Treatment of AICA ribosiduria by suppression of de novo purine synthesis.

AICA ribosiduria is an ultra-rare disorder of de novo purine biosynthesis associated with developmental delay of varying severity, seizures, and varying degrees of visual impairment due to chorioretinal atrophy. Caused by biallelic pathogenic variants in ATIC, accumulation of AICA-riboside is the biochemical hallmark and presumed pathomechanism of the condition. In this study, we report the case of a teenage patient compound-heterozygous for the variants c.1277 A > G (p.K426R) and c.642G > C (p.Q214H) in ATIC, with the latter not previously reported. Excessive secretion of AICA-riboside and succinyladenosine was significantly reduced following the introduction of a purine-enriched diet. By suppressing de novo purine biosynthesis in favour of purine salvage, exogenous purine substitution represents a promising treatment approach for AICA ribosiduria. SYNOPSIS: Suppression of de novo purine biosynthesis by increased exogeneous purine supply leads to decreased accumulation of AICA-riboside and succinyl-adenosine and thus is a promising treatment approach for AICA ribosiduria.

Lipofuscin-dependent stimulation of microglial cells.

PURPOSE: To examine the reaction of microglial cells (MG) when incubated with lipofuscin (LP) in vitro with emphasis on the immunological reaction of the MG toward LP and the suppression of this reaction by immunomodulatory agents. MG are involved in the pathogenesis of degenerative eye disorders such as age-related macular degeneration (AMD). LP is a heterogeneous waste material that accumulates in the retinal pigment epithelium (RPE) cells with advancing age. LP is known to have toxic effects on RPE cells and therefore an elevated LP-derived fundus autofluorescence is a risk factor for AMD development. MG in the subretinal space have been reported in eyes affected by AMD. Moreover, in senescent mice, subretinal MG were found, which display an autofluorescence that may be derived from LP uptake. METHODS: In this study, we incubated MG (BV-2 cell line and primary cells from murine brain) in vitro with LP isolated from the human RPE. We observed phagocytosis, studied cell morphologies, and analyzed the cell culture supernatants. We also investigated the effect of the immunomodulatory agents hydrocortisone (HC), minocycline, and the tripeptide TKP. RESULTS: The MG phagocytosed the LP quickly and completely. We detected highly elevated levels of pro-inflammatory cytokines (especially of IL-6, IL-23p19, TNF-α, KC, RANTES, and IL-1α) in the cell culture supernatants. Furthermore, levels of vascular endothelial growth factor (VEGF) were raised in BV-2 cells. Anti-inflammatory agents added to the cell cultures inhibited the inflammatory reaction, in particular hydrocortisone (HC). Minocycline and TKP had less impact on the cytokine release. CONCLUSION: The interaction of MG and LP could play a role in the development of retinal degeneration by triggering an inflammatory reaction and angiogenesis.

Attitudes and Knowledge Regarding Postmortem Cornea Donation among Young and Elderly People in Germany: Sufficient for Decision Making?

OBJECTIVES: To evaluate the knowledge of and attitudes toward postmortem cornea donation in living young and elderly potential donors in a German city. METHOD: High-school students and seniors participated in a nonrandomized prospective survey focusing on willingness to donate corneas postmortem and factors that might influence underlying specific attitudes. Statistical analysis was descriptive and included logistic regression. RESULTS: The survey showed that 73.3% of the high-school students and 41.6% of the seniors, 53.2% of whom had already signed an advanced medical directive, felt insufficiently informed about donation. High-school students were significantly less willing to donate their corneas postmortem (p < 0.001), and fewer of them possessed a donor card (p < 0.001). High-school students specified the internet as their favored source of information about donation in 82.7% of cases, while the family physician was the first preference for 47.8% of the seniors. CONCLUSIONS: The willingness to donate and the proportion of donor card ownership were significantly lower in the high-school students than among the seniors, corresponding to their respective knowledge in matters of donation. Young people should be systematically informed about cornea donation at school, as soon as they reach the legal minimum age for donation, and primary-care physicians should provide relevant information to every new patient to aid their decision making concerning postmortem cornea donation.

Intravitreal treatment in patients with exudative age-related macular degeneration and visual acuity ≤ 0.05.

