Vascularization and Reperfusion of Autologous Retinal Transplant for Giant Macular Holes

This case series examines vascularization and reperfusion of autologous retinal graft after transplant for giant macular holes demonstrated by multimodal imaging.

Key Points

Question

What happens to the blood supply for a large transplanted retina tissue?

Findings

In this study of 2 patients with giant macular holes who underwent autologous retinal transplant, vascularization and reperfusion of retinal graft was demonstrated by multimodal imaging within a few weeks of transplant.

Meaning

Vascular reperfusion of large autologous retinal grafts has implications for transplant survival.

Abstract

Importance

Autologous retinal transplant is a recently described treatment modality for myopic and other refractory macular holes (MH). Establishment of blood supply may influence survival of a transplanted tissue. However, there are currently no reports on the vascular status of a transplanted retinal graft.

Objective

To report on vascularization and reperfusion of autologous retinal graft after transplant for giant MHs demonstrated by multimodal imaging.

Design, Setting, Participants

Two patients with giant MH (basal diameter ≥2000 μm) who underwent autologous retinal transplant at Retina-Vitreous Associates Medical Group in Los Angeles, California, in June 2018 and February 2019, respectively, were included.

Main Outcomes and Measures

Status of MH, Snellen visual acuity, optical coherence tomography, optical coherence tomography angiography, and fluorescein angiography findings.

Results

Two eyes of 2 female patients were included. The mean age was 68.5 years. Baseline visual acuity was counting fingers and 20/200, and MHs measured 3441 μm and 2387 μm, respectively. Six weeks postoperatively, MHs were closed and the superficial inner retina blood vessels within the graft appeared perfused. Optical coherence tomography and optical coherence tomography angiography demonstrated early integration of the graft into the surrounding retina and perfused graft vasculature in both patients. Fluorescein angiography confirmed perfusion of retinal graft. At the last follow-up, visual acuity was 20/200 and 20/150, respectively, the MH was closed, and the retinal grafts were perfused.

Conclusions and Relevance

Autologous neurosensory retinal transplant may be used for the treatment of giant MHs. Vascularization and reperfusion of the retinal graft is observed within 6 weeks of transplant. It is hypothesized that visual improvement occurs as a result of flattening of the MH rim, partial centripetal migration of MH edges during the early healing phase, and further centripetal migration in the later phase associated with the shrinkage of the retinal graft.

Introduction

Since the original study by Kelly and Wendel, macular hole (MH) surgery has undergone a number of modifications.^1,2 Although primary anatomic success rates of more than 90% have been reported for idiopathic MHs, there remain a minority of cases that continue to present a surgical challenge. Macular holes associated with high myopia, very large MHs, and refractory MHs with multiple prior surgeries are associated with a worse outcome. A number of techniques have been used to improve anatomic outcomes including removal of internal limiting membrane, free or inverted internal limiting membrane flaps, radial relaxing retinotomies, and autologous lens capsule and amniotic membrane flaps.^3,4,5,6 In a seminal 2016 report, Grewal and Mahmoud⁷ described the use of autologous retinal transplant (ART) for treatment of a refractory myopic MH. Retinal transplant provides a potentially beneficial additional treatment modality for a subgroup of patients with typically suboptimal outcomes with other surgical techniques.

There currently is no literature on the vascular supply of transplanted retinal tissue, to my knowledge. The current article describes closure of giant MHs after ART and vascularization and reperfusion of retinal grafts.

Methods

Two eyes of 2 patients with giant MH (diameter, ≥2000 μm) underwent ART. Surgical technique included 23-gauge pars plana vitrectomy (Constellation; Alcon), harvesting of an oversized retinal graft from the supratemporal or inferotemporal midperiphery, tucking of the graft under the edges of the MH, and silicone oil tamponade. Perfluoro-n-octane heavy liquid was not required for stabilization of the retinal graft; however it was used to reattach the localized retinal detachment surrounding the harvest site.

