The Inability of the Choroid to Revascularize in Oxygen-Induced Retinopathy Results from Increased p53/miR-Let-7b Activity.

Retinopathy of prematurity (ROP) is characterized by an initial retinal avascularization, followed by pathologic neovascularization. Recently, choroidal thinning has also been detected in children formerly diagnosed with ROP; a similar sustained choroidal thinning is observed in ROP models. But the mechanism underlying the lack of choroidal revascularization remains unclear and was investigated in an oxygen-induced retinopathy (OIR) model. In OIR, evidence of senescence was detected, preceded by oxidative stress in the choroid and the retinal pigment epithelium. This was associated with a global reduction of proangiogenic factors, including insulin-like growth factor 1 receptor (Igf1R). Coincidentally, tumor suppressor p53 was highly expressed in the OIR retinae. Curtailing p53 activity resulted in reversal of senescence, normalization of Igf1r expression, and preservation of choroidal integrity. OIR-induced down-regulation of Igf1r was mediated at least partly by miR-let-7b as i) let-7b expression was augmented throughout and beyond the period of oxygen exposure, ii) let-7b directly targeted Igf1r mRNA, and iii) p53 knock-down blunted let-7b expression, restored Igf1r expression, and elicited choroidal revascularization. Finally, restoration of Igf1r expression rescued choroid thickness. Altogether, this study uncovers a significant mechanism for defective choroidal revascularization in OIR, revealing a new role for p53/let-7b/IGF-1R axis in the retina. Future investigations on this (and connected) pathway could further our understanding of other degenerative choroidopathies, such as geographic atrophy.

Visual Outcomes and Complications of Type I Boston Keratoprosthesis in Children: A Retrospective Multicenter Study and Literature Review.

PURPOSE: To report outcomes and complications of Boston type 1 keratoprosthesis (KPro) implantation in children. DESIGN: Retrospective, multicenter case series. PARTICIPANTS: All children 16 years of age or younger who underwent KPro surgery at 3 ophthalmology centers in Canada between January 2010 and November 2014. METHODS: Records of patients having undergone KPro implantation were reviewed. Data on preoperative characteristics, surgical procedure(s) performed, and postoperative outcomes were collected and analyzed. MAIN OUTCOME MEASURES: Intraoperative and postoperative complications, device retention, and best-corrected visual acuity (BCVA). RESULTS: The KPro was implanted in 11 eyes of 11 patients 0.9 to 15.5 years of age, with 6 being primary corneal procedures. Best-corrected visual acuity recorded before surgery ranged from 20/600 to light perception (LP), and vision in 2 eyes was fix and follow. All patients had been diagnosed with glaucoma and 6 eyes had glaucoma drainage devices (GDDs) inserted before KPro implantation. At last follow-up (mean, 41.8 months; range, 6.5-85.0 months), 2 eyes retained BCVA of 20/400 or better, whereas 5 eyes lost LP. Postoperative complications included retroprosthetic membrane (9 eyes), corneal melt (5 eyes), infectious keratitis (3 eyes), endophthalmitis (3 eyes), GDD erosion (2 eyes), and retinal detachment (5 eyes). The initial KPro was retained in 4 eyes (36.4%). CONCLUSIONS: Boston type 1 keratoprosthesis implantation in children is associated with a substantially higher rate of complications, higher chance of device failure, and worse visual outcomes than observed in adults. In view of these results, the authors do not recommend the use of the KPro in the pediatric population.

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.

Management of vernal keratoconjunctivitis: Navigating a changing treatment landscape.

Vernal keratoconjunctivitis (VKC) is a chronic, progressive, and potentially sight-threatening form of ocular inflammatory disease that primarily affects children and young adults. Prevalence varies by region, ranging from <2 per 10,000 in the United States to as high as 1,100 per 10,000 in parts of Africa. The rarity of VKC in developed countries can make differential diagnosis challenging, and treatment is often delayed until the disease is advanced, and symptoms are significantly impacting patients' quality of life. Although once viewed primarily as an immunoglobulin E-mediated condition, approximately 50% of patients with VKC do not exhibit allergic sensitization. It is now recognized that the immunopathology of VKC involves multiple inflammatory pathways that lead to the signs, symptoms, and conjunctival eosinophilic and fibroproliferative lesions that are a hallmark of the disease. We examine the evolution of our understanding of the immunopathology of VKC, the expanding VKC treatment armamentarium, the clinical implications of emerging treatment approaches, and future directions for VKC research and practice.

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.

Disseminated juvenile xanthogranulomas with ocular involvement: A case report and literature review.

