bluuebunny/crossref_metadata_2025 huggingface dataset:
Detecting Hydroxychloroquine Retinal Toxicity using a Novel Multifocal Electroretinography Stimulus
Authors: Coupland Stuart , Tsang Adrian , Gottlieb Chloe , Gostimir Miso , Dollin Michael , Nithianandan Harrish
Published: December 2019

Purpose

To evaluate a novel 5‐ring multifocal electroretinogram (mfERG) stimulus as a screening test for detecting hydroxychloroquine (HCQ) retinopathy.

Study Design

A stratified case‐control study conducted in accordance to the Standards for Reporting of Diagnostic Accuracy Studies (STARD).

Methods

Consecutive patients referred to the University of Ottawa for HCQ retinopathy screening from July 2018 to September 2018 underwent testing using a novel 5‐ring mfERG stimulus and the standard 61‐hexagon mfERG stimulus. Patients with amblyopia, high myopia or hyperopia, coexisting retinal disease, and prior retinal surgery were excluded. mfERG parameters were compared between protocols and against cumulative dose (CD), dose by real body weight (RBW), and duration of HCQ therapy. Ring amplitudes (R1‐R5) and ring ratios (R1‐R4/R5) were collected for each stimulus protocol. mfERG data was collected from an additional group of controls with no previous exposure to HCQ. Stata 15.1 software was used to perform the regression analyses, and to compute Spearman correlation coefficients between variables.

Results

24 eyes (10 patients, 2 controls) were included in the final analysis. The novel R2 and R3 P1 amplitudes and R2/R5 were moderately correlated with the respective R2 (r = 0.434, p = 0.034) and R3 (r = 0.429, p = 0.036) P1 amplitudes and R2/R5 (r = 0.422, p = 0.040) of the 61‐hexagon stimulus. The novel R2 P1 amplitude was highly correlated with CD (r = −0.687, p < 0.001), treatment duration (r = −0.687, p < 0.001), and dose by RBW (r = −0.763, p < 0.001). Similarly, novel R2/R5 was highly correlated with CD (r = −0.743, p < 0.001), treatment duration (r = −0.743, p < 0.001), and dose by RBW (r = −0.567, p = 0.004). The correlations between the 61‐hexagon stimulus R2/R5 and HCQ risk factors also reached significance but were not as robust. Linear regression analysis showed that CD may account for almost half of the variance in the novel R2/R5. (r2 = 0.486, R2/R5 = 9.68063 + cumulative dose ‐0.00286)

Conclusions

The 2016 AAO guidelines focused primarily on the use of subjective functional testing and objective structural testing and relegated mfERG based on a lack of accessibility. This pilot study describes a new 5‐ring mfERG protocol specific for HCQ retinopathy screening and suggests equivalence to the 61‐hexagon protocol at characterizing parafoveal function. This novel 5‐ring stimulus has a significantly shorter acquisition period and the ring design may be more sensitive to HCQ induced electrophysiologic change in the parafoveal region. R2 P1 amplitude and R2/R5 ring ratios acquired using this novel mfERG stimulus are strongly correlated to treatment duration and HCQ dosing. Additional prospective cohort studies are needed to validate this novel stimulus which may decrease the resource burden associated with objective functional testing.
Activating mutations in discoidin domain receptor 2 cause Warburg‐Cinotti syndrome
Authors: Zi Yan Xu Linda , Jensen Hanne , Johnston Jennifer J. , Di Maria Emilio , Kloth Katja , Cristea Ileana , Sapp Julie C. , Darling Thomas N. , Huryn Laryssa A. , Tranebjærg Lisbeth , Cinotti Elisa , Kubisch Christian , Rødahl Eyvind , Bruland Ove , Biesecker Leslie G. , Houge Gunnar , Bredrup Cecilie
Published: December 2019

Purpose

In 2006 Warburg et al. described a patient with blepharophimosis, corneal vascularization, retinal degeneration, deafness, loss of subcutanous tissue, flexion contractures of the fingers and acro‐osteolysis. Some years later Cinotti et al. reported a similar patient. In addition, we identified tree individuals from two different families with a similar clinical picture. In total, all six individuals from four different families were examined to identify the gene mutation associated with this disease

Methods

Exome sequencing was performed on affected individuals. Patient skin fibroblasts was obtained and examined using Elisa and Western blot analysis to determine levels of phosphorylated DDR2 and downstream effector proteins. Patient fibroblasts were also treated with Dasatabib, a protein kinase inhibitor affecting DDR2.

Results

We found two recurrent de novo mutations in DDR2, p.Leu610Pro or p.Tyr740Cys, to be associated with the condition. Increased phosphorylation of DDR2 was found suggesting reduced receptor autoinhibition and ligand‐independent activation of the kinase. Dasatinib prevented DDR2 autophosphorylation. No effect of the mutations were found on the examined downstream effector proteins of DRR2.

Conclusion

We found two recurrent, activating mutations in DDR2, p.Leu610Pro and p.Tyr740Cys, to be associated with this progressive fibrotic condition that we suggest to be called Warburgh‐Cinotti syndrome. In vitro dasatinib prevented autophosphorylation of DDR2 suggesting an approach to patient treatment.

Reference

et al. (2018): . The American Journal of Human Genetics. https://doi.org/10.1016/j.ajhg.2018.20.013.
Digital carcinoma of a sweat gland metastasizing to the lacrimal gland: report of a rare case
Authors: Philips Simon , Jadnanansing Jayant , Fordel Nerea , Vanclooster Andreas , Geldhof Kurt , De Schryver Ilse
Published: December 2019

Purpose

To report a rare case of a digital carcinoma of the sweat gland with lacrimal gland metastasis.

