Long-term outcomes of type 1 retinopathy of prematurity following monotherapy with bevacizumab: a Canadian experience.

OBJECTIVE: To report long-term structural, visual, and refractive outcomes after monotherapy with intravitreal bevacizumab injection. DESIGN: Cohort retrospective chart review. PARTICIPANTS: A total of 56 premature infants with type 1 retinopathy of prematurity. METHODS: This is a chart review at 2 Canadian institutions. Inclusion criteria were single injection of 0.625 mg  intravitreal bevacizumab and minimum age at last follow-up of 3 years. Primary outcome was retinal structure. Secondary outcomes were refractive error in spherical equivalent, monocular visual acuity, strabismus, and amblyopia. RESULTS: Fifty-six infants (101 eyes) met inclusion criteria. Mean birth weight was 707 ± 178 g (range, 420-1520 g). Mean gestational age was 25.0 ± 1.3 weeks (range, 22.9-29.7 weeks). Twenty-four eyes were in zone I (24%) and 77 in zone II (76%). Mean postmenstrual age at treatment was 36.9 ± 2.1 weeks (range, 32.8-42.0 weeks). At a mean age of 5.4 ± 1.6 years (range, 3.0-8.0 years), all eyes had a favourable structural outcome with no reactivation requiring treatment. Mean monocular visual acuity was 0.29 ± 0.27 logMAR (range, 0.0-1.3 logMAR; 89 of 101 eyes). Mean spherical equivalent was -1.98 ± 4.91 D (range, -16.63 to +5.38 D; 101 of 101 eyes). Prevalence of emmetropia (>-1.0 to ≤1 D) was 43.6%; low myopia (≥1.0 to <5 D) was 17.8%; high myopia (≥5 to <8 D) was 8.9 %; very high myopia (≥8.0 D) was 12.9%; and hyperopia (>1 D) was 16.8%. Twelve children (23%) had amblyopia, and 17 (32%) developed strabismus. CONCLUSIONS: All patients demonstrated a favourable structural outcome with a single bevacizumab injection without the need for additional laser. We suggest regular monitoring following regression of acute retinopathy of prematurity as an alternative to universal, preplanned delayed prophylactic laser treatment. Future studies to evaluate other aspects of visual function are needed.

Pediatric Ocular Injuries: A 3-Year Follow-up Study of Patients Presenting to a Tertiary Care Clinic in Canada.

PURPOSE: To identify age groups or activities at risk for ocular injuries to provide parents, sports teams, schools, and hospitals with the appropriate tools for prevention strategies. METHODS: A retrospective chart review was conducted of all trauma-related cases from 2013 to 2015 and data were obtained with the use of an electronic medical record. All patients younger than 18 years who presented to the ophthalmology clinic with traumatic ocular injuries were included. RESULTS: A total of 409 patients met the inclusion criteria and all were included in this study. The mean age was 7.74 years. Boys were injured more frequently than girls (60.4%). Most ocular injuries occurred between the ages of 2 and 9 years (51.8%). The most common sport was soccer, followed by ball/ice hockey, which differs from previous study findings. This may highlight the increasing popularity of soccer and the risk it may entail. Injuries occurred at home in 23.2% of cases. Final visual acuity was 20/40 or better in 77% of patients. CONCLUSIONS: These findings are comparable to the authors' previous data and to those of the only other Canadian study done on this subject, with the exception of an increased incidence of soccer-related injuries in the current cohort, highlighting an area important to future prevention strategies. [J Pediatr Ophthalmol Strabismus. 2020;57(3):185-189.].

Three-year observation of children 12 to 35 months old with untreated intermittent exotropia.

PURPOSE: To describe the clinical course of untreated intermittent exotropia (IXT) in children 12-35 months of age followed for 3 years. METHODS: We enrolled 97 children 12-35 months of age with previously untreated IXT who had been randomly assigned to the observation arm of a randomised trial of short-term occlusion versus observation. Participants were observed unless deterioration criteria were met at a follow-up visit occurring at 3 months, 6 months, and 6-month intervals thereafter for 3 years. The primary outcome was deterioration of the IXT by 3 years, defined as (1) a constant exotropia ≥10 prism dioptres (∆) at distance and near (i.e., motor deterioration) or (2) treatment prescribed despite not having met motor deterioration. The primary analysis used the Kaplan-Meier method to determine the cumulative proportion of participants meeting deterioration by three years and 95% confidence interval (CI). RESULTS: The cumulative probability of deterioration by 3 years was 28% (95% CI = 20%-39%). Of the 24 participants meeting the primary outcome of deterioration, seven met motor deterioration and 17 were prescribed treatment without meeting motor deterioration. The cumulative probability of motor deterioration by 3 years was 10% (95% CI = 5%-19%). CONCLUSIONS: Given the modest rate of motor deterioration over three years, watchful waiting may be a reasonable management approach in 12- to 35-month-old children with IXT. To confirm this recommendation would require a long-term randomised trial of immediate treatment versus observation followed by deferred treatment if needed.

