Pediatric Ophthalmology

Maleki A, Anesi SD, Look-Why S, Manhapra A, Foster SC. Pediatric uveitis: A comprehensive review. Surv Ophthalmol 2021;Abstract
Pediatric uveitis accounts for 5-10% of all uveitis. Uveitis in children differs from adult uveitis in that it is commonly asymptomatic and can become chronic and cause chronic damage to ocular structures. The diagnosis might be delayed for multiple reasons, including the preverbal age and difficulties in examining young children. Pediatric uveitis may be infectious or non-infectious in etiology. The etiology of non-infectious uveitis is presumed to be autoimmune or autoinflammatory. The most common causes of uveitis in this age group are idiopathic and juvenile idiopathic arthritis-associated uveitis. The stepladder approach for the treatment of pediatric uveitis is based on expert opinion and algorithms proposed by multidisciplinary panels. Uveitis morbidities in pediatric patients include cataract, glaucoma, and amblyopia. Pediatric patients with uveitis should be frequently examined until remission is achieved. Once in remission, the interval between follow-up visits can be extended; however, it is recommended that even after remission the child should be seen every 8-12 weeks depending on the history of uveitis and the medications used. Close follow up is also necessary as uveitis can flare up during immunomodulatory therapy. It is crucial to measure the impact of uveitis, it's treatment, and it's complications on the child and the child's family. Visual acuity can be considered as an acceptable criterion for assessing visual function. Additionally, the number of cells in the anterior chamber can be a measure of disease activity. We review different aspects of pediatric uveitis. We discuss the mechanisms of noninfectious uveitis, including autoimmune and autoinflammatory etiologies, and the risks of developing uveitis in children with systemic rheumatologic diseases. We address the risk factors for developing morbidities, the Standardization of Uveitis Nomenclature (SUN) criteria for timing and anatomical classifications and describe a stepladder approach in the treatment of pediatric uveitis based on expert opinion and algorithms proposed by multi-disciplinary panels. We describe the most common entities for each type of anatomical classification and complications of uveitis for the pediatric population. Additionally, we address monitoring of children with uveitis and evaluation of Quality of Life.
Elhusseiny AM, Jabroun M, Rajabi F, Gonzalez E, Alkharashi M. A novel variant in the TSPAN12 gene-presenting as unilateral myopia, pediatric cataract, and heterochromia in a patient with familial exudative vitreoretinopathy. Eur J Ophthalmol 2021;:11206721211027415.Abstract
PURPOSE: To report a case of 16-month-old boy with a novel variant TSPAN12 gene-presenting as unilateral myopia, pediatric cataract, and heterochromia in a patient with familial exudative vitreoretinopathy. OBSERVATION: A 16-month-old otherwise healthy boy was referred to Boston Children's Hospital for evaluation of strabismus. Ocular examination revealed intermittent esotropia, left hypotropia, and limited left eye elevation in both adduction and abduction. Full cycloplegic hyperopic correction of +3.50 diopters (D) over both eyes was given to the patient. Over several months, refraction of the right eye showed progressive myopia (-6.00 D) with new onset iris heterochromia. Fundus examination showed there was a large area of chorioretinal atrophy with abrupt ending of the blood vessels; anterior to the ora serrata there were diffuse vitreous bands and veils that reached the lens anteriorly in direct contact with the lenticular opacity. A novel heterozygous nonsense likely pathogenic variant was identified in the TSPAN12 gene (NM_012338.3) c.315T>A (p.Cys105Ter) confirming the diagnosis of FEVR. CONCLUSION AND IMPORTANCE: Asymmetric FEVR rarely present with unilateral axial myopia however association with acquired heterochromia and cataract has never been reported. We report a case of FEVR caused by a novel TSPAN12 likely pathogenic nonsense variant presenting as unilateral progressive myopia, acquired heterochromia, and pediatric cataract.
