation itself; it may have caused the old blood clot to hemolyze or may have affected the coagulation process of the newly formed retinal hemorrhage. VEGF is known to be related to activation of coagulation cascades.25 Inhibition of VEGF by bevacizumab may break down the balance between the coagulation and fibrinolysis processes. This action of anti-VEGF may facilitate clearing of the various retinal hemorrhages including subretinal, intraretinal, preretinal, sub-ILM, and subhyaloid hemorrhages. The action of anti-VEGF agents may decrease macular edema and/or hemorrhage secondary to retinal arterial macroaneurysm. However, it remains uncertain whether these effects of anti-VEGF agents would affect the retinal arterial macroaneurysm itself. Our study has several limitations, including its retrospective nature and small sample size. However, it is difficult to find large numbers of patients for a higher statistical power in symptomatic retinal arterial macroaneurysm because of its infrequent occurrence. Moreover, to the best of our knowledge, the current study is the first study about the effectiveness of anti-VEGF treatment in retinal arterial macroaneurysm. Another limitation of our study was the selection of patients for bevacizumab injection. Between 2010 and 2012, the preferred treatment for retinal arterial macroaneurysm shifted from observation to anti-VEGF therapy. Therefore, almost all patients between 2008 and the first half of 2010 were either observed or treated with laser photocoagulation. Furthermore, if this selection bias was significant, it is likely that worse-appearing eyes would have received bevacizumab compared with betterappearing eyes. This would bias bevacizumab-treated eyes toward a poorer outcome. This was not the case because outcome measures were as good or better in treated eyes
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TABLE 3. Results of Retinal Arterial Macroaneurysm Patients With and Without Intravitreal Bevacizumab Treatment Bevacizumab-Treated Group (11 Eyes of 11 Patients)
Mean logMAR at final visit Mean logMAR change from baseline BCVA changes _logMAR 0.3 Gained > _logMAR 0.3 Loss > Mean CMT changes from baseline (mm)
Untreated Group (12 Eyes of 12 Patients)
0.50 6 0.33 0.26 63.6% 9.1% 118.8
0.59 6 0.48 0.34 66.7% 8.3% 176.9
P
.45a .39a .85b .71b .13a
BCVA ¼ best-corrected visual acuity; CMT ¼ central macular thickness; SD ¼ standard deviation. a P value by t test. b P value by x2 test.
FIGURE 3. Images from the left eye of a 68-year-old woman with symptomatic retinal arterial macroaneurysm treated with intravitreal bevacizumab injections (Patient 19). (Top left) Fundus photograph obtained at the initial visit showing subretinal hemorrhage and preretinal hemorrhage. Duration of symptoms was 1 day and best-corrected visual acuity (BCVA) was 20/100. (Top middle) Indocyanine green angiography showing a focal hyperfluorescence attributable to macroaneurysm. (Top right) Sectional spectraldomain optical coherence tomography (SD-OCT) image (with the arrow seen on top left) showing an elevated fovea, submacular hemorrhage, and sub–inner limiting membrane hemorrhage. (Bottom left) Fundus photograph 1 month after the first intravitreal bevacizumab injection showing resolution of the retinal hemorrhages and obliteration of the macroaneurysm. BCVA was recovered to 20/40. (Bottom right) Sectional SD-OCT image (with the arrow seen on Bottom left) showing resolved subretinal hemorrhage and flattened macula.
than in untreated eyes. Most importantly, the treated and untreated groups were well-balanced and showed no significant difference in baseline characteristics (Table 2). A planned randomized controlled study would be necessary for a more precise determination of the effect of anti-VEGF treatment for retinal arterial macroaneurysm.
In conclusion, intravitreal bevacizumab injection likely hastens resolution of macular edema and hemorrhage secondary to retinal arterial macroaneurysm. This study supports the use of intravitreal bevacizumab as an effective treatment option for symptomatic retinal arterial macroaneurysm.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and none were reported. There was no sponsor or funding organization involved in the study. Contributions of authors: involved in design of study (H.J.C., S.W.C., J.W.K.); acquisition of data (H.J.C., T.K.R., H.S.K., J.I.H., D.W.L.); analysis data (H.J.C., H.S.K., J.I.H., J.W.K.); interpretation of data (H.J.C., C.G.K., T.G.L.); preparation of manuscript (H.J.C.); review of manuscript (D.W.L., S.W.C., J.W.K.); and approval of manuscript (D.W.L., J.W.K.).