Pediatric ocular injuries: a 3-year review of patients presenting to an emergency department in Canada.

BACKGROUND: Ocular traumas represent the most common cause of noncongenital blindness in children. Sports are the second most common cause in children less than 14 years old in Canada. To our knowledge, there have not yet been any reports regarding the causes of pediatric ocular trauma in the Quebec population. The goal of our study was to gather data from the Quebec pediatric population to determine high-risk age groups, sports, or other activities. METHODS: A retrospective study evaluating all patients younger than 18 years who presented with ocular trauma to the Ste-Justine Hospital emergency department between 2007 and 2010. Data obtained included age, sex, activity at the time of injury, mechanism of injury, and visual outcomes. RESULTS: Trauma was more common in males (65%). The mean age was 7.2 years. Injuries occurred more often in the 5-9 year age group, at home, and during free play. Sports-related injuries occurred more often in the 10-18 year age group, with hockey being associated most often with injuries. Visual acuity at presentation was variable, but final acuity was 20/30 or better in 86.7% of cases. In 89% of cases, there was no mention of ocular protection and prevention of injuries in the chart by emergency physicians. CONCLUSION: Our study suggests that ocular injuries may be prevented by better supervision and parental education in the younger population and by mandating ocular protection for sports in high school-aged patients.

Co-delivery of miR-181a and melphalan by lipid nanoparticles for treatment of seeded retinoblastoma.

Melphalan is an efficient chemotherapeutic agent that is currently used to treat retinoblastoma (Rb); however, the inherent risk of immunogenicity and the hazardous integration of this drug in healthy cells is inevitable. MicroRNAs are short non-coding single-stranded RNAs that affect a vast range of biological processes. Previously, we focused on the regulatory role of miR-181a during cancer development and progression. In this manuscript, 171 nm switchable lipid nanoparticles (LNP) co-delivered melphalan and miR-181a with encapsulation efficiencies of 93%. Encapsulation of melphalan in LNP significantly improved its therapeutic efficiency. Gene analysis shows that miR-181a decreases the expression of anti-proliferative gene MAPK1 and anti-apoptotic gene Bcl-2, but significantly increased the expression of pro-apoptotic gene BAX. Our results suggest that the two agents have a complementary effect in reducing the viability of cultured Rb cells (primary and cell line) and decreasing Rb cell counts in an in-vivo xenograft Rb model in rats. Our results suggest that the proposed co-delivery technique significantly increases the therapeutic impact, allows for lower administration of melphalan, and consequently, could minimize the cytotoxic side-effects of this drug.

A Randomized Clinical Trial of Immediate versus Delayed Glasses for Moderate Hyperopia in 1- and 2-Year-Olds.

PURPOSE: Two strategies were compared for managing moderate hyperopia without manifest strabismus among 1- and 2-year-old children: (1) immediate prescription of glasses versus (2) observation without glasses unless reduced distance visual acuity (VA), reduced stereoacuity, or manifest strabismus. DESIGN: Prospective randomized clinical trial. PARTICIPANTS: A total of 130 children aged 1 to 2 years with hyperopia between +3.00 diopters (D) and +6.00 D spherical equivalent (SE) in at least 1 eye, anisometropia ≤1.50 D SE, and astigmatism ≤1.50 D based on cycloplegic refraction and no manifest strabismus. METHODS: Participants were randomly assigned to glasses (1.00 D less than full cycloplegic hyperopia) versus observation and followed every 6 months for 3 years. Glasses were prescribed to those assigned to observation if they met prespecified deterioration criteria of distance VA or near stereoacuity below age norms, or development of manifest strabismus. MAIN OUTCOME MEASURES: At the 3-year primary outcome examination, participants were classified as failing the randomized management regimen if distance VA or stereoacuity was below age norms or manifest strabismus was observed (each with and without correction in trial frames, confirmed by masked retest, irrespective of whether deterioration had occurred previously), or if strabismus surgery had been performed. RESULTS: Of the 106 participants (82%) completing the 3-year primary outcome examination, failure occurred in 11 (21%) of 53 in the glasses group and 18 (34%) of 53 in the observation group (difference = -13%; 95% confidence interval [CI], -31 to 4; P = 0.14). Sixty-two percent (95% CI, 49-74) in the observation group and 34% (95% CI, 23-48) in the glasses group met deterioration criteria (requiring glasses if not wearing). CONCLUSIONS: For 1- and 2-year-olds with uncorrected moderate hyperopia (+3.00 D to +6.00 D SE), our estimates of failure, after 3 years of 6-month follow-ups, are inconclusive and consistent with a small to moderate benefit or no benefit of immediate prescription of glasses compared with careful observation (with glasses only if deteriorated).