Godfrey D, Torres A, Heidary G, Zahoor H, Lee A, Berry G, Engle E. A 7-year old female with arthrogryposis multiplex congenita, Duane retraction syndrome, and Marcus Gunn phenomenon due to a ZC4H2 gene mutation: a clinical presentation of the Wieacker-Wolff syndrome. Ophthalmic Genet 2021;42(5):612-614.Abstract
Background: Duane retraction syndrome and arthrogryposis multiplex congenita have an incidence of approximately 1:1500-1:3000 live births. However, the association of these two entities with a Marcus-Gunn might be a rare and, until now, under-recognized clinical presentation of the Wieacker-Wolff Syndrome.Patient and methods: We report a 7-year-old female with dysmorphic features, global developmental delay, arthrogryposis multiplex congenita (AMC), Duane retraction syndrome (DRS), and unilateral Marcus Gunn jaw winking.Results: Whole Exome Sequencing showed a de novo premature stop codon in ZC4H2. Extensive genetic and metabolic work was negative otherwise and Brain MRI showed delayed non-specific myelination abnormalities. She continues to have significant delays but does not have regression, seizures or other neurological complications. She has required a multidisciplinary approach for the management of her multiple contractures.Conclusion: This case confirms ZC4H2 as a cause of syndromic DRS and extends the ZC4H2 phenotype to include Marcus Gunn jaw winking.
da Cunha LP, Cavalcante Costa MAA, de Miranda HA, Reis Guimarães J, Aihara T, Ludwig CA, Rosenblatt T, Callaway NF, Pasricha M, Al-Moujahed A, Vail D, Ji MH, Kumm J, Moshfeghi DM. Comparison between wide-field digital imaging system and the red reflex test for universal newborn eye screening in Brazil. Acta Ophthalmol 2021;99(7):e1198-e1205.Abstract
PURPOSE: To compare neonatal eye screening using the red reflex test (RRT) versus the wide-field digital imaging (WFDI) system. METHODS: Prospective cohort study. Newborns (n = 380, 760 eyes) in the Maternity Ward of Irmandade Santa Casa de Misericórdia de São Paulo hospital from May to July 2014 underwent RRT by a paediatrician and WFDI performed by the authors. Wide-field digital imaging (WFDI) images were analysed by the authors. Validity of the paediatrician's RRT was assessed by unweighted kappa [κ] statistic, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). RESULTS: While WFDI showed abnormalities in 130 eyes (17.1%), RRT was only abnormal in 13 eyes (1.7%). Wide-field digital imaging (WFDI) detected treatable retina pathology that RRT missed including hyphema, CMV retinitis, FEVR and a vitreous haemorrhage. The sensitivity of the paediatrician's RRT to detect abnormalities was poor at 0.77% (95% confidence interval, CI, 0.02%-4.21%) with a PPV of only 7.69% (95% CI, 1.08%-38.85%). Overall, there was no agreement between screening modalities (κ = -0.02, 95% CI, -0.05 to 0.01). The number needed to screen to detect ocular abnormalities using WFDI was 5.9 newborns and to detect treatable abnormalities was 76 newborns. CONCLUSION: While RRT detects gross abnormalities that preclude visualization of the retina (i.e. media opacities and very large tumours), only WFDI consistently detects subtle treatable retina and optic nerve pathology. With a higher sensitivity than the current gold standard, universal WFDI allows for early detection and management of potentially blinding ophthalmic disease missed by RRT.
Oke I, Vanderveen D. Machine Learning Applications in Pediatric Ophthalmology. Semin Ophthalmol 2021;36(4):210-217.Abstract
Purpose : To describe emerging applications of machine learning (ML) in pediatric ophthalmology with an emphasis on the diagnosis and treatment of disorders affecting visual development. Methods : Literature review of studies applying ML algorithms to problems in pediatric ophthalmology. Results : At present, the ML literature emphasizes applications in retinopathy of prematurity. However, there are increasing efforts to apply ML techniques in the diagnosis of amblyogenic conditions such as pediatric cataracts, strabismus, and high refractive error. Conclusions : A greater understanding of the principles governing ML will enable pediatric eye care providers to apply the methodology to unexplored challenges within the subspecialty.
