Disease Course of Clinically Isolated Optic Neuritis.

BACKGROUND AND OBJECTIVES: Optic neuritis is the most common optic neuropathy in young adults and a frequent manifestation of multiple sclerosis. Its clinical course is pertinent to the design of visual pathway neuroprotection trials. METHODS: This is a secondary analysis of longitudinal data from the TONE trial, which included 103 patients from 12 German academic tertiary centers with acute unilateral optic neuritis as a clinically isolated syndrome and baseline high-contrast visual acuity <0.5 decimal. Patients were randomized to 1,000 mg methylprednisolone i.v./d plus either erythropoietin (33,000 IU/d) or placebo (saline solution) for 3 days. They were followed up at standardized intervals with a battery of tests including high-contrast visual acuity, low-contrast letter acuity, contrast sensitivity, visual fields, visual evoked potentials, and retinal optical coherence tomography. At 6 months, participants answered a standardized questionnaire on vision-related quality of life (NEI-VFQ 25). We describe the disease course with mixed-effects piecewise linear models and calculate structure-function correlations using Pearson r. Because erythropoietin had no effect on the visual system, we use pooled (treatment-agnostic) data. RESULTS: Patients experienced initial rapid and then decelerating improvements of visual function with thinning of inner and thickening of outer retinal layers. At 6 months, visual parameters were positively correlated with inner and negatively correlated with outer retinal thickness changes. Peripapillary retinal nerve fiber layer thinning predominantly occurred in sectors without previous swelling. At 6 months, macular ganglion cell and inner plexiform layer thinning was weakly correlated with the P100 peak time (r = -0.11) and moderately correlated with the amplitude of visual evoked potentials (r = 0.35). Only functional outcomes were at least moderately correlated with vision-related quality of life. DISCUSSION: The longitudinal data from this large study cohort may serve as a reference for the clinical course of acute optic neuritis. The pattern of correlation between visual evoked potentials and inner retinal thinning may argue that the latter is mostly due to ganglion cell loss, rather than dysfunction. Visual pathway neuroprotection trials with functional outcomes are needed to confirm that candidate drugs will benefit patients' vision-related quality of life. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov, NCT01962571.

The Freiburg Acuity Test in Preschool Children: Testability, Test-Retest Variability, and Comparison With LEA Symbols.

Purpose: To determine the testability, performance, and test-retest variability (TRV) of visual acuity (VA) assessment using the Freiburg Visual Acuity Test (FrACT) compared to the LEA Symbols Test (LEA) in preschool children. Methods: In 134 preschool children aged 3.0 to 6.8 years, monocular VA of each eye was measured twice with a four-orientation Landolt C version of the FrACT and once with the LEA. FrACT runs were preceded by a binocular run for explanatory purposes. Test order alternated between subjects. Optotypes were presented on a computer monitor (FrACT) or on cards (LEA) at a distance of 3 m. Results: Overall, 68% completed the FrACT (91/134 children) and 88% completed the LEA (118/134 children). Testability depended on age: FrACT, 19% (<4 years) and 87% (≥4 years); LEA, 70% (<4 years) and 95% (≥4 years). Mean ± SD VA difference between tests was 0.11 ± 0.19 logarithm of the minimum angle of resolution [logMAR], with LEA reporting better acuity. The difference depended on age (0.27 ± 0.23 logMAR [<4 years], 0.09 ± 0.18 logMAR [≥4 years], P < 0.001) and on test sequence (higher age dependence of FrACT VAs for LEA first, P < 0.001). The 95% limits of agreement for the FrACT TRV were ±0.298 logMAR. Conclusions: The examiner-independent FrACT, using international reference Landolt C optotypes, can be used to assess VA in preschool children aged ≥4 years, with reliability comparable to other pediatric VA tests. Translational Relevance: Use of the automated FrACT for VA assessment in preschool children may benefit objectivity and validity as it is a computerized test and employs the international reference Landolt C optotype.

Visual Pathway Outcomes Based on Sample Size in Clinical Neuroprotection Research.

This cohort study calculates clinical trial sample sizes powered by visual pathway outcomes of acute optic neuritis in neuroprotection research.

