Case of Repeated Full-Thickness Macular Hole Formations and Spontaneous Closure following Intravitreal Bevacizumab Treatment for Central Retinal Vein Occlusion

Abstract

The development of a full-thickness macular hole (FTMH) is a rare complication of intravitreal injections, and only a small subset of eyes with an FTMH has a spontaneous closure. We report a case of repeated FTMH formations and a spontaneous closure following an intravitreal injection of bevacizumab (IVB) for a central retinal vein occlusion (CRVO). A 39-year-old male patient presented with reduced vision in his right eye and was diagnosed with a CRVO. Two months later, neovascular glaucoma and macular edema (ME) developed and IVB was performed. After 2 weeks, optical coherence tomography revealed an improvement of the ME and the formation of an FTMH with a hyperreflective material in the FTMH. Two months later, there was a recurrence of the ME and a closure of the FTMH, but the hyperreflective material was still present in the retina. Then, another IVB and panretinal photocoagulation were performed. One month later, the ME had improved and the FTMH was closed, but the hyperreflective material was still present in the retina. After another 2 months, the ME recurred and a third IVB was performed. The ME improved without a recurrence of an FTMH. After that, there were no recurrences of the ME, but the FTMH recurred with the progression of a posterior vitreous detachment and development of an epiretinal membrane 1 year after the third IVB. We suggest that an FTMH be included as a complication of intravitreal injections, and it may close spontaneously during the course of the primary disease.

Introduction

An intravitreal injection of anti-vascular endothelial growth factor is widely used to treat several types of retinal diseases. A full-thickness macular hole (FTMH), a relatively rare complication, can develop after an intravitreal injection [1, 2, 3, 4, 5, 6, 7]. However, there is no report of repeated FTMH formation after an intravitreal injection with a spontaneous closure. We reported our findings in a case that developed an FTMH after an intravitreal injection of bevacizumab (Avastin®; Roche, Basel, Switzerland) (IVB) to treat an macular edema (ME) caused by a central retinal vein occlusion (CRVO). Unexpectedly, there was a spontaneous closure of the FTMH after a recurrence of the ME and a recurrence of the FTMH development during the course of the primary disease.

Case Report

A 39-year-old man with poorly controlled diabetes visited a local eye clinic because of a sudden reduction of vision in his right eye. He was diagnosed with a CRVO in the right eye but declined therapy. Two months later, he developed iris neovascularization, extensive retinal hemorrhages, disc neovascularization, and white intraretinal material in the center of the macula (Fig. 1a). Optical coherence tomography (OCT) showed diffuse ME, hyperreflective material in the fovea that appeared to be connected to the vitreous, but a macular hole was not detected (Fig. 1b). His right eye developed neovascular glaucoma (NVG), and he was treated with IVB (“off-label” treatment) at the local clinic. Two weeks later, he was referred to our hospital for further treatment of the CRVO. Our ophthalmic examinations showed a decimal best-corrected visual acuity of 0.04 in his right eye and 1.2 in his left eye. The intraocular pressure was 14 mm Hg in his right eye and 15 mm Hg in his left eye. Slit-lamp and fundus examinations showed that there was iris neovascularization, disc neovascularization, retinal hemorrhages, and white materials at the center of the macular area (Fig. 1c). OCT showed an improvement of the ME, but an FTMH was detected with a hyperreflective material in the FTMH that was connected to the vitreous (Fig. 1d). Panretinal photocoagulation was performed for the NVG, and 2 months after the first IVB, fundus examination revealed an increase in the white materials in the foveal area (Fig. 1e). OCT showed an increase in the retinal thickness due to a recurrence of the ME and a closure of the FTMH, but the hyperreflective material was still present in the retina. There was also a hyperreflective line on the retinal surface (Fig. 1f). The IVB and panretinal photocoagulation were repeated because of the recurrence of the ME. One month after the second IVB, fundus examination and OCT showed an improvement of the ME and closure of the FTMH (Fig. 1g, h). In addition, the hyperreflective material remained in the retina together with the hyperreflective line on the retinal surface (Fig. 1h). After another 2 months, fundus examination and OCT revealed a recurrence of the ME without a recurrence of the FTMH (Fig. 2a, b). Therefore, a third IVB was performed, and fundus examination and OCT showed an improvement of the ME with no FTMH recurrence or the retinal surface hyperreflective line (Fig. 2c, d). Thereafter, there was no recurrence of the ME, but a progression of the posterior vitreous detachment (PVD) was detected with the development of an epiretinal membrane (ERM) (Fig. 3a, b). One year after the third IVB, there was a recurrence of the FTMH (Fig. 3c), and the best-corrected visual acuity was 0.15. The intraocular pressure was controlled to the middle teen without any medications, and there was no progression to proliferative retinopathy. No retinal neovascularization was observed, and the neovascularization on the iris and optic disc regressed and the NVG subsided. Because there was no desire for further surgical treatments for the FTMH, the patient was followed without treatment.