Olson HE, Costantini JG, Swanson LC, Kaufmann WE, Benke TA, Fulton AB, Hansen R, Poduri A, Heidary G. Cerebral visual impairment in CDKL5 deficiency disorder: vision as an outcome measure. Dev Med Child Neurol 2021;63(11):1308-1315.Abstract
AIM: To characterize the neuro-ophthalmological phenotype of cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) and assess visual acuity as a reproducible, quantitative outcome measure. METHOD: We retrospectively analyzed clinical data from patients with CDD. Complete neuro-ophthalmological assessments, including visual acuity, were evaluated. RESULTS: Of 26 patients (22 females, four males; median age 4y, interquartile range 2y 1mo-7y 10mo), cerebral visual impairment (CVI), defined as visual dysfunction in the absence of ocular or anterior visual pathway abnormalities, was diagnosed in all those over 2 years of age. Ophthalmological examinations revealed nystagmus in 10 patients and strabismus in 24 patients. Visual acuity was measured in 24 patients, by preferential looking in all and by sweep visual evoked potential in 13. Visual acuities were lower than age expectations and demonstrated improvement in the first 3 years. Adjusting for age and sex, average preferential looking visual acuity after 2 years of age was higher in patients with intact mobility than in those who were non-mobile. INTERPRETATION: CVI was observed in patients with CDD. Visual acuity improved over time and correlated with mobility. Visual acuity, as a quantifiable measure of visual function, should be considered as an outcome measure in pre-clinical and clinical studies for CDD. What this paper adds Cerebral visual impairment is highly prevalent in cyclin-dependent kinase-like 5 deficiency disorder (CDD). Visual acuity is a measurable quantitative outcome measure in CDD. Visual acuity in CDD correlates with gross motor ability.
Pivodic A, Johansson H, Smith LEH, Hård A-L, Löfqvist C, Yoder BA, Hartnett EM, Wu C, Bründer M-C, Lagrèze WA, Stahl A, Al-Hawasi A, Larsson E, Lundgren P, Gränse L, Sunnqvist B, Tornqvist K, Wallin A, Holmström G, Albertsson-Wikland K, Nilsson S, Hellström A. Development and validation of a new clinical decision support tool to optimize screening for retinopathy of prematurity. Br J Ophthalmol 2021;Abstract
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.
Shoshany TN, Chinn RN, Staffa SJ, Bishop K, Michalak S, Hunter DG. Identifying Characteristics Predictive of Lost-to-follow-up (LTFU) Status in Amblyopia. Am J Ophthalmol 2021;Abstract
PURPOSE: To identify demographic and disease-related characteristics predictive of LTFU status in amblyopia treatment and create a risk model for predicting LTFU status. DESIGN: Retrospective cohort study METHODS: Setting: Single center, ophthalmology department at Boston Children's Hospital (BCH). PATIENTS: 2037 patients treated for amblyopia at BCH between 2010-2014. OBSERVATION PROCEDURE: LTFU was defined as patients who did not return after initial visit, excluding those who came for second opinion. Multiple variables were tested for association with LTFU status. OUTCOME MEASURE: Odds ratio of LTFU risk associated with each variable. Multivariate logistic regression was used to create a risk score for predicting LTFU status. RESULTS: A large proportion of patients (23%) were LTFU after first visit. Older age, non-white race, lack of insurance, previous glasses or atropine treatment, and longer requested follow-up intervals were independent predictors of LTFU status. A multivariable risk score was created to predict probability of LTFU (AUC 0.68). CONCLUSIONS: Our comprehensive amblyopia database allows us to predict which patients are more likely to be LTFU after baseline visit, and develop strategies to mitigate these effects. These findings may help with practice efficiency and improve patient outcomes in the future by transitioning these analyses to an electronic medical record that could be programmed to provide continually updated decision support for individual patients based on large datasets.
Gjerde H, Mantagos IS. Charting the Globe: How Technologies Have Affected Our Understanding of Retinal Findings in Abusive Head Trauma/Shaken Baby Syndrome. Semin Ophthalmol 2021;36(4):205-209.Abstract
Purpose: Ocular findings such as retinal hemorrhages are common in abusive head trauma (AHT). Binocular indirect ophthalmoscopy has been the standard for assessing the eyes of children who are victims of AHT. However, technological advances have changed our understanding of retinal findings in AHT.Methods: Literature review on AHT - retinal findings, imaging technologies, models of representation, and telemedicine applications.Results: Many studies suggest vitreoretinal traction from repetitive acceleration-deceleration shearing forces during shaking plays an important role in the development of retinal findings in AHT. This is further supported by different imaging modalities [optical coherence tomography (OCT); magnetic resonance imaging (MRI); fluorescein angiography (FA)] and models of representation (animal and mechanical models; finite element analysis).Conclusion: Emerging technologies have augmented our diagnostic abilities, enhanced our understanding regarding the pathophysiology of retinal findings, and strengthened the link between vitreoretinal traction and ocular pathology in AHT. Telemedicine is also starting to play an important role in AHT.