ZEISS PLEX Elite 9000 Widefield Optical Coherence Tomography Angiography as Screening Method for Early Detection of Retinal Hemangioblastomas in von Hippel-Lindau Disease.

Purpose: To evaluate early detection of retinal hemangioblastomas (RHs) in von Hippel-Lindau disease (VHLD) with widefield optical coherence tomography angiography (wOCTA) compared to the standard of care in ophthalmologic VHLD screening in a routine clinical setting. Methods: We conducted prospective comparisons of three screening methods: wOCTA, standard ophthalmoscopy, and fluorescein angiography (FA), which was performed only in uncertain cases. The numbers of detected RHs were compared among the three screening methods. The underlying causes for the lack of detection were investigated. Results: In 91 eyes (48 patients), 67 RHs were observed (mean, 0.74 ± 1.59 RH per eye). FA was performed in eight eyes. Ophthalmoscopy overlooked 25 of the 35 RHs detected by wOCTA (71.4%) due to the background color of the choroid (n = 5), small tumor size (n = 13), masking by a bright fundus reflex (n = 2), and masking by surrounding retinal scars (n = 5). However, wOCTA missed 29 RHs due to peripheral location (43.3%). The overall detection rates were up to 37% on the basis of ophthalmoscopy alone, up to 52% for wOCTA, and 89% for FA. Within the retinal area covered by wOCTA, the detection rates were up to 46.7% for ophthalmoscopy alone, up to 92.1% for wOCTA, and 73.3% for FA. Conclusions: The overall low detection rate of RHs using wOCTA is almost exclusively caused by its inability to visualize the entire peripheral retina. Therefore, in unclear cases, FA is necessary after ophthalmoscopy. Translational Relevance: Within the imageable retinal area, wOCTA shows a high detection rate of RHs and therefore may be suitable to improve screening for RHs in VHLD.

Interrelation Between Cerebrospinal Fluid Pressure, Intracranial Morphology and Venous Hemodynamics Studied by 4D Flow MRI.

PURPOSE: To quantify the effects of CSF pressure alterations on intracranial venous morphology and hemodynamics in idiopathic intracranial hypertension (IIH) and spontaneous intracranial hypotension (SIH) and assess reversibility when the underlying cause is resolved. METHODS: We prospectively examined venous volume, intracranial venous blood flow and velocity, including optic nerve sheath diameter (ONSD) as a noninvasive surrogate of CSF pressure changes in 11 patients with IIH, 11 age-matched and sex-matched healthy controls and 9 SIH patients, before and after neurosurgical closure of spinal dural leaks. We applied multiparametric MRI including 4D flow MRI, time-of-flight (TOF) and T2-weighted half-Fourier acquisition single-shot turbo-spin echo (HASTE). RESULTS: Sinus volume overlapped between groups at baseline but decreased after treatment of intracranial hypotension (p = 0.067) along with a significant increase of ONSD (p = 0.003). Blood flow in the middle and dorsal superior sagittal sinus was remarkably lower in patients with higher CSF pressure (i.e., IIH versus controls and SIH after CSF leak closure) but blood flow velocity was comparable cross-sectionally between groups and longitudinally in SIH. CONCLUSION: We were able to demonstrate the interaction of CSF pressure, venous volumetry, venous hemodynamics and ONSD using multiparametric brain MRI. Closure of CSF leaks in SIH patients resulted in symptoms suggestive of increased intracranial pressure and caused a subsequent decrease of intracranial venous volume and of blood flow within the superior sagittal sinus while ONSD increased. In contrast, blood flow parameters from 4D flow MRI did not discriminate IIH, SIH and controls as hemodynamics at baseline overlapped at most vessel cross-sections.

Treated Cases of Retinopathy of Prematurity in Germany: 10-Year Data from the Retina.net Retinopathy of Prematurity Registry.

