PREDISPOSING CHARACTERISTICS OF OPTICAL COHERENCE TOMOGRAPHY FOR PATIENTS WITH PERSISTENT SUBRETINAL FLUID AFTER SUCCESSFUL REPAIR OF RHEGMATOGENOUS RETINAL DETACHMENT.

PURPOSE: To investigate the predisposing clinical parameters and characteristics of fundus imaging of patients with persistent subretinal fluid (PSF) after successful repair of rhegmatogenous retinal detachment. METHODS: A retrospective study recruiting 57 patients was conducted. All patients underwent pars plana vitrectomy with silicone oil tamponade. Patients were divided into two groups: patients presenting PSF by the time of silicone oil removal as PSF group and patients presenting no PSF by the time of silicone oil removal as control group. All patients were followed up for 3 months or longer after primary surgery. Ophthalmic examinations, including fundus photography and optical coherence tomography, were performed. RESULTS: There were significant differences between the two groups in average age, durations of preoperative symptoms, and type of retinal breaks ( P < 0.05). These clinical parameters showed statistical correlations with PSF ( P < 0.05). The proportions of patients presenting distinctive boundaries of the detached retina on fundus photograph and patients showing a hyperreflective line underlying the detached retina on optical coherence tomography in the PSF group were both significantly higher than the control group ( P < 0.05). The macular detachment heights on optical coherence tomography in the PSF group were significantly lower than the control group ( P < 0.05). These imaging characteristics also showed strong correlations with PSF ( P < 0.05). CONCLUSION: This study suggests that patients with PSF have younger age, longer symptom duration, and higher incidence of retinal holes. The distinctive detachment boundary on fundus photograph, lower macular detachment height, and hyperreflective line underlying the detached retina on optical coherence tomography may be the predisposing characteristics of PSF.

Comparative Study of a Modified Sub-Tenon's Capsule Injection of Triamcinolone Acetonide and the Intravenous Infusion of Umbilical Cord Mesenchymal Stem Cells in Retinitis Pigmentosa Combined With Macular Edema.

Retinitis pigmentosa (RP) is a hereditary retinal degenerative disease leading to eventual blindness. When RP is combined with macular edema (ME), the visual impairment further worsens. We compared a modified sub-Tenon's capsule injection of triamcinolone acetonide (TA) and the intravenous infusion of umbilical cord mesenchymal stem cells (UCMSCs) in the treatment of RP combined with ME (RP-ME) to assess their safety and efficacy in eliminating ME and restoring visual function. A phase I/II clinical trial enrolled 20 patients was conducted. All patients were followed up for 6 months. There were no severe adverse effects in both groups. In retinal morphological tests, the central macular thickness (CMT) in TA group significantly decreased at first week, first and second month after injection (p < 0.05). The CMT in UCMSCs group significantly decreased at first month after infusion. The rate of reduction of CMT in TA group was significantly greater than that in UCMSCs group at second month (p < 0.05). Reversely, the rate of reduction of CMT in UCMSCs group was significantly greater than that in TA group at sixth month (p < 0.05). In visual functional test, although there were no significant differences in visual acuity or visual fields within each group or between groups, but the amplitude of P2 wave of flash visual evoked potential (FVEP) showed significant increasing in TA group at second month in UCMSCs group at sixth month (p < 0.05). At 6th month, the rate of growth in the amplitude of P2 wave in USMCSs group was significantly greater than that in TA group (p < 0.05). This study suggests both modified sub-Tenon's capsule injection of TA and intravenous infusion of UCMSCs are safe for RP-ME patients. TA injection is more effective at alleviating ME while improving visual function in a short term. UCMSC intravenous infusion shows slow but persistent action in alleviating ME, and can improve the visual function for a longer time. These approaches can be applied separately or jointly depending on the disease condition for patients to benefit maximumly. Clinical Trial Registration: http://www.chictr.org.cn, identifier ChiCTR-ONC-16008839.

A phase I clinical trial of human embryonic stem cell-derived retinal pigment epithelial cells for early-stage Stargardt macular degeneration: 5-years' follow-up.

