The human fluorescence discrimination as precondition for the use of fluorescence-aided identification techniques (FIT).

OBJECTIVES: The fluorescence-aided identification technique (FIT) is based on the fluorescence properties of dental materials, specifically the intensity of their fluorescence compared to the autofluorescence of hard dental substances; this creates a perceived contrast between dental material and tooth. However, no studies to date have determined the extent to which the fluorescence intensity of tooth-colored dental materials must differ from that of natural autofluorescence to ensure reliable visual detection. The aim of this study was therefore to determine, for the first time, how pronounced the difference between fluorescence intensity and autofluorescence must be to reliably identify tooth-colored material. METHODS: Ten dentists assessed six different resin-based composite (RBC) samples of varying fluorescence intensity placed in the cavities of ten extracted teeth under standardized fluorescence-exciting illumination. The outcome variable was fluorescence perceptibility. Their assessments of the outcome variable were compared with measurements of the fluorescence intensities of the RBCs and the surrounding dental hard tissues, which were expressed as a fluorescence intensity ratio. Demographic data of the participants, including age, gender, and professional experience, were also recorded. RESULTS: No significant differences were found for visual fluorescence perceptibility in relation to the explanatory variables of gender (p = 0.14), age (p = 0.13), and professional experience (p = 0.34). In contrast, the fluorescence intensity ratio was significantly different (p < 0.0001). SIGNIFICANCE: For both clinicians and manufacturers, fluorescence intensity levels are important when selecting or developing FIT-compatible materials. Our results suggest that the fluorescence intensity levels of dental materials should be no more than 75% and no less than 200% of tooth natural autofluorescence to ensure reliable detection of tooth-colored materials.

Two-Year Results of XEN Gel Stent Implantation for Pseudoexfoliative Glaucoma in Phakic versus Pseudophakic Eyes.

Objectives: To investigate whether phakia affects the outcome of XEN-45 gel stent implantation in the treatment of pseudoexfoliative glaucoma (PXG). Methods: A retrospective, comparative cohort study of 30 phakic and 55 pseudophakic PXG patients who received the XEN-45 gel stent at a tertiary centre. The primary outcome measure was two-year success defined as a ≥20% lowering of intraocular pressure (IOP) and a target IOP of 6-21 mmHg. Success was complete without and qualified irrespective of antiglaucoma medication use. Further glaucoma surgery other than needling was regarded as a failure. The secondary outcome measures included changes in IOP, revision and complication rates. Results: The complete two-year success rates were 70% and 59% in the phakic and pseudophakic groups, respectively (p = 0.75, log-rank test), and the qualified rates were 80% and 72%, respectively (p = 0.89). The median IOP reduction from baseline was 54% in phakic, and 46% in pseudophakic eyes. While needling rates were similar, the incidence of early incisional bleb revisions was significantly higher in the phakic eyes (13% vs. 0% within 3 months; p = 0.0098, chi-square). Increasing after a year, significantly more pseudophakic eyes failed due to secondary glaucoma surgery (16% vs. 0%; p = 0.0191). Conclusions: The XEN-45 gel stent offers equally effective IOP control for both phakic and pseudophakic patients. However, the onset of bleb revisions and the necessity for secondary glaucoma surgery differed significantly between the groups.

Long-term efficacy and safety of XEN-45 gel stent implantation in patients with normal-tension glaucoma.

BACKGROUND: Minimally invasive bleb surgery using the XEN-45 gel stent has not been established for the treatment of normal-tension glaucoma (NTG). The main objective of this study was to evaluate the long-term treatment efficacy and safety of XEN-45 in eyes with uncontrolled NTG. METHODS: A retrospective analysis of patients with NTG who underwent XEN-45 gel stent implantation at university hospital Tuebingen between 2016 and 2021. The primary outcome measure was surgical success after three years defined as lowering of intraocular pressure (IOP) of ≥ 20%, with target IOP between 6 and 15 mmHg. Success was complete without and qualified irrespective of topical antiglaucoma medication use. The need for further glaucoma surgery, except for needling, was regarded as a failure. The secondary outcome measures included changes in mean IOP, number of antiglaucoma medications, and needling and complication rates. RESULTS: Twenty-eight eyes from 23 patients were included in the final analysis. Complete and qualified success rates were 56.5% and 75% after three years, respectively. Mean postoperative IOP ± standard deviation decreased significantly after three years from 19.3 ± 2.0 mmHg at baseline to 13.7 ± 4.2 mmHg (n = 22; p < 0.0001). The median number of antiglaucoma medications decreased from 2 (range 0-4) to 0 after three years (range 0-3; p < 0.0001). Sixteen eyes (57%) required a median of 1 (range 1-3) needling procedures. One eye required further glaucoma surgery. No sight-threatening complications were observed. CONCLUSION: The XEN-45 stent is effective and safe for the long-term treatment of NTG. However, needling was frequently required to improve outcomes.

