PURPOSE: To evaluate the finding of anomalous superior oblique muscles in congenital fibrosis of the extraocular muscles (CFEOM), a feature not previously emphasized in this condition. METHODS: The medical records of all patients clinically or genetically diagnosed with CFEOM at Boston Children's Hospital between 2010 and 2018 were reviewed retrospectively. Those who underwent strabismus surgery during the study period were included in the analysis. Baseline patient characteristics, type of CFEOM, results of genetic testing, and intraoperative features of the superior oblique muscle or tendon were recorded. RESULTS: Of 24 patients identified (age range, 1 month to 62 years), 10 (42%) had genetically confirmed CFEOM, and 22 underwent strabismus surgery, 14 (64%) involving the superior oblique muscle. Of these, 7 (50%) had anomalously inserted tendons (most commonly attached nasal to the superior rectus muscle), whereas 7 (50%) had increased superior oblique muscle tension. CONCLUSIONS: Half of CFEOM patients who underwent superior oblique surgery had abnormally inserted superior oblique tendons, and 50% had tight muscles or abnormally thin tendons, findings that have not been well-characterized in this condition. The findings suggest that abnormal insertion of the superior oblique muscles and tendons are additional features of the disease process in CFEOM that have not been described previously. These features may contribute to the severe upgaze limitation in CFEOM and highlight the importance of superior oblique tenotomy in surgical management.
PURPOSE: Many bilateral amblyopia patients have asymmetric visual acuity (VA). There is no standard treatment for these patients, and outcomes have not been well described. Our goal is to compare VA outcomes in this group based on timing of occlusion therapy. DESIGN: Retrospective interventional comparative case series. METHODS: Setting: Institutional practice. PatientPopulation: Patients diagnosed with amblyopia at Boston Children's Hospital between 2010 and 2014. InclusionCriteria: VA ≥ 0.3 logMAR bilaterally by objective optotype-based measures, interocular difference (IOD) ≥ 0.18 logMAR, age 2-12 years. ExclusionCriteria: Loss to follow-up, managed surgically, deprivation amblyopia. Patients had either primary or secondary occlusion (primary = initiated when VA ≥ 0.3 logMAR bilaterally; secondary = initiated to correct residual IOD once VA improved to ≤0.18 logMAR in the stronger eye). ObservationProcedure: Patient demographics, VA, IOD, and stereopsis were compared between groups. OutcomeMeasures: VA improvement at 12-18 months and at last visits. RESULTS: Of 2,200 patients reviewed, 167 (7.6%) had asymmetric, bilateral amblyopia; 98 met inclusion and exclusion criteria. Patients were equally divided between primary (n = 50) and secondary (n = 48) occlusion groups. There were no differences in demographics, baseline VA, or IOD between groups (P ≥ .22), although the primary occlusion group had a higher proportion of strabismic amblyopia (P = .007). VA in both eyes, IOD, and stereopsis improved similarly between groups, even after stratifying by amblyopia subtype (P ≥ .48). The secondary occlusion group was more likely to achieve 20/30 bilaterally and IOD ≤ 1 line at 12-18 months (P ≤ .4), although this equalized by the last visit. CONCLUSION: In patients with asymmetric, bilateral amblyopia, VA improved by 4 lines in the weaker eye and 2 lines in the stronger eye, while IOD improved by 2 lines, irrespective of occlusion status. Primary occlusion thus provided no further benefit over spectacle correction alone.
We analyzed clinical and histopathologic data of 97 pediatric patients who underwent excision of dermoid cysts. On review, 16.5% of the sample population demonstrated localized chronic inflammatory changes, including the presence of giant cells and epithelial disruption. These features were considered indicative of prior cyst rupture. Age at time of initial presentation was significantly older and cyst size was significantly larger in patients with histopathologic signs of previous rupture. Longer time to presentation and time to excision were associated with increased odds of spontaneous rupture.