OBJECTIVES: To evaluate the long-term biosafety and efficacy of transplantation of human embryonic stem cells-derived retinal pigment epithelial (hESC-RPE) cells in early-stage of Stargardt macular degeneration (STGD1). MATERIALS AND METHODS: Seven patients participated in this prospective clinical study, where they underwent a single subretinal transplantation of 1 × 105 hESC-RPE cells in one eye, whereas the fellow eye served as control. These patients were reassessed for a 60-month follow-up through systemic and ophthalmic examinations. RESULTS: None of the patients experienced adverse reactions systemically or locally, except for two who had transiently high intraocular pressure post-operation. Functional assessments demonstrated that all of the seven operated eyes had transiently increased or stable visual function 1-4 months after transplantation. At the last follow-up visit, two of the seven eyes showed visual function loss than the baseline; however, one of them showed a stable visual acuity when compared with the change of fellow eye. Obvious small high reflective foci in the RPE layer were displayed after the transplantation, and maintained until the last visit. Interestingly, three categories of patients who were classified based on autofluorescence, exhibited distinctive patterns of morphological and functional change. CONCLUSIONS: Subretinal transplantation of hESC-RPE in early-stage STGD1 is safe and tolerated in the long term. Further investigation is needed for choosing proper subjects according to the multi-model image and function assessments.

RETINAL AND CHOROIDAL BLOOD PERFUSION IN PATIENTS WITH BIETTI CRYSTALLINE DYSTROPHY.

PURPOSE: To compare changes of chorioretinal blood perfusion between Bietti crystalline dystrophy (BCD) and typical retinitis pigmentosa and perform a staging and a longitudinal analysis of chorioretinal perfusion in BCD. METHODS: Twenty-eight patients with BCD (56 eyes), 28 patients with typical retinitis pigmentosa (56 eyes), and 28 healthy subjects (56 eyes) were enrolled. Macular structural parameters and subfoveal choroidal thickness were measured using optical coherence tomography. Retinal vessel and perfusion densities were calculated using optical coherence tomography angiography. Choroidal blood perfusion was assessed through indocyanine green angiography. The results of the BCD group were compared with those of the retinitis pigmentosa and control groups and followed by a staging and a longitudinal analysis of BCD. RESULTS: Macular structural and perfusion parameters were decreased less in the BCD group than those in the retinitis pigmentosa group. Subfoveal choroidal thickness was significantly thinner in the BCD group, with a remarkable choroidal perfusion deficit using indocyanine green angiography. The staging analysis revealed damage of both retinal and choroidal perfusion in BCD; however, the longitudinal analysis showed the impairment of choroidal perfusion outweighed retinal. CONCLUSION: Both retinal and choroidal blood perfusion are impaired in BCD, but choroidal perfusion deficit caused by CYP4V2 mutations may play a more vital pathologic role.

Intravenous Infusion of Umbilical Cord Mesenchymal Stem Cells Maintains and Partially Improves Visual Function in Patients with Advanced Retinitis Pigmentosa.

Retinitis pigmentosa (RP) is a hereditary retinal degeneration disease with no effective therapeutic approaches. Inflammatory and immune disorders are thought to play an important role in the pathogenesis of RP. Human umbilical cord mesenchymal stem cells (UCMSCs), with multiple biological functions such as anti-inflammation and immunoregulation, have been applied in different systemic diseases. We conducted a phase I/II clinical trial aiming to evaluate the safety and efficacy of intravenous administration of UCMSCs in advanced RP patients. All 32 subjects were intravenously infused with one dose of 108 UCMSCs and were followed up for 12 months. No serious local or systemic adverse effects occurred in the whole follow-up. Most patients improved their best corrected visual acuity (BCVA) in the first 3 months. The proportions of patients with improved or maintained BCVA were 96.9%, 95.3%, 93.8%, 95.4%, 90.6%, and 90.6% at the 1st, 2nd, 3rd, 6th, 9th, and 12th month follow-up, respectively. Most of the patients (81.3%) maintained or improved their visual acuities for 12 months. The average NEI VFQ-25 questionnaire scores were significantly improved at the third month (P < 0.05). The average visual field sensitivity and flash visual evoked potential showed no significant difference (P = 0.185, P = 0.711). Our results indicated that the intravenous infusion of UCMSCs was safe for advanced RP patients. Most of the patients improved or maintained their visual functions in a long term. The life qualities were improved significantly in the first 3 months, suggesting that the intravenous infusion of UCMSCs may be a promising therapeutic approach for advanced RP patients.