PURPOSE: To analyze changes in demographic parameters and retreatment patterns over a 10-year period in a clinical routine setting of infants with retinopathy of prematurity (ROP) requiring treatment documented in the German Retina.net ROP registry. DESIGN: Multicenter, noninterventional, observational registry study recruiting patients treated for ROP. SUBJECTS: A total of 692 eyes of 353 infants treated for ROP were documented in the Retina.net ROP registry over a 10-year period between 2011 and 2020. These cases cover about 15% of all infants treated for ROP in Germany. METHODS: The Retina.net ROP registry was established in 2012 to jointly collect information on infants treated for ROP. The database collects information on demographic parameters (gestational age [GA], birth weight, neonatal comorbidities) as well as treatment parameters (type of treatment, weight and age at treatment, and stage of ROP). A total of 19 centers contributed to the analysis. This is the 10-year analysis of data from 2011 to 2020, in which we focus on changes over time regarding the respective parameters. MAIN OUTCOME MEASURES: Changes over time in demographic parameters and treatment patterns for ROP in Germany. RESULTS: The overall incidence of treatment requiring ROP was 3.5% of all infants screened for ROP at participating centers. Gestational age, weight at birth, and weight at treatment remained stable over the 10-year period, whereas postmenstrual and postnatal age at treatment increased moderately but statistically significantly over the years. The most prevalent ROP severity stage at treatment was stage 3+ in zone II (76.6% of all treated eyes). Treatment patterns changed considerably from predominantly laser treatments in 2011 (75% of all treated eyes) to predominantly ranibizumab treatments in 2020 (60.9% of all treated eyes). The overall retreatment rate was 15.6%. Retreatment rates differed between initial treatment modalities (14.1% after laser coagulation, 12% after bevacizumab and 24.5% after ranibizumab). Treatment-associated systemic or ophthalmic complications were rare. CONCLUSIONS: This data analysis represents one of the largest documented cohorts of infants treated for ROP. The data on demographic parameters and treatment patterns provide useful information for further improvement of ROP management. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Computer-Assisted Visual Training in Children and Adolescents with Developmental Visual Disorders.

BACKGROUND: In this systematic review, we address the question whether children and adolescents with developmental visual disorders benefit from computer-assisted visual training. METHODS: Systematic literature searches were carried out in three bibliographic databases (initial search in October 2021) and trial registries. Included were randomized controlled trials that evaluated the efficacy of computer-assisted visual training in children and adolescents with developmental visual disorders in comparison to no training, sham training, or conservative treatment. RESULTS: The inclusion criteria were met by 17 trials (with a total of 1323 children and adolescents) focusing on binocular or monocular computer-assisted visual training for the treatment of amblyopia. In these trials, visual training was carried out for 2 to 24 weeks, either as "stand alone" therapy or in addition to occlusion therapy. Six trials showed a statistically significant difference in favor of the visual training for the outcome "best corrected visual acuity of the amblyopic eye." However, this difference was small and mostly below the threshold of clinical relevance of -0.05 logMAR (equivalent to an improvement of 0.5 lines on the eye chart, or 2.5 letters per line). Only few data were available for the outcomes "binocular vision" and "adverse events"; the differences between the groups were similarly small. CONCLUSION: The currently available data do not permit any firm conclusions regarding the efficacy of visual training in children and adolescents with amblyopia. Moreover, treatment adherence was often insufficient and the treatment durations in the trials was relatively short. No results from randomized trials have yet been published with respect to other developmental visual disorders (refractive errors, strabismus).

Treatment With Erythropoietin for Patients With Optic Neuritis: Long-term Follow-up.

