Two-Year Results of 0.01% Atropine Eye Drops and 0.1% Loading Dose for Myopia Progression Reduction in Danish Children: A Placebo-Controlled, Randomized Clinical Trial.

We investigated the two-year safety and efficacy of 0.1% loading dose and 0.01% low-dose atropine eye drops in Danish children for reduction in myopia progression in an investigator-initiated, placebo-controlled, double-masked, randomized clinical trial. Ninety-seven six- to twelve-year old myopic participants were randomized to 0.1% loading dose for six months and then 0.01% for eighteen months (loading dose group, N = 33), 0.01% for two years (0.01% group, N = 32) or placebo for two years (placebo, N = 32). Axial length (AL) and spherical equivalent refraction (SER) were primary outcomes. Secondary outcomes included adverse events and reactions, choroidal thickness, and other ocular biometrical measures. Outcomes were measured from baseline and at six-month intervals. Individual eyes nested by participant ID were analyzed with linear-mixed model analysis. Data were analyzed with intention-to-treat. Mean AL was 0.08 mm less (95% confidence interval (CI): -0.01; 0.17, p-value = 0.08) in the 0.1% loading dose and 0.10 mm less (95% CI: 0.01; 0.19, p-value = 0.02) in the 0.01% group after two years of treatment compared to placebo. Mean SER progression was 0.12 D (95% CI: -0.10; 0.33) less in the loading dose and 0.26 D (95% CI: 0.04; 0.48) less in the 0.01% groups after two years of treatment compared to placebo (p-value = 0.30 and 0.02, respectively). In total, 17 adverse events were reported in the second-year follow-up, and all were rated as mild. Adjusting for iris color did not affect treatment effect estimates. Intra-ocular pressure increased over two years comparably between all groups but remained within normal limits. Two-year treatment with 0.01% low-dose atropine eye drops is a safe and moderately efficacious intervention in Danish children for reducing myopia progression.

Safety and efficacy of 0.01% and 0.1% low-dose atropine eye drop regimens for reduction of myopia progression in Danish children: a randomized clinical trial examining one-year effect and safety.

BACKGROUND: To investigate the efficacy and safety of 0.1% and 0.01% low-dose atropine eye drops in reducing myopia progression in Danish children. METHODS: Investigator-initiated, placebo-controlled, double-masked, randomized clinical trial. Ninety-seven six- to twelve-year old myopic participants were randomized to 0.1% loading dose for six months followed by 0.01% for six months (loading dose group, Number (N) = 33), 0.01% for twelve months (0.01% group, N = 32) or vehicle for twelve months (placebo, N = 32). Primary outcomes were axial length and spherical equivalent refraction. Secondary outcomes included adverse events and reactions, choroidal thickness and ocular biometry. Outcomes were measured at baseline and three-month intervals. Data was analyzed with linear-mixed model analysis according to intention-to-treat. RESULTS: Mean axial elongation was 0.10 mm less (95% confidence interval (CI): 0.17; 0.02, adjusted-p = 0.06) in the 0.1% loading dose and 0.07 mm less (95% CI: 0.15; 0.00, adjusted-p = 0.16) in the 0.01% group at twelve months compared to placebo. Mean spherical equivalent refraction progression was 0.24 D (95% CI: 0.05; 0.42) less in the loading dose and 0.19 D (95% CI: 0.00; 0.38) less in the 0.01% groups at twelve months, compared to placebo (adjusted-p = 0.06 and 0.14, respectively). A total of 108 adverse events were reported during the initial six-month loading dose period, primarily in the loading dose group, and 14 were reported in the six months following dose switching, all deemed mild except two serious adverse events, unrelated to the intervention. CONCLUSIONS: Low-dose atropine eye drops are safe over twelve months in otherwise healthy children. There may be a modest but clinically relevant reduction in myopia progression in Danish children after twelve months treatment, but the effect was statistically non-significant after multiple comparisons adjustment. After dose-switching at six months the loading dose group approached the 0.01% group, potentially indicating an early "rebound-effect". TRIAL REGISTRATION: this study was registered in the European Clinical Trials Database (EudraCT, number: 2018-001286-16) 05/11/2018 and first posted at www. CLINICALTRIALS: gov (NCT03911271) 11/04/2019, prior to initiation.