Methods

Observational case report

Results

A 62‐year‐old woman presented with right proptosis and diplopia. General examination showed unilateral lymphedema of the left upper limb, initially restricted to the forearm and progressively involving the upperarm with an axillary lymphadenopathy. Work‐up included a whole‐body 18F‐FDG‐PET/CT showing high uptake in the right lacrimal gland, the cervical and axillary glands. Screening for breast carcinoma was negative. A biopsy of the axillary lymph nodes was performed. Immunohistochemical analysis was positive for CK7 and negative for GATA3, ER, PR, TTF1 and SOX10. The diagnosis of a metastatic process of a CK7 positive undifferentiated tumor of unknown primary origin was withheld. Physical examination of the left upper limb showed a small scar at the level of the thumb. Retrograde investigation revealed resection of a lesion in 2016 with the histopathological diagnosis of an eccrine ductal carcinoma of a sweat gland. Immunohistochemical analysis showed concordance between primary and metastatic lesions.

Conclusion

Although the clinical presentation and the general work‐up are highly suggestive for a metastatic process in the lacrimal gland, the final diagnosis relies on the histopathology or cytology. To the best of our knowledge, metastasis of a primary cutaneous sweat gland carcinoma to the lacrimal gland has not been reported in the literature.
Non‐invasive, needle‐free drug delivery for treatment of retinal degeneration on Bardet‐Biedl syndrome
Authors: Roberto Ajoy Moreno Daniel , Basetto Marco , Obringer Obringer Cathy , Messaddeq Nadia , Poulhès Florent , Zelphati Olivier , Dollfus Hélène , Marion Vincent
Published: December 2019

Purpose

To develop a non‐invasive drug delivery system based on superparamagnetic nanoparticles (NP) for the treatment of retinal degeneration on Bardet‐Biedl syndrome (BBS). The delivery system will be used to deliver two small molecules, valproic acid (VPA) and Guanabenz (GBZ).

Methods

A mixture of two NP (one loaded with VPA and other with GBZ) was applied as eyedrops on 14‐days old mice with the use of a magnetic field. The treatment was assessed in both wild type and a mice model for BBS (Bbs12−/−). The effects of the treatment were evaluated 2 weeks post treatment at 1‐month‐old. Retinal structure and function were analysed using electroretinogram recordings (ERG), histology and transmission electron microscopy (TEM).

Results

In vitro studies showed no important toxic effects in cell cultures for retinal pigmented epithelium (RPE1) and 661W (murine photoreceptor precursor) after treatment with unloaded NP. Scotopic and photopic ERG recordings showed no toxic effect of the NP on photoreceptor (PR) function. TEM analysis indicated the presence of the NP in the PR layer of the retina after eyedrop application. TEM images showed a decrease in Endoplasmic Reticulum (ER) dilatation. The treated group with loaded NP showed an increase in the thickness of the inner nuclear layer, outer nuclear layer, inner PR segment and outer PR segment.

Conclusions

These results highlight the potential for these NP for non‐invasive drug delivery to the retina. Both the presence of the NP and biological effect were shown in our mouse model. The VPA and GBZ combination has already shown decrease of cell death mediated by ER stress in the Bbs12−/− model. This is an unmet clinical need with no curative treatment for retinal ciliopathies. The possibility of delaying PR death would increase the therapeutic window of gene therapy potentially increasing its effectivity.
Retinal oximetry as a biomarker in multiple sclerosis
Authors: Drobnjak Nes Dragana , de Rodez Benavent Sigrid A. , Berg‐Hansen Pål , Høgestøl Einar A. , Beyer Mona K. , Rinke Dan A. , Veiby Nina , Addorisio Vito , Petrovski Beata Eva , Celius Elisabeth G. , Harbo Hanne F. , Petrovski Goran
Published: December 2019

Purpose

Structural and physiological abnormalities have been reported in the retina in patients with multiple sclerosis (MS). Retinal oximetry has recently detected changes in retinal oxygen metabolism in Alzheimer’s disease, mild cognitive impairment and in a small cohort of MS patients with history of optic neuritis. Our goal was to determine whether oxygen saturation in retinal blood vessels of newly diagnosed MS patients is different from that of a healthy population.

Methods

Oxygen saturation of hemoglobin was measured in retinal blood vessels, using imaging with spectrophotometric non‐invasive retinal oximeter. Six newly diagnosed MS patients were measured and compared to six healthy individuals that were age‐ and gender‐matched with the MS patients.

Results

Venular oxygen saturation was increased in patients with MS compared to healthy individuals (mean: 61.9% versus 56.3%). Retinal venular diameter (138.2 µm versus 160.2 µm: mean) and retinal arteriolar diameter were smaller in MS patients (111.8 µm versus 131.3 µm: mean) when compared to healthy individuals. No big difference could be measured in the oxygen saturation in arterioles when patients with MS (mean: 91.2%) and healthy individuals (mean: 92.3%) were compared.

Conclusion

Increased venular oxygen saturation and smaller retinal venular and arteriolar diameter in patients with MS may indicate reduced oxygen uptake in the retina. This may be due to less oxygen demand following axonal loss and may be a useful objective biomarker for MS. Further studies are needed to confirm and expand these findings.
Safety and effects of intravitreal or subretinal injections of human bone marrow‐derived mononuclear cells to P23H‐1 and RCS rats
Authors: Di Pierdomenico Johnny , González‐Herrero María Elena Rodríguez , Blanquer Miguel Blanquer , Ayuso Diego García , Barriuso Marta Agudo , Sanz Manuel Vidal , Pérez María Paz Villegas
Published: December 2019

Purpose

To determine the safety and effects of intravitreal or subretinal injections of human bone marrow‐derived mononuclear cells (HBMNCs) in two different rat models of hereditary photoreceptor (FR) degeneration.