Nilsson AK, Andersson MX, Sjöbom U, Hellgren G, Lundgren P, Pivodic A, Smith LEH, Hellström A. Sphingolipidomics of serum in extremely preterm infants: Association between low sphingosine-1-phosphate levels and severe retinopathy of prematurity. Biochim Biophys Acta Mol Cell Biol Lipids 2021;1866(7):158939.Abstract
BACKGROUND: Extremely preterm infants are at risk of developing retinopathy of prematurity (ROP) that can cause impaired vision or blindness. Changes in blood lipids have been associated with ROP. This study aimed to monitor longitudinal changes in the serum sphingolipidome of extremely preterm infants and investigate the relationship to development of severe ROP. METHODS: This is a prospective study that included 47 infants born <28 gestational weeks. Serum samples were collected from cord blood and at postnatal days 1, 7, 14, and 28, and at postmenstrual weeks (PMW) 32, 36, and 40. Serum sphingolipids and phosphatidylcholines were extracted and analyzed by LC-MS/MS. Associations between sphingolipid species and ROP were assessed using mixed models for repeated measures. RESULTS: The serum concentration of all investigated lipid classes, including ceramide, mono- di- and trihexosylceramide, sphingomyelin, and phosphatidylcholine displayed distinct temporal patterns between birth and PMW40. There were also substantial changes in the lipid species composition within each class. Among the analyzed sphingolipid species, sphingosine-1-phosphate showed the strongest association with severe ROP, and this association was independent of gestational age at birth and weight standard deviation score change. CONCLUSIONS: The serum phospho- and sphingolipidome undergoes significant remodeling during the first weeks of the preterm infant's life. Low postnatal levels of the signaling lipid sphingosine-1-phosphate are associated with the development of severe ROP.
Elhusseiny AM, VanderVeen DK. Early Experience With Ahmed Clear Path Glaucoma Drainage Device in Childhood Glaucoma. J Glaucoma 2021;30(7):575-578.Abstract
PURPOSE: The aim was to evaluate the short-term outcomes of Ahmed clear path (ACP) valveless glaucoma drainage device in childhood glaucoma. METHODS: Retrospective chart review of all patients 16 years or below with childhood glaucoma who had ACP implantation at Boston Children's Hospital from December 2019 to June 2020 with at least 6 months follow-up period. RESULTS: The study included 7 eyes of 5 patients implanted by a single surgeon. The median follow-up was 12 months. The mean intraocular pressure (IOP) was reduced from 36±3.5 mm Hg on a mean of 2.7±0.6 glaucoma medications preoperatively to a mean IOP of 12.4±2.8 mm Hg (P<0.001) on a mean of 0.7±0.8 medications postoperatively at final follow-up (P=0.0009). Complete success was achieved in 4 eyes while qualified success was achieved in 3 eyes. CONCLUSION: The ACP glaucoma drainage device provided good short-term IOP control and technical advantages for implantation for pediatric eyes were observed.
Elhusseiny AM, MacKinnon S, Zurakowski D, Huynh E, Dagi LR. Long-term ophthalmic outcomes in 120 children with unilateral coronal synostosis: a 20-year retrospective analysis. J AAPOS 2021;Abstract
BACKGROUND: Prior studies comparing ophthalmic outcomes after treating unicoronal synostosis (UCS) by early endoscopic strip craniectomy (ESC) versus later fronto-orbital advancement (FOA) are modest in sample size, or lack consistent age adjustment. We report long-term, age-adjusted ophthalmic outcomes for a large cohort after nonrandomized treatment by one of these two options. METHODS: The following data was retrieved from a retrospective review of the medical records of patients with treated UCS born since 2000: cycloplegic refractions, sensorimotor examinations, and strabismus procedures before craniofacial repair and postoperatively at approximately 18 and 60 months of age. V-pattern strabismus was graded as mild (absent or + 1/-1 oblique dysfunction) versus moderate-to-severe (≥+2/-2 oblique dysfunction or left to right vertical alignment change of ≥20Δ or ocular torticollis >15°). RESULTS: A total of 120 infants were included: 60 treated by FOA and 60 by ESC. By the late examination, aniso-astigmatism was present in 71.8% of FOA-treated patients and 46% of ESC-treated patients (P < 0.0001). By late examination, the age-adjusted odds ratio of moderate-to-severe V-pattern strabismus after treatment by FOA versus ESC was 2.65 (95% CI, 1.37-6.28; P = 0.02); strabismus surgery was performed in 26 infants treated by FOA compared with 13 treated by ESC (OR = 2.8; P = 0.02). Amblyopia developed in 60% of FOA-treated patients compared with 35% of those treated by ESC (OR 3.0; 95% CI, 1.3-6.7; P = 0.02). CONCLUSIONS: Our age-adjusted ophthalmic results confirm better long-term outcomes after treatment of USC by endoscopic strip craniectomy. Recognition and referral of affected infants by the earliest months of life facilitates the opportunity for endoscopic repair.