XEN45 gel stent in the treatment of pigmentary glaucoma: A two-year follow-up.

PURPOSE: To investigate safety and efficacy of the XEN gel stent in patients with pigmentary glaucoma (PG). METHODS: A retrospective analysis of 26 eyes of 19 patients with PG undergoing XEN gel stent implantation was performed. Best-corrected visual acuity, intraocular pressure (IOP), and number of antiglaucoma medications were analyzed preoperatively, and at 2 weeks and 3, 6, 12, and 24 months after surgery. Success, needling, and complications were analyzed. Complete success was defined as an IOP reduction of >20% and achieving a target IOP of ≤18, ≤15, or ≤12 mmHg without antiglaucoma medication. Qualified success was indicated if the IOP target was reached with or without medication. RESULTS: Mean IOP decreased significantly from 27.6 ± 14.3 (standard deviation, SD) mmHg to 14.3 ± 4.6 mmHg after one year (p < 0.001) and 15.1 ± 2.7 mmHg (p < 0.001) after two years. The median number of hypotensive drugs declined significantly from 4 (range: 3-5) to 0 (0-2) and 0 (0-3) after one and two years, respectively. After two years, complete success with an IOP of ≤18 mmHg and ≤15 mmHg was achieved in 73.1% and 61.5%, respectively. Half of the eyes required needling after a median time of 8 months (0.5-34 months). No sight-threatening complications were observed. CONCLUSION: The XEN gel stent is a safe and effective surgical treatment option for PG. Needling is an important part of the procedure and should be communicated preoperatively to the patients.

Intermediate-term impact on corneal endothelial cells and efficacy of Preserflo MicroShunt implantation in patients with open-angle glaucoma - a prospective study over two years.

INTRODUCTION: Preserflo MicroShunt is a novel microinvasive bleb forming device for the treatment of primary open-angle glaucoma. The intermediate- and long-term success and the impact of this procedure on corneal endothelial cell density remain to be investigated. METHODS: In this prospective observational study, 62 eyes of 55 glaucoma patients (mean age ± SD: 67.0 ± 15.0 years) receiving a Preserflo MicroShunt were included. Corneal endothelial cell density, intraocular pressure and best corrected visual acuity were assessed preoperatively and at 3, 6, 9, 12, 18 and 24 months postoperatively. Success rates, bleb revision rates and complications were analysed. Complete success was defined as an intraocular pressure reduction of ≥ 20% and achieving a target pressure of ≤ 18, ≤ 15 or ≤ 12 mmHg without antiglaucoma medication. Qualified success indicated that the criteria were reached with or without medication. RESULTS: Corneal endothelial cells showed no significant decline over 24 months (p > 0.05). Intraocular pressure showed a substantial reduction postoperatively (p < 0.001), decreasing from 29.6 ± 8,3 mmHg to 13.0 ± 4.3 mmHg after 24 months (p < 0.001). Complete and qualified success with a target pressure ≤ 15 mmHg was achieved in 52.9% and 54.6% of cases after 24 months, respectively. Best corrected visual acuity did not change after 24 months. CONCLUSION: Preserflo MicroShunt had no negative side effects on corneal endothelial cells and showed favourable success rates after 2 years in patients with open-angle glaucoma.

Histopathological findings of failed blebs after microinvasive bleb surgery with the XEN Gel Stent and Preserflo MicroShunt.