Importance: To facilitate drug and device development for neonates, the International Neonatal Consortium brings together key stakeholders, including pharmaceutical companies, practitioners, regulators, funding agencies, scientists, and families, to address the need for objective, standardized clinical trial outcome measurements to fulfill regulatory requirements. Retinopathy of prematurity (ROP) is a disease that affects preterm neonates. The current International Classification of Retinopathy of Prematurity does not take into account all of the characteristics of ROP and does not adequately discriminate small changes in disease after treatment. These factors are critical for evaluating outcomes in clinical trials. Observations: There is need for an updated ROP acute disease activity and structure scale as well as end-stage structure and ophthalmologic outcome measures designed for use at different ages. The scale and measures, based on current diagnostic methods and treatments, could be used as a guideline for clinical intervention trials. The scale is intended to be validated against retrospective data and revised for use in future trials. An iterative revision process can be accomplished if new measures are added to clinical trials and evaluated at the end of each trial for prognostic value. The new measures would then be incorporated into a new version of the activity scale and the outcome measures revised. Conclusions and Relevance: An ROP activity scale and outcome measures to obtain the most robust and discriminatory data for clinical trials are needed. The scales should be dynamic and modified as knowledge and imaging modalities improve and then validated using data from well-documented clinical trials. This approach is relevant to improving clinical trial data quality.
Retinopathy of prematurity occurs because the retina of a preterm infant at birth is incompletely vascularized, and if the postnatal environment does not match the in utero environment that supported retinal development, the vessels and neural retina will not grow normally. Risk factors determined from many clinical studies and animal studies fall into 2 categories: prenatal factors and postnatal factors.
We present a case of bilateral ankyloblepharon filiforme adnatum in 1-day-old girl and describe our surgical approach. The bands connecting the upper and lower eyelids of both eyes were severed using blunt scissors. Point bleeding at the cut bands stopped in 1-2 minutes, without the need for cauterization or compression. The patient was able to open her eyes shortly after the procedure, as she woke up from anesthesia. Examination under general anesthesia showed normal eye examination appropriate for age. Postoperatively, the patient maintained open palpebral fissures. Visual development over 3 years' follow-up was normal.
Importance: Anti-vascular endothelial growth factor (VEGF) therapies are a novel treatment option in retinopathy of prematurity (ROP). Data on dosing, efficacy, and safety are insufficient. Objective: To investigate lower doses of anti-VEGF therapy with ranibizumab, a substance with a significantly shorter systemic half-life than the standard treatment, bevacizumab. Design, Setting, and Participants: This randomized, multicenter, double-blind, investigator-initiated trial at 9 academic medical centers in Germany compared ranibizumab doses of 0.12 mg vs 0.20 mg in infants with bilateral aggressive posterior ROP; ROP stage 1 with plus disease, 2 with plus disease, or 3 with or without plus disease in zone I; or ROP stage 3 with plus disease in posterior zone II. Patients were recruited between September 2014 and August 2016. Twenty infants were screened and 19 were randomized. Interventions: All infants received 1 baseline ranibizumab injection per eye. Reinjections were allowed in case of ROP recurrence after at least 28 days. Main Outcomes and Measures: The primary end point was the number of infants who did not require rescue therapy at 24 weeks. Key secondary end points included time-to-event analyses, progression of physiologic vascularization, and plasma VEGF levels. Stages of ROP were photodocumented and reviewed by an expert committee. Results: Nineteen infants with ROP were enrolled (9 [47.4%] female; median [range] postmenstrual age at first treatment, 36.4 [34.7-39.7] weeks), 3 of whom died during the study (1 in the 0.12-mg group and 2 in the 0.20-mg group). Of the surviving infants, 8 (88.9%) (17 eyes [94.4%]) in the 0.12-mg group and 6 (85.7%) (13 eyes [92.9%]) in the 0.20-mg group did not require rescue therapy. Both ranibizumab doses were equally successful in controlling acute ROP (Cochran-Mantel-Haenszel analysis; odds ratio, 1.88; 95% CI, 0.26-13.49; P = .53). Physiologic intraretinal vascularization was superior in the 0.12-mg group. The VEGF plasma levels were not systematically altered in either group. Conclusions and Relevance: This pilot study demonstrates that ranibizumab is effective in controlling acute ROP and that 24% of the standard adult dose (0.12 mg) appears equally effective as 40% (0.20 mg). Superior vascularization of the peripheral retina with 0.12 mg of ranibizumab indicates that the lower dose may be favorable. Unchanged plasma VEGF levels point toward a limited systemic drug exposure after ranibizumab. Trial Registration: clinicaltrials.gov Identifier: NCT02134457 and clinicaltrialsregister.eu Identifier: 2013-002539-13.
