Introduction: We report on one case of age-related macular degeneration and one case of diabetic macular edema with concomitant retinal arterial macroaneurysm (RAM) that were treated with anti-vascular endothelial growth factor (VEGF) intravitreal injections. Case Presentation: Case 1 involved a 71-year-old woman with a 30-year history of diabetes who was undergoing dialysis. Pretreatment visual acuity in the right eye was 0.4. Fundus fluorescein angiography (FA) showed that numerous microaneurysms and RAM were located at a distance of two papillary diameters from the macular area. Diabetic macular edema was diagnosed. After 12 anti-VEGF injections, the macular edema resolved, microaneurysms decreased, and the RAM also disappeared. Visual acuity in the right eye improved to 0.7. Case 2 involved an 81-year-old woman receiving treatment for disorders including hypertension and dyslipidemia. Pretreatment visual acuity in the right eye was 0.03. And vitreous hemorrhage was present. After one ranibizumab intravitreal injection, the fundus became clearly visible. Macular subretinal hemorrhage and an RAM in the upper macula area were evident on FA and optical coherence tomography. After four intravitreal injections of ranibizumab, macular hemorrhage resolved, RAM disappeared, and visual acuity improved to 0.2. All cases were treated by intravitreal injection of anti-VEGF. After several injections, the macular hemorrhage or macular edema was resolved. RAM disappeared, and visual acuity improved. Conclusion: Intravitreal injection of anti-VEGF appears effective for age-related macular degeneration or diabetic macular edema with concomitant RAM. Although anti-VEGF intravitreal injections are not covered by health insurance for the treatment of RAM, their effectiveness means that the expansion of indications is desirable.

A wide variety of methods have been attempted in the treatment of retinal arterial macroaneurysm (RAM), including active surveillance [1‒6], YAG laser treatment [2, 6], vitreous surgery by means of gas injection [7], vitreous surgery using tissue plasminogen activator [8‒10], and more recently, intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) [11‒18]. We treated patients who were diagnosed with age-related macular degeneration or diabetic macular edema. They responded well to anti-VEGF intravitreal injections and were then determined during active surveillance to have concomitant RAM. RAMs observed during active surveillance transformed into white fibrotic tissue after anti-VEGF intravitreal injections. We report two cases in which anti-VEGF therapy was considered to have been effective against RAM.

Case 1

A 71-year-old woman presented on December 26, 2017, as a referral from a clinic. She had become aware of decreased visual acuity in the right eye 5 days earlier.

Medical History

Diabetes for 30 years, dialysis 3 times a week, and a pacemaker fitted.

Findings at Presentation

Visual acuity was 0.4 in the right eye and 0.9 in the left, and intraocular pressure was 16 mm Hg in both eyes. The crystalline lens in the right eye had been replaced by an intraocular lens, and that in the left eye exhibited an incipient senile cataract. In the fundus, the macular annular reflex had disappeared, and RAM was evident in the upper part of the vascular arcade at a distance of two papillary diameters from the macular area (Fig. 1a).

Fig. 1.

a Case 1: A 71-year-old woman. Color fundus photograph of the right eye on presentation (December 20, 2017) shows disappeared macular reflex. RAM is evident in the upper part of the vascular arcade (white arrow). b On fundus FA in the intermediate phase, numerous capillary aneurysms are evident. Fluorescein pooling in the retinal macroaneurysm is evident (white arrow). c Color fundus photography on January 20, 2020, shows the macular annular reflex. The RAM seen in the upper part on presentation has disappeared. d Fundus FA (January 20, 2020). The RAM evident on presentation has disappeared, and capillary aneurysms have also decreased. e After the first intravitreal injection of ranibizumab on January 9, 2018. OCT on January 23, 2018, shows serous retinal detachment in the macular area and edema of the outer layer of the retina in horizontal section. f After the fourth intravitreal injection of ranibizumab on April 19, 2018, OCT on May 1, 2018, shows a further decrease in serous retinal detachment in the macular area, and edema of the outer layer of the retina has disappeared. g After the five injections of ranibizumab and the second intravitreal injection of aflibercept on November 1, 2018, OCT on November 12, 2018, shows a further decrease in serous retinal detachment in the macular area. h After the five intravitreal injections of ranibizumab and the seventh intravitreal injection of aflibercept on December 2, 2019, OCT on January 20, 2020, shows that the serous retinal detachment in the macular area has kept disappearing, and visual acuity has improved to 0.7.