PURPOSE: The success of XEN Gel Stent (XEN) and Preserflo MicroShunt (Preserflo) implantation depends mainly on the development of bleb fibrosis. This study aimed to describe the histological findings of bleb fibrosis after XEN and Preserflo surgery. METHODS: This retrospective study included patients with different types of glaucoma who underwent revision surgery after XEN or Preserflo implantation. The available clinical information and histological samples of removed fibrotic tissue were analyzed. RESULTS: Thirty-six patients were included. Revision surgery was performed at a median of 195 (range = 31-1264) days after primary surgery. The mean intraocular pressure changed from 29.1 (± 10.3) mmHg at baseline to 18.3 (± 8.7) mmHg (- 37%; p < 0.0001) and 16.2 (± 4.2) mmHg (- 45%; p < 0.0001) after 6 and 12 months, respectively. Histological analysis revealed an increase in activated fibroblasts and macrophages in all specimens and a parallel orientation of fibroblasts in a minor part of the probe in 60% of the specimens. No pronounced inflammatory reaction in the form of lymphocytic or granulocytic infiltration was observed. The comparison of specimens from uveitic glaucoma and primary open-angle glaucoma patients revealed no significant differences. CONCLUSIONS: The histological analysis of fibrotic blebs from the XEN and Preserflo implants did not show any pronounced immune or foreign-body reaction and revealed a similar histological pattern of failed blebs after trabeculectomy.

MERCURY-3: a randomized comparison of netarsudil/latanoprost and bimatoprost/timolol in open-angle glaucoma and ocular hypertension.

PURPOSE   : To compare the efficacy and safety of the fixed-dose combination (FDC) of netarsudil 0.02%/latanoprost 0.005% ophthalmic solution (NET/LAT; Roclanda®) with bimatoprost 0.03%/timolol maleate 0.5% (BIM/TIM; Ganfort®) ophthalmic solution in the treatment of open-angle glaucoma (OAG) and ocular hypertension (OHT). METHODS: MERCURY-3 was a 6-month prospective, double-masked, randomized, multicenter, active-controlled, parallel-group, non-inferiority study. Patients (≥ 18 years) with a diagnosis of OAG or OHT in both eyes that was insufficiently controlled with topical medication (IOP ≥ 17 mmHg in ≥ 1 eye and < 28 mmHg in both eyes) were included. Following washout, patients were randomized to once-daily NET/LAT or BIM/TIM for up to 6 months; efficacy was assessed at Week 2, Week 4, and Month 3; safety was evaluated for 6 months. Comparison of NET/LAT relative to BIM/TIM for mean IOP at 08:00, 10:00, and 16:00 h was assessed at Week 2, Week 6, and Month 3. Non-inferiority of NET/LAT to BIM/TIM was defined as a difference of ≤ 1.5 mmHg at all nine time points through Month 3 and ≤ 1.0 mmHg at five or more of nine time points through Month 3. RESULTS: Overall, 430 patients were randomized (NET/LAT, n = 218; BIM/TIM, n = 212), and all received at least one dose of study medication. Efficacy analyses were performed at Month 3 on 388 patients (NET/LAT, n = 184; BIM/TIM, n = 204). NET/LAT demonstrated non-inferiority to BIM/TIM, with a between-treatment difference in IOP of ≤ 1.5 mmHg achieved at all time points and ≤ 1.0 mmHg at the majority of time points (six of nine) through Month 3. Mean diurnal IOP during the study ranged from 15.4 to 15.6 mmHg and 15.2 to 15.6 mmHg in the NET/LAT and BIM/TIM groups respectively, with no between-group statistically significant difference. No significant differences were observed in key secondary endpoints. No serious, treatment-related adverse events (AEs) were observed, and AEs were typically mild/moderate in severity. The most common treatment-related AEs were conjunctival hyperemia (NET/LAT, 30.7%; BIM/TIM, 9.0%) and cornea verticillata (NET/LAT, 11.0%; BIM/TIM, 0%). CONCLUSIONS: Once-daily NET/LAT was non-inferior to BIM/TIM in IOP reduction in OAG and OHT, with AEs consistent with previous findings. NET/LAT offers a compelling alternative FDC treatment option for OAG and OHT.

TRPP2 is located in the primary cilia of human non-pigmented ciliary epithelial cells.