BACKGROUND AND OBJECTIVE: Erythropoietin (EPO) is a candidate neuroprotective drug. We assessed its long-term safety and efficacy as an adjunct to methylprednisolone in patients with optic neuritis and focused on conversions to multiple sclerosis (MS). METHODS: The TONE trial randomized 108 patients with acute optic neuritis but without previously known MS to either 33,000 IU EPO or placebo in conjunction with 1,000 mg methylprednisolone daily for 3 days. After reaching the primary end point at 6 months, we conducted an open-label follow-up 2 years after randomization. RESULTS: The follow-up was attended by 83 of 103 initially analyzed patients (81%). There were no previously unreported adverse events. The adjusted treatment difference of peripapillary retinal nerve fiber layer atrophy in relation to the fellow eye at baseline was 1.27 µm (95% CI -6.45 to 8.98, p = 0.74). The adjusted treatment difference in low-contrast letter acuity was 2.87 on the 2.5% Sloan chart score (95% CI -7.92 to 13.65). Vision-related quality of life was similar in both treatment arms (National Eye Institute Visual Functioning Questionnaire median score [IQR]: 94.0 [88.0 to 96.9] in the EPO and 93.4 [89.5 to 97.4] in the placebo group). The rate of multiple sclerosis-free survival was 38% in the placebo and 53% in the EPO group (hazard ratio: 1.67, 95% CI 0.96 to 2.88, p = 0.068). DISCUSSION: In line with the results at 6 months, we found neither structural nor functional benefits in the visual system of patients with optic neuritis as a clinically isolated syndrome, 2 years after EPO administration. Although there were fewer early conversions to MS in the EPO group, the difference across the 2-year window was not statistically significant. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with acute optic neuritis, EPO as an adjunct to methylprednisolone is well tolerated and does not improve long-term visual outcomes. TRIAL REGISTRATION INFORMATION: The trial was preregistered before commencement at clinicaltrials.gov (NCT01962571).

Low-dose AtropIne for Myopia Control in Children (AIM): protocol for a randomised, controlled, double-blind, multicentre, clinical trial with two parallel arms.

INTRODUCTION: Myopia is a major cause of degenerative eye disease and increases the risk of secondary visual impairment. Mitigating its progression therefore has great potential of clinically relevant benefit as shown by using highly diluted atropine eye drops in children of Asian origin. However, limited evidence is available regarding the efficacy and safety of low-dose atropine therapy in non-Asian populations. Hence, the Low-dose AtropIne for Myopia Control in Children (AIM) study will test the efficacy and safety of 0.02% atropine vs placebo in a German population. METHODS AND ANALYSIS: AIM is a national, multicentre, prospective, randomised, placebo-controlled, double-blind trial with two parallel arms. The primary objective is to assess the efficacy of atropine 0.02% eyedrops for myopia control in children of Caucasian origin. The primary outcome is the change in cycloplegic refraction after 1 year of treatment (D/year). Secondary and tertiary outcome measures comprise the change in axial length (mm/year) in children treated with 0.02% atropine compared with placebo, the myopic progression of participants treated with 0.01% compared with 0.02% atropine (D/year and mm/year), and the safety profile of both 0.02% and 0.01% atropine. Furthermore, the myopic progression 1 year after cessation of therapy with 0.02% atropine will be evaluated. Inclusion criteria are an age of 8-12 years and myopia of -1 D to -6 D with an estimated annual myopia progression of ≥0.5 D. After randomisation, patients will receive either atropine 0.02% (arm A) or placebo eye drops (arm B) in the first year of treatment. In the second year, they will continue to receive atropine 0.02% (arm A) or switch to atropine 0.01% (arm B). In the third year, they will switch to placebo (arm A) or continue with atropine 0.01% (arm B). To achieve a statistical power of 80%, the calculated sample size is 300. The trial has started in October 2021 with a planned recruitment period of 18 months. ETHICS AND DISSEMINATION: AIM has been approved by the Central Ethics Committee of the University Medical Center Freiburg (21-1106), local ethics committees of each participating centre and the German Federal Institute for Drugs and Medical Devices (61-3910-4044659). It complies with the Declaration of Helsinki, local laws and ICH-GCP. Results and underlying data from this trial will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT03865160.

[Glaucoma in infancy and childhood]. / Glaukom im Säuglings- und Kindesalter.

Glaucoma in infancy and childhood is a rare disease. An immediate diagnosis and treatment are absolutely necessary to prevent blindness of affected children. Childhood glaucoma is characterized by a heterogeneous phenotype: besides primary congenital glaucoma, secondary types often exist and the individualized treatment requires an experienced interdisciplinary team. The pathogenesis is not always discernible and genetic alterations sometimes cause the disease. A surgical procedure is usually necessary to lower the intraocular pressure. Refractive and orthoptic care are equally important to avoid amblyopia. This article gives an overview of childhood glaucoma and outlines the most important diagnostic and therapeutic aspects.

Retinal Thinning in Adults with Autism Spectrum Disorder.