Fig. 1.

a Case 1: A 71-year-old woman. Color fundus photograph of the right eye on presentation (December 20, 2017) shows disappeared macular reflex. RAM is evident in the upper part of the vascular arcade (white arrow). b On fundus FA in the intermediate phase, numerous capillary aneurysms are evident. Fluorescein pooling in the retinal macroaneurysm is evident (white arrow). c Color fundus photography on January 20, 2020, shows the macular annular reflex. The RAM seen in the upper part on presentation has disappeared. d Fundus FA (January 20, 2020). The RAM evident on presentation has disappeared, and capillary aneurysms have also decreased. e After the first intravitreal injection of ranibizumab on January 9, 2018. OCT on January 23, 2018, shows serous retinal detachment in the macular area and edema of the outer layer of the retina in horizontal section. f After the fourth intravitreal injection of ranibizumab on April 19, 2018, OCT on May 1, 2018, shows a further decrease in serous retinal detachment in the macular area, and edema of the outer layer of the retina has disappeared. g After the five injections of ranibizumab and the second intravitreal injection of aflibercept on November 1, 2018, OCT on November 12, 2018, shows a further decrease in serous retinal detachment in the macular area. h After the five intravitreal injections of ranibizumab and the seventh intravitreal injection of aflibercept on December 2, 2019, OCT on January 20, 2020, shows that the serous retinal detachment in the macular area has kept disappearing, and visual acuity has improved to 0.7.

Close modal

Fluorescein Angiography (FA) Findings

Numerous capillary aneurysms were evident, including around the macula. They were considered to be the cause of macular edema. Fluorescein leakage from the aneurysms was evident in the intermediate phase. There was a retinal macroaneurysm which was distinct on the temporal arcade. It was larger than the capillary aneurysm (Fig. 1b). On optical coherence tomography (OCT), intraretinal edema and serous retinal detachment were evident in the macular area. Diabetic macular edema was diagnosed, and the first intravitreal injection of ranibizumab was administered on January 9, 2018. Five injections of ranibizumab and seven injections of aflibercept were administered. Color fundus photograph on January 20, 2020, showed that the RAM seen in the upper part on presentation has disappeared (Fig. 1c). FA at a final follow-up on January 20, 2020, showed some residual macular edema, but the numerous capillary aneurysms that had been evident on initial examination had almost disappeared, along with the RAM (Fig. 1d). The serial OCT after anti-VEGF injection showed decreasing of macula edema and serous retinal detachment (Fig. 1e–h). OCT on December 9, 2019, showed that macular edema had disappeared (Fig. 1h). Visual acuity in the right eye improved to 0.7.

Case 2

An 81-year-old woman presented on June 9, 2016, as a referral by a local clinic. She had become aware of decreased visual acuity in the right eye 7 days earlier.

Medical History

Colon cancer surgery in 2000, gastric cancer surgery in 2005, hypertension, hyperlipidemia, unruptured cerebral aneurysm.

Finding at Presentation

Visual acuity was 0.03 in the right eye and 0.5X + 2.0 D in the left eye. Intraocular pressure was 14 mm Hg in both eyes, and incipient senile cataracts were evident in the crystalline lenses of both eyes. In the fundus of the right eye, vitreous hemorrhage meant that the optic papilla was only dimly visible and a detailed observation was impossible. This was considered to represent age-related macular degeneration, and intravitreal injection of ranibizumab was administered on June 24, 2016. Seven days later, the fundus was clearly visible. Color fundus photography revealed hemorrhage in the macular area and intraretinal hemorrhage in the upper part of the vascular arcade (Fig. 2a). On FA, in the intermediate phase, the RAM was visible in a vessel in the upper part of the vascular arcade (Fig. 2b). On OCT, fibrin was evident in the macular area below and within the retina (Fig. 2c). Second, third, and fourth intravitreal injections of ranibizumab were administered on July 29, September 7, and November 8, 2016, respectively. Subsequently, the macular hemorrhage disappeared and visual acuity improved to 0.2. Color fundus photography on June 7, 2017, showed that the macular area was normal, with RAM in vascular arcade. The retinal hemorrhage in the upper macular area had also disappeared (Fig. 2d). On fundus FA, the RAM that had been visible on July 1, 2016, appeared to have been obliterated (Fig. 2e).