PURPOSE: Mechanosensitive channels (MSCs) and primary cilium possess a possible relevance for the sensation of intraocular pressure (IOP). However, there is only limited data on their expression and localization in the ciliary body epithelium (CBE). The purpose of this study was to characterize the expression and localization of TRPP2 in a human non-pigmented ciliary epithelial cell (HNPCE) line. METHODS: The expression of the TRPP2 was studied by quantitative (q)RT-PCR and in situ hybridization in rat and human tissue. Protein expression and distribution were studied by western blot analysis, immunohistochemistry, and immunoelectron microscopy. Cellular location of TRPP2 was determined in rat and human CBE by immunofluorescence and immunoblot analysis. Electron microscopy studies were conducted to evaluate where and with substructure TRPP2 is localized in the HNPCE cell line. RESULTS: The expression of TRPP2 in rat and human non-pigmented ciliary epithelium was detected. TRPP2 was mainly located in nuclei, but also showed a punctate distribution pattern in the cytoplasm of HNPCE of the tissue and the cell line. In HNPCE cell culture, primary cilia did exhibit different length following serum starvation and hydrostatic pressure. TRPP2 was found to be colocalized with these cilia in HNPCE cells. CONCLUSION: The expression of TRPP2 and the primary cilium in the CB may indicate a possible role, such as the sensing of hydrostatic pressure, for the regulation of IOP. Functional studies via patch clamp or pharmacological intervention have yet to clarify the relevance for the physiological situation or aqueous humor regulation.

New XEN63 Gel Stent Implantation in Open-Angle Glaucoma: A Two-Year Follow-Up Pilot Study.

Purpose: The XEN gel stent was developed to reduce the risks of filtration surgery by standardizing the outflow of aqueous humor into the subconjunctival space. Recently, a modified version of the XEN63 gel stent was introduced. The goal of this study was to assess its efficacy and safety. Methods: This is a prospective, nonrandomized, observational, consecutive case series study at a single tertiary centre. Patients with open-angle glaucoma with above target intraocular pressure (IOP) despite maximal tolerated medication were included. The primary outcome was a change of median IOP. Secondary outcomes included a change in the number of medications, complete success, needling and complication rates. Success was defined as a lowering of IOP > 20% from baseline and IOP ≤ 14 mmHg. Complete success indicated that the target IOP was reached without medications. Results: Six patients were included. The median IOP decreased from 35.5 mmHg (25.0-40.0 mmHg) at baseline to 11.5 mmHg (4.0-15.0 mmHg, p = 0.03), and median IOP-lowering medication was reduced from 4.0 (3.0-4.0) at baseline to 0 (0-1.0, p = 0.03) after two years. Five patients (83.0%) had a complete success after two years. Two patients (33.0%) required a needling procedure. Three patients (50.0%) required an intervention due to symptomatic hypotony within the first three weeks postoperatively. Hypotony resolved completely or was asymptomatic after three months. Conclusion: Our study demonstrated a statistically significant reduction in both IOP and number of IOP-lowering medications. Complications were well manageable and had no long-term sequelae.

Detailed intraocular pressure curve by telemetric tonometry with an implanted pressure sensor before and after PreserFlo® MicroShunt implantation: a case report.

Continuous control of intraocular pressure (IOP) is crucial to preventing long-term damage to the optic nerve in glaucoma. Recently, a novel telemetric IOP sensor (EYEMATE-IO™, Implandata Ophthalmic Products GmbH, Hannover, Germany) has been developed that continuously records IOP. The patient can read the IOP measurements wirelessly using a hand-held reading device. We present the case of a 70-year-old patient with primary open-angle glaucoma who had been implanted with an EYEMATE-IO™ and recently underwent minimally invasive bleb-filtering surgery with the PreserFlo® MicroShunt (Santen, Osaka, Japan). This case demonstrates both the benefits of continuous pressure measurement with EYEMATE-IO™ and the ability of the PreserFlo® MicroShunt to significantly reduce IOP fluctuations.

XEN45 Gelstent Implantation in the Treatment of Glaucoma Secondary to Fuchs Uveitis Syndrome.

PURPOSE: Evaluation of treatment efficacy of XEN45 gelstent for glaucoma secondary to Fuchs uveitis syndrome (FUS). METHODS: This retrospective case series evaluated patients with glaucoma secondary to FUS, who underwent XEN45 implantation. Complete success was defined as IOP lowering of ≥ 20% and cutoff IOP at ≤18 mmHg. Success was qualified if additional glaucoma medication was necessary. Additional glaucoma surgery except for needling and open bleb revision was regarded as failure. RESULTS: Twelve eyes of 12 patients were included. Qualified and complete success rates were 50% after one year (n = 10). Qualified success was achieved in 66.6% of patients with 33.3% of patients achieving complete success after two years (n = 6). CONCLUSIONS: XEN45 implantation had some success in the treatment of glaucoma secondary to FUS, but needling was frequently necessary to improve outcome.