Cutaneous juvenile xanthogranuloma is an uncommon disorder usually arising during infancy. Systemic involvement of juvenile xanthogranuloma remains rare, and there are no published guidelines to date on screening extracutaneous manifestations in these patients. Ocular involvement is the most common extracutaneous manifestation of juvenile xanthogranuloma. We present the case of an infant with disseminated juvenile xanthogranulomas and associated ocular involvement and present a review of literature, focusing on identifying risk factors for ocular and systemic involvement in disseminated cases.

An Infant with Bilateral Keratitis: From Infectious to Genetic Diagnosis.

BACKGROUND Tyrosinemia Type II (TYRII) is a rare autosomal recessive inborn error of metabolism caused by deficiency of tyrosine aminotransferase (TAT), leading to hypertyrosinemia. TYRII patients often present in the first year of life with ocular and cutaneous findings, including corneal ulcers, pseudodendritic keratitis, and palmoplantar hyperkeratosis. The corneal involvement is often mistaken for herpes simplex virus (HSV) keratitis, which is a much commoner condition. CASE REPORT A previously healthy 10-month-old male infant was referred to Ophthalmology for acute onset photophobia. Bilateral dendritiform corneal lesions raised the suspicion for herpetic keratitis. Additionally, a papular, crusted lesion was found on his thumb after a few days of hospitalization, also raising concerns about HSV. The patient's clinical condition seemed to improve under intravenous acyclovir and supportive treatment. A conjunctival swab and crusted lesion on the thumb were tested for HSV using a polymerase chain reaction (PCR) technique, and both were negative. Nevertheless, given the clinical presentation and the favorable course of signs and symptoms, hospital discharge was planned with oral acyclovir. It was halted by an alternative diagnosis of autosomal recessive inborn error of metabolism, tyrosinemia type II, confirmed by elevated plasma tyrosine level and later by molecular analysis requested as a confirmatory investigation by the genetics medical team. CONCLUSIONS The corneal involvement in TYRII is often mistaken for HSV keratitis, and clinical course alone should not halt further investigations to rule out TYRII. Clinicians should suspect TYRII clinically when its characteristic ocular dendritiform lesions are present, namely in infancy or early childhood, and even in the absence of its typical cutaneous palmoplantar hyperkeratosis plaques.

Treatment of periocular infantile hemangiomas with propranolol: case series of 18 children.

PURPOSE: To study the efficacy of propranolol in the treatment of periocular infantile hemangiomas (IHs). DESIGN: Retrospective interventional case series. PARTICIPANTS: Eighteen children presenting periocular IH with occlusion of the pupil, anisometropic astigmatism, proliferating eyelid IH, or cosmetically disfiguring periocular IH. METHODS: All patients received treatment with propranolol started at 0.5 mg/kg/day with an incremental increase by 0.5 mg/kg/day every 4 days, up to a maximum of 2 to 3 mg/kg/day. Complete eye examinations and serial photographs were obtained before, during, and after treatment. Doppler ultrasound and magnetic resonance imaging performed pre- and post-treatment were compared when available. MAIN OUTCOME MEASURES: Evolution of the treated IH was evaluated with respect to astigmatism, amblyopia, and size of the lesion. RESULTS: The IH size decreased in 17 of 18 patients. We noted a greater reduction when treatment was administered during the proliferative phase of growth of IHs. At the conclusion of treatment, none of our patients had amblyopia. The mean value of amblyogenic astigmatism (n = 7) decreased from 2.71 diopters (D) pretreatment to 1.03 D post-treatment. On radiology, 8 patients had significant regression of the lesion size of their IH and 1 patient had a limited progression. Propranolol had to be temporarily discontinued in only 1 patient because of symptomatic hypotension. CONCLUSIONS: Propranolol seems to be an effective modality of treatment for periocular IH. It seems to be most efficacious when initiated in the proliferative phase of IH but may be beneficial even in the later stage. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Allgrove Syndrome: A Report of New Pathological Variants in the AAAS Gene.

PURPOSE: To report 2 novel variants in the AAAS gene consistent with the diagnosis of Allgrove syndrome. METHODS: A 12-year-old girl was referred to our clinic for progressive bilateral decrease in visual acuity. She was known for achalasia that had been surgically treated at a very early age. On examination, she was found to have dry eye disease secondary to lacrimal insufficiency. She also had anisocoria, light-near dissociation, and bilateral optic nerve atrophy. RESULTS: Neurological examination and brain magnetic resonance imaging were within normal limits. Genetic workup revealed compound heterozygosity for 2 novel variants in the AAAS gene, confirming the diagnosis of Allgrove syndrome. The patient was referred to endocrinology to screen for adrenocorticotropic hormone insufficiency. She was started on topical lubricating therapy that improved her symptoms. CONCLUSIONS: Allgrove syndrome is a rare genetic disease that is characterized by the triad of achalasia, alacrima, and adrenal insufficiency. Early diagnosis, confirmed with genetic testing, is essential to initiate an appropriate follow-up and prevent a life-threatening addisonian crisis. Report of novel mutations is important to further characterize this disease.