Methods

21‐days‐old Homozygous P23H‐1 albino rats, Royal College of Surgeons (RCS) pigmented rats or control SD and PVG rats received one intravitreal injection or one subretinal injection of HBMNCs (5µl; 50,000 cells/µl). As controls, intact animals of P23H‐1, RCS, SD and PVG strains were used. All animals were immunosuppressed with oral cyclosporine and intraperitoneal dexamethasone and were processed 7, 15, 30 or 60 days after transplantation. The eyes were cross‐sectioned in a cryostat and the sections immunodetected to visualize HBMNCs (□‐human CD45), photoreceptors (□‐Recoverin), astrocytes and Müller cells (□‐GFAP), or microglial cells (□‐Iba‐1). Sections were examined under fluorescence and confocal microscopy to investigate retinal structure and photoreceptor cell survival

Results

In HBMNCs treated eyes no macro or microscopic anomalies, tumours, necrosis, inflammation or infective phenomena were observed. In the intravitreally injected eyes, HBMNCs‐CD45+ were found in the vitreous and attached to the inner limiting membrane. In the eyes with subretinal injections, HBMNCs‐CD45+ were found forming a layer in the subretinal space. When compared to control animals, the transplanted eyes of P23H‐1 and RCS rats showed decreased GFAP expression, indicating a reduction of gliosis. However, we did not observe increased photoreceptor survival in dystrophic animals after transplantation.

Conclusions

HBMNCs injection to the vitreous or subretinal space in immunosupresed rats lack adverse effects and in P23H‐1 and RCS rats decrease the retinal gliosis but do not elicit photoreceptor neuroprotective effects.
Photo‐ablation of human vitreous opacities by light‐induced vapor nanobubbles
Authors: Sauvage Félix , Fraire Juan , Remaut Katrien , Sebag J. , Peynshaert Karen , de Velde Frans Van , Xiong Ranhua , Tassignon Marie‐José , Brans Toon , Braeckmans Kevin , De Smedt Stefaan
Published: December 2019

Purpose

Floaters are collagen aggregates that can form in the vitreous of the eye due to structural changes and which cast shadows on the retina. Current therapies are based on laser treatment with an yttrium garnet laser (YAG) or vitrectomy (i.e. the replacement of the vitreous by a saline solution) but most of the time, floaters are left untreated. Besides, the efficacy of YAG laser treatment is still controversial and vitrectomy can be associated with important side effects (cataract formation, endophthalmitis).

Methods

In this work we propose a nanotechnology‐based approach for the treatment of floaters using the plasmon properties of gold nanoparticles (AuNPs). When exposed to pulsed‐laser light (typically a nanosecond laser), AuNPs able to bind floaters, heat up and generate vapour nanobubbles (VNBs) due to the evaporation of the surrounding water. These VNBs will then burst providing sufficient mechanical energy to fragment floaters.

Results

To maximize the probability of AuNPs to reach and bind floaters after intravitreal injection, we coated them with hyaluronic acid (HA‐AuNPs) and observed they had a better diffusion in vitreous and could bind and fragment collagen I fibers and human floaters obtained from patients. Since smaller AuNPs have a higher threshold to generate VNBs we hypothesized smaller HA‐AuNPs (10 nm), would be able to clusterize on the floaters to locally decrease the threshold to generate VNBs preserving the surrounding vitreous and ocular tissues from being damaged. With smaller particles we were able to destroy human vitreous opacities, in a fast and reproductive manner.

Conclusion

Our strategy can effectively and rapidly destroy floaters by using lower energy levels compared to current YAG therapy and paves the way for the use of pulsed‐lasers and nanotechnologies in the posterior segment of the eye.
Do macular OCT‐A measures correlate with functional outcomes in diabetic patients?
Authors: Bontzos Georgios , Garnavou‐Xirou Christina , Xirou Tina , Gkizis Ilias , Kabanarou Stamatina , Chatziralli Irini
Published: December 2019

Purpose

To investigate the association between anatomic changes, as measured optical coherence tomography‐angiography (OCT‐A), and functional visual outcomes in diabetic patients.

Methods

Participants in this cross‐sectional study were 60 patients (60 eyes) with diabetes mellitus and 20 normal subjects (20 eyes). Patients underwent complete ophthalmologic examination, including staging of diabetic retinopathy (DR). Patients were divided in 3 groups: (i) diabetes without retinopathy (noDR); (ii) background retinopathy (NPDR) and (iii) proliferative retinopathy (PDR). Best‐corrected distance visual acuity (BCVA) was measured using ETDRS charts, while contrast sensitivity was evaluated with the Pelli‐Robson charts. Patients underwent OCT‐A to measure the area of FAZ (mm2) and the vessel density (%) at the macular and paramacular area.

Results

BCVA was 83.7 ± 5.3 for the healthy subjects and did not differ significantly compared to diabetic group (78.8 ± 10.6, p = 0.281). There was a statistically significant difference (p < 0.01) in contrast sensitivity between control(28.1 ± 3.4) and diabetic group (22.2 ± 6.7).In NPDR group, vessel density was reduced in the deep capillary plexus (mean = 21.4%). In the PDR group, vessel density was significantly reduced in the superficial (mean = 35.8%) and the deep (mean = 18.3%) capillary plexus. BCVA was significantly associated with FAZ area only in the PDR group (r = 0.61; p < 0.01), while contrast sensitivity was not associated with vessel dropout, nor with FAZ area in all groups.