BACKGROUND/AIMS: To describe the design and baseline characteristics of patients enrolled in the multicenter, prospective natural history study of Stargardt disease type 4. METHODS: Fifteen eligible patients aged 6 years and older at baseline, harboring disease-causing variants in the PROM1 gene, and with specified ocular lesions were enrolled. They were examined at baseline using a standard protocol, with 6 monthly follow-up visits for a 2-year period including best-corrected ETDRS visual acuity, spectral-domain optical coherence tomography, fundus autofluorescence (FAF), mesopic and scotopic microperimetry (MP). Areas of definitely decreased FAF (DDAF) and questionably decreased FAF were outlined and quantified on FAF images. RESULTS: Amongst the 15 patients (29 eyes) that were enrolled at 5 centers in the USA and Europe, 10 eyes (34.5%) had areas of DDAF with an average lesion area of 3.2 ± 3.5 mm2 (range 0.36-10.39 mm2) at baseline. The mean retinal sensitivity of the posterior pole derived from mesopic MP was 8.8 ± 5.8 dB. CONCLUSIONS: Data on disease progression in PROM1-related retinopathy from this study will contribute to the characterization of the natural history of disease and the exploration of the utility of several modalities to track progression and therefore to potentially be used in future interventional clinical trials.
The retina is one of the most metabolically active tissues in the body, consuming high levels of oxygen and nutrients. A well-organized ocular vascular system adapts to meet the metabolic requirements of the retina to ensure visual function. Pathological conditions affect growth of the blood vessels in the eye. Understanding the neuronal biological processes that govern retinal vascular development is of interest for translational researchers and clinicians to develop preventive and interventional therapeutics for vascular eye diseases that address early drivers of abnormal vascular growth. This review summarizes the current knowledge of the cellular and molecular processes governing both physiological and pathological retinal vascular development, which is dependent on the interaction among retinal cell populations, including neurons, glia, immune cells, and vascular endothelial cells. We also review animal models currently used for studying retinal vascular development.
We report a case of juvenile xanthogranuloma in a 12-month-old girl presenting with heterochromia, hyphema, and elevated intraocular pressure. This case demonstrates new ultrasound biomicroscopy iris findings of a generalized bumpy iris contour, suggesting diffuse heterogeneous involvement. This imaging finding has not been previously described. Untreated, iris juvenile xanthogranuloma may lead to corneal blood staining, glaucoma, and amblyopia. An understanding of the full range of ultrasound features of juvenile xanthogranuloma expands our appreciation for the clinical findings in this condition.