Results

Case 1

A 66-year-old woman presented with long-standing vision loss, history of multiple MH surgeries, visual acuity (VA) of counting fingers, and a giant MH associated with retinal pigment epithelial disturbance and pre–retinal pigment epithelial proliferation OD (Figure 1A). Optical coherence tomography (OCT) demonstrated MH with a basal diameter of 3441 μm (Figure 1B). The patient underwent ART with silicone oil tamponade in June 2018.

Figure 1. Patient 1: Baseline and 6 Weeks After Autologous Retinal Transplant.

A, Fundus photograph showing a giant macular hole in the right eye. Retinal pigment epithelial disturbance and pre–retinal pigment epithelial proliferation were present within the base of the macular hole. B, Optical coherence tomography (OCT) showed a giant macular hole measuring 3441 μm at the base. C, Six weeks after autologous retinal transplant, OCT demonstrated early structural integration of the graft edges and the surrounding retina. D, Optical coherence tomography angiography (OCT-A) indicated partial perfusion of the retinal graft.

Six weeks postoperatively, the patient reported subjective visual improvement. Visual acuity was 20/400, the retinal graft was well positioned, and the original large superficial retinal vessels appeared perfused on biomicroscopy. Optical coherence tomography showed early structural integration of the graft edges into the surrounding retina (Figure 1C) and OCT angiography demonstrated partial vascularization and perfusion of the superficial and inner retinal vessels (Figure 1D).

At 3 months, VA was 20/200, MH was closed, and retinal blood vessels were perfused. Optical coherence tomography showed further integration of the graft and the surrounding retina. Optical coherence tomography angiography and fluorescein angiography demonstrated perfused retinal graft vasculature (Figure 2A). At 6 months, silicone oil had been removed, the patient’s VA was 20/200, MH was closed, and retinal pigment epithelial atrophy and mild epiretinal membrane were present (Figure 2B). Optical coherence tomography angiography and fluorescein angiography demonstrated perfused vasculature within the retinal graft (Figure 2C and D).

Figure 2. Patient 1: 3 and 6 Months After Autologous Retinal Transplant.

A, Three months after autologous retinal transplant, fluorescein angiography (FA) demonstrated perfused retinal graft vasculature. Mild localized hyperfluorescence and leakage, consistent with retinal neovascularization, was present at the superior and inferior aspect of graft-host junction. B, Six months after autologous retinal transplant, optical coherence tomography (OCT) showed closed macular hole, integration of the retinal graft into the surrounding retina, and mild epiretinal membrane. Optical coherence tomography angiography (OCT-A) (C) and FA (D) demonstrated perfused retinal graft vasculature and small area of vascular leakage, suggestive of fine retinal neovascularization at the inferior aspect of graft-host junction.

Case 2

A 71-year-old woman presented with history of reduced VA and multiple surgeries for MH and retinal detachment OS. Examination showed VA of 20/200 and a large MH with a basal diameter of 2387 μm (Figure 3A).

Figure 3. Patient 2: Baseline, 6 Weeks, and 3 Months After Autologous Retinal Transplant.

A, Baseline fundus photograph and optical coherence tomography (OCT) show a giant macular hole in the left eye. B, Six weeks after autologous retinal transplant, OCT showed a closed macular hole, retinal edema, and a well-positioned graft with early integration of the edge with the surrounding retina. C, Fluorescein angiography (FA) at 6 weeks demonstrated perfused vasculature within the retinal graft. Small areas of leakage, suggestive of retinal neovascularization, are present. D, Three months after autologous retinal transplant, FA demonstrated perfused graft vasculature.