The effects of the age of onset of strabismus on monocular and binocular visual function in genetically identical twins.

OBJECTIVE: Both genetic and environmental factors are thought to play a role in the pathogenesis of strabismus and subsequent ocular dominance and amblyopia. Our purpose was to compare the characteristics of sensory visual function in 2 adult monozygotic (genetically identical) twins who presented with esotropia at different ages. METHODS: Monocular and binocular visual function was measured in the twins. Contrast sensitivity was used to assess monocular function. Suppressive and stereoscopic measurements were undertaken to assess binocular function. All tests were run using a 2-alternative forced choice psychophysical procedure. Eighteen short tandem repeats (STR) were genotyped across the genome in both twins to determine their exact relationship. RESULTS: Twin 1 (nondominant eye OD) was diagnosed with esotropia at 6 months of age, whereas twin 2 (nondominant eye OS) was diagnosed with esotropia at 5 years of age. They underwent a similar corrective surgical intervention soon after diagnosis to correct their esodeviations. Monocular contrast sensitivity was poorer for twin 1, particularly at intermediate spatial frequencies. In addition, twin 1 demonstrated complete suppression and unmeasurable stereoscopic function (>300 seconds). On the other hand, twin 2 demonstrated fusion, exhibited only mild suppression, and had near-normal (28 seconds) stereoscopic function. All STR alleles were identical in the twins, proving monozygosity. CONCLUSIONS: Sensory measurements of monocular and binocular visual function in these genetically proven monozygotic twins were significantly different, with the earlier onset of esotropia associated with reduced visual function. Twin 2, whose esotropia was diagnosed at the age of 5 years, had near-normal visual function, both monocularly and binocularly. To the best of our knowledge, this represents the first study of a genetically identical sibling pair with strabismus. By eliminating the genetic differences between these patients, we are able to make powerful observations about the effect of environment on visual function in strabismus.

Relationship among clinical factors in childhood intermittent exotropia.

PURPOSE: To determine the relationships between stereoacuity, control of exotropia, and angle of deviation in children with intermittent exotropia (IXT). METHODS: Data collected for 652 participants 3 to <11 years of age with IXT meeting eligibility criteria for enrollment into one of two multicenter, randomized clinical trials were used to evaluate relationships between stereoacuity, control, and angle of deviation at enrollment. RESULTS: Any level of stereoacuity and angle of deviation could be accompanied by any level of control. Worse distance exotropia control was weakly associated with poorer distance stereoacuity (R = 0.26; 99% CI, 0.17-0.36) and larger angles of deviation at distance (R = 0.27; 99% CI, 0.17-0.36). Worse near exotropia control was weakly associated with poorer near stereoacuity (R = 0.17; 99% CI, 0.07-0.27) and moderately associated with larger angles of deviation at near (R = 0.37; 99% CI, 0.28-0.45). There was no association between stereoacuity and angle of deviation at distance (R = 0.07; 99% CI, -0.03 to 0.17) or at near (R = 0.02; 99% CI, -0.08 to 0.12). CONCLUSIONS: Although weak and moderate associations were found between stereoacuity, control, and angle of deviation, a child may exhibit any combination of stereoacuity, control, and angle of deviation. The specific roles of control, stereoacuity, and angle of deviation in the diagnosis, management, and pathogenesis of IXT are unclear, and each appears to yield somewhat independent information.

Multiple Cranial Nerve Palsies in Giant Cell Arteritis.