Rosenblatt TR, Ji MH, Vail D, Ludwig CA, Al-Moujahed A, Pasricha MV, Callaway NF, Kumm J, Moshfeghi DM. Key factors in a rigorous longitudinal image-based assessment of retinopathy of prematurity. Sci Rep 2021;11(1):5369.Abstract
To describe a database of longitudinally graded telemedicine retinal images to be used as a comparator for future studies assessing grader recall bias and ability to detect typical progression (e.g. International Classification of Retinopathy of Prematurity (ICROP) stages) as well as incremental changes in retinopathy of prematurity (ROP). Cohort comprised of retinal images from 84 eyes of 42 patients who were sequentially screened for ROP over 6 consecutive weeks in a telemedicine program and then followed to vascular maturation or treatment, and then disease stabilization. De-identified retinal images across the 6 weekly exams (2520 total images) were graded by an ROP expert based on whether ROP had improved, worsened, or stayed the same compared to the prior week's images, corresponding to an overall clinical "gestalt" score. Subsequently, we examined which parameters might have influenced the examiner's ability to detect longitudinal change; images were graded by the same ROP expert by image view (central, inferior, nasal, superior, temporal) and by retinal components (vascular tortuosity, vascular dilation, stage, hemorrhage, vessel growth), again determining if each particular retinal component or ROP in each image view had improved, worsened, or stayed the same compared to the prior week's images. Agreement between gestalt scores and view, component, and component by view scores was assessed using percent agreement, absolute agreement, and Cohen's weighted kappa statistic to determine if any of the hypothesized image features correlated with the ability to predict ROP disease trajectory in patients. The central view showed substantial agreement with gestalt scores (κ = 0.63), with moderate agreement in the remaining views. Of retinal components, vascular tortuosity showed the most overall agreement with gestalt (κ = 0.42-0.61), with only slight to fair agreement for all other components. This is a well-defined ROP database graded by one expert in a real-world setting in a masked fashion that correlated with the actual (remote in time) exams and known outcomes. This provides a foundation for subsequent study of telemedicine's ability to longitudinally assess ROP disease trajectory, as well as for potential artificial intelligence approaches to retinal image grading, in order to expand patient access to timely, accurate ROP screening.
Scelfo C, Mantagos IS. Neurotrophic Keratopathy in Pediatric Patients. Semin Ophthalmol 2021;36(4):289-295.Abstract
Purpose: This review provides an overview of the causes and treatment of neurotrophic keratopathy in the pediatric population.Methods: A thorough review of the current literature discussing neurotrophic keratopathy was conducted then summarized.Results:Fourty-nine papers were reviewed. Congenital and acquired causes of neurotrophic keratopathy exist in the pediatric population. Both medical and surgical approaches to treatment have been trialed, albeit to a limited extent, in pediatric patients. Conservative treatment includes topical lubrication and antibiotics to prevent concurrent infectious ulcer formation. Various neurotrophic factors have been trialed in the form of serum drops to restore corneal sensation when conservative measures fail. Surgically, different corneal neurotization techniques have been developed whereby a donor nerve is routed to the anesthetized cornea to restore innervation and sensation. Conclusions: Advances in the treatment of neurotrophic keratopathy have made corneal reinnervation and restoration of vision more easily attainable in pediatric patients.

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