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13. Javey G, Moshfeghi AN, Moshfeghi AA. Management of ruptured retinal arterial macroaneurysm with intravitreal bevacizumab. Ophthalmic Surg Lasers Imaging 2010;41(4): 1–5. 14. Tsakpinis D, Nasr MB, Tranos P, et al. The use of bevacizumab in a multilevel retinal hemorrhage secondary to retinal macroaneurysm: a 39-month follow-up case report. Clin Ophthalmol 2011;5:1475–1477. 15. Panton RW, Goldberg MF, Farber MD. Retinal arterial macroaneurysms: risk factors and natural history. Br J Ophthalmol 1990;74(10):595–600. 16. Schatz H, Madeira D, McDonald HR, Johnson RN. Progressive enlargement of laser scars following grid laser photocoagulation for diffuse diabetic macular edema. Arch Ophthalmol 1991;109(11):1549–1551. 17. Lewis H, Schachat AP, Haimann MH, et al. Choroidal neovascularization after laser photocoagulation for diabetic macular edema. Ophthalmology 1990;97(4):503–510. 18. Guyer DR, D’Amico DJ, Smith CW. Subretinal fibrosis after laser photocoagulation for diabetic macular edema. Am J Ophthalmol 1992;113(6):652–656. 19. Abdel-Khalek MN, Richardson J. Retinal macroaneurysm: natural history and guidelines for treatment. Br J Ophthalmol 1986;70(1):2–11. 20. Russell SR, Folk JC. Branch retinal artery occlusion after dye yellow photocoagulation of an arterial macroaneurysm. Am J Ophthalmol 1987;104(2):186–187. 21. Battaglia Parodi M, Iacono P, et al. Subthreshold laser treatment versus threshold laser treatment for symptomatic retinal arterial macroaneurysm. Invest Ophthalmol Vis Sci 2012;53(4): 1783–1786. 22. Stefansson E. Treatment of branch retinal vein occlusion. Acta Ophthalmol 2008;86(2):122–123. 23. Scheppke L, Aguilar E, Gariano RF, et al. Retinal vascular permeability suppression by topical application of a novel VEGF2/src kinase inhibitor in mice and rabbits. J Clin Invest 2008;118(6):2337–2346. 24. Campochiaro PA, Hafiz G, Shah SM, et al. Ranibizumab for macular edema due to retinal vein occlusions: implication of VEGF as a critical stimulator. Mol Ther 2008;16(4):791–799. 25. Verheul HM, Pinedo HM. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer 2007;7(6):475–485.
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Biosketch Han Joo Cho, MD, graduated from the Yonsei University College of Medicine, Seoul, Korea in 2001. In 2006, he completed his residency at the Department of Ophthalmology of the same university. After a fellowship at the Kim’s Eye Hospital, Konyang University College of Medicine, Seoul, Korea, he has been a vitreoretinal surgeon at the same hospital since 2010. His primary areas of interest are vitreoretinal disorders and vitreous surgery.
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To evaluate the therapeutic effect of intravitreal bevacizumab injection for symptomatic retinal arterial macroaneurysm. DESIGN: Retrospective interventional case series. METHODS: The study included 23 patients (23 eyes) with symptomatic retinal arterial macroaneurysm. They were categorized according to treatment method into 2 groups: an intravitreal bevacizumab–treated group (11 eyes) and an untreated group (12 eyes). Bevacizumab was injected at the initial visit, followed by as-needed monthly reinjection. Best-corrected visual acuity (BCVA) and central macular thickness were documented and analyzed between groups. RESULTS: The mean follow-up period for all subjects was 10.83 ± 4.6 months. The mean number of injections for the treated group was 1.42 ± 0.69. The mean logarithm of the minimal angle of resolution (logMAR) of BCVA improved from baseline at the last follow-up by 0.26 in the bevacizumab-treated group (P [ .02) and by 0.34 in the untreated group (P [ .005). Average central macular thickness decreased from 384.4 ± 150.1 mm to 265 ± 112.5 mm in the bevacizumab-treated group (P [ .0002) and from 413.2 ± 155.2 mm to 236.3 ± 103.5 mm in the untreated group (P [ .008). The BCVA was significantly improved from baseline after 1 month in the bevacizumab-treated group (P [ .02) and after 3 months in the untreated group (P [ .01). However, there was no statistically significant difference in BCVA improvement or central macular thickness improvement achieved at the final visit. CONCLUSIONS: Intravitreal bevacizumab injection likely hastens resolution of macular edema and hemorrhage secondary to retinal arterial macroaneurysm. Intravitreal bevacizumab injection could be an effective treatment option for symptomatic retinal arterial macroaneurysm. (Am J Ophthalmol 2013;155: 898–904. Ó 2013 Published by Elsevier Ltd.)