BACKGROUND: To investigate intravitreal treatment efficiencies in patients suffering from exudative ARMD with a BCVA ≤ 0.05. METHODS: Retrospective analysis: Analysis parameters were lesion type, BCVA at baseline and at follow-up, the intravitreal drug used, and its application frequency. Patients were divided into: 1) following injections of bevacizumab, triamcinolone, their combination, or ranibizumab regardless of their lesion subtype, 2) or by lesion subtype. Statistical tests were performed using Wilcoxon signed-rank tests, Kruskal-Wallis tests and multivariable logistic regressions. RESULTS: Seventy four eyes of 74 patients were analyzed. Follow-up was at 12.0 to 15.7 weeks. Median difference of BCVA (logMAR) between baseline and follow-up was 0.000 (-0.030, 0.175) in classic (p = 0.105), 0.000 (-1.15, 0.20) in occult (p = 0.005), -0.200 (-1.20, 0.60) in cases with subretinal fluid (p = 0.207), 0.000 (-0.60, 0.30) in pigment epithelial detachment (p = 0.813), and 0.050 (-0.40, 0.70) in Junius Kuhnt maculopathy (p = 0.344). BCVA increased ≥ 0.2 logMAR in 4 (24 %) classic, 9 (47 %) occult, 6 (33 %) pigment epithelial detachment, 6 (55 %) subretinal fluid, in 29 (39 %) eyes regardless of the lesion type, and reached a BCVA ≥ 0.05 in 7 (9 %) of those with a baseline BCVA <0.05. CONCLUSIONS: Results indicate that in patients with ARMD and a BCVA lower 0.05, intravitreal treatment may improve visual acuity, most probably in cases with occult lesions.

Pterygium recurrence, astigmatism and visual acuity following bare-sclera excision and conjunctival autograft with or without additional phototherapeutic keratectomy.

BACKGROUND: Treatment outcome in patients with pterygium following bare-sclera excision and conjunctival autograft (CAG) with and without phototherapeutic keratectomy (PTK). METHODS: Retrospective comparative analysis of 81 eyes, with primary and recurrent pterygia, that were analyzed for recurrence, best-corrected visual acuity (BCVA) and astigmatism in primary (P1 without PTK, P2 with PTK) and recurrent pterygia (R1 without PTK, R2 with PTK). BCVA and astigmatism were compared in patients with simple CAG alone (group I) or in combination with PTK (group II). RESULTS: Recurrence rates were 4.7, 11.6, 16.2, 23.2 and 32.5% at 3, 6, 12, 24 and >24 months (P1), 7.1% at >24 months (P2). Recurrence rates were 5.3, 10.5, 21.1, 21.1 and 26.3% at 3, 6, 12, 24 and >24 months (R1) and 1 recurrence (7.7%) till month 24, and 3 (23.1%) thereafter (R2). BCVA increased from logarithm of the minimal angle of resolution 0.095 ± 0.141 (mean ± SD) at baseline to 0.066 ± 0.09 (group I), and from 0.090 ± 0.164 to 0.054 ± 0.124 (group II). Astigmatism decreased from -1.01 ± 0.90 dpt at baseline to -0.97 ± 1.24 dpt (group I), and from -1.19 ± 1.55 to -0.75 ± 0.87 dpt (group II). CONCLUSION: In comparison to CAG alone, additional excimer smoothing with PTK tends to increase BCVA and reduces recurrence rates in patients with primary pterygia.

Efficacy of Emergency Penetrating Keratoplasty with Cryopreserved Human Donor Corneas.