Giant cell arteritis (GCA) is a systemic vasculitis of medium and large arteries often with ophthalmic involvement, including ischemic optic neuropathy, retinal artery occlusion, and ocular motor cranial nerve palsies. This last complication occurs in 2%-15% of patients, but typically involves only 1 cranial nerve. We present 2 patients with biopsy-proven GCA associated with multiple cranial nerve palsies.

Two Cases of Retinoblastoma Invading the Optic Nerve Sheath.

The authors report two cases of retinoblastoma with extension along the optic nerve sheath with negative surgical margins, a pattern not considered in current classifications but suggesting a high risk of metastasis. Both patients were treated with adjuvant chemotherapy alone and remain free of extraocular disease 15 and 22 months later. [J Pediatr Ophthalmol Strabismus. 2016;53:e51-e53.].

Adjustable surgical treatment of adult exotropia: postoperative target angles and surgical success.

OBJECTIVES: This study had 3 objectives: (i) to characterize clinical profiles of adults with consecutive exotropia (CXT), intermittent exotropia (IXT), and sensory exotropia (SXT); (ii) to correlate immediate postoperative target angles with successful long-term ocular alignment; and (iii) to compare the efficacy of adjustable versus nonadjustable medial rectus resection ± advancement. STUDY DESIGN: Retrospective, observational, and interventional cohort study. PARTICIPANTS: A total of 133 adult exotropic patients treated surgically at 3 different hospitals between July 2012 and June 2013. METHODS: The patients were divided according to clinical profiles (CXT, IXT, and SXT) based on ophthalmic and orthoptic assessments. Two treatment groups were established: group I-adjustable medial rectus resection ± advancement and adjustable lateral rectus recession; group II-nonadjustable medial resection ± advancement and adjustable lateral rectus recession. Measurements of immediate postadjustment alignment (target angle) and 4-6 months of follow-up alignment were performed and compared between groups. Surgical success was defined as distance primary position alignment within 10 prism diopters (PD) of orthotropia 4-6 months postoperatively. RESULTS: Comparison of clinical profile groups showed that CXT patients had more hyperopia and amblyopia and smaller preoperative deviations; IXT patients had more diplopia and larger preoperative deviations (near > distance); and SXT patients had poor vision in the deviating eye and larger preoperative deviations. Immediate postoperative alignment was 5.2 PD of esodeviation in group I and 3.2 PD of esodeviation in group II. Overall success rates for ocular alignment at 4-6 months postoperatively were comparable with both surgical techniques (74.6% for group I and 74.3% for group II). Patients with a preoperative deviation ≥40 PD had a lower surgical success rate (63.8%) than patients with a deviation <40 PD (80%). Patients presenting with a significant (-1 or worse) abduction deficit in the operated eye at their first visit after surgery had a better success rate at 4-6 months' follow-up (83.3% vs 67.8%). CONCLUSIONS: Adjustable and nonadjustable medial rectus surgeries seem equally successful. Creation of an abduction deficit in the early postoperative period seems predictive of a better outcome. Larger preoperative angles (≥40 PD) were associated with more exotropic drift and a lower percentage of surgical success. Future studies will continue to search for surgical strategies and the ideal target angle that will produce the best long-term alignment stability.

Neurodevelopmental Outcomes Following Bevacizumab Injections for Retinopathy of Prematurity.

BACKGROUND AND OBJECTIVE: Bevacizumab intravitreal injection, a vascular endothelial growth factor inhibitor, is used to treat retinopathy of prematurity (ROP). However, concerns have been raised regarding its systemic absorption and effect on developing tissues including brain. This study compared neurodevelopment at 18 months' corrected age in preterm infants of <29 weeks' gestation treated with bevacizumab versus laser ablation. METHODS: Data from the Canadian Neonatal Network and the Canadian Neonatal Follow-Up Network databases were retrospectively reviewed. Infants born at <29 weeks' in 2010-2011 with treated ROP were studied. Neurodevelopmental outcome at 18 months was assessed by using neurologic examination and the Bayley Scales of Infant and Toddler Development Third Edition. Regression analyses were performed. RESULTS: Of 125 treated infants, 27 received bevacizumab and 98 laser. The bevacizumab group, compared with laser, obtained a median Bayley Scales of Infant and Toddler Development Third Edition motor composite score of 81 (interquartile range, 70-91) versus 88 (79-97), a language composite score of 79 (65-97) versus 89 (74-97), and a cognitive score of 90 (80-100) versus 90 (85-100). Difference was detected on the motor score only (P = .02). Odds of severe neurodevelopmental disabilities (Bayley scores <70, severe cerebral palsy, hearing aids, or bilateral blindness) was 3.1 times higher (95% confidence interval: 1.2-8.4) in infants treated with bevacizumab versus laser after adjusting for gestational age, gender, maternal education, Score for Neonatal Acute Physiology-II score, bronchopulmonary dysplasia, sepsis, and severe brain injury. CONCLUSIONS: Preterm infants treated with bevacizumab versus laser had higher odds of severe neurodevelopmental disabilities. Further investigation on the long-term safety of antivascular endothelial growth factor treatment of ROP is needed.