R
ETINAL
ARTERIAL
MACROANEURYSM
IS
AN
acquired large arteriolar dilation that usually occurs within the first 3 orders of the retinal arterial vasculature bifurcations, typically in the macular or postequato-
Accepted for publication Dec 5, 2012. From the Department of Ophthalmology, Kim’s Eye Hospital, MyungGok Eye Research Institute, Konyang University College of Medicine, Seoul, South Korea. Inquiries to Jong Woo Kim, Kim’s Eye Hospital, 156, 4ga, Yeoungdeungpodong, Yeoungdeungpo-gu, Seoul, Korea; e-mail: [email protected]
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rial regions.1,2 Retinal arterial macroaneurysms most commonly develop in hypertensive women aged between 50 and 80.2 This condition may lead to visual loss secondary to macular edema or hemorrhage in 1 or all retinal layers.1,2 The treatment of retinal arterial macroaneurysm with macular edema or hemorrhage is controversial. Some authors have reported a good visual outcome simply with observation.3,4 Even though there is no consensus about the management of retinal arterial macroaneurysm, treatment is advised in cases of exudative manifestations involving the fovea with visual acuity deterioration.5 Therapeutic interventions for eyes with retinal arterial macroaneurysm include direct photocoagulation to the aneurysm itself,2,6 pneumatic displacement with tissue plasminogen activator for submacular hemorrhage secondary to retinal arterial macroaneurysm,7,8 surgical removal of associated hemorrhage with pars plana vitrectomy,9,10 and photodisruption of the internal limiting membrane (ILM) or the posterior hyaloid using neodymium:yttrium-aluminum-garnet (Nd:YAG) or argon laser to release the hemorrhage.11,12 Recently, intravitreal injections of anti–vascular endothelial growth factor (VEGF) drugs have been considered as a treatment option for retinal arterial macroaneurysm. Several case reports have shown encouraging results of intravitreal anti-VEGF agents for retinal macroaneurysms.13,14 However, there have not been sufficient reports about anti-VEGF treatment for retinal arterial macroaneurysm. We hypothesized that intravitreal bevacizumab administration may be effective in treating retinal arterial macroaneurysm with macular edema and/or hemorrhage. The purpose of the current study was to evaluate the efficacy of intravitreal bevacizumab in treating eyes with retinal arterial macroaneurysm.
PUBLISHED
METHODS WE RETROSPECTIVELY REVIEWED THE MEDICAL RECORDS OF
58 consecutive patients with retinal arterial macroaneurysm who were treated at the Retina Center of Kim’s Eye Hospital in Konyang University College of Medicine from June 2008 through February 2012. This study was approved by the Institutional Review Board of Kim’s Eye Hospital, Konyang University College of Medicine. BY
ELSEVIER LTD.
0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2012.12.003
Clinical research in this study followed the tenets of the Declaration of Helsinki. INCLUSION AND EXCLUSION CRITERIA: Records for patients who met the following criteria were included in this study: (1) diagnosis of symptomatic retinal arterial macroaneurysm (defined as retinal arterial macroaneurysm with exudative foveal manifestations [including subretinal/ intraretinal fluid, hard exudates, and/or hemorrhages]); (2) vision loss attributable to macular exudates or hemorrhage; (3) retinal arterial macroaneurysm confirmed by fluorescein angiography (FA) and indocyanine green angiography (ICGA), performed using a confocal laser scanning system (HRA-2; Heidelberg Engineering, Dossenheim, Germany) at the first visit; (4) treatment naivete´; and (5) a minimum follow-up period of 6 months. No limits on visual acuity were set for either inclusion or exclusion criteria. Exclusion criteria included the following: (1) no edema or hemorrhage involving the macula despite definite retinal arterial macroaneurysm; (2) any other treatment except intravitreal bevacizumab injection; (3) cases complicated by thick vitreous hemorrhage requiring vitrectomy; (4) other ocular diseases that could affect visual acuity; and (5) previous vitreoretinal surgery. Patients were divided into 2 groups according to the treatment method: (1) the bevacizumab-treated group, in which intravitreal bevacizumab injection was performed; and (2) the untreated group, in which patients were observed but not treated. OUTCOME MEASURES: The primary outcome was the mean change from