INTRODUCTION: To investigate the long-term outcomes of emergency penetrating keratoplasty using cryopreserved human donor corneas in the management of actual or imminent corneal perforation. METHODS: A retrospective analysis was performed of the treatment efficacy of emergency penetrating keratoplasty using a cryopreserved human donor cornea, in 14 eyes of 14 patients with corneal ulcers of different etiology. For comparison, the medical histories of 14 patients who had undergone penetrating keratoplasty with the same indication, but received a regularly processed human corneal graft, were retrospectively analyzed. In both groups, the primary endpoint for graft failure was repeat surgery, defined as the necessity for amniotic membrane transplantation, conjunctival flap, or repeat penetrating keratoplasty, during a follow-up time of maximally 12 months. RESULTS: The difference in the need for repeated surgeries between the cryopreserved human donor cornea group and cultivated tissue graft group was not statistically significant (p = 0.835). Specifically, repeat complex surgery of any kind within 6 months was necessary in 50% of the cryopreserved cornea group and in 57.1% of the control group, with no further surgical interventions during the remainder of the follow-up period. However, repeat penetrating keratoplasty occurred more frequently in the cryopreserved cornea group (n = 5) than in the control group (n = 1) during the first 12 months after treatment (p = 0.048). CONCLUSION: Cryopreserved corneas appear to be a viable option for promptly addressing emergencies and stabilizing the corneal situation, providing a faster solution compared to waiting for fresh tissue availability. However, repeat penetrating keratoplasty is more frequent when cryopreserved human donor corneas are used. Cryopreserved human donor corneas may be useful if surgical treatment is urgent and alternative options, such as tissue use, a conjunctival flap, or multilayer amniotic membrane transplantation, are not available.

Sub-Retinal Injection of Human Lipofuscin in the Mouse - A Model of "Dry" Age-Related Macular Degeneration?

Lipofuscin (LF) accumulates during lifetime in the retinal pigment epithelium (RPE) and is thought to play a crucial role in intermediate and late age-related macular degeneration (AMD). In an attemt to simulate aged retina and to study response of retinal microglia and RPE cells to LF, we injected a suspension of LF into the subretinal space of adult mice. LF suspension was obtained from human donor eyes. Subretinal injection of PBS or sham injection served as a control. Eyes were inspected by autofluorescence and optical coherence tomography, by electroretinography and on histological and ultrastructural levels. Levels of cytokine mRNA were determined by quantitative PCR separately in the RPE/choroid complex and in the retina. After injection of LF, microglial cells migrated quickly into the subretinal space to close proximity to RPE cells and phagocytosed LF particles. Retinal function was affected only slightly by LF within the first two weeks. After longer time, RPE cells showed clear signs of melanin loss and degradation. Levels of mRNA of inflammatory cytokines increased sharply after injection of both PBS and LF and were higher in the RPE/choroid complex than in the retina and were slightly higher after LF injection. In conclusion, subretinal injection of LF causes an activation of microglial cells and their migration into subretinal space, enhanced expression of inflammatory cytokines and a gradual degradation of RPE cells. These features are found also in an aging retina, and subretinal injection of LF could be a model for intermediate and late AMD.

Sub-Retinal Injection of Human Lipofuscin in the Mouse - A Model of "Dry" Age-Related Macular Degeneration?

Lipofuscin (LF) accumulates during lifetime in the retinal pigment epithelium (RPE) and is thought to play a crucial role in intermediate and late age-related macular degeneration (AMD). In an attemt to simulate aged retina and to study response of retinal microglia and RPE cells to LF, we injected a suspension of LF into the subretinal space of adult mice. LF suspension was obtained from human donor eyes. Subretinal injection of PBS or sham injection served as a control. Eyes were inspected by autofluorescence and optical coherence tomography, by electroretinography and on histological and ultrastructural levels. Levels of cytokine mRNA were determined by quantitative PCR separately in the RPE/choroid complex and in the retina. After injection of LF, microglial cells migrated quickly into the subretinal space to close proximity to RPE cells and phagocytosed LF particles. Retinal function was affected only slightly by LF within the first two weeks. After longer time, RPE cells showed clear signs of melanin loss and degradation. Levels of mRNA of inflammatory cytokines increased sharply after injection of both PBS and LF and were higher in the RPE/choroid complex than in the retina and were slightly higher after LF injection. In conclusion, subretinal injection of LF causes an activation of microglial cells and their migration into subretinal space, enhanced expression of inflammatory cytokines and a gradual degradation of RPE cells. These features are found also in an aging retina, and subretinal injection of LF could be a model for intermediate and late AMD.

Use of intravitreal triamcinolone and bevacizumab in Coats' disease with central macular edema.