Fig. 2.

a Case 2: an 81-year-old woman. On presentation, vitreous hemorrhage in the right eye means that the optic papilla is only dimly visible, and detailed observation of the fundus is impossible. Intravitreal injection of ranibizumab was administered on June 24, 2016. Fundus photography of the right eye on July 1, 2016. The fundus is clearly part of the vascular arcade which is evident. Retinal hemorrhage is apparent on the upper temporal side of the macular area. b Fundus FA. In the intermediate phase, fluorescence pooling (white arrow) is evident in the upper part. c OCT shows a fibrin mass in the macular area. d After intravitreal injection of ranibizumab into the right eye on July 29 and September 7, 2016, color fundus photography on June 7, 2017, shows that intraretinal hemorrhage in the vascular arcade and upper part of the macular has disappeared. e Fundus FA on the same day. Intravitreal hemorrhage has disappeared, and the aneurysm visible in (b) has been obliterated. f OCT on September 23, 2020. The fibrin mass in the macular area disappeared. Visual acuity has improved to 0.2.

Fig. 2.

a Case 2: an 81-year-old woman. On presentation, vitreous hemorrhage in the right eye means that the optic papilla is only dimly visible, and detailed observation of the fundus is impossible. Intravitreal injection of ranibizumab was administered on June 24, 2016. Fundus photography of the right eye on July 1, 2016. The fundus is clearly part of the vascular arcade which is evident. Retinal hemorrhage is apparent on the upper temporal side of the macular area. b Fundus FA. In the intermediate phase, fluorescence pooling (white arrow) is evident in the upper part. c OCT shows a fibrin mass in the macular area. d After intravitreal injection of ranibizumab into the right eye on July 29 and September 7, 2016, color fundus photography on June 7, 2017, shows that intraretinal hemorrhage in the vascular arcade and upper part of the macular has disappeared. e Fundus FA on the same day. Intravitreal hemorrhage has disappeared, and the aneurysm visible in (b) has been obliterated. f OCT on September 23, 2020. The fibrin mass in the macular area disappeared. Visual acuity has improved to 0.2.

Close modal

With regard to mechanisms of onset, Gass [19] conjectured that RAMs were caused by damage to the vessel wall by the atheroembolus of locally yellow arteries, and this theory is generally supported. Mansour et al. [18] inferred that congenital weakness of vessels is another possibility leading to gradual long-term thinning. When an embolus impacts the vessel wall, the resultant damage and impaired perfusion cause expression of VEGF, which enhances vascular permeability and causes vascular dilation. Concerning location, Pichi et al. [16] reported that RAMs tend to appear before the third arterial bifurcation or at arteriovenous crossings, supporting the hypothesis of Gass [19]. RAMs which are formed from endothelium are hypothesized to be relevant to VEGFs. On the other hand, artery aneurysms are products of hypertension and hyperlipidemia. Therefore, RAM is supposed to be the abnormality of capillary artery and be deformed by VEGF. RAM might complicate ARMD or DME. Intravitreal anti-VEGF injections for these two cases were approved by our Ethics Committee because of concomitant with ARMD or DME. The treatment of RAMs with anti-VEGF antibodies has already been widely reported [9‒15].

According to Noda et al. [5], the prognosis for visual acuity depends on the location of the hematoma within the retinal layer. They reported that premacular hematoma shows the best prognosis of treatment, while preretinal and intraretinal hemorrhage can be effectively treated by vitreous surgery, and subretinal hemorrhage (SRH) shows poor prognosis for visual acuity regardless of treatment.