The patient underwent ART and silicone oil tamponade with harvesting of retinal graft from the inferotemporal equatorial region in February 2019. Two weeks after ART, OCT demonstrated a well-positioned edematous retinal graft with edges secured under the MH rim. At 6-week follow-up, the patient reported subjective improvement in central vision, VA was 20/250, retinal graft was well positioned, and the large superficial retinal blood vessels within the graft appeared perfused. Optical coherence tomography showed early integration of the graft edges with the surrounding retina (Figure 3B). Optical coherence tomography angiography and fluorescein angiography demonstrated perfused superficial and inner retinal vessels within the graft (Figure 3C). Three months after the transplant, VA was 20/150, retinal pigment epithelial dropout was present, and the MH was closed with shrinkage of the retinal graft and further integration with the surrounding retina. Perfused graft vasculature were demonstrated by OCT angiography and fluorescein angiography (Figure 3D).

Discussion

Likely mechanism for closure of MH involves centripetal migration of the edges of the MH after alleviation of anteroposterior and tangential traction. Gas tamponade provides a microenvironment conducive to migration. Coverage of MH by internal limiting membrane or amniotic membrane flaps provides a scaffold and an additional barrier from the aqueous environment of vitreous cavity, aiding closure of MH. Grewal and Mahmoud⁷ described closure of a refractory myopic MH after ART and hypothesized that the retinal free flap serves as a scaffold for MH rim migration and a plug that secludes communication between the vitreous cavity and the subretinal space. De Giacinto et al⁸ reported closure of a large MH after ART. Wu et al⁹ reported on use of autologous blood clot for stabilization of retinal graft.

In 2019, Grewal et al¹⁰ reported on 41 eyes with refractory MHs and mean basal diameter of 1468 μm. Anatomic closure was achieved in 88% and VA improvement in 37% of eyes. Optical coherence tomography indicated incorporation of the retinal graft, some migration of the surrounding retina, and partial restoration of the outer layers including ellipsoid zone and external limiting membrane.

In the present cases, the MHs measured 3441 and 2387 μm. Both patients underwent ART using an oversized retinal patch secured under the edges of the MH. Placement of the transplanted retina under the edges of the MH is advantageous as it is technically simple, stable, and avoids covering of the most visually sensitive area of the retina, namely the MH rim, with a translucent retinal patch. In both patients, structural integration of the retina graft into the surrounding retina and vascular perfusion was evident by 6 weeks. The retinal graft decreased in size, with further approximation of the rim of the original MH. Both patients reported modest visual improvement. Improvement in vision likely occurs by a number of mechanisms. In the early phase, there is flattening of the edges of the MH, reducing the size of the central void corresponding to the MH. In the intermediate phase there is partial centripetal migration of the edges of the MH, reducing the size. In the intermediate/late phase, there is additional centripetal migration associated with a decrease in the size of the retinal patch, further approximating the MH rims. The effect on vision during the late phase warrants further studies. Hypothetically, late visual improvement could occur by progressive shrinkage of the retinal patch and possibly by neuronal integration.

Anatomic integration of the transplanted retina has been demonstrated in cases reported by Grewal and Mahmoud,⁷ Wu et al,⁹ De Giacinto et al,⁸ Grewal et al,¹⁰ and the present cases. In addition, the present patients demonstrate vascular reperfusion of the transplanted retina. Reperfusion process likely involves localized upregulation of angiogenic pathways by an ischemic retinal graft. In the present patients, the retinal graft was oversized by 1 mm, corresponding to an approximate graft size of 4 to 5 disc areas. It may be hypothesized that a totally ischemic 5–disc area retinal graft produces enough angiogenic stimulus to initiate angiogenesis, resulting in neovascularization and anastomosis between the 2 vascular systems, reperfusing the graft. As the retinal graft is reperfused, ischemic signal diminishes, downregulating angiogenic drive and discouraging uncontrolled angiogenesis.

Limitations

Limitations of the study include the small size and the relatively short follow-up period. Further studies involving larger numbers and longer follow-up are warranted.

Conclusions

In summary, 2 cases of giant macular hole treated with ART are reported. Both patients demonstrated structural integration and vascular reperfusion of the transplanted retinal graft. The findings have implications for the feasibility of survival of large retinal transplants.