Fig. 1.

Fundus photographs (FPs) and horizontal macular optical coherence tomographic (OCT) images before and after the first and second intravitreal injection of bevacizumab (IVB). a, b Before the first IVB, FP shows severe retinal hemorrhage and corresponding OCT image shows diffuse macular edema (ME) and a hyperreflective material connected to the vitreous in the fovea (arrow). c, d After the first IVB, the FP and OCT image show a reduction of the ME and the presence of a full-thickness macular hole (FTMH) with a hyperreflective material in the FTMH (asterisk). e, f Images before the second IVB. FP shows an increase in the white materials in the fovea, and corresponding OCT image shows a recurrence of the ME, closure of FTMH, and the presence of a hyperreflective material in the retina which is connected to the vitreous (asterisk). A hyperreflective line can be seen on the foveal retinal surface (arrow). g, h After the second IVB, FP shows an increase in the hard exudates around the fovea, and OCT image shows a reduction of the ME, closed FTMH, but the hyperreflective material is still present in the retina and connected to the vitreous (asterisk). The hyperreflective line around the fovea is more visible (arrow).

Fig. 2.

Fundus photographs (FPs) and horizontal macular OCT images before and after the third IVB. a, b Before the third IVB, FP shows a larger retinal hemorrhage, and corresponding OCT image shows a recurrence of the ME and the presence of the hyperreflective material in the retina (asterisk) with a hyperreflective line on the retinal surface (arrow). c, d After the third IVB, FP shows an increase of the hard exudates in the macular area, and the corresponding OCT image shows a reduction of the ME with the hyperreflective material remaining in the retina (asterisk) with the retinal surface hyperreflective line (arrows).

Fig. 3.

Horizontal macular OCT images after the third IVB. a Four months after the third IVB, OCT shows a PVD on the nasal side of the fovea (arrowheads). b Five months after the third IVB, OCT shows that the hyperreflective material is closer to the vitreous (asterisk), the presence of a retinal break (arrow), and an EPM (arrowheads). c One year after the third IVB, OCT shows an FTMH, and the hyperreflective material is pulled closer to the vitreous (asterisk).