Conclusions

Functional impairment related to contrast sensitivity may precede visual acuity decrease in diabetic patients. However, only BCVA and not CS recordings were significantly associated with OCT‐A measurements, such as FAZ area and vessel density in diabetic patients and mainly with proliferative disease. OCT‐A is a valuable tool for documenting early structural alterations in diabetic retina, which can be related to some functional visual parameters.
Using 3D simulation in reconstructive‐rehabilitation surgery in patients with defects in orbital walls
Authors: Petrenko Oksana , Prusak Olha
Published: December 2019

Introduction

Restoration of the volume of the orbit and its integrity, elimination of aesthetic and functional complications in patients with defects in the walls of the orbit remains an urgent problem of ophthalmology and maxillofacial surgery.

Purpose

To evaluate the results of surgical treatment of patients with defects in orbital walls using individually‐made implants using 3D modeling based on CT data.

Methods

CT Toshiba Activion 16, CT Philips Diamond Select Brilliance CT 64, software environment Sim Plant 13.02 and Geomagic Freeform Plus, statistical data processing.

Results

After treatment of patients with orbital bone defects using individually‐made implants using computer 3D modeling based on CT data, the mean difference in orbital volume was 2.7 ± 0.9 cm3.

Conclusion

The use of computer 3D modeling in the manufacture of individual implants for the treatment of patients with defects in the orbital walls increases the accuracy of the recovery of the orbital volume, and, accordingly, minimizes the number of postoperative complications.
Conjunctival melanoma is a molecular distinct mucosal melanoma with high expression of PD‐L1
Authors: Hjorth Mikkelsen Lauge , Maag Emil , Kruhøffer Mogens , Bjerre Toft Peter , Klarskov Andersen Mette , Wadt Karin , Larsen Ann‐Cathrine , Heegaard Steffen
Published: December 2019

Purpose

Conjunctival melanoma is a unique mucosal melanoma due to its location in the sunexposed conjunctiva. The purpose of this study was to contextualize conjunctival melanoma as a mucosal melanoma based on molecular profiling. This is the first study of its kind.

Material and Methods

12 primary conjunctival melanomas and 28 primary mucosal melanomas from non‐sunexposed sites (nasal cavity, vagina, and rectum) were subjected to molecular profiling using targeted next‐generation sequencing (Oncomine Comprehensive Cancer Panel) and NanoString gene expression profiling (PanCancer Pathways Panel, 770 cancer genes). Normal conjunctiva and mucosa were used as internal controls.

Results

Genetically, conjunctival melanomas harboured BRAF‐V600E mutations and NF1 mutations, whereas other mucosal melanomas harboured more unspecific mutations, such as atypical BRAF mutations and mutations in KIT. Non‐sunexposed mucosal melanomas frequently presented amplification of MYC. When comparing the gene expression profile of conjunctival melanoma and non‐sunexposed mucosal melanoma, 41 genes were found to be significantly deregulated. 24 genes were upregulated, whereas 17 were downregulated in conjunctival melanoma. Many of the deregulated genes were involved in immunological pathways when performing an in silico pathway analysis. Most intriguingly, programmed death‐ligand 1 (PD‐L1) presented a significant 6‐fold upregulation in conjunctival melanoma. This finding could be validated with immunohistochemistry (p = 0.041, Fisher’s exact test). A network analysis revealed that PD‐L1 was co‐expressed with 8 other genes.

Conclusions

Comprehensive molecular profiling on the DNA and mRNA level revealed that conjunctival melanoma is a distinct molecular mucosal melanoma characterized by a higher frequency of BRAF‐V600E mutations, low expression of MYC and a high expression of PD‐L1 and other genes involved in immune response. This finding is important, as this suggests a higher response to checkpoint inhibition in conjunctival melanoma metastases when compared to other mucosal melanomas.
Significance of corneal rigidity at measuring of intraocular pressure
Authors: Shargorodska Iryna , Dziameshka Dziyana
Published: December 2019

Purpose

To optimize tactics of determination of IOP for emmetropic and myopic eyes by application a correction to the coefficient on cornea rigidity (KER).

Methods

The 160 myopic and 80 emmetropic eyes were included in the study. All eyes were examined with the methods of the measuring of cornea rigidity in vivo (Sergienko N.M., Shargorodska I.V. 2013).

Results

The results showed no dependence of cornea rigidity was educed from the cornea central thickness (r = 0.04) and sagital front‐back size of eyes for all inspected patients (r = 0.12). Cross‐correlation dependence between these indexes was statistically not reliable (p > 0.05). The results of analysis testified to high the degree of dependence of coefficient cornea rigidity from age and sex of patient (r = 0.53 and r = 0.59 accordingly, p < 0.05), refraction (r = 0.77, p < 0.05), spherical equivalent (r = 0.79, p < 0.05). The most strong cross‐correlation dependence was educed between KER and degree of curvature of cornea in a «steep» meridian (r = 0.78, p < 0.05), elevation of back cornea surface of (r= 0.93, p < 0.05) and exentrisite (r = 0.87).

Conclusion

The cornea rigidity index are forward as an integral index that takes into account influence of different factors: age, sex, clinical refraction, spherical equivalent and others. Using of cornea rigidity index for measuring of level IOP will allow more exactly to estimate, removing influence of central cornea thickness on level IOP.