Since the retina shares its embryological origin with the central nervous system, optical coherence tomography (OCT), an imaging technique frequently employed in ophthalmology to analyze the macula and intraretinal layer thicknesses and volumes, has recently become increasingly important in psychiatric research. We examined 34 autistic and 31 neurotypical adults (NT) using OCT. Autistic adults had reduced overall macular and outer nuclear layer (ONL) thickness and volume compared to NT. Both macular and ONL thickness showed significant inverse associations with the severity of autistic symptoms measured with the Social Responsiveness Scale 2 (SRS-2). Longitudinal studies across different age groups are required to clarify whether retinal changes may represent a possible trait marker.

[Scientific performance of ophthalmological research institutions in Germany 2018-2020 : Studies, publications, third-party funding and more-The research map of the German Ophthalmological Society (DOG)]. / Wissenschaftliche Leistungen augenheilkundlicher Forschungseinrichtungen in Deutschland 2018 bis 2020 : Studien, Publikationen, Drittmittelförderungen und mehr ­ Die Forschungslandkarte der Deutschen Ophthalmologischen Gesellschaft (DOG).

BACKGROUND: The German Ophthalmological Society (DOG) regularly records the scientific activities of ophthalmological research institutions in Germany. OBJECTIVE: With this publication the DOG wants to make the performance of scientific ophthalmology in Germany transparent and increase the options for future research cooperation with facilities of research institutions. METHODS: Systematic survey of German research centers in ophthalmology. RESULTS: The current research map records the data from 41 German research centers for the reporting period 2018-2020. Compared to previous editions of the research map, there has been a significant increase in scientific activity. The number of studies reported rose to 496. The number of government funded research projects (n = 121) and projects funded by foundations (n = 108) also increased. Furthermore, the number of scientific publications has almost doubled: while 1919 were published in the period from 2012 to 2014 and 2305 in the period from 2015 to 2017, there were 4215 in the current reporting period. The map also reports on a continuous increase in the number of young scientists in ophthalmology. CONCLUSION: The research map demonstrates the performance of German scientific ophthalmology. At the same time, the need for research in ophthalmology remains high because many diseases that affect the eyes are not yet or not yet completely curable.

Pediatric Cataract Surgery: Rate of Secondary Visual Axis Opacification Depending on Intraocular Lens Type.

PURPOSE: To assess the time course of secondary visual axis opacification (VAO) leading to additional surgery after primary intraocular lens (IOL) implantation in children and to describe further surgical outcomes. Comparison of lens types. DESIGN: Single-center, retrospective analysis of children aged 1 to 14 years who underwent cataract surgery with primary IOL implantation. The surgical technique was either in-bag IOL placement with primary posterior capsulotomy and anterior vitrectomy or bag-in-lens IOL placement. We excluded eyes with visually significant ocular comorbidities. PARTICIPANTS: Total of 135 eyes of 95 children. Of these, 64 had received an acrylic 3-piece IOL, 51 had an acrylic single-piece IOL, and 20 had an acrylic single-piece bag-in-lens IOL. The median ages at surgery were 53 months (interquartile range [IQR], 35-75), 52 months (27-65), and 60 months (40-84) in the 3-piece, 1-piece, and bag-in-lens groups, respectively. METHODS: Analysis of medical records. We used the Kaplan-Meier method and a Cox proportional hazards model with predefined adjustments for age at surgery, year of surgery, and the German Index of Socioeconomic Deprivation (score by postal code) to analyze VAO-free survival by lens type. Patients were invited to attend a clinical visit to achieve longer follow-ups. MAIN OUTCOME MEASURES: The rate of survival without VAO that required clearing of the visual axis after cataract surgery with primary IOL implantation. Any other surgical complications. RESULTS: The overall median follow-up was 19 months (IQR, 3-58). There were 13 cases of VAO, occurring at a median of 10 months (IQR, 10-12) after surgery. Of these, 1 eye had a 3-piece in-bag IOL, 10 eyes had 1-piece in-bag IOLs, and 2 eyes had bag-in-lens IOLs. The adjusted hazard ratio was 32.8 (95% confidence interval [CI], 3.3-327, P = 0.003) for 1-piece acrylic IOLs and 19.6 (CI, 1.22-316, P = 0.036) for bag-in-lens IOLs, compared with 3-piece acrylic in-bag IOLs. Two eyes with bag-in-lens surgery (10%) had an iris capture. There was 1 case of endophthalmitis. We found no cases of postoperative retinal detachment or new glaucoma. CONCLUSIONS: Children with secondary VAO who required a procedure to clear the visual axis generally presented within 15 months. Opacification rates were lowest when a 3-piece acrylic IOL was used.

