Fatal child abuse detected by systematic post-mortem fundus photograph in sudden death in infancy.

In living children, the use of a wide field fundus camera such as RetCam is the gold standard practice to document retinal haemorrhages in suspected cases of abusive head trauma (AHT). In case of sudden unexpected death in infancy (SUDI), child abuse must be considered as a possible cause of death and an eye examination is required. However, no example of post-mortem fundus photograph (PMFP) of retinal haemorrhages related to AHT is yet available for clinicians.We report a SUDI case, with no external traumatic lesions or limb fractures, for which prompt PMFP showed retinal haemorrhages typical of AHT: child abuse was subsequently confirmed by the forensic investigation. We discuss why PMFP is a relevant screening test to detect retinal haemorrhages in the case of SUDI and why the use of the RetCam should be further investigated.

Mannose-coupled AAV2: A second-generation AAV vector for increased retinal gene therapy efficiency.

Inherited retinal diseases are a leading and untreatable cause of blindness and are therefore candidate diseases for gene therapy. Recombinant vectors derived from adeno-associated virus (rAAV) are currently the most promising vehicles for in vivo therapeutic gene delivery to the retina. However, there is a need for novel AAV-based vectors with greater efficacy for ophthalmic applications, as underscored by recent reports of dose-related inflammatory responses in clinical trials of rAAV-based ocular gene therapies. Improved therapeutic efficacy of vectors would allow for decreases in the dose delivered, with consequent reductions in inflammatory reactions. Here, we describe the development of new rAAV vectors using bioconjugation chemistry to modify the rAAV capsid, thereby improving the therapeutic index. Covalent coupling of a mannose ligand, via the formation of a thiourea bond, to the amino groups of the rAAV capsid significantly increases vector transduction efficiency of both rat and nonhuman primate retinas. These optimized rAAV vectors have important implications for the treatment of a wide range of retinal diseases.

Unplanned 30-day readmission rate after ophthalmological surgery as a quality-of-care indicator.

BACKGROUND: The 30-day readmission rate provides a standardised quantitative evaluation of some postoperative complications. It is widely used worldwide in many medical and surgical specialities, and the World Health Organization recommends its use for monitoring healthcare system performance. In ophthalmology, its measurement is biased by the frequent and close planned surgery on one eye and then the other, particularly in the case of cataract surgery. This study measures the 30-day unplanned readmission rate in ophthalmology, globally and by surgery subtype, and describes the causes of readmission. METHODS: All patients readmitted within 30 days of ophthalmic surgery at Nantes University Hospital between January 2017 and December 2020 were identified in the Medical Information System. An ophthalmologist examined each medical record and collected the following data: the reason for readmission, comorbidities, the pathology treated, surgery type, surgery duration, the surgeon's experience, anaesthesia type, severity and readmission morbidity. RESULTS: For the 8522 ophthalmic surgeries performed in the four-year study period, 282 30-day unplanned readmissions were identified. The overall 30-day unplanned readmission rate was 2.07% for elective surgery, with a high variability depending on the surgery type: 0.95% for phacoemulsification, 4.95% for vitreoretinal surgery (3.42% for non-elective vitreoretinal surgery, 5.44% for retinal detachment surgery), 5.66% for deep lamellar keratoplasty and 11.90% for trabeculectomy. The unplanned 30-day readmission rate for ocular trauma surgery (emergency care) was 11.0%. Seven percent of all unplanned 30-day readmissions were not associated with an ophthalmological problem. CONCLUSIONS: This study is the first to report 30-day unplanned readmission in ophthalmology, globally and by surgical subtype, for elective and urgent procedures. This indicator can be used longitudinally to detect an increase in risk or transversely to compare the quality of care between different public or private hospitals.

Fluocinolone Acetonide Implant Injected 1 Month after Dexamethasone Implant for Diabetic Macular Oedema: the ILUVI1MOIS Study.