School performances in children with cataract: results from a population-based cohort study.

OBJECTIVES: Childhood cataract is a chronic condition that may interfere with the child's learning capacities. We aimed to investigate whether childhood cataract influences academic development by comparing school performance in reading and mathematics in children with cataract to a matched control group. DESIGN: Nationwide registry-based cohort study. SETTINGS: Two surgical centres that perform all treatments for childhood cataract in Denmark. PARTICIPANTS: Children born between 2000 and 2009 diagnosed with cataract before 10 years of age (n=275) and an age-matched and sex-matched control group (n=2473). MAIN OUTCOME MEASURES: School performance was assessed as test scores in national tests performed at regular intervals from grade 2 to grade 8 in reading and mathematics. Analyses were corrected for birth origin, child somatic and mental disorder and parental socioeconomic status and mental disorders. RESULTS: Of 275 children, 85 (30.9%) were operated for bilateral cataract, 79 (28.7%) unilateral cataract and 111 (40,4%) were not operated. We found that children with cataract have lower participation rate in the tests (62.5%) compared with the control cohort (77.2%) (p value=0.0001). After adjusting the pooled analyses for birth origin, somatic and mental disease in the child and parental socioeconomic status and mental disorders, we found that the children with cataract scored significantly lower in mathematics compared with those without cataract (mean difference=-4.78, 95% CI: -8.18 to -1.38, p value=0.006), whereas no difference was found regarding scores in reading (p=0.576). The lower score in mathematics was driven by children who had been operated for bilateral cataract (p-value=0.004). CONCLUSION: Children with cataract without somatic or neurodevelopmental comorbidities or psychosocial adversities seem to do well in school, whereas children operated for bilateral cataract have higher frequencies of difficulties in mathematical tasks.

Prevalence of allergic sensitization with vernal keratoconjunctivitis: A systematic review with meta-analyses.

To determine the prevalence of allergic sensitization in patients with vernal keratoconjunctivitis (VKC) and to provide an overview of published studies on this topic. We systematically searched 11 literature databases on 24 May 2021, for studies with cross-sectional data on the prevalence of positive allergy tests in patients with VKC. Our main outcome of interest was the prevalence of allergic sensitization and the allergens involved. Prevalence meta-analyses were made to provide summary estimates. We identified 33 eligible studies for qualitative review with 2122 patients with VKC. Studies were predominantly based on patients seen in ophthalmology clinics. Overall, studies reported that the most prevalent positive allergen tests were the inhaled allergens house dust mites and pollen. Twenty-nine studies were eligible for the quantitative analysis. Here, we calculated the prevalence of allergen-positive patients to 57.7% (95% confidence interval: 52.5%-62.8%). Subgroup analyses of pooled estimates on sensitization based on specific testing methods found prevalence estimates of 51.4% for conjunctival provocation test, 68.7% for total tear IgE, 58.9% for specific tear IgE, and 58.2% for skin prick test. The prevalence of allergic sensitization in patients with VKC is 57.7%, and mostly towards inhaled allergens. The most frequent positive allergens are house dust mites and pollen. Identifying possible clinically relevant allergens provide information that may aid in managing VKC, such as environmental allergy-avoidance or allergy-specific treatment.

Socio-economic status in families affected by childhood cataract.

PURPOSE: To investigate the socio-economic status of families affected by childhood cataract and to assess how the socio-economic status is affected by cataract diagnosis. MATERIALS AND METHODS: Children born between 2000 and 2017, seen between the age 0 and 10 years in the same period at Rigshospitalet or Aarhus University Hospital for cataract (N = 485), were included and compared to a matched children group without cataract (N = 4358). Socio-economic status was evaluated by the parents' income, employment, education, marital status and family structure. RESULTS: Parents of children with cataract were more likely to have a low yearly income (OR = 1.60, 95% CI (1.12-2.27)), be out of work (OR = 1.74, 95% CI (1.34-2.26)) and have basic education as the highest attained education (OR = 1.64, 95% CI (1.27-2.13)) prior to diagnosis. This social gradient was not affected by the diagnosis. In addition, a higher number of children with cataract lived in multi-family residencies (13.8% versus 8% in group of children without cataract) and they had a greater number of siblings (6.2% had ≥4 siblings versus 2.1% in group of children without cataract). CONCLUSION: Families affected by childhood cataract have a lower socio-economic status and educational background even before cataract is diagnosed but the diagnosis does not aggravate the differences between these families and the background population. The lower socio-economic status and parental educational background should be taken into consideration in the management of these families.