Vessel Evaluation in Patients with Primary Open-Angle Glaucoma, Normal Tension Glaucoma and Healthy Controls.

PURPOSE: To compare changes in central retinal arterial equivalent (CRAE), central retinal vein equivalent (CRVE), arteriovenous ratio (AVR), tortuosity and fractal dimension in primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG) and in a control group (CG) on fundus photographs. Further, to provide further evidence of vascular change in glaucoma patients using a novel method of tortuosity. PATIENTS AND METHODS: The primary endpoint was the change in CRAE, CRVE, AVR, fractal dimension and tortuosity of the retinal vasculature from baseline, retrospectively analyzed from 2011 to 2017 at the University Eye Hospital Tuebingen. Fundus photos of POAG (N = 49), NTG (N = 38) and CG (N = 18) were computer evaluated and analyzed in the quantities mentioned above. RESULTS: CRAE in NTG and POAG and CRVE in NTG significantly decreased (P = 0.02, P = 0.01; P = 0.03) whereas CRVE in POAG increased insignificantly (P = 0.72). In NTG, AVR decreased significantly (P = 0.05), but to a lesser extent than in POAG (P < 0.001). In CG, CRAE decreased insignificantly (P = 0.10), CRVE decreased significantly (P = 0.03) and AVR increased insignificantly (P = 0.77). In POAG tortuosity calculated using standard methods as well as our novel method, increased significantly (P = 0.015-0.04), whereas it did not occur in NTG (P = 0.18-0.57) and CG (P = 0.11-0.21). Fractal dimensions in POAG decreased significantly (P = 0.001-0.002), whereas in NTG and CG changes were insignificant (P = 0.33-0.92). CONCLUSION: Based on a retrospective analysis of fundus photographs, specific retinal vasculature features of the retinal vasculature display significant alterations associated with NTG and POAG. The assessment of tortuosity using our novel method was consistent with previously established methods for analyzing tortuosity.

Results of different strategies to manage complicated retinal re-detachment.

PURPOSE: Complicated retinal re-detachment with inferior proliferative vitreoretinopathy (PVR) remains a challenge. This study's aim was to compare vitrectomy with conventional silicon oil (CSO) combined with an encircling band (EB) and vitrectomy with heavy silicon oil (HSO) alone to treat retinal re-detachment through inferior PVR, where standard procedures have already failed. METHODS: A retrospective analysis was done on patients with inferior complex re-detachment with secondary PVR after primary surgery, who received pars plana vitrectomy (PPV) with CSO combined with EB (group 1) or PPV alone with HSO (group 2) between December 2006 and August 2017. The primary endpoint was retinal reattachment, and the secondary endpoint was visual acuity (VA) change and complications in both groups. RESULTS: This study included 119 eyes. Total single surgery anatomical success (SSAS) was 64%, with 80% (52/65) achieved in group 1 and 44.5% (24/54) in group 2 (p < 0.0001). The total final anatomical success (FAS) rate was 79% (94/119). In group 1, FAS was 91% (59/65) compared with 65% (35/54) in group 2 (p = 0.003). The pretreatment VA of group 1 had a median of 1.4 logMAR (95% CI 0.3-1.8), and group 2 showed a median of 1.4 logMAR (95% CI 0.2-1.8). The post-treatment decrease in group 1 was a median equal to - 0.6 versus - 0.1 for group 2 (p = 0.0001). Serious complications were similar in both groups. CONCLUSION: For complicated retinal re-detachment through inferior PVR, the combination of PPV with EB may lead to better anatomical (SSAS, FAS) and functional success compared with PPV alone with HSO.

Scleral Inflammation around Collector Channels in Eyes with Primary Open-Angle Glaucoma.

