Subretinal recombinant tissue plasminogen activator and pneumatic displacement for the management of subretinal hemorrhage occurring after anti-VEGF injections for wet AMD.

We describe three cases of submacular hemorrhage that occurred two to four days after anti-VEGF intravitreal injection for occult choroidal neovascularisation in age-related macular degeneration and their management with 25 gauge pars plana vitrectomy with injection of subretinal recombinant tissue plasminogen activator (rTPA) followed by fluid-air exchange and postoperative prone position. Vitrectomy, subretinal rTPA injection and fluid-gas exchange apply as a safe and effective treatment in these cases. Functional results seem to be positive especially if surgical treatment is promptly performed.

Introduction

We describe three cases of submacular hemorrhage (SMH) that occurred two to four days after anti-vascular endothelial growth factor (anti-VEGF) intravitreal injection for occult choroidal neovascularisation (CNV) in age related macular degeneration1 (AMD) and their management.

Methods

Almost 2500 anti-VEGF intravitreal injections for neovascular AMD were performed in our Department between January 2007 and December 2009. Three patients developed an acute SMH after the injection involving most of the macular region. Fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA) and optical coherence tomography (OCT) were carried out. After diagnosis, patients underwent 25 gauge pars plana vitrectomy with posterior hyaloid removal. An injection of 0.2 mL of subretinal recombinant tissue plasminogen activator (rTPA) (125 μg/mL) through a 41-gauge flexible translocation microcannula (DORC-dual bore BSS injection needle 0.1 mm tip) followed.2 The rTPA was injected inferiorly to the SMH in order to create a bullous retinal detachment encompassing the entire blood clot. Finally a fluid-air exchange was performed and patients maintained a supine position for 45 minutes followed by a postoperative prone position.

Case 1

In January 2008, a 67-year old woman with 20/20 visual acuity and metamorphopsia in her right eye (RE) had been treated for seven months with an injection of ranibizumab each month for an occult CNV. The FFA performed at that time demonstrated, in the RE, a paramacular pigment epithelial detachment of 8.07 mm2 and a serous neuroepithelial detachment involving the fovea (Figure 1). Four days after the 8th intravitreal anti-VEGF injection a SRH developed and the visual acuity dropped to light perception. The patient underwent surgical treatment the day after the appearance of the hemorrhage. No intraoperative or postoperative complications occurred. A complete displacement of submacular hemorrhage from the fovea was obtained. Visual acuity one month after treatment rose to 20/63 with metamorphopsia. The patient had four further intravitreal injections of bevacizumab between May 2008 and August 2008. Significant cataract developed which required extraction in August 2008. One year following cataract surgery the patient’s visual acuity was stable at 20/63.

Figure 1

Fundus fluorescein angiography of case 1. The DEP area is measured in mm2.

Case 2

An 84-year old woman, affected by cardiac arrhythmia treated with amiodarone, presented in January 2008 complaining of metamorphopsia in her RE. An occult CNV due to AMD was identified and she underwent three intravitreal bevacizumab injections in the RE. In April 2008 her visual acuity was 20/125 in the RE and 20/63 in the left eye (LE), and the FFA and ICGA demonstrated an occult choroidal neovascularisation of 18.55 mm2 in the LE. Two days after the first intravitreal injection of bevacizumab, she developed a thick SMH and her visual acuity decreased to hand motion. Two days after the hemorrhage occurred, she underwent surgical treatment. No intra or postoperative complications were observed. Four days after surgery the hemorrhage was displaced from the fovea. The visual acuity in the LE one month after treatment was 20/160 with metamorphopsia. Two months after surgery she underwent another bevacizumab injection in the LE. Her visual acuity remained 20/160 for the following year.

Case 3

In June 2007 a 72-year old woman, who had already undergone in her RE four ranibizumab injections for a wet AMD, started complaining of metamorphopsia in her LE with a visual acuity of 20/20. FFA and ICGA demonstrated a lesion area of 4.15 mm2 due to occult CNV. A ranibizumab intravitreal injection was carried out in her LE and two days after a SMH occurred (Figure 2). The visual acuity in the LE dropped to counting fingers. Two days later she underwent surgical treatment. No intraoperative complications were noticed. Four days after treatment an almost complete displacement of the hemorrhage was achieved. Visual acuity was 20/160 one month after surgery and she underwent another ranibizumab injection. One year after surgery (Figure 3) her visual acuity was unmodified and no other treatment was performed.

Figure 2

Submacular hemorrhage of case 3 pre-treatment.

Figure 3

Submacular hemorrhage of case 3 post treatment.