Tonic pupil after botulinum toxin-A injection for treatment of esotropia in children.

A total of 27 children with esotropia (mean age, 3.9 years; range, 9 months to 13.8 years) were enrolled in a 9-month observational study following botulinum toxin A (BTX-A) injection of one (n = 7) or both (n = 20) medial rectus muscles. BTX-A dosage ranged from 3.0 to 6.0 units per muscle. Three participants developed tonic pupil, noted at the first follow-up visit, occurring 12-19 days after injection. All 3 cases occurred in the left eye of participants who underwent bilateral BTX-A injection by the same surgeon. Anisocoria diminished from a maximum of 4 mm at the 2-week visit to 1-2 mm in all patients over the 9-month postinjection data collection period. No adverse visual outcomes were noted. Tonic pupil is an infrequently reported complication of BTX-A injection for strabismus. The experience of our investigator group suggests the need for careful injection technique and thorough preinjection counseling.

SYK is a target of lymphocyte-derived microparticles in the induction of apoptosis of human retinoblastoma cells.

Retinoblastoma (Rb) is an aggressive childhood cancer of the developing retina. This disease is associated with epigenetic deregulation of several cancer pathways including upregulation of the proto-oncogene spleen tyrosine kinase (SYK). We have previously demonstrated that lymphocyte-derived microparticles (LMPs) possess strong cytotoxic effect on cancer cells. This report demonstrated that LMPs have potent pro-apoptotic properties on human Rb cells, which was associated with a strong reduction of SYK expression. Perturbing SYK activity in Rb cells induced cell apoptosis and upregulated expression of p53 and p21. Interestingly, inhibition of p53 or knockdown of p21, abolished LMP-induced caspase-3 activity and cell death. Blocking oxidized phospholipid-rich LMPs with a specific antibody significantly prevented LMP-induced Rb apoptosis and reversed the expression patterns of SYK, p53, p21. In summary, our results suggest that LMPs are important pro-apoptotic regulators for Rb cells through reduction of SYK expression and upregulation of the p53-p21 pathway which ultimately activates caspase-3. These data may open unexpected avenues for the development of LMPs as a novel therapeutic strategy that would be particularly useful and relevant for the treatment of Rb.

Anti-proliferative and anti-tumour effects of lymphocyte-derived microparticles are neither species- nor tumour-type specific.

BACKGROUND: Unregulated cell proliferation or growth is a prominent characteristic of cancer. We have previously demonstrated that LMPs (cell membrane microparticles derived from apoptotic human CEM T lymphoma cells stimulated with actinomycin D) strongly suppress the proliferation of not only human endothelial cells but also mouse Lewis lung carcinoma cells. METHODS: LMPs were generated either from CEM T cells using different stimuli or from 3 different types of lymphocytes. The effects of LMPs on cancer cell proliferation were examined using cell lines from different species and tissues. The cell cycle kinetics was evaluated by FACS and the expression of cell cycle-related genes was determined using quantitative RT-PCR. The in vivo anti-tumor effect of LMPs was investigated using xenografts and allografts. RESULTS: LMPs at doses far above physiological levels dramatically suppressed the proliferation of cancer cells in a non species-specific manner. LMPs selectively target high proliferating cells and their anti-proliferative effect is not dependent on parental cell origin or stimuli. The anti-proliferative effect of LMPs was due to induction of cell-cycle arrest in G0/G1, with associated increases in expression of the cyclin-dependent kinase inhibitors p15(INK4b), p16(INK4a), and p21(Cip1). In vivo, LMPs significantly suppressed tumor growth in animal tumor models. CONCLUSION: These results highlight the potential role of LMPs in modulating the growth of high proliferating cells. Given that cell-based therapies are considered less toxic than pharmacologic approaches and have the potential to target multiple pathways in a synergistic manner, LMPs may serve as a veritable option for cancer treatment.