INTRODUCTION: The aim of this study was to assess the efficacy and safety of fluocinolone acetonide implant (FAci) injected 1 month after the last dexamethasone intravitreal implant (DEXi) in chronic diabetic macular oedema (DME) patients. METHODS: Retrospective multicentric study conducted in pseudophakic patients with chronic DME frequently treated with dexamethasone intravitreal implant (DEXi; time to DME recurrence ≤ 6 months), receiving FAci 1 month after the last DEXi, with at least a 6-month follow-up. Best-corrected visual acuity (BCVA), central macular thickness (CMT) on optical coherence tomography, intraocular pressure (IOP) and additional treatments were assessed on the day of FAci injection (M0), 1 (M1) and 3 months (M3) later and then every 3 months. RESULTS: A total of 41 eyes from 34 patients were included. At M0, patients' mean age was 68.7 ± 9.8 years, the mean DME duration was 63.9 ± 22.9 months, the mean interval between two DEXi was 14.2 ± 3.3 weeks. M12 data were available for 71% of patients. At baseline, the mean BCVA, CMT and IOP were 63.2 ± 16.6 letters, 299.4 ± 103.3 µm, and 16.2 ± 4.5 mmHg, respectively, and remained stable during the follow-up. At M12, 14% of patients required additional intravitreal treatments. CONCLUSION: In pseudophakic patients with chronic DME showing good response to DEXi but requiring repeated injections every < 6 months, switching to FAci 1 month after the last DEXi was effective and safe. Further prospective randomized controlled studies are needed to confirm these findings, and to determine the best interval between the last DEXi and the first FAci.

Intravitreal air tamponade after AAV2 subretinal injection modifies retinal EGFP distribution.

The subretinal injection protocol for the only approved retinal gene therapy (voretigene neparvovec-rzyl) includes air tamponade at the end of the procedure, but its effects on the subretinal bleb have not been described. In the present study, we evaluated the distribution of enhanced green fluorescent protein (EGFP) after subretinal injection of AAV2 in non-human primates (NHP) without (group A = 3 eyes) or with (group B = 3 eyes) air tamponade. The retinal expression of EGFP was assessed 1 month after subretinal injection with in vivo fundus photographs and fundus autofluorescence. In group A (without air), EGFP expression was limited to the area of the initial subretinal bleb. In group B (with air), EGFP was expressed in a much wider area. These data show that the buoyant force of air on the retina causes a wide subretinal diffusion of vector, away from the injection site. In the present paper, we discuss the beneficial and deleterious clinical effects of this finding. Whereas subretinal injection is likely to become more common with the coming of new gene therapies, the effects of air tamponade should be explored further to improve efficacy, reproducibility, and safety of the protocol.

Assessing retinal hemorrhages with non-invasive post-mortem fundus photographs in sudden unexpected death in infancy.

INTRODUCTION: In the case of sudden unexpected death in infancy (SUDI), eye examination is systematic to detect retinal hemorrhages (RH) that are a crucial hallmark for abusive head trauma (AHT). The aim of this study is to assess the ability of non-invasive post-mortem fundus photographs (PMFP) to detect RH in case of SUDI. METHODS: Bicentric retrospective analysis of consecutive cases of SUDI under 2 years of age were managed by two French SUDI referral centers with PMFP by RetCam (Clarity Medical Systems USA). PMFP were reviewed randomly, twice, by three independent ophthalmologists blinded for clinical data. RESULTS: Thirty cases (60 eyes) were included. Median age was 3.5 months (interquartile [1.6; 6.0]). No child died of AHT. Image quality was sufficient to assert presence or absence of RH in 50 eyes (83%). Sufficient quality rate was significantly higher when the post-mortem interval was inferior to 18 h (91%, 42/46) as opposed to over 18 h (57%, 8/14, p=0.0096). RH were found in six eyes (10%), four children (13%), with excellent inter and intra-raters' concordance (Cohen's Kappa from 0.81 [0.56-1.00] to 1.00 [1.00-1.00]). CONCLUSION: PMFP can detect RH in case of SUDI and is a relevant systematic screening test to be carried out as soon as the deceased child arrives in the hospital. It can decrease the need of eye removal for pathological examination, but further studies are needed to define the best decision algorithm.

Ophthalmological Impairments at Five and a Half Years after Preterm Birth: EPIPAGE-2 Cohort Study.