BACKGROUND: Intravitreal application of triamcinolone and bevacizumab in Coats' disease with macular edema to improve visual outcome. METHODS: Testing of best-corrected visual acuity (BCVA), ophthalmoscopy, optical coherence tomography, fluorescein angiography, 30° perimetry, and full-field electroretinography were performed at initial and follow-up visits. Medical treatment consisted of intravitreal injection of 1.25 mg bevazicumab and 1.25 mg triamcinolone, followed by intravitreal injections of 1.25 mg bevazicumab at weeks 4 and 10. Follow-up was 87 weeks. RESULTS: Perimetric results, including a temporal absolute scotoma and reduced electroretinographic amplitudes (photopic and scotopic conditions), did not significantly change during the follow-up, but foveal retinal thickness decreased from 505 µm to 212 µm, and BCVA increased from 0.3 at baseline to 1.25 and remained stable during subsequent follow-up. CONCLUSIONS: Combined intravitreal treatment with bevacizumab and triamcinolone resulted in significant decrease of central retinal thickness and improved visual acuity in this case report. Severe local or systemic side-effects were not observed.

SARS-CoV-2: Impact on, Risk Assessment and Countermeasures in German Eye Banks.

INTRODUCTION: Since the beginning of the COVID-19 pandemic there has been some debate regarding the risk of transmission through tissue transplantation and tissue banking processes. AIM OF THE STUDY: To analyze the changes that SARS-CoV-2 has caused regarding the harvesting of corneal donor tissue and eye bank activities in Germany. METHODS: A questionnaire was provided to 26 eye banks in Germany, consisting of questions about adaptations made in the screening of potential donors and the harvesting of corneal tissue following the pandemic spread of SARS-CoV-2. RESULTS: Eighteen eye banks actively reduced recruitment of donors and two banks ceased all activity. Additional diagnostic screening was performed in eight banks, using conjunctival swabs and/or nasopharyngeal swabs. In six eye banks, additional protective measures, such as FFP2 masks and/or facial shields, were implemented. Overall, a mean reduction in the number of obtained donor tissues of 17% was observed. DISCUSSION: Conjunctival and/or nasopharyngeal swabs of donors have been implemented by a minority. Reasons for not performing additional tests may be moderate sensitivity and lack of validation for postmortem use of RT-PCR testing. Also, the hazard of SARS-CoV-2 entering the corneal donor pool with subsequent transmission might be perceived as theoretical. Face shields provide a sufficient barrier against splash and splatter contamination but may be insufficient against aerosols. Additional face masks would provide support against aerosols, but it remains debatable if corneal harvesting can be considered an aerosol-producing procedure. In the future we expect to see changes in current guidelines because of a surge in scientific activities to improve our understanding of the risks involved with cornea donation in the COVID-19 pandemic, and because current practice may reduce the availability of donor corneas due to new exclusion criteria while the demand remains unchanged.

Results of Resorbable and Running Sutured Amniotic Multilayers in Sterile Deep Corneal Ulcers and Perforations.

PURPOSE: To present the results of a modified surgical technique for secure tightening and fixation of multilayer amniotic membranes (AMs) in sterile deep or perforating corneal ulcers. METHODS: We retrospectively analyzed the data of patients suffering from corneal ulcers who had been treated between February 2016 and June 2018 with running and resorbable sutures to fixate multilayer AMs. The parameters analyzed were gender, age, etiology of corneal ulcer, ulcer diameter, corneal thickness (CST) before and after the microsurgical procedure as measured with optical coherence tomography, number of inlays, repeat surgical procedures, follow-up duration in months, and rate of success (defined as a stable anterior chamber with improved CST, a negative Seidel test, and no need for any microsurgical keratoplasty during the first 6 months after treatment). The results were statistically evaluated using the Wilcoxon test. A P-value ≤0.05 was considered to show a statistically significant difference. RESULTS: The CST increased significantly after AM transplantation (from 206.26 ± 114.93 µm at baseline to 454.70 ± 244.08 µm at 1-3 months; P < 0.001). Repeat multilayer transplantation was required in 7 of the 23 patients included (30.4%), in 6 of whom the treated eye was stable at month 6. In 2 of the 23 patients, perforating keratoplasty became necessary. One patient also demanded such a procedure to improve his visual acuity. The success rate was 91.3% (n = 21). CONCLUSIONS: Running resorbable suture fixation of multilayer AMs proved to be an efficient means for the treatment of noninfectious deep or small perforating corneal ulcers.