Testi I, Agrawal R, Mahajan S, Agarwal A, Gunasekeran DV, Raje D, Aggarwal K, Murthy SI, Westcott M, Chee S-P, McCluskey P, Ho SL, Teoh S, Cimino L, Biswas J, Narain S, Agarwal M, Mahendradas P, Khairallah M, Jones N, Tugal-Tutkun I, Babu K, Basu S, Carreño E, Lee R, Al-Dhibi H, Bodaghi B, Invernizzi A, Goldstein DA, Herbort CP, Barisani-Asenbauer T, González-López JJ, Androudi S, Bansal R, Moharana B, Esposti SD, Tasiopoulou A, Nadarajah S, Agarwal M, Abraham S, Vala R, Singh R, Sharma A, Sharma K, Zierhut M, Kon OM, Cunningham ET, Kempen JH, Nguyen QD, Pavesio C, Gupta V. The Collaborative Ocular Tuberculosis Study (COTS)-1: A Multinational Descriptive Review of Tubercular Uveitis in Paediatric Population. Ocul Immunol Inflamm 2020;:1-7.Abstract
PURPOSE: To examine disease profile of tubercular uveitis (TBU) in Paediatric population. METHODS: Among 945 patients of the retrospective multinational study by the Collaborative Ocular Tuberculosis Study (COTS)-1, 29 Paediatric patients diagnosed with TBU were analyzed. RESULTS: Mean age of disease presentation was 12.8 (range 4-18 years), with predominance of males (n = 14/20; 70.0%) and Asian ethnicity (n = 25/29; 86.2%). Posterior uveitis (n = 14/28; 50%) was the most frequent uveitis phenotype, with choroidal involvement occurring in 64.7% (n = 11/17). Incidence of optic disc edema and macular edema was higher in children (n = 8/18; 44.4% and n = 5/18; 27.8%, respectively) than in adults (n = 160/942; 16.9% and n = 135/942; 14.3%, respectively). Comparison of optic disc edema between subgroups showed a significant difference (). All patients received oral corticosteroids, most of them with antitubercular therapy. Treatment failure developed in 4.8% (n = 1/21). CONCLUSIONS: Children have a more severe inflammatory response to the disease, and an intensive anti-inflammatory therapeutic regimen is required to achieve a positive treatment outcome.
A 13-year-old male with suprasellar cystic craniopharyngioma initially controlled with sequential subtotal resections and proton-beam irradiation was later treated with intracystic pegylated interferon α-2b due to progression and a lack of further surgical options. After initial successful control of recurrent cyst enlargement and stabilization of the ophthalmic examination, progressive and irreversible visual field loss ensued. Imaging revealed intracranial leakage from the intracystic catheter, and direct administration of interferon α-2b was discontinued. Given the recent interest in interferon α-2b, oncologists are advised to vigilantly monitor patients for signs of local toxicity that may result from unintended leakage during intracystic delivery.
Dural cerebral veins (CV) are required for cerebrospinal fluid reabsorption and brain homeostasis, but mechanisms that regulate their growth and remodeling are unknown. We report molecular and cellular processes that regulate dural CV development in mammals and describe venous malformations in humans with craniosynostosis and TWIST1 mutations that are recapitulated in mouse models. Surprisingly, Twist1 is dispensable in endothelial cells but required for specification of osteoprogenitor cells that differentiate into preosteoblasts that produce bone morphogenetic proteins (BMPs). Inactivation of Bmp2 and Bmp4 in preosteoblasts and periosteal dura causes skull and CV malformations, similar to humans harboring TWIST1 mutations. Notably, arterial development appears normal, suggesting that morphogens from the skull and dura establish optimal venous networks independent from arterial influences. Collectively, our work establishes a paradigm whereby CV malformations result from primary or secondary loss of paracrine BMP signaling from preosteoblasts and dura, highlighting unique cellular interactions that influence tissue-specific angiogenesis in mammals.
An orbital neoplasm in children is an uncommon clinical finding. Clinical suspicion should be based on many factors, including its location, the nature of onset, associated systemic signs and symptoms, family and social histories, examination findings, and radiographic characteristics. We present two cases of young children of similar age with a rapid-onset orbital mass. In both cases, a circumscribed round lesion was found in the superomedial orbit. An orbital schwannoma, a benign and usually slow growing tumor, was found in the first patient. In contrast, the biopsy of the second patient, who was nearly asymptomatic, revealed a rhabdomyosarcoma. In this review, we have explored the differential diagnosis of relatively common circumscribed round orbital tumors in the pediatric population from both the radiographic (magnetic resonance imaging, MRI) and histopathologic perspectives. A review of highly unusual orbital tumors in children is also provided.