Asano et al. [7] reported that the distance between the central fovea and RAM was associated with the prognosis for visual acuity. If the hemorrhage was beneath the fovea, the prognosis for visual acuity was poor.

Juncal et al. [10] reported a study of 99 patients who underwent vitreous surgery involving subretinal injection of tissue plasminogen activator and gas injection to move the hematoma, and found that the hematoma moved and visual function improved. Complications included vitreous hemorrhage in 13.1%, retinal detachment in 8.1% of patients, retinal pigment tear in 4%, expulsive choroidal hemorrhage in 2%, and recurrent SRH in 12%.

Kitagawa et al. [8] classified hemorrhage sites into four groups: subretinal limiting membrane hemorrhage (SILMH); SRH; internal retinal hemorrhage (IRH); and multilayer hemorrhage (SILMH/SRH/IRH). The prognosis for visual acuity was best for SILMH, followed by multilayer hemorrhage.

According to previous reports, the position of the hematoma in retinal layers is more closely associated with the prognosis for visual acuity than size is [4, 5, 7, 8]. In the present report, visual acuity improved in case 1, who suffered IRH, and case 1, in whom the RAM was located distant to the macular area. In case 2, the hemorrhage was beneath the retina in the macular region, and visual acuity was therefore poor (0.2).

In case 1, treatment was focused on diabetic macular edema. Anti-VEGF intravitreal injections are currently becoming the mainstream for the condition [20, 21]. In the first year after gaining approval, aflibercept was somewhat more favored, but in the second year no significant difference in improvement was reported for visual acuity when aflibercept or ranibizumab intravitreal injections were compared [20]. The maximum number of injections is 15, and in this case we administered six injections of ranibizumab followed by seven injections of aflibercept (total, 13), by which time the macular edema had resolved. Wells et al. [20] also reported similar results. In our patients, macular edema improved as the injections were given, and laser treatment was not performed. Both Wells et al. [20] and Glassman et al. [21] discussed visual acuity and OCT data, but FA results from our patient showed that microaneurysms were dramatically reduced by anti-VEGF intravitreal injections. Such findings indicate that anti-VEGF is a ground-breaking treatment for diabetic retinopathy.

There are only two cases, which are not enough to demonstrate the efficacy of anti-VEGF against RAM. Wang Y reported that subgroup analysis revealed that anti-VEGF therapy was used in patients with worse VA than patients who underwent laser photocoagulation, but achieved better improvement in VA than laser photocoagulation group. They concluded that all management strategies (observation, laser treatment, anti-VEGF) should consider the unique needs of each patient [6].

We have reported two cases of patients treated with anti-VEGF intravitreal injections who also suffered from macroaneurysms. Our findings suggest that as the aneurysms were transformed into white fibrous masses and their vasopermeability was halted, anti-VEGF may also have been effective on these macroaneurysms. The distance between the RAM and central fovea [6] and the position of the RAM in the retinal layers [5, 22] were identified as factors associated with the prognosis for visual acuity. Confirmation of the location of the RAM by OCT and choosing the appropriate treatment are clearly important. Intravitreal anti-VEGF injection for complicated RAM might be easier and safer than laser photocoagulation or vitrectomy. This is more beneficial for special older patients.

The use of anti-VEGF agents to treat RAM is not yet covered by Japanese health insurance. VEGF is believed to be implicated in retinal vitreous vascular lesions, and anti-VEGF agents are considered effective for their treatment. Further expansion of indication for their agents in the future is awaited. The CARE checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000538998).

This study received approval from the Yonezawa City Hospital Institutional Review Board (Approval No. Yonerin 2105). Written informed consent was obtained from the patients for publication of the details of their medical case and any accompanying images.

The author has no conflicts of interest to declare.

There are no sources of funding to declare.

Michiko Takamiya, MD was involved in the patient’s diagnosis and treatment, contributed to the manuscript revision and image evaluation, and read and approved the final manuscript.

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.

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