References

The problem of study of biomechanics properties of cornea a long ago attracts attention researchers (Perkins E.S., 1981; Phillips J.R., 1990; Iomdina E.N., 2006; Svetlova O.V., 2010). The functional features of co‐operation of biomechanical properties of cornea with other eye regulator systems of eye can play substantial influence on exactness to measuring of ophthalmotonus (Young F.A., Leary G.A., 1991; Koshitz I.N., 2001).
Contact lens and eye glass wearers with and witouth ocular symptoms: differences in corneal sensitivity, blinking, tearing and corneal surface temperature
Authors: Pastor‐Zaplana José Ángel , Gallar Juana , Acosta M. Carmen
Published: December 2019

Purpose

To analyze corneal sensitivity, blink frequency (BF), tearing rate (TR), TBUT, and corneal surface temperature (CST) in young contact lens (CLs) and eye glass (EGs) wearers with and without ocular discomfort symptoms.

Methods

EGs (n = 18) and CLs (n = 23) young subjects (18–40 years old, both sexes) participated voluntarily. CLs were classified as asymptomatic (A) or symptomatic (S) depending on their OSDI score (< 13 or ≥ 13, respectively). Corneal sensitivity to mechanical and chemical air puffs (3s duration, applied with a gas esthesiometer) and cold (4°C) saline drops was explored. Sensations evoked by each stimulus was scored with 0 to 10 VAS. BR (1 min at rest or during a task), TR (mm of wet phenol red threads, 15 s), TBUT (s), and CST (IR video thermography) were also measured.

Results

VAS values of irritation sensation evoked by mechanical and chemical stimulation (p < 0.05) were higher in CLs than in EGs while VAS values of cold sensation evoked by saline drops were similar in both groups. Although CST and TR were similar in EGs and CLs, TBUT was significantly shorter (p < 0.001) and BR was higher in CLs both at rest (p < 0.001) and during a visual task (p < 0.01). Although VAS values scored to corneal mechanical, chemical and cold stimulation were lower in CL‐S than in CL‐A, no differences were found in BR at rest or during the task, TR, TBUT and CST. Corneal sensitivity and CST were also similar in EG‐A and EG‐S, although TR (p < 0.05) and BF at rest (p < 0.05), but not during the task, were higher in EG‐S.

Conclusions

Results show a reduced corneal sensitivity in symptomatic CL wearers, which suggests that corneal sensory nerve activity must be altered in a different degree in asymptomatic and symptomatic individuals, thus leading to changes in tearing and blinking regulation.

Support: AEI‐ERDF SAF‐2017‐83674‐C2‐1‐R and 2‐R
Environmental light intensity determines the temporal progression of retinal degeneration in rd10 mice
Authors: Kutsyr Oksana , Sánchez‐Sáez Xavier , Albertos‐Arranz Henar , Maneu Victoria , Lax Pedro , Cuenca Nicolás
Published: December 2019

The rd10 mouse is a model of autosomal recessive retinitis pigmentosa (RP). This animal model carries a mutation in the Pde6b gen that generates a progressive loss of photoreceptors which leads to complete blindness. The aim of this study was to evaluate the effect of environmental light intensity on the degenerative process of the rd10 model. Three rd10 mice groups have been exposed from birth to P30 to different environmental light intensities: low (5 lux), medium (50 lux) and high (300 lux) intensity. Age‐matching C57BL/6J mice were used as controls. At the end of the experimental procedure, retinal function was assessed by electroretinography (ERG) and optomotor test. In addition, OCT images, hematoxylin staining, and immunohistochemistry were performed to analyze the structural integrity of the retinas of the three experimental groups. The rd10 mice housed at 5 lux intensity showed better functional response that the rd10 mice maintained at 50 or 300 lux, exhibiting significantly higher amplitudes in a‐ and b‐waves, as well as higher visual acuity. In the same line, the rd10 mice at 50 lux presented higher responses than the mice at 300 lux. Furthermore, the thickness of the ONL showed differences between the three rd10 groups. As the light intensity is lower, the thickness of the measured ONL is greater. These findings correlated with the morphology of the cones where better‐preserved photoreceptor morphology was found in the dystrophic animals housed at 5 lux. No significant differences were found between normal C57BL/6J animals kept at different light intensities. Environmental light intensity accelerates or delays the degeneration in rd10 mice. These data indicate that light intensity is a key factor to consider in studies carried out in retinal degenerative animal models, determining the temporal progression of the disease.

MINECO‐FEDER BFU2015‐67139‐R, RETICS‐FEDER RD16/0008/0016, Prometeo 2016/158, ACIF/2016/055, FPU16/04114.
Uveitis and immune checkpoint inhibition: when a blockage isn’t just a blockage
Authors: Potvin Arnaud , Rottey Sylvie , Geldhof Kurt , Demedts Ingel , De Zaeytijd Julie , De Schryver Ilse
Published: December 2019

Purpose

To report uveitis triggered by immune checkpoint inhibition.

Methods

Retrospective analysis of 5 charts of patients with metastatic cancer on immunotherapy.

Results

Five male patients, mean age 68.4 years, received immune checkpoint inhibition (pembrolizumab n =1, nivolumab n = 2, ipilimumab+nivolumab n = 2) with a mean duration of 2.05 months before onset of ocular symptoms. The primary malignancies were two cutaneous melanomas, a NSCLC, an oesophageal adenocarcinoma and an urothelial carcinoma of the bladder. Two patients presented with a bilateral acute anterior uveitis (AU) with fine keratic precipitates, anterior chamber (AC) cells grade 1+ (Standardization of the Uveitis Nomenclature), no posterior synechiae and no other abnormalities on dilated fundus examination and sd‐OCT. Two other patients presented with a bilateral panuveitis with AC cells 2+, vitreal cells and serous retinal detachments in the posterior pole. One patient showed serous retinal detachments in the posterior pole without AC or vitreal cells. The cases with AU responded to topical steroids with clinical remission within 4 weeks. Topical treatment failed to control the cases with panuveitis. Systemic steroids were successfully added. Nonetheless, checkpoint inhibition needed to be discontinued in all cases with serous retinal detachments.

