Perifoveal vascular anomalous complex (PVAC) has been described as an uncommon macular disorder defined by a unilateral, isolated, perifoveal aneurysm in otherwise healthy patients and recently renamed with exudative stage (ePVAC) and the nonexudative stage (nePVAC).1,2 It is assumed to be the result of a focal and progressive, retinal, vascular, endothelial cell injury in the absence of retinal ischemia or inflammation. Therefore, this could explain the reason for the unresponsiveness of PVAC to intravitreal anti–vascular endothelial growth factor (VEGF) injection.2–4 Mrejen et al4 reported on a PVAC treated with focal thermal laser photocoagulation, but there is currently no standard treatment protocol for PVAC.
Rather than conventional laser photocoagulation, nondamaging retinal laser therapy with a subthreshold micropulse laser (SMPL) has been demonstrated as a promising treatment option for macular diseases because of the safety of SMPL treatment without detectable damage in retinal pigment epithelium or photoreceptors.5
In this report, we describe an unusual case of ePVAC treated with multiple sessions of SMPL that was previously unresponsive to intravitreal injection treatment.
A 65-year-old woman presented to our clinic with blurred vision in the left eye lasting 1 month. She had no other relevant medical or surgical history. Her best-corrected visual acuity was 20/20 in the right eye and 20/25 in the left eye. Intraocular pressure was normal, and anterior segment examination was unremarkable in both eyes except mild nuclear cataracts. Fundus examination of the right eye showed normal reuslts. However, fundus examination and photography of the left eye showed an isolated perifoveal aneurysm surrounded by small retinal hemorrhages and hard exudates. The bulb-like aneurysm was located at one of the terminal arteriolar ends in the superior perifoveal area (within 500 µm). Multimodal imaging was performed using a fundus camera (Visucam 224; ZEISS, Oberkochen, Germany), spectral-domain optical coherence tomography, and optical coherent tomography angiography (Spectralis; Heidelberg Engineering, Heidelberg, Germany). Fluorescein angiography revealed a well-defined hyperfluorescent lesion in the early phase but with leakage in the late phase. Optical coherence tomography showed macular edema with 542 µm of central macular thickness and a round lesion (diameter, 314 µm) with a hyperreflective wall, subretinal fluid, and an intraretinal cyst. Optical coherent tomography angiography revealed blood flow of the isolated large aneurismal lesion in the deep capillary plexus corresponding to the leaking point on the fluorescein angiography (Figure 1).
Based on these characteristics, the patient was diagnosed with ePVAC. Initially, intravitreal injection of anti-VEGF was considered, although this method has been reported to be less effective. The patient received three monthly intravitreal injections of two bevacizumab (Avastin; Genetech Inc, San Francisco, CA) and one aflibercept (Eylea; Regeneron Pharmaceuticals Inc, Tarrytown, NY), but there was no distinct treatment effect. We performed additional injection of triamcinolone acetonide (MaQaid; Wakamoto Pharmaceutical, Tokyo, Japan). The subretinal fluid and hard exudates decreased slightly, but the intraretinal cyst remained, then gradually increased for 3 months (central macular thickness, 511 µm). The patient's best-corrected visual acuity decreased from 20/25 to 20/200 in the left eye over the 6 months during which she received 4 intravitreal injections. Moreover, a round lesion with a hyperreflective wall persisted. The intraretinal cyst and hard exudates also remained in fundus photography and optical coherence tomography examination. Optical coherent tomography angiography continued to show the blood flow of the lesion in the deep capillary plexus (Figure 2).
We performed multiple sessions of 532 nm SMPL around the aneurysm (IQ 532; Iridex, Mountain View, CA) using an Ocular Mainster focal/grid (×1.05) lens (Ocular Instruments Inc, Bellevue, WA) with following setting: 100-µm spot diameter, 2 × 2 matrix pattern mode (0.25 width), and low power ranging from 300 to 400 mW, which was increased in 50-mW increments every 3 to 4 weeks. In the first session, we used a 50-millisecond duration, 5% duty cycle, and 300 mW power. Subthreshold micropulse laser was applied only around the ePVAC lesion except for the fovea directly, and three or four shots were applied repeatedly on the aneurysmal point, which was considered the main leakage point (Figure 3). However, macular edema with an intraretinal cyst remained 2 weeks after the first SMPL. We applied the second session with modified settings: 100-millisecond duration, 10% duty cycle, and 300 mW power. An optical coherence tomography examination 1 month after the second session showed that the macular edema with intraretinal cyst decreased (central macular thickness, 462 µm). We applied the third session according to the modified settings. Three month after the third session, the patient's best-corrected visual acuity had improved to 20/50, and the retinal hemorrhage and hard exudates had decreased. Optical coherence tomography showed the shrinkage of the round lesion (diameter, 125 µm) compared with the previous image and resolution of macular edema (central macular thickness, 222 µm); however, focal disruption of ellipsoid zone around the round lesion was remained. The aneurysmal lesion was no longer visible on optical coherent tomography angiography slabs, and fluorescein angiography did not show leakage from the lesion in the early and late phases (Figure 4). Humphrey 10-2 visual field examination (HFA 720i; Carl Zeiss, Dublin, CA) demonstrated that there was no scotoma around the lesion (Figure 5). The patient's best-corrected visual acuity had improved to 20/32 in the left eye at 6 months after the last SMPL treatment.