Cases of visual impairment caused by cerebral venous sinus occlusion-induced intracranial hypertension in the absence of headache.

BACKGROUND: Cerebral venous sinus thrombosis or stenosis (here collectively referred to as cerebral venous sinus occlusion, CVSO) can cause chronically-elevated intracranial pressure (ICP). Patients may have no neurological symptoms other than visual impairment, secondary to bilateral papilledema. Correctly recognizing these conditions, through proper ophthalmological examination and brain imaging, is very important to avoid delayed diagnosis and treatment. CASE PRESENTATION: We report a case series of 3 patients with chronic CVSO, who were admitted to an ophthalmological department in Chongqing, China, from 2015 March to 2017 February. All patients presented with decreased vision and bilateral papilledema, but had no headache or other neurological symptoms. The visual fields of all patients were impaired. Flash visual evoked potentials (VEPs) in two patients showed essentially normal peak time of P2 wave, and pattern VEPs in one patient displayed decreased P100 amplitude in one eye, while a normal P100 wave in the other eye. In all patients, lumbar puncture (LP) revealed significantly elevated ICP. And magnetic resonance venography (MRV) demonstrated cerebral venous sinus abnormalities in every patient: one right sigmoid sinus thrombosis, one superior sagittal sinus thrombosis, and one right transverse sinus stenosis. CONCLUSIONS: CVSO can cause chronically-elevated ICP, leading to bilateral papilledema and visual impairment. A considerable amount of patients have no apparent neurological symptoms other than visual loss. Unlike other optic nerve lesions, such as neuritis or ischemic optic neuropathy, the optic disc edema in CVSO is usually bilateral, the flash or pattern VEP is often normal or only mildly affected, and patients are often not sensitive to steroid therapy. CVSO should be suspected in such patients when unenhanced brain imaging is normal. Further investigations, such as LP and contrast-enhanced imaging (MRV and digital subtraction angiography), should be performed to diagnose or exclude CVSO.

Efficacy and Safety of Autologous Bone Marrow Mesenchymal Stem Cell Transplantation in Patients with Diabetic Retinopathy.

BACKGROUND/AIMS: The treatment options for diabetic retinopathy (DR) are limited. Mesenchymal stem cells (MSCs) are a promising treatment option for diabetes and its complications. In this pilot clinical trial, we evaluated the safety and efficacy of intravenous autologous bone marrow MSCs (ABMSC) for the treatment of DR. METHODS: In total, 34 eyes with non-proliferative or proliferative DR (NPDR, n = 19; PDR, n = 15) from 17 patients were analyzed. Treatment involved one intravenous infusion of 3 × 106/kg ABSMCs. The patients' vital signs were monitored, along with immune and allergic reactions. Treatment efficacy was evaluated via measurements of the following parameters at baseline, and at 1, 3, and 6 months after treatment: the levels of fasting blood glucose (FBG), Hemoglobin A1C (HbA1C), interleukin-6 (IL-6), and hypersensitive C-reactive protein (CRP); best corrected visual acuity (BCVA); and central macular and subfield thickness (via optical computed tomography). RESULTS: ABMSC infusion led to a significant decrease in FBG and CRP levels (P < 0.05). There were no significant differences in HbA1C or IL-6 levels. Sub-group analysis revealed that only eyes in the NPDR group had the macular thickness reductions and a significant improvement in BCVA from baseline (P = 0.006 at 3 months and 0.027 at 6 months), while those in the PDR group did not. There were no acute reactions during the treatment or severe adverse events during the follow-up period. CONCLUSION: ABSMCs are a potentially safe and effective treatment option for DR, and the optimum therapeutic window appears to be during the NPDR stage.