PURPOSE: To review the published evidence to evaluate the ability of orthokeratology (Ortho-K) treatment to reduce myopic progression in children and adolescents compared with the use of spectacles or daytime contact lenses for standard refractive correction. METHODS: Literature searches of the PubMed database, the Cochrane Library, and the databases of clinical trials were last conducted on August 21, 2018, with no date restrictions but limited to articles published in English. These searches yielded 162 citations, of which 13 were deemed clinically relevant for full-text review and inclusion in this assessment. The panel methodologist then assigned a level of evidence rating to the selected studies. RESULTS: The 13 articles selected for inclusion include 3 prospective, randomized clinical trials; 7 nonrandomized, prospective comparative studies; and 3 retrospective case series. One study provided level I evidence, 11 studies provided level II evidence, and 1 study provided level III evidence. Most studies were performed in populations of Asian ethnicity. Change in axial length was the primary outcome for 10 of 13 studies and change in refraction was the primary outcome for 3 of 13 studies. In these studies, Ortho-K typically reduced axial elongation by approximately 50% over a 2-year study period. This corresponds to average axial length change values of approximately 0.3 mm for Ortho-K patients compared with 0.6 mm for control patients, which corresponds to a typical difference in refraction of approximately 0.5 diopters (D). Younger age groups and individuals with larger than average pupil size may have a greater effect with Ortho-K. Rebound can occur after discontinuation or change to alternative refractive treatment. CONCLUSIONS: Orthokeratology may be effective in slowing myopic progression for children and adolescents, with a potentially greater effect when initiated at an early age (6-8 years). Safety remains a concern because of the risk of potentially blinding microbial keratitis from contact lens wear.
PURPOSE: To review the available evidence on the ocular safety and efficacy of anti-vascular endothelial growth factor (VEGF) agents for the treatment of retinopathy of prematurity (ROP) compared with laser photocoagulation therapy. METHODS: A literature search of the PubMed and Cochrane Library databases was conducted last on September 6, 2016, with no date restrictions and limited to articles published in English. This search yielded 311 citations, of which 37 were deemed clinically relevant for full-text review. Thirteen of these were selected for inclusion in this assessment. The panel methodologist assigned ratings to the selected articles according to the level of evidence. RESULTS: Of the 13 citations, 6 articles on 5 randomized clinical trials provided level II evidence supporting the use of anti-VEGF agents, either as monotherapy or in combination with laser therapy. The primary outcome for these articles included recurrence of ROP and the need for retreatment (3 articles), retinal structure (2 articles), and refractive outcome (1 article). Seven articles were comparative case series that provided level III evidence. The primary outcomes included the effects of anti-VEGF treatment on development of peripheral retinal vessels (1 article), refractive outcomes (1 article), or both structural and refractive or visual outcomes (5 articles). CONCLUSIONS: Current level II and III evidence indicates that intravitreal anti-VEGF therapy is as effective as laser photocoagulation for achieving regression of acute ROP. Although there are distinct ocular advantages to anti-VEGF pharmacotherapy for some cases (such as eyes with zone I disease or aggressive posterior ROP), the disadvantages are that the ROP recurrence rate is higher, and vigilant and extended follow-up is needed because retinal vascularization is usually incomplete. After intravitreal injection, bevacizumab can be detected in serum within 1 day, and serum VEGF levels are suppressed for at least 8 to 12 weeks. The effects of lowering systemic VEGF levels on the developing organ systems of premature infants are unknown, and there are limited long-term data on potential systemic and neurodevelopmental effects after anti-VEGF use for ROP treatment. Anti-VEGF agents should be used judiciously and with awareness of the known and unknown or potential side effects.