Conclusions

Checkpoint inhibition is a promising new treatment for metastatic cancer. Several adverse effects of immunotherapy have been reported, including uveitis. In the two cases with AU, immunotherapy was continued after therapeutic response to topical steroids. Checkpoint inhibition needed to be discontinued in the three cases with serous retinal detachment despite treatment with systemic steroids. Although AU is the most common ocular side effect, serous retinal detachment can be related to checkpoint inhibition in very rare cases.
EU COST Action ANIRIDIA‐NET: A new, inclusive pan‐European network for aniridia research
Authors: Lagali Neil
Published: December 2019

Congenital aniridia is a rare but devastating pan‐ocular disease resulting from mutations in the PAX6 gene causing under‐ or mis‐developed ocular structures and serious vision impairment or blindness. Aniridia is often associated with early development of cataract, glaucoma, and a keratopathy originating from a progressive limbal stem cell insufficiency. Recently new diagnostic, genetic and molecular methods have become available and are for the first time being applied to better characterize aniridia with the hope of developing more effective treatments to improve vision in this underserved population. In parallel, more detailed phenotypic and genetic studies are being undertaken to examine individuals and cohorts with aniridia, with new information rapidly advancing our understanding. Patients and advocacy associations are becoming better informed and engaged in their medical care, while also supporting and promoting research. To bring together the various existing efforts to understand, manage, and treat aniridia, and to develop harmonized approaches for addressing some of the most difficult challenges, a new EU COST Action ANIRIDIA‐NET (2019‐2023) has just been established. This pan‐European network is open and inclusive, and to date participants from over 20 European countries have joined. Here, a brief description of the network, its planned goals and activities, and opportunities for interested researchers and practitioners to participate will be presented.
Pediatric OVCR what’s new?
Authors: Bremond‐Gignac Dominique
Published: December 2019

Central retinal vein occlusion (CRVO) is the second cause of visual loss due to vascular disease after diabetic retinopathy. Its pathogenesis remains unclear but risk factors such as hypertension, glaucoma and age have been recognized. Indeed, CRVO occurs mainly after 50 years, and only 10–15% of patients are under 40 years of age. CRVO has been rarely reported in children, but often associated with a local cause (compressive or inflammatory), or a systemic condition as thrombophilic and hyperviscosity syndromes. The clinical presentation includes visual loss and the fundus shows optic disc edema, tortuous dilated retinal veins, retinal hemorrhages and signs of neovascularization at various levels as in adult cases. In children, the role of genetic variants of thrombophilia in the occurrence of CRVO remains unclear. We report 4 cases of central retinal vein occlusion (CRVO) in healthy children showing combined genetic variant of thrombophilia. Mutation of MTHFR (C677T) and GPIIIa PlA1/A2 seems to demonstrate implication in CRVO in children. In those cases, multidisciplinary consultation staff has to discuss preventive low‐dose aspirin therapy.
Targeting lymphangiogenesis: improving the success of high‐risk corneal transplantation
Authors: Cursiefen Claus
Published: December 2019

Novel strategies for preoperative regression of pathologic corneal blood and lymphatic vessels to improve high risk corneal graft survival are outlined.
Modeling of Aniridia‐related keratopathy and identification of novel drugs for potential treatment
Authors: Aberdam Daniel
Published: December 2019

Haploinsufficiency of PAX6 in humans is the main cause of congenital aniridia, a rare eye disease characterized by iris hypoplasia and reduced visual acuity. Patients have also progressive disorders including cataract, glaucoma and corneal abnormalities making their condition very challenging to manage. Aniridia‐related keratopathy (ARK), caused by a combination of factors including limbal stem‐cell deficiency, impaired healing response, abnormal differentiation, and infiltration of conjunctival cells onto the corneal surface, affects up to 95% of patients. It usually begins in the first decade of life resulting in recurrent corneal erosions, sub‐epithelial fibrosis with corneal decompensation and opacification. Unfortunately, current treatment options for aniridia patients are currently limited. Although animal models partially recapitulate this disease, there is no in vitro cellular model of AKT needed for drug/therapeutic tools screening and validation. We used genome editing to introduce a nonsense mutation into one allele of the PAX6 gene in limbal cells, a reservoir of stem cells able to differentiate into corneal cells. The mutated cells displayed reduced cell proliferation and cell migration but enhanced cell adhesion. Known PAX6 targets expression was also altered. By High Throughput Screening of a FDA‐approved library, we identified two small compounds that rescued both PAX6 endogenous protein level and altered cell migration of the mutant limbal stem cells. Since these two compounds are already used in psychiatric medicine, their repurposed use to treat topically aniridia eye could become realistic as soon as validated in vivo for efficacy and safety on aniridia‐like mice.
Insights into the Farnsworth D15 test and its efficacy in occupational protocols
Authors: Evans Benjamin
Published: December 2019