baseline in best-corrected visual acuity (BCVA) at 1, 3, and 6 months and at the final visit. The secondary outcome was the mean change from baseline for central macular thickness (as measured by spectral-domain optical coherence tomography [SD-OCT, Spectral OCT/ SLO; OTI Ophthalmic Technologies Inc, Miami, Florida, USA]) at 1, 3, and 6 months and at the final visit. The percentage of patients gaining or losing more than 3 lines of vision, as measured from baseline, was also examined. BCVA was assessed using the Snellen chart at baseline and at each monthly follow-up visit after intravitreal bevacizumab injection treatment. For statistical analysis, the Snellen BCVA was converted to logarithm of the minimal angle of resolution (logMAR) values. Central macular thickness was assessed by measurement of retinal thickness of the 1-mm central retina, which was obtained by a macular scan. Only well-centered scans without overt algorithm failure messages were selected for analysis. INTRAVITREAL BEVACIZUMAB INJECTION TREATMENT: The off-label nature of the treatment and its poten-
tial risks and benefits were discussed in detail with patients. Informed consent was obtained from all patients before intravitreal injection of bevacizumab. Patients were chosen VOL. 155, NO. 5
for intravitreal bevacizumab injection if they declined other treatment methods such as laser photocoagulation or vitrectomy. Cases were also included if it was not possible to perform direct laser photocoagulation to the aneurysm because of thick preretinal hemorrhage or if patients were unable to keep the required face-down position after expansive gas injection for submacular hemorrhage. Intravitreal bevacizumab (1.25 mg/0.05 mL; Avastin; Genentech Inc, South San Francisco, California, USA) injections were performed for all patients with the same treatment and retreatment protocols. After the first injection, patients were retreated if any of the following were observed: (1) evidence of persistent fluid or hemorrhage involving the macula on OCT at least 1 month after the previous injection; (2) visual deterioration of more than 2 lines; or (3) evidence of an active retinal arterial macroaneurysm lesion, as found on fundus examination, FA, ICGA, or OCT. STATISTICAL ANALYSIS:
SPSS software version 13.0 (SPSS Inc, Chicago, Illinois, USA) was used for all analyses. Frequencies were compared between treatment groups using Fisher exact test. Comparative statistics were determined using unpaired 2-sided t tests. For the nonparametric data, the Mann-Whitney U test and the Kruskal-Wallis test were used. A P value of less than .05 was considered statistically significant.
RESULTS OUT OF THE 58 PATIENT RECORDS EXAMINED, 23 EYES (23
patients) were included in analysis and 35 eyes (35 patients) were excluded from analysis. Eleven eyes had no macular hemorrhage or exudates, 12 required vitrectomy because of a thick vitreous hemorrhage, and 12 were treated using laser photocoagulation or a combination of intravitreal anti-VEGF and laser photocoagulation. Table 1 summarizes patient characteristics and their treatment results. The mean age of the subjects was 70.3 6 9.5 years (range, 59-83 years). The mean BCVA of all the subjects at baseline was 0.85 6 0.32 logMAR units and the mean central macular thickness at baseline was 398.8 6 144.2. The mean follow-up period was 10.83 6 4.6 months (range, 6-23 months). The bevacizumab-treated group contained 11 eyes of 11 patients, and the untreated group contained 12 eyes of 12 patients. Both groups had similar baseline characteristics for age, sex, duration of symptoms, baseline BCVA, baseline central macular thickness, and complication type (Table 2). At baseline, the mean logMAR of BCVA in the bevacizumab-treated group and the untreated group was 0.76 6 0.38 (Snellen equivalent: 20/115) and 0.93 6 0.42 (Snellen equivalent: 20/170), respectively. With
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TABLE 1. Clinical Characteristics of Patients With Retinal Arterial Macroaneurysm Age/ Sex
Complication Type
Duration of Symptoms (d)
1 2
77/F 73/F
Hemorrhagic Hemorrhagic
14 4
3 4 5 6
81/F 62/F 73/F 64/F
Hemorrhagic Hemorrhagic Hemorrhagic Hemorrhagic
15 10 14 1
7 8 9 10 11
63/M 70/F 73/F 82/F 76/F
Exudative Exudative Exudative Hemorrhagic Hemorrhagic
30 20 28 21 2
12 13 14 15
59/F 60/F 74/F 75/M
Hemorrhagic Exudative Hemorrhagic Hemorrhagic
3 2 7 2
16
64/F
Hemorrhagic