Purpose: Investigating the existence of inflammation in the distal outflow system posterior of the Schlemm's canal in primary open-angle glaucoma (POAG).Methods: Scleral biopsies (n = 62) from POAG-patients were taken during deep sclerectomy and fixed either in formalin or RNAlater®. Histologic (hematoxylin & eosin) and immunohistological staining for CD 3 and CD 45RO were performed.Results: Cellular infiltration of immunocompetent cells (CD 3 and CD 45RO positive cells) exists around collector channels (CC). This inflammation is limited to the area around the CCs. Ninety-two percent of the biopsies are positive for inflammation. Untreated, dysgenetic glaucoma eyes and 8% of POAG eyes were negative for inflammation. Neither the use of benzalkonium chloride nor the number and type of preoperative antiglaucomatous medication correlated to the immunohistological result.Conclusion: In POAG a diverse cellular infiltration exists around the CCs in the vast majority of biopsies. This could have major diagnostic and therapeutic consequences for the treatment of POAG.Abbreviations: POAG: primary open-angle glaucoma; CC: collector channel; AH: aqueous humor; TM: trabecular meshwork; SC: Schlemm's canal; HE: hematoxylin & eosin; APC: antigen-presenting cell.

Identification of a New Genetic Mutation Associated With Peters Anomaly.

PURPOSE: To report a new genetic mutation in the COL4A1 gene, which was identified in a baby girl with Peters anomaly (PA), a rare anterior segment mesenchymal dysgenesis, which is characterized by unilateral or bilateral corneal opacities often accompanied by glaucoma, cataract, and systemic malformations and associated with various genetic mutations. METHODS: Ophthalmologic examination of one baby girl and whole exome sequencing and Sanger sequencing of blood samples of the child and her biological parents were performed. RESULTS: Ophthalmologic examination led to the diagnosis of PA type I in the baby girl. Whole exome sequencing and Sanger sequencing identified the de novo mutation c.181_189delinsAGGTTTCCG; p.Gly61Arg in the COL4A1 gene in the child, whereas no other putatively causative variants in established genes associated with anterior segment dysgenesis were present. CONCLUSIONS: PA might be associated with the mutation c.181_189delinsAGGTTTCCG; p.Gly61Arg in the COL4A1 gene. The COL4A1 gene encodes for collagen IVα1, an essential component of basal membranes, and mutations are associated with an increased risk for renal and cerebrovascular disorders and stroke. This should be considered when advising and monitoring patients.

[Glaucoma surgery today]. / Aktuelle Glaukomchirurgie.

BACKGROUND: The main goals of glaucoma treatment are to preserve the visual function and maintain as high a quality of life as possible at a cost acceptable to society. Therefore, it is crucial to carefully observe each individual patient in order to determine an individual and personalized treatment approach. MATERIAL AND METHODS: This article summarizes the advantages and disadvantages of medicinal glaucoma treatment as well as traditional methods of glaucoma surgery, based on the current state of knowledge. The article explains the various mechanisms of action of new minimally invasive procedures, introduces the methods mostly commonly used in Germany and gives recommendations for preoperative care and postoperative follow-up. RESULTS/CONCLUSION: In addition to the plethora of medicinal glaucoma treatments and classical surgical procedures, new minimally invasive treatment alternatives have become available in the past few years. The latter are an option for an earlier surgical intervention, especially in naïve or previously treated patients who appear to be unsuitable for medicinal treatment.

Interferon Alpha for Refractory Pseudophakic Cystoid Macular Edema (Irvine-Gass Syndrome).

Purpose: To assess the efficacy and safety of systemic interferon alpha-2a (IFN) for refractory pseudophakic cystoid macular edema (PCME).Methods: Retrospective observational study. The primary outcome was the decrease of central retinal thickness (CRT). Secondary endpoints were the improvement of best-corrected visual acuity (BCVA) and the assessment of IFN-related side effects.Results: Twenty-four eyes of 20 patients were included. The median CRT was 513 µm (range 220-980 µm) at baseline and decreased to 190 µm (range 140-520 µm) at the last follow-up visit (p < 0.001). Reduction of CRT greater than 100 µm was observed in 22 eyes (92%). The median BCVA (logMAR) increased statistically significant from 0.5 (range 0.2-1.5) at baseline to 0.3 (0-0.8) at the last follow-up (p < 0.001). The BCVA improved in 18 eyes (75%) and remained stable in five eyes (21%). No severe treatment-related side effects occurred.Conclusion: IFN is a very effective agent for treatment of refractory PCME.