Since their introduction, occupational colour vision (CV) standards have, in many ways, driven the development of CV tests. One test designed for occupational use is the Farnsworth D15 and despite having been introduced over 70 years ago, this test continues to be used to determine occupational suitability. To complete the test subjects are required to place 15 caps in order so as to minimise perceived differences between adjacent caps when illuminated with daylight (D65). Both red‐green (RG), yellow‐blue (YB) colour and luminance signals can contribute to what a subject perceives as a minimum difference between adjacent caps. The D15 aims to fail all monochromats, dichromats and subjects with severe anomalous trichromacy whilst passing all normal trichromats and only the least severe subjects with colour vision deficiency (CVD). The purpose of this study was to investigate the D15 test and its efficacy in occupational protocols. The different signals rod monochromats, dichromats and subjects with normal CV make use of most when presented with the D15 test were established, along with reliable D15 statistics for normal, deutan and protan subjects. A model was also developed to predict the colour signals involved, and the expected cap orders generated when subjects with a range of CVD carry out the test. When no crossings and up to two adjacent transpositions are allowed on the D15 test, 100% of normal trichromats (N = 95), 56% of deutans (N = 325) and 47% of protans (N = 170) pass. 43% of protans and 23% of the deutans that pass have RG thresholds above 10 CAD units (one CAD unit describes the mean RG colour signal strength for young normal trichromats). As one would expect the pass rate can vary significantly under different occupational protocols. As predicted by the model, rod monochromats, deuteranopes and protanopes were able to complete the Farnsworth D15 test when the caps were separated into two groups, despite severe loss or even complete absence of colour vision.
Colour assessment in patients at risk of developing diabetes
Authors: Rodriguez‐Carmona Marisa
Published: December 2019

Diabetes has frequently been linked to loss of colour vision. A recent study has shown that over 70% of diabetics have significant loss of both Yellow/Blue (YB) and Red/Green (RG) colour vision (https://doi.org/10.1111/j.1755-3768.2012.f073.x), in the absence of clinical signs of retinopathy. This study also showed poor correlation between the severity of RG or YB loss and parameters such as duration of diabetes, age, HbA1c, body mass index, visual acuity or central retinal thickness. The aim of this study was to investigate whether clinically ‘normal’ subjects, who have been identified as being at ‘risk’ of developing diabetes, show significant changes in colour vision and rod and cone sensitivities.

A ‘high‐risk’ group (n = 62) and subjects diagnosed with diabetes (n = 23) were recruited from a healthcare centre that offers diagnostic and screening services, including vision assessment. The inclusion criteria for ‘high‐risk’ group required 3 or more recognised risk factors for diabetes (e.g., age >45, HbA1C >5.7, high blood pressure, smoking history, high BMI, family history of diabetes, FPG levels >100 mg/dl). All subjects had full ophthalmic assessment and their RG and YB colour vision, Functional Contrast Sensitivity, Visual Acuity and Rod‐ and Cone‐mediated flicker sensitivity were measured using the Advanced Vision and Optometric Tests (AVOT) developed at City University (www.avot/city.ac.uk).

Consistent with previous findings, the diabetic group show significant loss of both RG and YB colour vision. They also have higher thresholds for rod‐ and cone‐mediated vision. Surprisingly, the ‘high‐risk’ subject group who do not meet the clinical criteria for early diabetes also show significant loss of colour and rod and cone sensitivity. These findings suggest that accurate assessment of colour vision and rod and cone mediated thresholds can be used as early biomarkers in in prediabetic screening.
Megalocornea in the Czech Republic‐additional clinical features and novel disease‐causing variants
Authors: Liskova Petra
Published: December 2019

X‐linked megalocornea is a congenital disorder, characterised by bilaterally enlarged corneas, with a horizontal white‐to‐white measurement of ≥13 mm, reduced central corneal thickness, and deep anterior chamber, without increase of the intraocular pressure. The results of clinical examination and mutational analysis in four families with the occurrence of megalocornea will be presented, including previously unreported phenotypic features and novel CHRDL1 mutations.
Mini‐DMEK for focal defects of Descemet's membrane
Authors: Bachmann Björn
Published: December 2019

Introduction

Descemet Membrane Endothelial Keratoplasty (DMEK) has evolved into a standard procedure for patients with corneal endothelial diseases. Recent reports suggest that DMEK can also improve corneal edema in patients with breaks in Descemet's membrane (DM) as in acute hydrops.

Methods

This is a retrospective analysis of consecutive patients after DMEK with small grafts (Mini‐DMEK) for the treatment of defects of DM. The size of the graft in Mini‐DMEK was adapted to the size of the defect of DM.

Results

Four out of six Mini‐DMEKs were performed in patients with acute hydrops in keratoconus. One Mini‐DMEK was performed in a patient with a large central tear after DALK and one Mini‐DMEK was performed in a patient with Haab's striae in primary congenital glaucoma. Incomplete graft attachment necessitated one re‐Mini‐DMEK in a patient with acute keratoconus. Intraoperatively, unfolding and positioning of small grafts turned out to be more complex than in DMEK with grafts of normal size (≥7 mm). After successful Mini‐DMEK corneal thickness and corneal edema decreased in all patients.

Conclusion

Mini‐DMEK is a viable treatment option for patients with ruptures or breaks of DM. Future analysis are needed for better identification of patients with defects of DM who will benefit from Mini‐DMEK.
Combined surface ablation+CXL for keratoconus
Authors: Balidis Miltos
Published: December 2019