Discussion

The cause of FTMHs after an intravitreal injection has not been definitively determined. It has been reported that an FTMH may develop due to the rapid changes in the shape of the retina due to the reduction in the ME after the intravitreal injection [1, 7]. In addition, it has been suggested that the FTMH may be due to an increase in the pigment epithelial detachment as in eyes with age-related macular degeneration [5, 6]. These changes combined with the macular thinning due to the long-duration ME and the enhanced vitreous traction may have contributed to the development of the FTMH [8]. In our case, the diffuse ME persisted for 2 months after the onset of the CRVO. In addition, the central foveal hyperreflective material was connected to the vitreous and was always found without floating into the vitreous cavity during the treatment. These findings indicate that the macula is fragile due to the long duration of the edema and has tractional force due to strong adhesions between the macular retina and the vitreous. Therefore, a possible mechanism for the FTMH formation in our case is an increased anterior-posterior traction on the fragile retina with an incomplete PVD caused by the rapid shrinkage of the retina due to resolution of the ME. In fact, there have been two reports of FTMH formation in eyes with persistent diabetic macular edema [8, 9], and it was also suggested that vitreous injections in eyes with an incomplete PVD may create focal traction which increased the chance of FTMH formation [6]. On the other hand, a spontaneous closure of an idiopathic macular hole has been reported to occur with the release of vitreous traction due to a complete PVD. However, a different mechanism is possible in our case because there was no evidence of a release of the traction. In our case, the retinal thickness increased with the recurrence of ME, and the hyperreflective material in the FTMH was trapped in the retina. As a result, the FTMH was closed with the edges of the FTMH touching, and after the second IVB, a hyperreflective line was observed on the retinal surface. However, the second and third IVBs reduced the retinal thickness, and there was no recurrence of the FTMH. These findings suggest that the mechanism for the spontaneous closure of the FTMH may be associated with two factors: the hyperreflective material which acted as a filler to close the FTMH after the approximation of the edges of the FTMH due to the recurrence of ME and the bridging between the retina and the hyperreflective material by the hyperreflective line on the surface of fovea. In a similar way, it was recently reported that an MH could be closed by the inverted internal limiting membrane (ILM) flap technique in which the FTMH is covered by the peeled ILM flap [10] or inserted into the FTMH [11]. In our case, it is possible that the hyperreflective material in the FTMH and hyperreflective membrane on the retinal surface functionally served as the peeled ILM in closing the FTMH. Similar to our case, a case has been reported in which an FTMH formed after an intravitreal injection of ranibizumab and closed spontaneously due to a recurrence of the retinal edema. In addition, no FTMH occurred following subsequent intravitreal injection of ranibizumab [1]. However, unlike the past report, the FTMH in our case recurred 1 year later. OCT images showed the hyperreflective material in the retina which was pulled toward the vitreous by the progression of the PVD. Furthermore, ERM development was also observed. These findings suggest that both the tangential traction by the ERM and the enhanced anterior-posterior traction by the development of a PVD played a role in the reopening of the closed FTMH. And in cases of severe macular edema, hard exudates may be deposited intraretinally or subretinally in the central foveal area. The exact composition of the central foveal hyperreflective material in this case was not determined, but the central foveal hyperreflective material had heterogeneous internal reflections in the OCT images. In addition, the white material was seen on the fundus photographs in the corresponding area, and the material changed shape over time. These findings are not different from those of hard exudates, and we suggest that the hyperreflective material in this case was an aggregation of hard exudates.

Conclusions

In conclusion, the possibility of the development of an FTMH as a complication of intravitreal injections should be considered. The risk of FTMH development may be enhanced especially in eyes with the macular fragility due to long-term edema and an incomplete PVD. Although a recurrence of edema may cause the FTMH to close, it should be remembered that once the FTMH closes spontaneously, it may reopen, so the possibility of surgical treatment should be considered.

Statement of Ethics

This study adhered to the tenets of the Declaration of Helsinki. The IVB was approved by the Ethics Committee of Mie University Hospital, approval number 702. The patient was informed the off-label situation of IVB. Written informed consent was obtained from the patient to publish this case report and any accompanying images.

Conflict of Interest Statement

The authors have no conflict of interests in this study.

Funding Sources

No funding or grant support.

Author Contributions

Rika Furukawa, Hisashi Matsubara, and Eriko Uchiyama treated the subject. Rika Furukawa and Hisashi Matsubara wrote the manuscript and collected the data. Rika Furukawa, Hisashi Matsubara, Eriko Uchiyama, Masahiko Sugimoto, and Mineo Kondo read and approved the final version of the manuscript.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

Funding Statement

No funding or grant support.