The patients’ severe visual loss after the injection was associated with ocular hypertension, hemorrhagic retinopathy, vitreous hemorrhage, combined traction and rhegmatogenous retinal detachment, or lens dislocation.
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(Discussion)
Here we describe a consecutive case series of serious adverse events associated with intravitreal stem-cell injections performed in the United States. Blinding visual outcomes occurred in three patients after they received bilateral intravitreal injection of autologous adipose tissue–derived stem cells at the same stem-cell clinic
These 1-year outcomes are dramatically worse than the typical 1-year visual-loss outcomes that have been reported with the use of vitamin supplementation for non-neovascular AMD, which has been associated with a moderate visual loss in 3.3% of patients,11 and the 1-year outcomes that have been reported with the use of anti-VEGF therapy for neovascular AMD, which has been associated with a moderate visual loss in less than 5% of patients.12
Although numerous stem-cell therapies for medical disorders are being investigated at research institutions with appropriate regulatory oversight, many stem-cell clinics are treating patients with little oversight and with no proof of efficacy.10 A distinction has been made between clinical studies of stem-cell therapies that are founded on solid preclinical research with strong scientific design and programs that lack preclinical research justification. These programs are often funded by patients at nonacademic centers,8 and they may not receive FDA oversight if these procedures are performed without the filing of an investigational new drug application with the FDA, which requires extensive safety data. At least one of the patients thought the procedure was performed within the context of a clinical trial (NCT02024269). However, the consent forms signed by all three patients do not mention a clinical trial. The patients paid for a procedure that had never been studied in a clinical trial, lacked sufficient safety data, and was performed in both eyes on the same day. Experimental bilateral intravitreal injections are both atypical and unsafe.
In patients with non-neovascular AMD, stem cells have been investigated as a way to replace the diseased retinal pigment epithelium, photoreceptors in the macula, or both. Previous studies have shown that suspensions of autologous retinal pigment epithelium cells were limited in their ability to recreate a monolayer on the diseased Bruch’s membrane in patients with non-neovascular AMD.13 Moreover, although suspensions of human embryonic stem cell–derived retinal pigment epithelium that have been injected under the retina in patients with non-neovascular AMD have been shown to have a good safety profile, they have limited benefit with respect to visual acuity in patients with geographic atrophy.14 In addition, there is sparse evidence that cultures of mesenchymal or adipose-derived stem cells can differentiate into retinal pigment epithelium or photoreceptors.15,16
Since ophthalmologists have administered millions of intravitreal injections of other medications for various retinal diseases without similar complications, the complications seen in the three patients described in this series are probably due to the stem-cell preparations rather than to the injection procedure. If the eyes had been injected with excessive volume, then we would expect elevation of the intraocular pressure, pain, and transient loss of vision due to ischemia of the retina or optic nerve. However, retinal detachments with severe proliferative vitreoretinopathy developed in all six eyes in this series while the patients were undergoing observation after the injection.
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The outcome of poor visual acuity in these three patients arouses concern about the performance of procedures at stem-cell clinics that charge patients for their services and that lack clinical or preclinical data to support their practices. Many stem-cell clinics have claimed that autologous stem-cell injections do not fall under the auspices of FDA regulations.7-10 Our case reports establish the possibility of devastating outcomes from such procedures. Other case reports have shown a lack of efficacy in cases of medical tourism in which nothing was injected into the patient’s eye.8 The need for oversight of such clinics and for the education of patients by physicians and regulatory bodies is paramount to protecting patients while advancing proper research and innovation.
http://www.nejm.org/doi/full/10.1056/NEJMoa1609583#t=articleTop
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