Discussion
retinal degeneration, swelling, edema, NA-AION, inflammation, dehiscence, tractional retinal detachment, papillary atrophy, idiopathic ERMs, cataract, RNFL loss, ERMs, traumatic, atrophy, lens opacities, PVD
RETINAL DEGENERATION, POSTERIOR VITREOUS DETACHMENT, CATARACT, ADVERSE EFFECTS, SAID, PVD, PROLIFERATION, EDEMA, INFLAMMATION, RECRUITMENT, RETINA, SECONDARY GLAUCOMA, ATROPHY, PATHOGENESIS, ISCHEMIC OPTIC NEUROPATHY, TRACTIONAL RETINAL DETACHMENT, REACTIVE GLIOSIS, COMPLICATION, PROLIFERATIVE VITREORETINOPATHY, ADVERSE EVENT, CAVITY, LENS, DEGENERATION, DISEASE, EVENT, DEHISCENCE, ADHESION
The current results are encouraging because four patients had improved BCVA; the exception was the patient in whom an ERM developed. Nevertheless, spontaneous improvement is not unusual and recovery of at least three lines of Snellen vision has been reported in up to 40% of patients, although there is some controversy regarding this improvement, as discussed below.It is also important to highlight the improvement of the P100 amplitude on the PRVEPda60´ that seems consistent with the visual results at 6 months. The decrease of the P100 amplitude registries observed in its registry at 12 months in patients 1 and 4 may be due to the cataract progression that especially disturbs this kind of test without affecting that much to the FVEP. Also, the unrecordable registries of PRVEP in patient 2 could be explained considering the appearance of significant lens opacities soon after treatment (Fig. Histologic study of the retrolental aggregates seen in rabbits in As expected, the OCT RNFL and GCL thickness measurements showed significant decreases, which agreed with the resolution of the edema and the visible papillary atrophy seen in all patients.The current study is not the first to offer stem cell therapy for NA-AION. As mentioned, in 2017, the SCOTS group published the results of 10 patients treated with cell therapy and although their results seemed good, with 80% of patients experiencing improvement in the Snellen binocular vision, the study had many design weaknesses [Recently, the SCOTS group published new results [The current pilot study was classified by the AEMPS as a phase II CT; thus, its aim was primarily focused on assessing the safety and potential side effects of intravitreal BM-MSCs. Although the improvements in BCVA were striking and detectable, but we should compare these visual changes with that reported in a series of natural evolution. Thus, Raizada and Margolin recently looked at the results of the control group from the Ischemic Optic Neuropathy Decompression Trial comprised of 500 consecutive cases of NA-AION to describe the natural history of the disease [When discussing readouts of RNFL and GCL thickness, it is important to note that RNFL measurements obtained closer to the acute episode are increased due to the swelling, thus, GCL changes could be more useful for detecting the structural changes in the first month. In the absence of any therapy improvements in RNFL and GCL thickness would generally not be expected during the natural history of NA-AION as the damaged cells do not spontaneously regenerate substantially, and the overall trend is toward progressive degeneration and atrophy progressive with RNFL loss and thinning observed at 3, 6, and 12 months [Considering safety, we did not expect to find signs of inflammation, as the work performed by our group in immunocompetent rabbits with the same cells of human origin did not show any sign other than slight inflammation that was related to the injection and resolved after a week [The intravitreal injection is straightforward and is often used in cell therapy. The MSCs were injected using a needle through the pars plana into the vitreous cavity. The BM-MSCs stayed in the place where were injected, near of ganglion cells (target cells). These cells did not migrate to subretinal space. For this reason, this route of administration was chosen even though cellular cluster formation of MSC in the vitreous can occur in some cases after intravitreal delivery [Without any doubt, the most serious complication we have had is the development of ERM. Causality assessment in pharmacovigilance implies evaluating the likelihood that a particular treatment causes an observed adverse event. For this reason, we explored several options to determine a possible relationship between the investigational medicinal product and/or the injection procedure and this relevant event. In our case, funduscopy and OCTs before inclusion did not show any sign of ERMs. So, it seems that ERMs might be related to the injection. Several factors may have caused this complication, which, due to its relevance, deserves extensive discussion.First, the vitreous of that patient visibly adhered to the retina at least partially on OCT at the first visit, and injection probably may have induced a total posterior vitreous detachment (PVD) that together with the presence of BM-MSCs cells could have caused the ERM. This may be a biologically plausible explanation given that PVD is believed to play a critical role in the pathogenesis of idiopathic ERMs, because transient vitreoretinal traction caused by during the development of PVD may cause dehiscence in the internal limited membrane through which glial cells can migrate and proliferate on the inner retinal surface soon after a PVD. In addition, the proliferation and differentiation of hyalocytes located in the vitreous cortical remnants that remain on retinal surface after PVD could induce ERMs [However, new studies about proteomics have suggested that the growth factors and cytokines are related to the formation of ERM (mainly nerve growth factor, glial cell line-derived growth factor, and transforming growth factor β1). Maybe, MSCs could have been the source of these factors in this case [Also, in an in vivo experimental model of retinal degeneration in which stem cells were administrated by subretinal and intravitreal route, the authors showed a strong reactive gliosis and reported that deposits of chondroitin sulfate proteoglycans appeared, decreasing cell migration to target tissue [MSCs injected into the vitreous cavity also have been reported to cause ERM and proliferative vitreoretinopathy (PVR) formation and other severe adverse effects such as secondary glaucoma [Therefore, the rapid evolution of the ERM observed in our patient leading to tractional retinal detachment may have been related to proliferation, migration, and glial-to-mesenchymal transition in myofibroblasts during ERM progression, as in some experimental studies and treated patients [Considering all what previously said and being a single case, this therapeutic modality can continue to be tested but implementing additional measures to closely monitor the vitreoretinal interface, so that EMRs can be prevented or diagnosed early and treated, to maintain patient’s safety. The risk of inducing ERMs should not be minimized, but given the severity of the underlying process, the lack of therapeutic alternatives, and the good results obtained in this short series, we believe that the risk/benefit ratio still justifies continuing the recruitment of patients, with special consideration of the steps needed for early diagnosis of this possible complication. Adding new inclusion criteria and excluding patients with vitreoretinal adhesion are other measures taken to prevent this complication.As mentioned, the other interesting finding concerning safety was the presence of a retrolental aggregate in one patient. The traumatic effect on the lens derived from the intravitreal injection was ruled out. We do not know its composition, but in our rabbit experimental studies, the stem cells gathered over the ONH and at the retrolental space with a similar appearance, so we assume it has the same composition. The condensation decreased slightly throughout the follow-up, but a significant posterior subcapsular cataract appeared after 6 months in this patient (Fig. Interestingly, the appearance of ERM or retrolental aggregates is not mentioned in the series reported by SCOTS group [