Perifoveal vascular anomalous complex, which was first reported in 2011 by Querques et al,2 is described as an isolated aneurysmal lesion, occurring unilaterally with no systemic or ocular conditions associated with the aneurysmal lesion and recently characterized with exudative and nonexudative type.1 However, its prevalence, pathogenesis, course, and treatment had remained unclear. Sacconi et al3 reported that approximately half of the eyes with PVAC had concomitant retinal disorders, such as concomitant age-related macular degeneration or myopia. Kim et al6 also reported that the majority of patients were healthy and that two patients also had age-related macular degeneration.
Unlike other macular diseases, PVAC is known to be unresponsive to intravitreal injection of anti-VEGF.2–4 In addition, in this case, intravitreal injection of triamcinolone acetonide was also ineffective. Perifoveal vascular anomalous complex is assumed to be the result of a focal and progressive retinal vascular endothelial cell injury in the absence of retinal ischemia or inflammation.2–4,6 It is postulated that PVAC is a response to an anatomical variation and is not associated with VEGF levels. Spaide and Barquet7 reported cases of retinal capillary macroaneurysms treated with the focal laser photocoagulation, which we presumed had the same pathogenesis as PVAC. They proposed that retinal capillary macroaneurysms were caused by the presence of matrix metalloproteinase-9, which may work to decrease the structural integrity of the basement membrane, potentially decreasing the wall strength and inducing the aneurysmal expansion. These expansionary factors are not necessarily VEGF dependent, and anti-VEGF agents may not have much of a beneficial effect. The coagulation effect of the laser was suggested as the treatment leading to the involution of the aneurysmal lesion and resolution of leakage.
The treatment of ePVAC has not been established. Recently, there was a single case report that described successful treatment with focal laser photocoagulation after the failure of intravitreal anti-VEGF injections.4 Laser photocoagulation has been used for many years as an effective treatment of retinal disease as a means to improve oxygenation of the retina and production of heat shock protein, which triggers the repair process of the retinal tissue. However, laser photocoagulation can also involve the destruction of retinal tissue, including visible retinal tissue scar, laser scar enlargement, secondary hemorrhage, or secondary choroidal neovascularization. It can lead to functional impairment such as scotoma or visual field loss and should not be considered in macular disease because of the risk of permanent paracentral scotoma.5
Subthreshold micropulse laser has emerged as a new noninvasive and effective treatment for retinal disease. The laser impact is delivered in a train of short impulses between which there are some intervals to allow the retinal tissue to cooldown, so the laser impact does not have any track on the retina. Consequently, SMPL has been used in the treatment of retinal diseases that involve the fovea, such as central serous chorioretinopathy, diabetic macular edema, or edema secondary to retinal vein occlusion.5
We had experiences with treating idiopathic macular telangiectasia (MacTel) Type 1 and central serous chorioretinopathy without retinal damage using SMPL therapy. We also applied SMPL to the patient reported herein, who was diagnosed with ePVAC that did not respond to intravitreal injection therapies. We followed a similar SMPL protocol as that described in previous reports.8,9 We increased the duty cycle and duration after the first session of SMPL on the aneurysmal lesion more repeatedly to expect closure of aneurysm. After treatment, the involution of aneurysm was achieved; however, it was not clear whether it means preclinical nonexudative stage PVAC stage or complete resolution.
In summary, this patient with ePVAC showed improved visual acuity and resolution of macular edema after SMPL treatment. According to these results, SMPL treatment could be a safe and effective method for treating patients with ePVAC that is unresponsive to intravitreal injection therapies. In the short-term follow-up, there has been remained focal ellipsoid zone disruption around the lesion after the resolution of macular edema. It seems necessary to observe the restoration of ellipsoid zone disruption after SMPL application in long-term follow-up.
1. Sacconi R, Borrelli E, Sadda S, et al. Nonexudative perifoveal vascular anomalous complex: the subclinical stage of perifoveal exudative vascular anomalous complex? Am J Ophthalmol 2020;218:59–67.
2. Querques G, Kuhn D, Massamba N, et al. Perifoveal exudative vascular anomalous complex. J Fr Ophtalmol 2011;34:559.e1–559.e4.
3. Sacconi R, Freund KB, Yannuzzi LA, et al. The expanded spectrum of perifoveal exudative vascular anomalous complex. Am J Ophthalmol 2017;184:137–146.
4. Mrejen S, Le HM, Nghiem-Buffet S, et al. Insights into perifoveal exudative vascular anomalous complex. Retina 2020;40:80–86.
5. Gawecki M. Micropulse laser treatment of retinal diseases. J Clin Med 2019;8:242.
6. Kim JH, Kim JW, Kim CG, Lee DW. Characteristics of perifoveal exudative vascular anomalous complex in Korean patients. Semin Ophthalmol 2019;34:353–358.
7. Spaide RF, Barquet LA. Retinal capillary macroaneurysms. Retina 2019;39:1889–1895.
8. Kang YK, Park HS. Subthreshold micropulse yellow laser (577 nm) for idiopathic macular telangiectasia type 1 resistant to intravitreal injection. Korean J Ophthalmol 2020;34:168–169.
9. Kim YJ, Kim SY, Ha S, et al. Short-duration multiple-session subthreshold micropulse yellow laser (577 nm) for chronic central serous chorioretinopathy: results at 3 years. Eye (Lond) 2019;33:819–825.