2
17
78/M
Hemorrhagic
5
18 19 20 21
83/F 68/F 62/M 79/F
Exudative Hemorrhagic Hemorrhagic Hemorrhagic
3 1 4 2
22
72/F
Hemorrhagic
10
23
64/F
Exudative
Patient
1
Foveal Condition at Presentation
Treatment
Initial BCVA
Final BCVA
Initial CMT (mm)
Final CMT (mm)
Follow-up Period (mo)
SRD, intraretinal edema Sub-ILM hemorrhage, preretinal hemorrhage SRD, intraretinal edema SRD, intraretinal edema SRD Sub-ILM hemorrhage, preretinal hemorrhage SRD Intraretinal edema SRD SMH Sub-ILM hemorrhage, preretinal hemorrhage SMH SRD, intraretinal edema SMH, preretinal hemorrhage Sub-ILM hemorrhage, preretinal hemorrhage Sub-IL M hemorrhage, preretinal hemorrhage Sub-ILM hemorrhage, preretinal hemorrhage Intraretinal edema SMH, sub-ILM hemorrhage SRD Sub-ILM hemorrhage, preretinal hemorrhage Sub-ILM hemorrhage, preretinal hemorrhage SRD, intraretinal edema
IVB #1 IVB #1
20/50 10/200
20/25 20/100
437 411
252 207
23 10
IVB #1 None None None
10/200 20/30 20/30 10/200
20/50 20/30 20/25 20/100
661 256 247 482
302 197 212 286
10 12 18 8
IVB #1 None IVB #1 None None
20/100 20/70 20/70 20/200 HM
20/25 20/40 20/40 10/200 20/25
284 256 448 321 586
184 221 273 225 311
8 20 12 6 10
IVB #3 IVB #2 None None
20/70 20/25 CF CF
CF 20/20 10/200 20/100
642 445 288 467
146 176 224 237
7 17 9 7
None
CF
20/30
334
205
6
IVB #2
CF
20/50
552
206
9
None IVB #1 IVB #2 None
CF 20/100 20/50 CF
20/40 20/40 20/30 20/200
356 552 256 412
188 221 195 224
7 10 6 10
None
5/200
20/50
399
212
13
IVB #1
5/200
20/50
446
233
11
BCVA ¼ best-corrected visual acuity; CF ¼ counting fingers; CME ¼ cystoid macular edema; CMT ¼ central macular thickness; HM ¼ hand movement; ILM ¼ inner limiting membrane; IVB ¼ intravitreal bevacizumab injection; SMH = submacular hemorrhage; SRD = serous retinal detachment.
follow-up, the mean logMAR BCVA significantly decreased over time in both groups (Figure 1). At the final visit, the mean logMAR BCVA in both groups had significantly decreased to 0.50 6 0.32 (Snellen equivalent: 20/ 63) (P ¼ .002) and 0.59 6 0.38 (Snellen equivalent: 20/ 77) (P ¼ .0005), respectively. The mean central macular thickness at baseline in the bevacizumab-treated group and untreated group was 384.4 6 150.1 mm and 413.2 6 155.2 mm, respectively. With follow-up, the mean central macular thickness significantly decreased over time in both groups (Figure 2). At the final visit, the central macular thickness of both the bevacizumab-treated group and the untreated group had significantly decreased to 265.6 6 112.5 mm (P ¼ .0002) and 236.3 6 103.5 mm (P ¼ .008), respectively. Both groups showed improvement in central macular thickness from baseline with follow-up. 900
Both groups showed significant improvement from baseline and stability of BCVA and central macular thickness over time. However, there was no statistically significant difference in BCVA improvement achieved with these 2 groups. Seven out of 11 eyes (63.6%) in the bevacizumab-treated group and 8 out of 12 eyes (66.7%) in the untreated group showed a gain of 3 or more lines of visual acuity at the final visit. No significant difference in the proportion of patients with more than 3 lines gain of visual acuity was observed in either group (P ¼ .85) (Table 3). One out of 11 eyes (9.1%) in the bevacizumab-treated group and 1 out of 12 eyes (8.3%) in the untreated group showed a loss of 3 or more lines of visual acuity. There was also no significant difference in the proportion of patients with 3 or more lines loss in visual acuity in either group (P ¼ .71) (Table 3). The mean logMAR change from baseline was 0.26 in the
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TABLE 2. Comparison of Baseline Characteristics Between the Bevacizumab-Treated Group and Untreated Group With Symptomatic Retinal Arterial Macroaneurysm Untreated Group (12 Eyes of 12 Patients)
P
62.6 6 10.42
72.8 6 6.88
.24a
2 (18.2%) 9 (81.8%) 10.3 6 9.5 0.76 6 0.38 384.4 6 150.1
2 (16.7%) 10 (83.3%) 8.7 6 7.5 0.93 6 0.42 413.2 6 155.2
.73b .53a .28a .22a
7 (63.6%) 4 (36.4%)
9 (75.0%) 3 (25.0%)
.66b
Bevacizumab-Treated Group (11 Eyes of 11 Patients)
Age (y) Sex Male Female Duration of symptoms (d 6 SD) Baseline BCVA (logMAR) Baseline CMT 6 SD (mm) Complication type Hemorrhagic Exudative
BCVA ¼ best-corrected visual acuity; CMT ¼ central macular thickness; logMAR ¼ logarithm of the minimal angle of resolution; SD ¼ standard deviation. a P value by t test. b P value by Fisher exact test.