First Description of Inheritance of a Postzygotic OPA1 Mosaic Variant.

Optic atrophy 1 (MIM #165500) is caused by pathogenic variants in the gene OPA1 (OPA1 MITOCHONDRIAL DYNAMIN-LIKE GTPase, MIM *605290) and is inherited in an autosomal dominant manner. We describe a 6-year-old male patient with severe early onset manifestation of optic atrophy, whose parents are subjectively asymptomatic. OPA1-sequence analysis revealed the heterozygous missense variant NM_015560.3:c.806C>T, p.(Ser269Phe) in the patient. Segregation analysis of the parents showed that the mother carried a low-grade postzygotic mosaic of this variant, which apparently also involves germline cells. In line with this, ophthalmological investigation of the mother showed subclinical manifestation of optic atrophy 1. This is the first report of an OPA1 postzygotic mosaic that was inherited to offspring.

Ranibizumab in retinopathy of prematurity - one-year follow-up of ophthalmic outcomes and two-year follow-up of neurodevelopmental outcomes from the CARE-ROP study.

PURPOSE: The primary endpoint results from the comparing alternative ranibizumab dosages for safety and efficacy in retinopathy of prematurity (CARE-ROP) core study identified ranibizumab as an effective treatment to control acute retinopathy of prematurity (ROP). This study reports the 1- and 2-year follow-up data focusing on long-term functional outcomes and safety. METHODS: The CARE-ROP trial compared 0.12 mg versus 0.20 mg ranibizumab in 20 infants with ROP in a multicentric, prospective, randomized, double-blind, controlled study design. Sixteen patients entered the follow-up period. An ophthalmologic assessment at one year postbaseline was acquired from all 16 patients and a neurodevelopmental assessment at two years postbaseline was acquired from 15 patients. RESULTS: Fifteen of 16 infants were able to fixate and follow moving objects at one year postbaseline treatment. One child progressed to stage 5 ROP bilaterally between the end of the core study and the 1-year follow-up (first seen at PMA 75 weeks). Mean spherical equivalents were -1.9 diopters (D) and -0.75 D in the 0.12 mg and the 0.20 mg treatment arms. Strabismus was present in seven and nystagmus in five out of 16 infants. Mental development scores were within normal limits in six out of ten patients with available data. No statistically significant difference was observed between the two treatment arms. CONCLUSION: Neurodevelopmental and functional ocular outcomes 1 and 2 years after treatment with ranibizumab are reassuring regarding long-term safety. Late reactivation of ROP, however, represents a challenge during the follow-up phase and it is of utmost importance that regular follow-ups are maintained.

Development and validation of a new clinical decision support tool to optimize screening for retinopathy of prematurity.

BACKGROUND/AIMS: Prematurely born infants undergo costly, stressful eye examinations to uncover the small fraction with retinopathy of prematurity (ROP) that needs treatment to prevent blindness. The aim was to develop a prediction tool (DIGIROP-Screen) with 100% sensitivity and high specificity to safely reduce screening of those infants not needing treatment. DIGIROP-Screen was compared with four other ROP models based on longitudinal weights. METHODS: Data, including infants born at 24-30 weeks of gestational age (GA), for DIGIROP-Screen development (DevGroup, N=6991) originate from the Swedish National Registry for ROP. Three international cohorts comprised the external validation groups (ValGroups, N=1241). Multivariable logistic regressions, over postnatal ages (PNAs) 6-14 weeks, were validated. Predictors were birth characteristics, status and age at first diagnosed ROP and essential interactions. RESULTS: ROP treatment was required in 287 (4.1%)/6991 infants in DevGroup and 49 (3.9%)/1241 in ValGroups. To allow 100% sensitivity in DevGroup, specificity at birth was 53.1% and cumulatively 60.5% at PNA 8 weeks. Applying the same cut-offs in ValGroups, specificities were similar (46.3% and 53.5%). One infant with severe malformations in ValGroups was incorrectly classified as not needing screening. For all other infants, at PNA 6-14 weeks, sensitivity was 100%. In other published models, sensitivity ranged from 88.5% to 100% and specificity ranged from 9.6% to 45.2%. CONCLUSIONS: DIGIROP-Screen, a clinical decision support tool using readily available birth and ROP screening data for infants born GA 24-30 weeks, in the European and North American populations tested can safely identify infants not needing ROP screening. DIGIROP-Screen had equal or higher sensitivity and specificity compared with other models. DIGIROP-Screen should be tested in any new cohort for validation and if not validated it can be modified using the same statistical approaches applied to a specific clinical setting.