The changes of potassium currents in RCS rat Müller cell during retinal degeneration.

Müller cells are the principal glial cells expressing membrane-bound potassium channel and predominantly mediating the homeostatic regulation of extracellular K+ produced by neuronal activity in retina. It's well known that Müller cells can be activated in many pathological conditions, but little is known about the change of potassium currents of Müller cells during the progression of retinitis pigmentosa. Herein, the Royal College of Surgeons rats (RCS rat) were employed to investigate some phenotypic and functional changes of Müller cells during retinal degeneration such as the expression of Kir4.1, membrane properties and K+ channel currents by using immunohistochemistry, RT-PCR, western blot and whole-cell patch clamping respectively. Compared with Müller cells in control retina, increased glutamine synthetase (GS) mRNA levels were seen at P30 and P60, and then decreased gradually in RCS rat retina. Morphologically, Müller cells showed significant hypertrophy and proliferation after p60. The increased expression of intermediate filament, glial fibrillary acidic protein (GFAP) and vimentin began at P30 and reached a peak at p60. Kir4.1 channels presented a peak expression at P30. Concomitantly, K(+) currents of Müller cells increased at P30 and decreased at P90 significantly. We concluded that retinal Müller cells of RCS rats underwent an activation initiated by the onset of retinal degeneration before p60 and then an obvious reactive gliosis, which led the basic membrane properties to suffer marked changes, and caused the Kir4.1 channels of Müller cells to occur a clear functional shift, even lose their normal electrophysiological properties. This process aggravates the impairment caused by the initial photoreceptor degeneration.

Increased Müller cell de-differentiation after grafting of retinal stem cell in the sub-retinal space of Royal College of Surgeons rats.

In several vertebrate classes, the Müller glia are capable of de-differentiating, proliferating, and acquiring a progenitor-like state in response to acute retinal injury or in response to exogenous growth factors. Our previous study has shown that Müller cells can be activated and de-differentiated into retinal progenitors during Royal College of Surgeons (RCS) rats' degeneration, although the limited proliferation cannot maintain retinal function. We now report that rat retinal stem cells (rSCs) transplanted into RCS rats slowed the progression of retinal morphological degeneration and prevented the functional disruption. Further, we found that retinal progenitor cells labeled with Chx10 were increased significantly after rSCs transplantation, and most of them are mainly from activated Müller cells. rSCs transplantation also enhances neurogenic potential by producing more recoverin-positive photoreceptors, which was proved coming from Müller glia-derived cells. These results provide evidence that stem cell-based therapy may offer a novel therapeutic approach for the treatment of retinal degeneration, and that Müller glia in mammalian retina can be activated and de-differentiated by rSC transplantation and may have therapeutic effects.

Activation of retinal stem cells in the proliferating marginal region of RCS rats during development of retinitis pigmentosa.

Retinal stem cells (RSCs) have been demonstrated at the proliferating marginal regions from the pars plana of ciliary body to the ciliary marginal zone (CMZ) in adult lower vertebrates and mammals. Investigations in the lower vertebrates have provided some evidence that RSCs can proliferate following retinal damage; however, the evidence that this occurs in mammals is not clear. In this study, we explored RSCs proliferation potential of adult mammalian in proliferating marginal regions of Royal College of Surgeons (RCS) rats, an animal model for retinitis pigmentosa (RP). The proliferation was evaluated using BrdU labeling, and Chx-10 as markers to discern progenitor cell of CMZ in Long-Evan's and RCS rats at different postnatal day (PND) after eye opening. We found that few Chx-10 and BrdU labeled cells in the proliferating marginal regions of Long-Evan's rats, which significantly increased in RCS rats at PND30 and PND60. Consistent with this, Chx-10/Vimentin double staining cells in the center retina of RCS rats increased significantly at PND30 after eye opening. In addition, mRNA expression of Shh, Ptch1 and Smo was up-regulated in RCS rats at PND60 compared to age-matched Long-Evan's rats, which revealed Shh/ptc pathway involving in the activation of RSCs. These results suggest that RSCs in the mammalian retinal proliferating marginal regions has the potential to regenerate following degeneration.