Keratoconus treatment should be aimed to improve the optical inefficiency of the irregular cornea and halt the disease progression that may lead to the need for corneal transplantation. Corneal collagen cross‐linking (CXL) using Riboflavin and ultraviolet A has been used to stabilize the cornea with progressive keratoconus or ectatic corneal disorders after corneal refractive procedures. Studies demonstrated that the simultaneous wavefront optimized (WG PRK) or topography guided (TG PRK) approach of photore‐fractive keratectomy (PRK) plus CXL offers improvements in uncorrected distance acuity (UDA), best distance acuity(BDA), and topographic irregularity, even if the surgical goal is not a refractive end point. Combining photorefractive keratectomy (PRK) with CXL or accelerated CXL offers keratoconus patients both stability and improvement in functional vision. However, different excimer laser platforms have different ablation patterns and different algorithms for topography‐guided ablation. Additionally, mechanical and laser debridement of the corneal epithelium (PRK versus transepithelial PRK) may result in different patterns of ablation and different clinical results. Though the conventional refractive components of sphere and cylinder may be simultaneously incorporated into the treatment profile, in the treatment of keratoconus, tissue sparing is the prime consideration, and therefore, PRK typically limits the maximum depth of tissue ablation to less than 50mm. Several CXL protocols result in more cross‐linking and a greater increase in Young's modulus, less corneal cross‐linking (a smaller increase in Young's modulus) may still have the same clinical effect (in terms of disease stabilization). In other words, the optimum CXL parameters to produce the clinically desired effect (in terms of stabilization or prophylaxis) are not known. A reduction in HOA after TG‐PRK in keratoconus eyes (with or without the addition of CXL) is not surprising and is a consistent finding in published studies. Diffuse corneal haze, which emerges in a few days after CXL in virtually all eyes, generally resolves over time. It is identified as a dust‐like change in the stroma. In addition, some patients suffer from scarring that persists and can decrease visual acuity. However, these two words— “haze” and “scar”—are sometimes used interchangeably in the literature.
Neurotrophic keratitis as a peripheral sensory neurodegenerative disease
Authors: Aracil Adolfo
Published: December 2019

Maintenance of the ocular surface critically depends on the nocifensive responses elicited by the proper functioning of corneal sensory innervation. Damage of any type caused to the trigeminal ganglion or its ophthalmic branch is associated to the development of chronic trophic disturbances of the corneal epithelium homeostasis, which may progress to corneal perforation and vision loss. Since the first observations by Magendie as early as in 1824, many efforts have been dedicated to identifying the molecular mechanisms underlying the trophic effects exerted by sensory neurons on corneal tissue.

Many molecules derived or released by sensory nerves have been involved in corneal epithelial wound healing, either in vivo or in vitro. Neuropeptides released from the intraepithelial free nerve endings of corneal polymodal nociceptors have been claimed as potential candidate molecules to explain the trophic effects of sensory neurons on the corneal epithelium. However, their precise role in basal maintenance of the corneal epithelium or during corneal wound healing is far from being clearly understood. Consequently, neurotrophic keratitis is still considered as an orphan disease, and its association to the trigeminal sensory neuron degeneration is the rationale for assaying neuroregenerative therapies, such as neurotrophin eyedrops or neurotization, as potential treatments.

(Supported by grants SAF‐2017‐83674‐C2‐1‐R and 2‐R from Agencia Estatal de Investigación, Spain, and ERDF, EU, and PROMETEO/2018/114 from Generalitat Valenciana, and in part by Horizon 2020 G.A. No 667400, European Commission)
Intracorneal Ring Segments in Keratoconus; an Evidenced‐based Approach
Authors: Gatzioufas Zisis
Published: December 2019

Implantation of intracorneal ring segments (ICRS) is an effective and safe surgical option for visual improvement in keratoconus. ICRS are small, PMMA devices, which are implanted into the cornea aiming to alter its geometry in a manner that it will enhance its refractive properties and thereby will improve visual acuity. Their implantation was initially managed mechanically, but over the last years femtosecond laser‐assisted implantation has been gaining increasing interest and is gradually replacing the conventional mechanical technique. Nowadays, there are implantation nomograms indicating the appropriate ring segment characteristics for each individual case and suggesting, in a customized manner, the most suitable parameters for ICRS implantation. There are also certain indications and contraindications regarding the patient selection in order to maximize the safety and efficacy of the treatment. The purpose of this presentation is to update the current status of ICRS implantation as a modern therapeutic option in the visual rehabilitation of patients with keratoconus, highlighting pearls and pitfalls for both young and experienced corneal surgeons.
Protective Role of Xtra‐Factor in Refractive Surgery
Authors: Gatzioufas Zisis
Published: December 2019

Combination of refractive surgery procedures (i.e. LASIK) with high‐fluence, accelerated corneal crosslinking (Xtra) has been proposed and introduced in clinical practice, aiming to restore corneal strength, increase stability of visual outcomes, and potentially lower the refractive enhancement rate. However, there is no consensus in the literature regarding the beneficiary effect of this procedure.

This presentation will review current clinical evidence on the topic, highlight advantages and disadvantages of this method and, finally, deliver relevant practical tips for young corneal surgeons.
The AkkoLens Lumina accommodative intraocular lens
Authors: Rombach Michiel
Published: December 2019

The AkkoLens Lumina is an accommodative intraocular lens based on cubic, Alvarez, optical elements. The Lumina is designed to be implanted into the ciliary plane with the Lumina customized for the individual eye with each eye having its specific combination of refraction and sizing. The lens provides up to 4D of accommodation and provides a visual acuity and contrast sensitivity similar to a monofocal lens. The current state of development of the Lumina and clinical results are presented.
Anti‐AQP4 and anti‐MOG optic neuropathies
Authors: Yu‐Wai‐Man Patrick
Published: December 2019

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system (CNS) that preferentially targets the optic nerve and the spinal cord. Due to the significant risk of permanent visual and neurological impairment in NMO, rapid diagnosis and the prompt initiation of the most appropriate treatment are essential. Antibodies against the aquaporin‐4 (AQP4) water channel and myelin oligodendrocyte glycoprotein (MOG) have been identified in patients with NMO phenotypes. In this presentation, the clinical and neuropathological features of anti‐AQP4 and anti‐MOG optic neuropathies will be reviewed with a critical appraisal of current treatment options.