We report the 51/2 year prevalence of visual and oculomotor impairments in preterm children born at 24−34 weeks' gestation (WG) using the population-based cohort study EPIPAGE-2, set in France, 2011. The main outcomes were imputed prevalence of refractive errors (REs), strabismus, and binocular visual acuity (VA). Children were clinically assessed by specially trained pediatricians. The population was also analyzed in terms of cerebral palsy at 51/2 years (no CP, stage 1, stage 2, or stage 3−5) and retinopathy of prematurity in the neonatal period (no ROP, stage 1 or 2, or severe ROP). Among the 4441 children included, 2718 (weighted percentage 58.7%) were clinically assessed. REs were reported in 43.1% (95% confidence interval 37.6−48.4), 35.2% (32.7−37.6), and 28.4% (25.0−31.8) of children born at 24−26, 27−31, and 32−34 WG (p < 0.01), respectively; strabismus rates were 19.5% (14.6−24.4), 14.8% (12.9−16.7), and 8.3% (6.2−10.4) (p < 0.001), respectively. Moderate/severe visual deficiencies (VA < 3.2/10) were present in 1.7% (0.2−3.3) of children born at 24−26 WG, and in less than 1% in other groups. A suboptimal VA 5/10−6.3/10 was measured in 40.6% (35.3−45.8) of children born at 24−26 WG, 35.8% (33.5−38.1) at 27−31 WG, and 33.7% (30.4−37.0) at 32−34 WG. CP and ROP were associated with strabismus and RE. The association between CP and VA was strong, while it was not observed for ROP. In this large cohort of preterm-born children, we found a high prevalence of RE and strabismus regardless of WG, supporting the need for specific attention in this population. High prevalence of suboptimal VA could be challenging for these children at the age of reading and writing acquisition.

First evidence of SOX2 mutations in Peters' anomaly: Lessons from molecular screening of 95 patients.

Peters' anomaly (PA) is a rare anterior segment dysgenesis characterized by central corneal opacity and irido-lenticulo-corneal adhesions. Several genes are involved in syndromic or isolated PA (B3GLCT, PAX6, PITX3, FOXE3, CYP1B1). Some copy number variations (CNVs) have also been occasionally reported. Despite this genetic heterogeneity, most of patients remain without genetic diagnosis. We retrieved a cohort of 95 individuals with PA and performed genotyping using a combination of comparative genomic hybridization, whole genome, exome and targeted sequencing of 119 genes associated with ocular development anomalies. Causative genetic defects involving 12 genes and CNVs were identified for 1/3 of patients. Unsurprisingly, B3GLCT and PAX6 were the most frequently implicated genes, respectively in syndromic and isolated PA. Unexpectedly, the third gene involved in our cohort was SOX2, the major gene of micro-anophthalmia. Four unrelated patients with PA (isolated or with microphthalmia) were carrying pathogenic variants in this gene that was never associated with PA before. Here we described the largest cohort of PA patients ever reported. The genetic bases of PA are still to be explored as genetic diagnosis was unavailable for 2/3 of patients. Nevertheless, we showed here for the first time the involvement of SOX2 in PA, offering new evidence for its role in corneal transparency and anterior segment development.

Predictive values of initial semi-quantitative assessment of relative afferent pupillary defect for neovascularization in central retinal vein occlusion.

PURPOSE: To measure the predictive values of relative afferent pupillary defect (RAPD) assessed semi-quantitatively, and visual acuity (VA) at onset of central retinal vein occlusion (CRVO), for neovascularization. METHODS: Retrospective analysis of the TROXHEMO trial that included patients with CRVO within 30 days after the onset. Inclusion criteria were as follows: semi-quantitative RAPD assessment at diagnosis and/or at one month. RAPD was 'severe' if ≥ 0.9 log. Exclusion criteria were as follows: prophylactic panretinal photocoagulation (PRP) before neovascularization. RESULTS: Among the 119 patients enrolled in the main centre, 101 were analysed. 26 had a neovascular complication during the twelve months of follow-up: rubeosis (19), glaucoma (7) and posterior neovascularization (15). The mean time to onset of a neovascular complication was 4.7 months (1 to 12, median 3 months). All the patients who had a neovascular complication had RAPD at first examination or at one month (negative predictive value (NPV) = 100%) but the positive predictive value (PPV) was low (31%, 95% CI [21%; 42%]). The association 'severe RAPD or VA < 35 letters (ETDRS) at inclusion or at one month' was the best compromise between PPV (53%, [39%; 68%]) and NPV (96%, [92%; 100%]). CONCLUSION: To predict neovascularization, RAPD should be routinely evaluated with filters: the risk of neovascular complication is (a) almost nil if there is no RAPD, (b) very low if there is no severe RAPD and if VA is higher than 35 letters, and (c) higher than 50% if RAPD is ≥ 0.9 log or if VA is less than 35 letters.