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.].

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.

Mucolipidosis type IV in a child.

Mucolipidosis type IV is a rare autosomal recessive lysosomal storage disorder with psychomotor developmental delay, visual impairment, and achlorhydria. A mutation in the MCOLN1 gene causes an alteration of the protein mucolipin-1 that results in the accumulation of lipids and proteins in cytoplasmic vacuoles derived from lysosomes. Visual impairment results mainly from corneal clouding and retinal degeneration. The involvement of the corneal epithelium has been proposed following clinical observation and confirmed by ultrastructural studies of the cornea. We present the case of a child of French Canadian origin affected by mucolipidosis type IV who showed abnormal optical coherence tomography imaging of the cornea, typical skin cell inclusions on electronic microscopy, and a novel pathogenic mutation.

Using the CanMEDS roles when interviewing for an ophthalmology residency program.

BACKGROUND: To improve the admissions process for the Université de Montréal (UdeM) ophthalmology residency program, the interview structure was modified to encompass the seven CanMEDS roles introduced by the Royal College of Physicians and Surgeons of Canada (RCPSC). These roles include an applicant's abilities as a communicator, collaborator, manager, health advocate, professional, scholar, and medical expert. METHODS: In this retrospective pilot study, the records of all applicants were reviewed by 8 members of the admissions committee, with a high intraclass correlation coefficient of 0.814. Four 2-person interview teams were then formed. The first 3 groups asked the applicants specific questions based on 2-3 of the CanMEDS roles, marking their impressions of each candidate on a visual analogue scale. The last group answered candidates' questions about the program but assigned no mark. RESULTS: The intraclass correlations for the teams were 0.900, 0.739, and 0.585, demonstrating acceptable interrater reliability for 2 of the teams. Pearson correlation coefficients between groups of interviewers were considered adequate at 0.562, 0.432, and 0.417 (p < 0.05). For each interviewer, the Pearson correlation coefficient between record marking and interview scoring was either not statistically significant or very low. INTERPRETATION: By basing the 2006 interview process on the CanMEDS roles defined by the RCPSC, information was obtained about the candidates that could not have been retrieved by a review of the medical students' records alone. Reliability analysis confirmed that this new method of conducting interviews provided sound and reliable judging and rating consistency between all members of the admissions committee.

Trabeculotomy in the Treatment of Pediatric Uveitic Glaucoma.

PURPOSE: To evaluate the efficacy and safety of trabeculotomy in the treatment of pediatric uveitic glaucoma (UG). MATERIALS AND METHODS: We retrospectively reviewed all cases that underwent trabeculotomy for pediatric UG at our center between 2008 and 2014. Up to 2 trabeculotomies per eye were performed in patients with medically controlled uveitis. Surgical success was defined as final intraocular pressure <22 mm Hg and ≥6 mm Hg after 1 or 2 trabeculotomies, with or without medications. Kaplan-Meier survival analyses were done. RESULTS: A total of 33 trabeculotomies were performed in 28 eyes of 22 patients. Diagnoses included UG associated with juvenile idiopathic arthritis (68.2%), idiopathic uveitis (22.7%), and pars planitis (9.1%). The average age at surgery was 9.8±3.7 (5 to 17) years. With a mean follow-up of 33.6±18.3 (10 to 78) months, the overall surgical success was 81.8%. The cumulative survival probability after up to 2 trabeculotomies was 0.86 (95% confidence interval, 0.71-0.93) at 12 months and 0.77 (95% confidence interval, 0.60-0.87) at 24 months. Four (11.5%) eyes required a second trabeculotomy to achieve surgical success and 4 (7.7%) required filtrating procedures. Intraocular pressure improved from 31.4±7.6 (18 to 50) mm Hg preoperatively to 15.0±3.6 (8 to 23) mm Hg at final visits, whereas the number of glaucoma medications decreased from 4.2±1.1 (1 to 5) to 0.4±1.0 (0 to 4). Visual acuity and intraocular inflammation remained stable (P>0.05) and there were no major complications. CONCLUSIONS: Trabeculotomy is a safe and effective surgery for pediatric UG.

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.].