A 60-year-old man with Stargardt's macular dystrophy and visual acuity of 20/400 in the right eye and 20/60 in the left eye underwent a subretinal injection of autologous bone marrow-derived stem cells in the right eye. The patient developed a retinal detachment in the right eye 2 months later that was initially treated with a scleral buckle, but the patient subsequently developed a recurrent retinal detachment with proliferative vitreoretinopathy. A pars plana vitrectomy, membrane peel, fluid-air exchange, endolaser, and silicone oil injection were then performed. The retina remained attached 5 months later, with improvement in visual acuity from hand motions to 20/300 post-vitrectomy. Retinal detachment may occur after subretinal injection of stem cells. Proliferative vitreoretinopathy may develop in these patients, but the visual acuity may return to baseline after retinal reattachment.
[Ophthalmic Surg Lasers Imaging Retina. 2016;47:600–601.]
There are currently more than 30 registered National Institutes of Health clinical trials on stem cell therapy. The indications range from age-related macular degeneration to retinitis pigmentosa to Stargardt's macular dystrophy. The long-term clinical efficacy and visual results are still pending, but the early safety and efficacy reports have been promising.1,2 The following case report describes a patient who developed a recurrent retinal detachment after undergoing a subretinal injection of autologous stem cells.
The patient was a 60-year-old man diagnosed with atypical macular degeneration (Stargardt's macular dystrophy) at 45 years old. Extensive work-up revealed ABCA4 gene mutations (pL1970F:c.5908C>T and p.G2074D:c.6221G>A). Fluorescein angiography demonstrated a dark choroid with hyperfluorescent flecks in both eyes, and an electroretinogram showed diminished cone and rod function. The patient's vision was 20/400 in the right eye and 20/60 in the left. The patient underwent a pars plana core vitrectomy and subretinal injection of 0.1 mL of autologous bone-marrow derived mesenchymal stem cells in the right eye at another facility (NCT01920867).3 A month later, he underwent an intravitreal injection of 0.05 mL of stem cells in the left eye.
The patient developed a macula-involving retinal detachment in the right eye 2 months after the stem cell injection. He underwent an encircling scleral buckle procedure with cryotherapy and drainage of subretinal fluid at the other facility. Two months later, he developed a recurrent retinal detachment extending from 12:30 to 10 o'clock, with areas of proliferative vitreoretinopathy (PVR) in the right eye (Figure). His visual acuity was hand motions in the right eye and 20/40 in the left. He had bilateral chorioretinal scars in the macula. The patient then underwent a pars plana vitrectomy, pars plana lensectomy, membrane peel, endolaser, fluid-air exchange, and injection of silicone oil (5,000 centistoke) in the right eye.
(A) The patient initially presented at our institution 4 months after his subretinal stem cell transplantation and 2 months after his scleral buckle procedure. The fundus photo demonstrates bilateral macular scars, a scleral buckle, and a retinal detachment from 12:30 to 10 o'clock. Retinal folds were noted inferiorly. (B) Optical coherence tomography (OCT) demonstrating a macula-involving retinal detachment. (C) Two months after surgery, the retina was reattached with fresh laser scars. His vision had improved to 20/400. (D) The postoperative OCT demonstrated a reattached retina with disruption of the outer retina.
During surgery, the posterior hyaloid was noted to be adherent to the retina, and significant epiretinal membranes were peeled. At the last follow-up 5 months later, the retina was attached. The patient's visual acuity had improved to 20/300.
As the field of stem cell therapy continues to progress, the safety of the procedure continues to be monitored. In animal and non-human primate models, stem cells have been successfully transplanted under the retina, with low rates of retinal detachment.4 In two human phase 2 clinical trials on sub-retinal stem cell therapy, the reported complications included epiretinal membranes, cataracts, and endophthalmitis.1 There were no incidences of retinal detachments.1 The low rate of retinal detachment may have been partly due to patients undergoing complete vitrectomies with surgical separation of the posterior vitreous up to the vitreous base during the stem cell transplantation. Manipulation of attached vitreous may increase the risk of developing a retinal tear. In the current study patient, the hyaloid was attached at the posterior pole after a prior pars plana vitrectomy and subretinal stem cell injection.
Other potential risk factors for developing retinal detachment after stem cell therapy include inflammation, migration, and traction. Disruption of the blood-retinal barrier or retinal pigment epithelium during surgery may release cytokines and inflammatory-mediators, which can lead to proliferative vitreoretinopathy or stem cell death.5 The stem cells could also reflux out of the injection site and provide a scaffold for membrane growth. In vitro studies of human embryonic stem cells have demonstrated strong adhesion forces between the stem cell colonies and the extracellular matrix;6 the stem cells could, therefore, exert traction on the adjacent retina. Combined pars plana vitrectomy, scleral buckling, membrane peel, and a long-acting retinal tamponade may be the preferred approach in patients who develop retinal detachment with proliferative vitreoretinopathy after stem cell transplantation.
- Schwartz SD, Regillo CD, Lam BL, et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet. 2015;385(9967):509–516. doi:10.1016/S0140-6736(14)61376-3 [CrossRef]
- Song WK, Park KM, Kim HJ, et al. Treatment of macular degeneration using embryonic stem cell-derived retinal pigment epithelium: preliminary results in Asian patients. Stem Cell Reports. 2015;4(5):860–872. doi:10.1016/j.stemcr.2015.04.005 [CrossRef]
- Weiss JN, Levy S, Malkin A. Stem Cell Ophthalmology Treatment Study (SCOTS) for retinal and optic nerve diseases: a preliminary report. Neural Regen Res. 2015;10(6):982–988. doi:10.4103/1673-5374.158365 [CrossRef]
- Francis PJ, Wang S, Zhang Y, et al. Subretinal transplantation of fore-brain progenitor cells in nonhuman primates: survival and intact retinal function. Invest Ophthalmol Vis Sci. 2009;50(7):3425–3431. doi:10.1167/iovs.08-2908 [CrossRef]
- Xian B, Huang B. The immune response of stem cells in subretinal transplantation. Stem Cell Res Ther. 2015;6:161. doi:10.1186/s13287-015-0167-1 [CrossRef]
- Rosowski KA, Mertz AF, Norcross S, Dufresne ER, Horsley V. Edges of human embryonic stem cell colonies display distinct mechanical properties and differentiation potential. Sci Rep. 2015;5:14218. doi:10.1038/srep14218 [CrossRef]