Pathogenic variants in IMPG1 cause autosomal dominant and autosomal recessive retinitis pigmentosa.

BACKGROUND: Inherited retinal disorders are a clinically and genetically heterogeneous group of conditions and a major cause of visual impairment. Common disease subtypes include vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). Despite the identification of over 90 genes associated with RP, conventional genetic testing fails to detect a molecular diagnosis in about one third of patients with RP. METHODS: Exome sequencing was carried out for identifying the disease-causing gene in a family with autosomal dominant RP. Gene panel testing and exome sequencing were performed in 596 RP and VMD families to identified additional IMPG1 variants. In vivo analysis in the medaka fish system by knockdown assays was performed to screen IMPG1 possible pathogenic role. RESULTS: Exome sequencing of a family with RP revealed a splice variant in IMPG1. Subsequently, the same variant was identified in individuals from two families with either RP or VMD. A retrospective study of patients with RP or VMD revealed eight additional families with different missense or nonsense variants in IMPG1. In addition, the clinical diagnosis of the IMPG1 retinopathy-associated variant, originally described as benign concentric annular macular dystrophy, was also revised to RP with early macular involvement. Using morpholino-mediated ablation of Impg1 and its paralog Impg2 in medaka fish, we confirmed a phenotype consistent with that observed in the families, including a decreased length of rod and cone photoreceptor outer segments. CONCLUSION: This study discusses a previously unreported association between monoallelic or biallelic IMPG1 variants and RP. Notably, similar observations have been reported for IMPG2.

Thresholds of glycemia, insulin therapy, and risk for severe retinopathy in premature infants: A cohort study.

BACKGROUND: Hyperglycemia in preterm infants may be associated with severe retinopathy of prematurity (ROP) and other morbidities. However, it is uncertain which concentration of blood glucose is associated with increased risk of tissue damage, with little consensus on the cutoff level to treat hyperglycemia. The objective of our study was to examine the association between hyperglycemia and severe ROP in premature infants. METHODS AND FINDINGS: In 2 independent, monocentric cohorts of preterm infants born at <30 weeks' gestation (Nantes University Hospital, 2006-2016, primary, and Lyon-HFME University Hospital, 2009-2017, validation), we first analyzed the association between severe (stage 3 or higher) ROP and 2 markers of glucose exposure between birth and day 21-maximum value of glycemia (MaxGly1-21) and mean of daily maximum values of glycemia (MeanMaxGly1-21)-using logistic regression models. In both the primary (n = 863 infants, mean gestational age 27.5 ± 1.4 weeks, boys 52.5%; 38 with severe ROP; 54,083 glucose measurements) and the validation cohort (n = 316 infants, mean gestational age 27.4 ± 1.4 weeks, boys 51.3%), MaxGly1-21 and MeanMaxGly1-21 were significantly associated with an increased risk of severe ROP: odds ratio (OR) 1.21 (95% CI 1.14-1.27, p < 0.001) and OR 1.70 (95% CI 1.48-1.94, p < 0.001), respectively, in the primary cohort and OR 1.17 (95% CI 1.05-1.32, p = 0.008) and OR 1.53 (95% CI 1.20-1.95, p < 0.001), respectively, in the validation cohort. These associations remained significant after adjustment for confounders in both cohorts. Second, we identified optimal cutoff values of duration of exposure above each concentration of glycemia between 7 and 13 mmol/l using receiver operating characteristic curve analyses in the primary cohort. Optimal cutoff values for predicting stage 3 or higher ROP were 9, 6, 5, 3, 2, 2, and 1 days above a glycemic threshold of 7, 8, 9, 10, 11, 12, and 13 mmol/l, respectively. Severe exposure was defined as at least 1 exposure above 1 of the optimal cutoffs. Severe ROP was significantly more common in infants with severe exposure in both the primary (10.9% versus 0.6%, p < 0.001) and validation (5.2% versus 0.9%, p = 0.030) cohorts. Finally, we analyzed the association between insulin therapy and severe ROP in a national population-based prospectively recruited cohort (EPIPAGE-2, 2011, n = 1,441, mean gestational age 27.3 ± 1.4, boys 52.5%) using propensity score weighting. Insulin use was significantly associated with severe ROP in overall cohort crude analyses (OR 2.51 [95% CI 1.13-5.58], p = 0.024). Adjustment for inverse propensity score (gestational age, sex, birth weight percentile, multiple birth, spontaneous preterm birth, main pregnancy complications, surfactant therapy, duration of oxygen exposure between birth and day 28, digestive state at day 7, caloric intake at day 7, and highest glycemia during the first week) and duration of oxygen therapy had a large but not significant effect on the association between insulin treatment and severe ROP (OR 0.40 [95% CI 0.13-1.24], p = 0.106). Limitations of this study include its observational nature and, despite the large number of patients included compared to earlier similar studies, the lack of power to analyze the association between insulin use and retinopathy. CONCLUSIONS: In this study, we observed that exposure to high glucose concentration is an independent risk factor for severe ROP, and we identified cutoff levels that are significantly associated with increased risk. The clinical impact of avoiding exceeding these thresholds to prevent ROP deserves further evaluation.