bevacizumab-treated group and 0.34 in the untreated group, and there was no significant difference (P ¼ .39) (Table 3). There was no statistically significant difference in BCVA improvement achieved and central macular thickness improvement achieved between the groups at the final visit; however, there was a significant rapid improvement of BCVA in the bevacizumab-treated group. The mean BCVA was significantly improved from baseline after 1 month in the bevacizumab-treated group, whereas the mean BCVA was significantly improved 3 months after the initial visit in the untreated group (Figure 1). At 1 month after the initial visit, there was a significant difference between the 2 groups in mean BCVA improvement and central macular thickness improvement (P ¼ .02; Figures 1 and 2). In the bevacizumab-treated group, the mean number of injections was 1.42 6 0.69. In 7 eyes (63.6%), macular edema, preretinal hemorrhage, or subretinal hemorrhage around the macula was resolved with 1 bevacizumab injection without additional injections (Figure 3). Total resolution of the associated preretinal, intraretinal, and subretinal hemorrhages and improved visual acuity occurred in all patients in the treated group within 3 injections of bevacizumab at 4-week intervals. No complications, such as endophthalmitis, traumatic lens injury, and retinal detachment, were associated with intravitreal injection. Also, no systemic adverse events were recorded for patients treated with intravitreal injection. Two patients (Patients 10 and 12) whose cases were complicated by submacular hemorrhage showed diffuse submacular retinal pigment epithelium (RPE) atrophy and degenerative changes in the photoreceptor layer after treatment, along with a decreased visual acuity that exceeded 0.3 logMAR units, despite complete macroaneurysm obliteration and resolution of subretinal hemorrhage. VOL. 155, NO. 5
DISCUSSION THE BEST APPROACH TO THE MANAGEMENT OF RETINAL
arterial macroaneurysm is still a matter of controversy. Spontaneous obliteration of aneurysm with functional recovery is well known.1–4 However, the long-term persistence of exudative manifestations or hemorrhages leads to a progressive photoreceptor deterioration with functional impairment.5 Thus, in cases of symptomatic retinal arterial macroaneurysm with exudative or hemorrhagic changes involving the fovea together with visual acuity deterioration, early treatment may be desirable in attempting to avoid irreversible anatomic and visual damage. Currently, conventional laser photocoagulation of the aneurysm is the most commonly employed treatment for symptomatic retinal arterial macroaneurysm.15 However, this technique has many complications, including enlargement of the laser scar, choroidal neovascularization, and subretinal fibrosis.16–18 In addition, branch retinal artery occlusion, increased retinal exudation, and scarring, with possible retinal traction, have also been reported in cases of retinal arterial macroaneurysm treated with laser photocoagulation.19–21 Moreover, in cases of thick preretinal hemorrhage located around the aneurysm or cases with a large macroaneurysm located in proximity to the retinal artery, direct laser photocoagulation still has limitations. Recently, several case reports have shown encouraging results of intravitreal anti-VEGF agents for retinal arterial macroaneurysms.13,14 In the current study, even though the bevacizumab-treated group showed significant improvement of BCVA and central macular thickness at the final visit, it did not show superiority in BCVA and central macular thickness improvement compared with the untreated group (Table 3). However, BCVA and central macular thickness in the bevacizumab-treated group showed
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901
FIGURE 1. Changes in the mean logarithm of minimal angle of resolution (logMAR) of the best-corrected visual acuity (BCVA) of both groups of patients with retinal arterial macroaneurysm between baseline and final visit (*P < .05, P < .05).