Safety and efficacy of erythropoietin for the treatment of patients with optic neuritis (TONE): a randomised, double-blind, multicentre, placebo-controlled study.

BACKGROUND: The human cytokine erythropoietin conveys neuroprotection in animal models but has shown ambiguous results in phase 2 clinical trials in patients with optic neuritis. We assessed the safety and efficacy of erythropoietin in patients with optic neuritis as a clinically isolated syndrome in a multicentre, prospective, randomised clinical trial. METHODS: This randomised, placebo-controlled, double-blind phase 3 trial, conducted at 12 tertiary referral centres in Germany, included participants aged 18-50 years, within 10 days of onset of unilateral optic neuritis, with visual acuity of 0·5 or less, and without a previous diagnosis of multiple sclerosis. Participants were randomly assigned (1:1) to receive either 33 000 IU erythropoietin or placebo intravenously for 3 days as an adjunct to high-dose intravenous methylprednisolone (1000 mg per day). Block randomisation was performed by the trial statistician using an SAS code that generated randomly varying block sizes, stratified by study site and distributed using sealed envelopes. All trial participants and all study staff were masked to treatment assignment, except the trial pharmacist. The first primary outcome was atrophy of the peripapillary retinal nerve fibre layer (pRNFL), measured by optic coherence tomography (OCT) as the difference in pRNFL thickness between the affected eye at week 26 and the unaffected eye at baseline. The second primary outcome was low contrast letter acuity at week 26, measured as the 2·5% Sloan chart score of the affected eye. Analysis was performed in the full analysis set of all randomised participants for whom treatment was started and at least one follow-up OCT measurement was available. Safety was analysed in all patients who received at least one dose of the trial medication. This trial is registered at ClinicalTrials.gov, NCT01962571. FINDINGS: 108 participants were enrolled between Nov 25, 2014, and Oct 9, 2017, of whom 55 were assigned to erythropoietin and 53 to placebo. Five patients were excluded from the primary analysis due to not receiving the allocated medication, withdrawn consent, revised diagnosis, or loss to follow-up, yielding a full analysis set of 52 patients in the erythropoietin group and 51 in the placebo group. Mean pRNFL atrophy was 15·93 µm (SD 14·91) in the erythropoietin group and 14·65 µm (15·60) in the placebo group (adjusted mean treatment difference 1·02 µm; 95% CI -5·51 to 7·55; p=0·76). Mean low contrast letter acuity scores were 49·60 (21·31) in the erythropoietin group and 49·06 (21·93) in the placebo group (adjusted mean treatment difference -4·03; -13·06 to 5·01). Adverse events occurred in 43 (81%) participants in the erythropoietin group and in 42 (81%) in the placebo group. The most common adverse event was headache, occuring in 15 (28%) patients in the erythropoietin group and 13 (25%) patients in the placebo group. Serious adverse events occurred in eight (15%) participants in the erythropoietin and in four (8%) in the placebo group. One patient (2%) in the erythropoietin group developed a venous sinus thrombosis, which was treated with anticoagulants and resolved without sequelae. INTERPRETATION: Erythropoietin as an adjunct to corticosteroids conveyed neither functional nor structural neuroprotection in the visual pathways after optic neuritis. Future research could focus on modified erythropoietin administration, assess its efficacy independent of corticosteroids, and investigate whether it affects the conversion of optic neuritis to multiple sclerosis. FUNDING: German Federal Ministry of Education and Research (BMBF).