[Gene therapy for retinitis pigmentosa]. / La thérapie génique des rétinites pigmentaires héréditaires.

Retinitis pigmentosa is the most common blinding inherited retinal dystrophy. Gene therapy is a burgeoning revolutionary approach that paves the way to treatment of previously incurable diseases. At the end of 2017 and 2018, a gene therapy, Luxturna®, obtained a marketing authorization by respectively the FDA (Food and Drug Administration) and the EMA (European Medicines Agency). This treatment, with proven efficacy, is available to patients with Leber congenital amaurosis and retinitis pigmentosa associated with bi-allelic mutations of the RPE 65 gene. In this paper, we present the current advances in gene therapy for retinitis pigmentosa and discuss the technological, economic and ethical challenges to overcome for gene therapy to improve medical practices.

TITLE: La thérapie génique des rétinites pigmentaires héréditaires. ABSTRACT: Les rétinites pigmentaires, ou dystrophies rétiniennes héréditaires, sont des maladies dégénératives cécitantes d'origine génétique. La thérapie génique est une approche révolutionnaire en plein essor qui ouvre la voie au traitement de maladies jusqu'ici incurables. Une thérapie génique, le Luxturna®, a obtenu une autorisation de mise sur le marché par la FDA (Food and Drug Administration) fin 2017 et l'EMA (European Medicines Agency) fin 2018. Ce traitement, à l'efficacité démontrée, destiné aux patients porteurs d'une amaurose congénitale de Leber ou d'une rétinopathie pigmentaire en lien avec une mutation bi-allélique du gène RPE65, apporte beaucoup plus de questions que de réponses. Nous présentons, dans cette revue, les avancées actuelles, puis les défis technologiques, économiques et éthiques à surmonter pour que la thérapie génique améliore nos pratiques médicales.

Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy.

Kinesin-2 enables ciliary assembly and maintenance as an anterograde intraflagellar transport (IFT) motor. Molecular motor activity is driven by a heterotrimeric complex comprised of KIF3A and KIF3B or KIF3C plus one non-motor subunit, KIFAP3. Using exome sequencing, we identified heterozygous KIF3B variants in two unrelated families with hallmark ciliopathy phenotypes. In the first family, the proband presents with hepatic fibrosis, retinitis pigmentosa, and postaxial polydactyly; he harbors a de novo c.748G>C (p.Glu250Gln) variant affecting the kinesin motor domain encoded by KIF3B. The second family is a six-generation pedigree affected predominantly by retinitis pigmentosa. Affected individuals carry a heterozygous c.1568T>C (p.Leu523Pro) KIF3B variant segregating in an autosomal-dominant pattern. We observed a significant increase in primary cilia length in vitro in the context of either of the two mutations while variant KIF3B proteins retained stability indistinguishable from wild type. Furthermore, we tested the effects of KIF3B mutant mRNA expression in the developing zebrafish retina. In the presence of either missense variant, rhodopsin was sequestered to the photoreceptor rod inner segment layer with a concomitant increase in photoreceptor cilia length. Notably, impaired rhodopsin trafficking is also characteristic of recessive KIF3B models as exemplified by an early-onset, autosomal-recessive, progressive retinal degeneration in Bengal cats; we identified a c.1000G>A (p.Ala334Thr) KIF3B variant by genome-wide association study and whole-genome sequencing. Together, our genetic, cell-based, and in vivo modeling data delineate an autosomal-dominant syndromic retinal ciliopathy in humans and suggest that multiple KIF3B pathomechanisms can impair kinesin-driven ciliary transport in the photoreceptor.