Increased Incidence of Mental Disorders in Children with Cataract: Findings from a Population-based Study.

PURPOSE: To examine the incidence of mental disorders in children with cataract compared with children without cataract. DESIGN: Nationwide cohort study based on entries in comprehensive national databases. METHODS: The incidence of mental disorders in children born between 2000 and 2017 diagnosed with cataract before 10 years of age (n = 485) was compared with sex- and age-matched controls (n = 4358). Analyses were corrected to somatic disease in the child and parental socioeconomic status and psychiatric morbidity. The study was conducted as 2 university hospitals in Denmark managing children 6 years of age our younger with cataract. RESULTS: The incidence of mental disorders was nearly doubled in children with cataract compared with controls (odds ratio [OR], 1.83; 95% CI, 1.28-3.63). The risk of anxiety disorders was quadrupled (OR, 4.10; 95% CI, 1.90-8.84) and the risk of developmental delay was doubled (OR, 2.66; 95% CI, 1.45-4.90). The risk of mental disorders was significantly higher in children diagnosed with cataract in the first 3 years of life compared with controls (OR, 2.36; 95% CI, 1.53-3.64), whereas those diagnosed with cataract later in childhood did not have an increased risk (OR, 1.24; 95% CI, 0.66-2.30). CONCLUSIONS: The risk of mental disorders, in particular anxiety and neurodevelopmental delay, is markedly increased in children with cataract and even more so in those diagnosed within the first 3 years of life. Psychiatric screening instruments may be integrated in the management of these children.

Optic pathway glioma and the sex association in neurofibromatosis type 1: a single-center study.

BACKGROUND: Low-grade optic pathway glioma (OPG) develops in 15-20% of children with neurofibromatosis type 1 (NF1). OPGs are symptomatic in 30-50% and one-third of these require treatment. A few studies have suggested female sex as a risk factor for visual impairment associated with NF1-OPG. This descriptive study investigated the correlation between NF1-OPG growth, sex and visual impairment. METHOD: We based our cross-sectional study on a systematic, retrospective data collection in a NF1 cohort of children and adolescents below 21 years of age followed at Center for Rare Diseases, Aarhus University Hospital, Denmark. For each patient with OPG a medical chart review was performed including demographics, ophthalmological examinations and magnetic resonance imaging (MRI) of OPG. RESULTS: Of 176 patients with NF1 (85 females, 91 males), we identified 21 patients with OPG (11.9%) with a preponderance of females, p = 0.184. Eight females (62%) and one male (13%) had visual impairment at the last ophthalmological evaluation. Five out of 21 children with OPG (24%) underwent diagnostic MRI because of clinical findings at the ophthalmological screening. Nine children (43%) had symptoms suggestive of OPG and seven (33%) experienced no OPG-related symptoms before the diagnostic MRI. Of eight children diagnosed with OPG ≤ two years of age, one had visual impairment. Of 13 children diagnosed > two years of age, eight had visual impairment; in each group, four of the children were treated with chemotherapy. The study suggested no correlation between NF1-OPG growth and sex. CONCLUSION: Our data suggest sex as a risk factor for visual impairment, while an OPG diagnose ≤ two years of age was a protective factor for visual impairment. Females with NF1-OPG had a higher prevalence of visual impairment outcome compared to males. Interestingly, our data also suggest a better response to treatment in children with OPG diagnosed ≤ two years of age compared to older children. The findings in our study suggest sex as a potential prognostic factor for visual impairment.