Discussion

Submacular hemorrhage is not a rare complication during the natural history of occult neovascularisation in AMD. It has been reported that it occurs in 17.0% of AMD cases with the presence of retinal pigment epithelial detachment (PED).3 This complication has been also described after photodynamic therapy especially in cases of AMD with PED.4–9 In our cases only in one of the three patients was a PED present before the treatment (case 1). In that case the area involving the PED was 8.07 mm 2 (Figure 1).

Recently a few studies have described the occurrence of large submacular hemorrhages after the intravitreal injection both of bevacizumab and ranibizumab. Karagiannis has hypothesized that this event might also be due to changing from bevacizumab to ranibizumab.10 In the cases that we report, only one kind of anti-VEGF was injected in each patient before the occurrence of the hemorrhage.

The mechanism of submacular hemorrhage in these cases remains unknown, but it has been hypothesized that the contraction of the neovascular membrane could lead to new vessels rupturing, especially in large lesions.11,12 In addition, a reduction of tight junctions in retinal pigment epithelial and endothelial cells related to the decrease in VEGF availability could promote the vessel rupture,13 even though recently Peng et al have demonstrated that permeability and selectivity of the junctions are not affected by VEGF, bevacizumab or ranibizumab.14

Vascular endothelial growth factor regulates crucial processes, such as embryo- and organogenesis as well as immune system, endocrinology, hematopoiesis, (lymphoid) vessel architecture and reparative processes in adults.15,16 It might be therefore expected that its inhibition could cause multiple adverse effects. Although the intravitreal administration of smaller doses can drastically reduce systemic exposure, and current and past clinical trials do not provide sufficient statistical power when evaluating whether systemic events significantly differ between the treatment and control groups,17–21 possible local side effects on retinal perfusion and survival of neuronal tissue must be taken into consideration.22

Goverdhan and Lochhead1 has described four cases of submacular hemorrhage after intravitreal bevacizumab all occurring in large neovascular lesions and the same finding was described by Baeteman et al reporting six cases of submacular hemorrhage after ranibizumab injection.23 In these series the hemorrhages developed at a median of 14 to 25 days after the anti-VEGF injection, while in our cases the median was 2.6 days.

Moreover it is interesting to note that the patient described in our third case developed a large subretinal hemorrhage after the injection but the initial lesion was relatively small and no PED was noticed.

The occurrence of submacular hemorrhage has been also related to anticoagulant therapy and to increased blood pressure.24–26 In our series no patients had history of systemic hypertension or anticoagulant treatment.

The toxicity of subretinal blood to the neurosensory retina has been demonstrated in clinical studies27 and in animal models.28 Possible mechanisms of blood-induced retinotoxicity include mechanical effects such as fibrotic shearing of photoreceptors, hypoxia, and metabolic disruption imposed by the clot as a diffusion barrier. Direct neurotoxicity seems to be induced by the migration of blood components, such as iron, to the photoreceptor layer.29

The management of submacular hemorrhage has evolved greatly during the past 15 years. A variety of therapeutic approaches have been developed, all with the common goal of clearing the submacular blood to minimize permanent damage to the photoreceptors and retinal pigment epithelium. Many options have been proposed including intravitreal gas injection;30,31 pars plana vitrectomy and submacular surgery, both with and without the assistance of rTPA;32–38 intravitreal injection of gas and pneumatic displacement of the submacular hemorrhage with associated intravitreal injection of rTPA;39–41 pars plana vitrectomy; subretinal injection of r-TPA and fluid gas exchange;42 pars plana vitrectomy and subretinal rTPA injection, followed by evacuation of the liquefied blood through a 500 μm retinotomy with the aid of perfluorocarbon compression of the overlying retina;43 intravitreal anti-VEGF;44 combined rTPA, expansile gas and bevacizumab;45 and co-application of rTPA and bevacizumab.46 Many procedures include the use of rTPA. Subretinal rTPA has recently been demonstrated to achieve best anatomical results than intravitreal rTPA.47

Patients with subretinal hemorrhages secondary to AMD are psychologically distressed as a result of acute loss of vision.48 In our series subretinal r-TPA injection followed by gas tamponade allowed the displacement of the hemorrhage in all the three cases enabling the follow-up and the further treatment of the AMD. No intraoperative or postoperative complications were noted.

In conclusion, large subretinal hemorrhage is a possible complication of intravitreal anti-VEGF treatment in AMD and it may occur days or weeks after the injection. Further studies are required for the complete comprehension of the mechanism of the pathogenesis.

The surgical approach with vitrectomy, subretinal rTPA injection and fluid-gas exchange is a safe and effective treatment. Functional results seem to be positive, especially if surgical treatment is promptly performed.