rapid improvement compared with the untreated group. One month after the baseline assessment, there was significant BCVA and central macular thickness improvement in the bevacizumab-treated group, whereas significant BCVA and central macular thickness change was not found until 3 months after the baseline assessment in the untreated group. Moreover, the BCVA of the bevacizumab-treated group was significantly more improved than that of the untreated group at 1 month after baseline assessment (Figure 1). The resolution of retinal hemorrhage and visual recovery in the natural course of retinal arterial macroaneurysm takes approximately 8-10 weeks.2 In the current study, it took 4 weeks for the resolution of macular edema and retinal hemorrhage in 63.3% of eyes in the bevacizumab-treated group after only 1 bevacizumab injection. The number of eyes included was too small for statistical analysis; however, more rapid visual acuity improvement and resolution of macular edema was found in the bevacizumab-treated group than in the group that took a natural course. There have not been sufficient reports about the association between VEGF and the pathogenesis of retinal arterial macroaneurysm. However, the rapid resolution of macular edema and retinal hemorrhage secondary to retinal arterial macroaneurysm after intravitreal bevacizumab injection might be explained by 2 possible mechanisms. First, intravitreal anti-VEGF drugs block the angiogenic and vasopermeability effects of VEGF.22 VEGF stimulates endothelial production of nitric oxide, a vasodilator. Anti-VEGF drugs thus theoretically reduce nitric oxide, leading to vasoconstriction. It has been reported that vasoconstriction reduces macular edema independent of the effect on vascular permeability.23,24 902
FIGURE 2. Changes in mean central macular thickness of both groups of patients with retinal arterial macroaneurysm between baseline and final visit (*P < .05, P < .05).
Second, bevacizumab may exert an effect on coagulation itself; it may have caused the old blood clot to hemolyze or may have affected the coagulation process of the newly formed retinal hemorrhage. VEGF is known to be related to activation of coagulation cascades.25 Inhibition of VEGF by bevacizumab may break down the balance between the coagulation and fibrinolysis processes. This action of anti-VEGF may facilitate clearing of the various retinal hemorrhages including subretinal, intraretinal, preretinal, sub-ILM, and subhyaloid hemorrhages. The action of anti-VEGF agents may decrease macular edema and/or hemorrhage secondary to retinal arterial macroaneurysm. However, it remains uncertain whether these effects of anti-VEGF agents would affect the retinal arterial macroaneurysm itself. Our study has several limitations, including its retrospective nature and small sample size. However, it is difficult to find large numbers of patients for a higher statistical power in symptomatic retinal arterial macroaneurysm because of its infrequent occurrence. Moreover, to the best of our knowledge, the current study is the first study about the effectiveness of anti-VEGF treatment in retinal arterial macroaneurysm. Another limitation of our study was the selection of patients for bevacizumab injection. Between 2010 and 2012, the preferred treatment for retinal arterial macroaneurysm shifted from observation to anti-VEGF therapy. Therefore, almost all patients between 2008 and the first half of 2010 were either observed or treated with laser photocoagulation. Furthermore, if this selection bias was significant, it is likely that worse-appearing eyes would have received bevacizumab compared with betterappearing eyes. This would bias bevacizumab-treated eyes toward a poorer outcome. This was not the case because outcome measures were as good or better in treated eyes
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TABLE 3. Results of Retinal Arterial Macroaneurysm Patients With and Without Intravitreal Bevacizumab Treatment Bevacizumab-Treated Group (11 Eyes of 11 Patients)
Mean logMAR at final visit Mean logMAR change from baseline BCVA changes _logMAR 0.3 Gained > _logMAR 0.3 Loss > Mean CMT changes from baseline (mm)
Untreated Group (12 Eyes of 12 Patients)
0.50 6 0.33 0.26 63.6% 9.1% 118.8
0.59 6 0.48 0.34 66.7% 8.3% 176.9
P
.45a .39a .85b .71b .13a
BCVA ¼ best-corrected visual acuity; CMT ¼ central macular thickness; SD ¼ standard deviation. a P value by t test. b P value by x2 test.