Resorbable and running suture for stable fixation of amniotic membrane multilayers: A useful modification in deep or perforating sterile corneal ulcers.

PURPOSE: To present a modified technique for secure tightening and fixing of multilayer amniotic membranes in deep or perforating corneal ulcers. OBSERVATIONS: The modified procedure for application and fixation of multilayer amniotic membranes is retrospectively described step by step, and the results of three patients treated with this technique were retrospectively analysed and presented.The modification consists basically in fixing the inlays with one mini-overlay that is sutured intracorneally with resorbable and running Vicryl 10.0, before a corneoscleral overlay is fixed on top conjunctivally with a running nylon 10.0 suture. The resorbable Vicryl suture is left in place permanently. CONCLUSIONS AND IMPORTANCE: The method described avoids any risk of destroying or displacing the inlays by removing sutures later. In each of the three patients demonstrated as case reports the cornea remained stable throughout the 3- to 5-month follow-up period. This modified technique represents a very useful auxiliary means of treating deep or perforating non-infectious corneal ulcers.

[Transthyretin Familial Amyloid Polyneuropathy - Disease Profile of a Multisystem Disorder]. / Transthyretin-assoziierte familiäre Amyloidpolyneuropathie.

Transthyretin-related Familial Amyloid Polyneuropathy (ATTR Amyloidosis, former FAP, here called TTR-FAP) is a rare, progressive autosomal dominant inherited amyloid disease ending fatal within 5 - 15 years after final diagnosis. TTR-FAP is caused by mutations of transthyretin (TTR), which forms amyloid fibrils affecting peripheral and autonomic nerves, the heart and other organs. Due to the phenotypic heterogeneity and partly not specific enough clinical symptoms, diagnosis of TTR-FAP can be complicated. False diagnoses can include idiopathic polyneuropathy, chronic inflammatory demyelinating polyneuropathy, diabetic neuropathy as well as paraneoplastic syndrome. Hence, it is assumed that many cases remain unreported. Early and correct diagnosis of TTR-FAP is crucial, since appropriate therapeutic options exist. TTR-FAP should always be differentially diagnosed, when apart from a progressive peripheral polyneuropathy, additional symptoms as autonomic dysfunction, cardiomyopathy, gastrointestinal disorders, unexpected loss of weight, carpal tunnel syndrome, restrictions of renal function, epileptic fits, and corneal and vitreous body clouding occur. Histological evidence of amyloid and successive immunohistochemical evidence of transthyretin as well as genetic testing for transthyretin mutations, lead to an accurate diagnosis.

A novel TACSTD2 gene mutation in a Turkish family with a gelatinous drop-like corneal dystrophy.

PURPOSE: To identify the molecular defect causing gelatinous drop-like corneal dystrophy in a Turkish family and assign affected and carriership status. METHODS: Visual activity of affected family members was measured using Snellen optotypes. To identify the molecular defect, mutation analysis of the TACSTD2 (M1S1) gene was performed. RESULTS: We report on a new TACSTD2 mutation, c.653delA, in a Turkish family. The identified molecular defect cosegregates with the disease among affected members of the family and is not found in 100 unaffected individuals of various ethnic origin. CONCLUSIONS: A few TACSTD2 gene mutations in the homozygous or compound heterozygous state have been described as causative for this abnormality, mainly in several Japanese families. The newly identified mutation is predicted to generate a shortened protein product, thereby completely altering the COOH-terminal region and deleting the transmembrane domain, required for anchoring at cell membranes and the phosphatidylinosyol2-binding site.

Use of fibrin glue in fixation of amniotic membranes in sterile corneal ulceration.

PURPOSE: To describe a method of fibrin glue fixation of single or multilayered amniotic membranes in sterile corneal ulceration. DESIGN: A modified microsurgical procedure. METHODS: The corneal ulcer is cleaned and the components of fibrin glue are applied separately. Amniotic membranes are rotated through the fibrinogen component and subsequently into the site of the ulceration where thrombin is already applied. An overlay membrane is sutured additionally on top. The results for one patient are illustrated as an example. RESULTS: The application technique prevents development of foam and leads to a thin fibrin film, which minimizes any irregularities of the fixed membranes and creates extra time to adjust the membranes' position. CONCLUSIONS: This method presents as an effective procedure for the treatment of sterile corneal ulceration and creates valuable time if any elective corneal graft procedure is required.