MOG-Ab prevalence in optic neuritis and clinical predictive factors for diagnosis.

OBJECTIVE: What is the proportion of antibodies to myelin oligodendrocyte glycoprotein (MOG-Ab) in optic neuritis (ON) in adults and what would be the ON presentation for which MOG-Ab should be tested? METHODS: Multicentric prospective study conducted during 1 year on all patients diagnosed with acute ON in all ophthalmological units in hospitals in a region in western France. RESULTS: Sixty-five patients were included. MOG-Ab prevalence was 14% (9/65) during an acute ON and 13% (7/55) after exclusion of patients already diagnosed with multiple sclerosis (MS) (8) or MOG+ON (2). Compared with MS and clinically isolated syndrome, MOG+ON had no female preponderance (67% of men in case of MOG+ON and 22% of men in case of MS and clinically isolated syndrome, p<0.05) were more often bilateral (44% vs 3%, p<0.005) and associated with optic disc swelling (ODS) (78% vs 14%, p<0.001). To predict MOG+ON, the positive predictive values (PPVs) of male sex, ODS and bilateral involvement were 29% (95% CI 9% to 48%), 41% (95% CI 18% to 65%) and 40% (95% CI 10% to 70%), respectively, while the negative predictive values (NPV) were 93% (95% CI 86% to 100%), 96% (95% CI 90% to 100%) and 91% (95% CI 83% to 99%), respectively. The combined factor 'ODS or bilateral or recurrent ON' was the best compromise between PPV (31% (95% CI 14% to 48%)) and NPV (100% (95% CI 100% to 100%)). CONCLUSION: Among ON episodes, MOG-Ab were found in 14% of cases. MOG+ON occurred without female preponderance and was significantly associated with ODS and/or bilateral ON. Testing MOG-Ab only in patients presenting with ODS or bilateral or recurrent ON would limit MOG-Ab tests to fewer than half of all patients without the risk of missing any MOG+ON cases.

Variable expressivity of syndromic BMP4-related eye, brain, and digital anomalies: A review of the literature and description of three new cases.

Microphthalmia with brain and digital anomalies (MCOPS6, MIM# 607932) is an autosomal dominant disorder caused by loss-of-function variants or large deletions involving BMP4, which encodes bone morphogenetic protein 4, a member of the TGF-ß protein superfamily. BMP4 has a number of roles in embryonic development including neurogenesis, lens induction, development of cartilage and bone, urogenital development, limb and digit patterning, hair follicle regeneration, as well as tooth formation. In addition to syndromic microphthalmia, BMP4 variants have been implicated in non-syndromic cleft lip with or without cleft palate and congenital healed cleft lip indicating different allelic presentations. MCOPS6 subjects may also lack some of the major phenotypic hallmarks of the disorder, including microphthalmia, indicating variable expressivity. As only a handful of individuals with MCOPS6 have been described, we review the clinical findings in previously reported cases with either deletions or loss-of-function variants in BMP4. We describe three new cases, including two subjects with novel deletions and one subject with a likely pathogenic de novo nonsense variant [c.1052C>G, p.(S351*)] in BMP4. One of the subjects had dual molecular diagnoses including a co-occurring microdeletion at 17q21.31 associated with Koolen de Vries syndrome, which has a partially overlapping disease phenotype. None of these individuals had clinically apparent microphthalmia or anopthalmia, which have been reported in a majority of previously described cases. One subject had exophthalmia and strabismus, while another had bilateral Peters anomaly and sclerocornea, thus expanding the phenotype associated with BMP4 loss-of-function variants.

Prospective evaluation of anesthetic protocols during pediatric ophthalmic surgery.

