Pediatric Ophthalmology

Elhusseiny AM, Bishop K, Staffa SJ, Zurakowski D, Hunter DG, Mantagos IS. Virtual reality prototype for binocular therapy in older children and adults with amblyopia. J AAPOS 2021;Abstract
PURPOSE: To evaluate the best-corrected visual acuity and stereoacuity gains in children >7 years of age and adults with unilateral amblyopia treated with a prototype virtual reality-based binocular amblyopia therapy. METHODS: In this randomized, double masked, cross-in clinical trial, patients at Boston Children's Hospital with unilateral anisometropic and/or strabismic amblyopia and history of prior amblyopia treatment failure were randomized to either a full-treatment group (8 weeks of binocular treatment using therapeutic software application in virtual reality headset) or a sham-crossover group (4 weeks of sham treatment followed by 4 weeks of binocular treatment). Amblyopic eye visual acuity and stereoacuity were evaluated at 4, 8, and 16 weeks' follow-up. RESULTS: The study cohort included 20 participants (10 females), with a median age of 9 years (range, 7-38 years). In the full-treatment group (11 patients), the mean amblyopic eye logMAR visual acuity at 16 weeks was 0.49 ± 0.26, compared with 0.47 ± 0.20 at baseline. In the sham-crossover group, it was 0.51 ± 0.18 at 16 weeks, compared with 0.53 ± 0.21 at baseline. Stereoacuity (log arcsec) was significantly improved, from 7.3 ± 2 at baseline to 6.6 ± 2.3 at 8 weeks (P < 0.001) and 6.7 ± 2.6 at 16 weeks (P < 0.001). No significant adverse events (diplopia, asthenopia, or worsening strabismus) were noted in either group. CONCLUSIONS: Although the virtual reality-based prototype for binocular amblyopia therapy did not significantly improve visual acuity in the amblyopic eyes of older children and adults, stereoacuity did significantly improve compared with baseline; improvements were clinically minute. However, larger studies are required to confirm the results.
Elhusseiny AM, VanderVeen DK. Optical coherence tomography in the setting of optic nerve head cupping reversal in secondary childhood glaucoma. J AAPOS 2021;Abstract
Reversal of optic nerve head (ONH) cupping has been considered an important clinical observation that signals surgical success and control of intraocular pressure (IOP) in childhood glaucoma. Many theories based on elasticity of pediatric eyes have been proposed, including anterior movement of the elastic lamina cribrosa or shrinkage of the scleral canal. The relationship between these factors and axonal loss is unclear when reversal of cupping has been observed. Retinal nerve fiber layer (RNFL) optical coherence tomography (OCT) can help to clarify this. We present a case series of 4 pediatric patients with secondary glaucoma that demonstrated ONH cupping reversal with pre- and postoperative clinical images and RNFL OCT.
Chang MY, Morrison DG, Binenbaum G, Heidary G, Trivedi RH, Galvin JA, Pineles SL. Home- and Office-Based Vergence and Accommodative Therapies for Treatment of Convergence Insufficiency in Children and Young Adults: A Report by the American Academy of Ophthalmology. Ophthalmology 2021;128(12):1756-1765.Abstract
PURPOSE: To review home- and office-based vergence and accommodative therapies for treatment of convergence insufficiency (CI) in children and young adults up to 35 years of age. METHODS: Literature searches were conducted through October 2020 in the PubMed database for English-language studies. The combined searches yielded 359 abstracts, of which 37 were reviewed in full text. Twelve of these were considered appropriate for inclusion in this assessment and assigned a level of evidence rating by the panel methodologist. RESULTS: Of the 12 studies included in this assessment, 8 were graded as level I evidence, 2 were graded as level II evidence, and 2 were graded as level III evidence. Two of the level I studies included older teenagers and young adults; the remainder of the studies exclusively evaluated children. Two randomized controlled trials found that office-based vergence and accommodative therapies were effective in improving motor outcomes in children with symptomatic CI. However, the studies reported conflicting results on the efficacy of office-based therapy for treating symptoms of CI. Data were inconclusive regarding the effectiveness of home-based therapies (including pencil push-ups and home computer therapy) compared with home placebo. In young adults, office-based vergence and accommodative therapies were not superior to placebo in relieving symptoms of CI. CONCLUSIONS: Level I evidence suggests that office-based vergence and accommodative therapies improve motor outcomes in children with symptomatic CI, although data are inconsistent regarding symptomatic relief. Evidence is insufficient to determine whether home-based therapies are effective.
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.
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.
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.
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.
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.
Jurgens JA, Barry BJ, Lemire G, Chan W-M, Whitman MC, Shaaban S, Robson CD, MacKinnon S, England EM, McMillan HJ, Kelly C, Pratt BM, Pratt BM, O'Donnell-Luria A, MacArthur DG, Boycott KM, Hunter DG, Engle EC. Novel variants in TUBA1A cause congenital fibrosis of the extraocular muscles with or without malformations of cortical brain development. Eur J Hum Genet 2021;29(5):816-826.Abstract
Variants in multiple tubulin genes have been implicated in neurodevelopmental disorders, including malformations of cortical development (MCD) and congenital fibrosis of the extraocular muscles (CFEOM). Distinct missense variants in the beta-tubulin encoding genes TUBB3 and TUBB2B cause MCD, CFEOM, or both, suggesting substitution-specific mechanisms. Variants in the alpha tubulin-encoding gene TUBA1A have been associated with MCD, but not with CFEOM. Using exome sequencing (ES) and genome sequencing (GS), we identified 3 unrelated probands with CFEOM who harbored novel heterozygous TUBA1A missense variants c.1216C>G, p.(His406Asp); c.467G>A, p.(Arg156His); and c.1193T>G, p.(Met398Arg). MRI revealed small oculomotor-innervated muscles and asymmetrical caudate heads and lateral ventricles with or without corpus callosal thinning. Two of the three probands had MCD. Mutated amino acid residues localize either to the longitudinal interface at which α and β tubulins heterodimerize (Met398, His406) or to the lateral interface at which tubulin protofilaments interact (Arg156), and His406 interacts with the motor domain of kinesin-1. This series of individuals supports TUBA1A variants as a cause of CFEOM and expands our knowledge of tubulinopathies.
Jabroun MN, AlWattar BK, Fulton AB. Optical Coherence Tomography Angiography in Prematurity. Semin Ophthalmol 2021;36(4):264-269.Abstract
Purpose: During normal foveal development there is a close interaction between the neurosensory and vascular elements of the fovea making it vulnerable to prematurity and retinopathy of prematurity (ROP). We aim to assess this potential effect on foveal development in preterms evaluated simultaneously with both optical coherence tomography (OCT) and OCT angiography (OCTA).Method: Unrestricted literature search in the PubMed and Cochrane library databases yielded 20 distinct citations. Fifteen were relevant and reviewed.Results: In preterms, OCTA demonstrated a significant decrease in the foveal avascular zone area and an increase in foveal vessel density. OCT showed a decrease in foveal pit depth and an increase in the thickness of the subfoveal retinal layers. Some studies correlated these changes with reduced vision.Conclusion: Changes in the vascular and neurosensory retina were found in premature children. It remains unclear whether this is related to prematurity alone or ROP and its treatment.

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