TUBB3 Arg262His causes a recognizable syndrome including CFEOM3, facial palsy, joint contractures, and early-onset peripheral neuropathy.

Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype-phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.

[Diagnosis, monitoring and treatment of tuberous sclerosis complex].

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder with highly varying disease manifestations, many of which cause extensive morbidity. There are international consensus criteria for the diagnosis, monitoring and treatment of TSC, and approved medical treatment for some of the most serious disease manifestations. However, organisation of a rational and coordinated care of TSC patients involves many different medical specialities and is only sparsely described. This review describes the interdisciplinary care of TSC patients at Aarhus University Hospital, Denmark.

Children with congenital and childhood cataract require frequent follow-up visits and examinations in general anaesthesia: considerations for the strain on families.

BACKGROUND: Children with cataract require frequent monitoring to detect complications, adjust refractive correction and treat amblyopia. This is time consuming for the families. The aim of the study was to evaluate how often children with cataract are seen as outpatients or under general anaesthesia during the first 7 years of life. METHODS: We performed a retrospective chart review of all children with congenital and childhood cataract born between 2000 primo and 2017 seen at our institution. The cumulated number of outpatient visits and examinations and/or surgeries in general anaesthesia was extracted for age 1, 3, 5 and 7 years. RESULTS: Children who had cataract surgery were seen significantly more often than children without surgery. During the first year of life, children with bilateral surgery had a median of nine outpatient visits, children with unilateral cataract had 11 and children without surgery had five outpatient visits. At 7 years of age, half of the children operated bilaterally before 1 year of age had undergone at least five procedures/examinations in general anaesthesia versus 1/4 of those with unilateral surgery and none of those without surgery. Children were seen less frequently with advancing age. CONCLUSION: The management, treatment and follow-up of children with cataract are demanding, requiring frequent hospital visits and repeated examinations and/or surgical procedures in general anaesthesia over many years, but mainly during the first year of life. Surgical patients are more complex and require closer follow-up. This message is important to convey to the parents at the onset of the disease.

The area of fixation covaries with short-term changes in visual acuity after anti-vascular endothelial growth factor treatment in patients with diabetic macular oedema.

PURPOSE: Diabetic maculopathy can be treated with intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors. However, the therapy is not effective in all patients, and it would be desirable to have parameters for differentiating patients who will benefit from treatment from those who will not. Retinal fixation has been shown to be impaired in patients with low visual acuity (VA) secondary to macular disease, but the changes in fixational eye movements after anti-VEGF treatment for diabetic maculopathy have not been investigated. METHODS: Retinal fixation was studied in 29 patients with diabetic macular oedema before three monthly anti-VEGF injections, and 1 and 4 months after the last injection. The change in VA was correlated with changes in area, frequency, amplitude and total number of fixational saccades. RESULTS: During three monthly injections, best-corrected visual acuity (BCVA) increased from (mean ± SD) 74.0 ± 11.5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters to 78.3 ± 9.8 ETDRS letters, (p = 0.003) and central retinal thickness (CRT) decreased from (mean ± SD) 441.7 ± 107.0 µm to 339.5 ± 74.2 µm, (p = <0.0001), which was followed by the opposite changes after treatment (BCVA reduced nonsignificantly to 77.5 ± 10.4 ETDRS letters (p = 0.06), and CRT increased to 393.0 ± 9.8 µm, p = <0.0001). Both improvement and worsening of BCVA correlated with the fixation area (r2  = 0.28, p = 0.003 and r2  = 0.14, p = 0.045, respectively), but only improvement of BCVA correlated with the frequency (r2  = 0.15, p = 0.037) and total number of saccades (r2  = 0.18, p = 0.02). BCVA showed no correlation with the amplitude and most frequently occurring saccade amplitude. CONCLUSION: Fixational eye movements may be used to monitor short-term effects of anti-VEGF treatment on diabetic macular oedema. Future studies should aim at investigating a possible predictive value of fixational eye movements for visual function in the long term.

Binocular Fixation Reduces Fixational Eye Movements in the Worst Eye of Patients with Center-Involving Diabetic Macular Edema.