Bilateral cataract and corectopia after laser eyebrow [corrected] epilation.

PURPOSE: To report a patient with bilateral cataract and corectopia after laser epilation of the eyebrows. DESIGN: Single interventional case report. METHODS: A 27-year-old woman with a history of bilateral eyebrow laser epilation complained of oval pupils, reduced visual acuity, and photophobia immediately after laser epilation of both upper-eyelid regions. The following examinations were performed: visual acuity, slit-lamp examination, pupillary light reflex, perimetry, tonometry, gonioscopy, and funduscopy with contact lenses. The follow-up period was 9 months. MAIN OUTCOME MEASURES: Visual acuity, intraocular pressure, inflammation, and pupillary distortion. RESULTS: Her best baseline visual acuities were 20/25 (right) and 20/40 (left). Examination showed bilateral corectopia with superior iris atrophy, iris stroma clump at the pupillary margin, and pigment residues in the inferior chamber. A cataract developed in the anterior subcapsular regions of the lenses. CONCLUSIONS: Laser epilation at the eyelid may result in irreversible cataract and iris atrophy.

Combined Excimer Laser Photoablation and Amniotic Membrane Overlay for Relief of Symptomatic Discomfort in Gelatinous Drop-like Corneal Dystrophy.

PURPOSE: To describe the efficacy of combined excimer laser photoablation and amniotic overlay membrane in the relief of symptomatic discomfort in a 17-year-old patient who had gelatinous drop-like corneal dystrophy. METHODS: The best-corrected visual acuity (BCVA) was measured with Snellen letters. Slit-lamp examination of the ocular surface and anterior chamber was performed at baseline. Results were photodocumented. Excimer laser photoablation was performed and subsequently 2 amniotic membranes were transconjunctivally fixated with 10.0 nylon sutures. Investigations and documentation were performed at baseline, every 2 months in the first year, and then every 6 months. The duration of follow-up was 22 months. RESULTS: At baseline, the BCVA was 20/70 in the right eye and 20/200 in the left eye. The patient reported distinct photophobia. Slit-lamp examination was difficult because of blepharospasm. Although gelatinous drops developed again and the BCVA decreased to 2/200, the patient reported significant relief after both microsurgical treatments and remained comfortable at 20 and 22 months. CONCLUSIONS: Excimer laser photocoagulation combined with amniotic membrane overlay does not stop the development of gelatinous drop-like corneal dystrophy but may improve subjective comfort. Such treatment does not hinder subsequent lamellar or penetrating grafts and is helpful in providing the necessary time for preparation of matched keratoplasties.

Attitudes Concerning Postmortem Organ Donation: A Multicenter Survey in Various German Cohorts.

BACKGROUND: The aim of this study was to characterize postmortem organ donation attitudes in various German cohorts. MATERIAL AND METHODS: Employees of 2 German cities and 2 German university hospitals, employees of a German automobile enterprise, and members of a German Medical Society were administered a questionnaire about postmortem organ and tissue donation attitudes. Demographic data and general attitudes were questioned and focused on: I) willingness to donate organs, II) holding a donor card, and III) having discussed the topic with the family. RESULTS: Of 5291 participants, 65.2% reported favoring postmortem organ donation. Missing negative experiences, the idea that donation is helpful, a non-medical professional environment, excellent general health, gender, agreement with the brain-death paradigm, and age significantly influenced the participants' attitudes. Participants were more likely to possess donor cards and had discussed more often with family members if they agreed with the brain-death paradigm and considered donation to be helpful. Males and older participants were the most likely to neglect donor cards, and Catholics, Protestants, and participants with poor health were the least likely to donate organs. Interest in receiving more information was expressed by 38.1% and 50.6% of participants refusing donation of all or of specific organs, respectively, and suggested the internet (60.0%) and family doctors (35.0%) as preferred sources of information. CONCLUSIONS: Public campaigns in Germany should focus on males and older people as regards donor cards, and females, younger, and religiously affiliated persons as regards the general willingness to donate organs postmortem.