PURPOSE: To compare accuracy of intraocular lens (IOL) power calculation formulae in infantile eyes with primary IOL implantation. DESIGN: Comparative case series. METHODS: The Hoffer Q, Holladay 1, Holladay 2, Sanders-Retzlaff-Kraff (SRK) II, and Sanders-Retzlaff-Kraff theoretic (SRK/T) formulae were used to calculate predicted postoperative refraction for eyes that received primary IOL implantation in the Infant Aphakia Treatment Study. The protocol targeted postoperative hyperopia of +6.0 or +8.0 diopters (D). Eyes were excluded for invalid biometry, lack of refractive data at the specified postoperative visit, diagnosis of glaucoma or suspected glaucoma, or sulcus IOL placement. Actual refraction 1 month after surgery was converted to spherical equivalent and prediction error (predicted refraction - actual refraction) was calculated. Baseline characteristics were analyzed for effect on prediction error for each formula. The main outcome measure was absolute prediction error. RESULTS: Forty-three eyes were studied; mean axial length was 18.1 ± 1.1 mm (in 23 eyes, it was <18.0 mm). Average age at surgery was 2.5 ± 1.5 months. Holladay 1 showed the lowest median absolute prediction error (1.2 D); a paired comparison of medians showed clinically similar results using the Holladay 1 and SRK/T formulae (median difference, 0.3 D). Comparison of the mean absolute prediction error showed the lowest values using the SRK/T formula (1.4 ± 1.1 D), followed by the Holladay 1 formula (1.7 ± 1.3 D). Calculations with an optimized constant showed the lowest values and no significant difference between the Holladay 1 and SRK/T formulae (median difference, 0.3 D). Eyes with globe AL of less than 18 mm had the largest mean and median prediction error and absolute prediction error, regardless of the formula used. CONCLUSIONS: The Holladay 1 and SRK/T formulae gave equally good results and had the best predictive value for infant eyes.
Children born very preterm are at greater risk of ophthalmic morbidities, including strabismus, than children born at term. We evaluated perinatal factors associated with strabismus at age 2 years in a large population of infants delivered before 28 weeks' gestation. A total of 996 infants in the multicenter ELGAN (Extremely Low Gestational Age Newborn) study who had a retinal exam in infancy and a developmental assessment at 2 years corrected age are included. Their mothers were interviewed about the pregnancy, and both mother and newborn charts were reviewed. Certified examiners administered the Bayley Scales of Infant Development-II and performed an examination of ocular alignment. Time-oriented logistic regression risk models were created to evaluate the associations of characteristics and exposures with the development of strabismus. Overall, 14% (n = 141) of the children had strabismus at 2 years, and 80% of strabismic children had esotropia. Characteristics associated with strabismus were birth before 26 weeks' gestation, severe fetal growth restriction, and maternal history of aspirin ingestion. Associated postnatal factors included a SNAP-II (Score for Neonatal Acute Physiology) illness severity value ≥30, brain ventriculomegaly, type I retinopathy of prematurity, and ventilator-dependent severe bronchopulmonary dysplasia. Strabismus in very preterm populations is associated with a number of antenatal and postnatal antecedents as well as clinical and imaging correlates indicative of brain damage in these children. Routine ophthalmologic assessments in the early years can allow appropriate and timely interventions.
OBJECTIVE: To report the accuracy of intraocular lens (IOL) power calculations and the early refractive status in pseudophakic eyes of infants in the Infant Aphakia Treatment Study. METHODS: Eyes randomized to receive primary IOL implantation were targeted for a postoperative refraction of +8.0 diopters (D) for infants 28 to 48 days old at surgery and +6.0 D for those 49 days or older to younger than 7 months at surgery using the Holladay 1 formula. Refraction 1 month after surgery was converted to spherical equivalent, and prediction error (PE; defined as the calculated refraction minus the actual refraction) and absolute PE were calculated. Baseline eye and surgery characteristics and A-scan quality were analyzed to compare their effect on PE. MAIN OUTCOME MEASURES: Prediction error. RESULTS: Fifty-six eyes underwent primary IOL implantation; 7 were excluded for lack of postoperative refraction (n = 5) or incorrect technique in refraction (n = 1) or biometry (n = 1). Overall mean (SD) absolute PE was 1.8 (1.3) D and mean (SD) PE was +1.0 (2.0) D. Absolute PE was less than 1 D in 41% of eyes but greater than 2 D in 41% of eyes. Mean IOL power implanted was 29.9 D (range, 11.5-40.0 D); most eyes (88%) implanted with an IOL of 30.0 D or greater had less postoperative hyperopia than planned. Multivariate analysis revealed that only short axial length (<18 mm) was significant for higher PE. CONCLUSIONS: Short axial length correlates with higher PE after IOL placement in infants. Less hyperopia than anticipated occurs with axial lengths of less than 18 mm or high-power IOLs. Application to Clinical Practice Quality A-scans are essential and higher PE is common, with a tendency for less hyperopia than expected. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00212134.