PURPOSE: Treatment of diabetic maculopathy with vascular endothelial growth factor inhibitors is in some patients ineffective, and, therefore, parameters predicting visual outcome after treatment should be identified. It has been shown that fixational saccades are increased in patients with reduced visual acuity secondary to diabetic maculopathy, but it is unknown to what extent these saccades in an eye affected by diabetic maculopathy are influenced by the other eye during binocular fixation. METHODS: In 57 eyes from 29 diabetic patients with clinically significant macular edema, fixational eye movements were recorded using the iView X™ video-based eye tracker, and quantitative measures of fixation with the worst eye obtained during monocular and binocular fixation were compared. RESULTS: Fixational saccades during monocular fixation had a significantly higher frequency (p = 0.005), a larger amplitude (p = 0.03), and involved a larger retinal area (p = 0.02) than during binocular fixation. There was a significant negative correlation (r2 = 0.18, p = 0.02) between visual acuity and the area of fixation during monocular but not during binocular fixation (r2 = 0.007, p = 0.68). CONCLUSION: Binocular fixation can reduce the area of fixation and the amplitude of fixational saccades in the worst eye of patients with diabetic maculopathy. Fixational saccades in diabetic maculopathy should be studied during monocular fixation.

The frequency of small saccades during fixation is age independent in children between 5 and 16 years of age.

PURPOSE: Fixational eye movements are necessary for maintaining normal vision by preventing a stabilized image on the retina that would result in visual fading. The movements can be divided into tremor, drifts and saccades that may be related to movements of gaze and to fixation. It has previously been shown that the frequency of fixational saccades with an amplitude larger than 3° depends on age. The purpose of this study was to investigate whether other parameters describing fixational saccades also depend on age which necessitates age correction in studies of fixation during visual development. METHODS: Fixational eye movements were recorded in 36 normal children aged 5-16 years. Parameters describing fixational saccades were characterized using a standardized algorithm and were correlated with age. RESULTS: There was a significant linear relation between the amplitude and duration of fixational saccades (r2  = 0.37, p < 0.0001). The relation between the number of saccadic movements and the amplitude was unimodal and showed no correlation with age. However, the number of saccades per examination with an amplitude larger than 1° showed a negative correlation with age (r2  = 0.23, p = 0.003). CONCLUSIONS: The overall frequency and amplitude of fixational saccades show no correlation with age that necessitates correction in clinical studies of visual development. The decreasing frequency of large saccadic eye movements with increasing child age may be due to improved attention.

The predictive value of subjective symptoms and clinical signs for the presence of treatment-requiring exudative age-related macular degeneration.

PURPOSE: The introduction of vascular endothelial growth factor inhibitors for the treatment of exudative age-related macular degeneration (AMD) has increased the referral rates of AMD patients with visual symptoms to treating centres considerably. However, a large proportion of the referred patients do not qualify for treatment implying that considerable resources could be saved if these patients could be identified on the basis of the clinical data available in the referring nonspecialized setting. METHODS: A prospective observational study of 1682 consecutive patients referred with suspicion of exudative AMD qualifying for intravitreal angiostatic treatment. On the basis of the structured interviewing about symptoms, ophthalmoscopy, optical coherence tomography scanning, and fluorescein angiography, the patients were divided into two groups: one qualifying for and another not qualifying for treatment. Multiple logistic regression was used to identify independent parameters predicting the need for treatment. RESULTS: The presence of metamorphopsia, dyschromatopsia, retinal haemorrhages and exudates, central retinal thickness, and the absence of micropsia were highly significant individual determinants of treatment-requiring AMD. Sudden onset and worsening of symptoms and the presence of a central dark spot covaried with the occurrence of retinal haemorrhages, whereas reduced visual acuity and blurred vision covaried with the presence of both haemorrhages and exudates. CONCLUSION: Patients with treatment-requiring AMD can be reliably identified by questioning about the presence of metamorphopsia and dyschromatopsia and the absence of micropsia, combined with ophthalmoscopical detection of retinal haemorrhages and exudates. This information may improve the triage of patients considered for referral.