PURPOSE: To date, no protocol of anesthesia for pediatric ophthalmic surgery is unanimously recognized. The primary anesthetic risks are associated with strabismus surgery, including oculocardiac reflex, postoperative nausea and vomiting, and postoperative pain. METHODS: This was a prospective, monocentric, observational study conducted in a tertiary pediatric ophthalmic unit. Our anesthetic protocol for strabismus surgery included postoperative nausea and vomiting prevention using dexamethasone and ondansetron. No drug-based prevention of oculocardiac reflex or local/locoregional anesthesia was employed. RESULTS: A total of 106 pediatric ophthalmic surgeries completed between November 2015 and May 2016 were analyzed. The mean patient age was 4.4 (range: 0.2-7.3, standard deviation: 2.4) years. Ambulatory rate was 90%. Oculocardiac reflex incidence was 65% during strabismus surgery (34/52), 50% during congenital cataract surgery (4/8), 33% during intramuscular injection of botulinum toxin (1/3), and 0% during other procedures. No asystole occurred. Postoperative nausea and vomiting incidence was 9.6% after strabismus surgery (5/52) and 0% following the other procedures. One child was hospitalized for one night because of persistent postoperative nausea and vomiting. Postoperative pain generally occurred early on in the recovery room and was quickly controlled. Its incidence was higher in patients who underwent strabismus surgery (27%) than in those who underwent other procedures (9%). CONCLUSION: Morbidity associated with ophthalmic pediatric surgery is low and predominantly associated with strabismus surgery. The benefit-risk ratio and cost-effectiveness of oculocardiac reflex prevention should be questioned. Our postoperative nausea and vomiting rate is low, thanks to the use of a well-managed multimodal strategy. Early postoperative pain is usually well-treated but could probably be more effectively prevented.

Expanding the phenotype of the X-linked BCOR microphthalmia syndromes.

Two distinct syndromes arise from pathogenic variants in the X-linked gene BCOR (BCL-6 corepressor): oculofaciocardiodental (OFCD) syndrome, which affects females, and a severe microphthalmia ('Lenz'-type) syndrome affecting males. OFCD is an X-linked dominant syndrome caused by a variety of BCOR null mutations. As it manifests only in females, it is presumed to be lethal in males. The severe male X-linked recessive microphthalmia syndrome ('Lenz') usually includes developmental delay in addition to the eye findings and is caused by hypomorphic BCOR variants, mainly by a specific missense variant c.254C > T, p.(Pro85Leu). Here, we detail 16 new cases (11 females with 4 additional, genetically confirmed, affected female relatives; 5 male cases each with unaffected carrier mothers). We describe new variants and broaden the phenotypic description for OFCD to include neuropathy, muscle hypotonia, pituitary underdevelopment, brain atrophy, lipoma and the first description of childhood lymphoma in an OFCD case. Our male X-linked recessive cases show significant new phenotypes: developmental delay (without eye anomalies) in two affected half-brothers with a novel BCOR variant, and one male with high myopia, megalophthalmos, posterior embryotoxon, developmental delay, and heart and bony anomalies with a previously undescribed BCOR splice site variant. Our female OFCD cases and their affected female relatives showed variable features, but consistently had early onset cataracts. We show that a mosaic carrier mother manifested early cataract and dental anomalies. All female carriers of the male X-linked recessive cases for whom genetic confirmation was available showed skewed X-inactivation and were unaffected. In view of the extended phenotype, we suggest a new term of X-linked BCOR-related syndrome.

Safety and Long-Term Efficacy of AAV4 Gene Therapy in Patients with RPE65 Leber Congenital Amaurosis.

The aim of this study was the evaluation of the safety and efficacy of unilateral subretinal injection of the adeno-associated vector (AAV) serotypes 2 and 4 (AAV2/4) RPE65-RPE65 vector in patients with Leber congenital amaurosis (LCA) associated with RPE65 gene deficiency. We evaluated ocular and general tolerance and visual function up to 1 year after vector administration in the most severely affected eye in nine patients with retinal degeneration associated with mutations in the RPE65 gene. Patients received either low (1.22 × 1010 to 2 × 1010 vector genomes [vg]) or high (between 3.27 × 1010 and 4.8 × 1010 vg) vector doses. An ancillary study, in which six of the original nine patients participated, extended the follow-up period to 2-3.5 years. All patients showed good ophthalmological and general tolerance to the rAAV2/4-RPE65-RPE65 vector. We observed a trend toward improved visual acuity in patients with nystagmus, stabilization and improvement of the visual field, and cortical activation along visual pathways during fMRI analysis. OCT analysis after vector administration revealed no retinal thinning, except in cases of macular detachment. Our findings show that the rAAV2/4.RPE65.RPE65 vector was well tolerated in nine patients with RPE65-associated LCA. Efficacy parameters varied between patients during follow-up.