FIGURE 3. Images from the left eye of a 68-year-old woman with symptomatic retinal arterial macroaneurysm treated with intravitreal bevacizumab injections (Patient 19). (Top left) Fundus photograph obtained at the initial visit showing subretinal hemorrhage and preretinal hemorrhage. Duration of symptoms was 1 day and best-corrected visual acuity (BCVA) was 20/100. (Top middle) Indocyanine green angiography showing a focal hyperfluorescence attributable to macroaneurysm. (Top right) Sectional spectraldomain optical coherence tomography (SD-OCT) image (with the arrow seen on top left) showing an elevated fovea, submacular hemorrhage, and sub–inner limiting membrane hemorrhage. (Bottom left) Fundus photograph 1 month after the first intravitreal bevacizumab injection showing resolution of the retinal hemorrhages and obliteration of the macroaneurysm. BCVA was recovered to 20/40. (Bottom right) Sectional SD-OCT image (with the arrow seen on Bottom left) showing resolved subretinal hemorrhage and flattened macula.
than in untreated eyes. Most importantly, the treated and untreated groups were well-balanced and showed no significant difference in baseline characteristics (Table 2). A planned randomized controlled study would be necessary for a more precise determination of the effect of anti-VEGF treatment for retinal arterial macroaneurysm.
In conclusion, intravitreal bevacizumab injection likely hastens resolution of macular edema and hemorrhage secondary to retinal arterial macroaneurysm. This study supports the use of intravitreal bevacizumab as an effective treatment option for symptomatic retinal arterial macroaneurysm.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and none were reported. There was no sponsor or funding organization involved in the study. Contributions of authors: involved in design of study (H.J.C., S.W.C., J.W.K.); acquisition of data (H.J.C., T.K.R., H.S.K., J.I.H., D.W.L.); analysis data (H.J.C., H.S.K., J.I.H., J.W.K.); interpretation of data (H.J.C., C.G.K., T.G.L.); preparation of manuscript (H.J.C.); review of manuscript (D.W.L., S.W.C., J.W.K.); and approval of manuscript (D.W.L., J.W.K.).
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13. Javey G, Moshfeghi AN, Moshfeghi AA. Management of ruptured retinal arterial macroaneurysm with intravitreal bevacizumab. Ophthalmic Surg Lasers Imaging 2010;41(4): 1–5. 14. Tsakpinis D, Nasr MB, Tranos P, et al. The use of bevacizumab in a multilevel retinal hemorrhage secondary to retinal macroaneurysm: a 39-month follow-up case report. Clin Ophthalmol 2011;5:1475–1477. 15. Panton RW, Goldberg MF, Farber MD. Retinal arterial macroaneurysms: risk factors and natural history. Br J Ophthalmol 1990;74(10):595–600. 16. Schatz H, Madeira D, McDonald HR, Johnson RN. Progressive enlargement of laser scars following grid laser photocoagulation for diffuse diabetic macular edema. Arch Ophthalmol 1991;109(11):1549–1551. 17. Lewis H, Schachat AP, Haimann MH, et al. Choroidal neovascularization after laser photocoagulation for diabetic macular edema. Ophthalmology 1990;97(4):503–510. 18. Guyer DR, D’Amico DJ, Smith CW. Subretinal fibrosis after laser photocoagulation for diabetic macular edema. Am J Ophthalmol 1992;113(6):652–656. 19. Abdel-Khalek MN, Richardson J. Retinal macroaneurysm: natural history and guidelines for treatment. Br J Ophthalmol 1986;70(1):2–11. 20. Russell SR, Folk JC. Branch retinal artery occlusion after dye yellow photocoagulation of an arterial macroaneurysm. Am J Ophthalmol 1987;104(2):186–187. 21. Battaglia Parodi M, Iacono P, et al. Subthreshold laser treatment versus threshold laser treatment for symptomatic retinal arterial macroaneurysm. Invest Ophthalmol Vis Sci 2012;53(4): 1783–1786. 22. Stefansson E. Treatment of branch retinal vein occlusion. Acta Ophthalmol 2008;86(2):122–123. 23. Scheppke L, Aguilar E, Gariano RF, et al. Retinal vascular permeability suppression by topical application of a novel VEGF2/src kinase inhibitor in mice and rabbits. J Clin Invest 2008;118(6):2337–2346. 24. Campochiaro PA, Hafiz G, Shah SM, et al. Ranibizumab for macular edema due to retinal vein occlusions: implication of VEGF as a critical stimulator. Mol Ther 2008;16(4):791–799. 25. Verheul HM, Pinedo HM. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer 2007;7(6):475–485.
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Biosketch Han Joo Cho, MD, graduated from the Yonsei University College of Medicine, Seoul, Korea in 2001. In 2006, he completed his residency at the Department of Ophthalmology of the same university. After a fellowship at the Kim’s Eye Hospital, Konyang University College of Medicine, Seoul, Korea, he has been a vitreoretinal surgeon at the same hospital since 2010. His primary areas of interest are vitreoretinal disorders and vitreous surgery.
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