Acute and post-acute multidisciplinary outcomes of newborns born from mothers with SARS-CoV-2 infection during pregnancy or the perinatal period.

INTRODUCTION: We performed a single-center, prospective, observational study of newborns born from mothers with microbiologically confirmed SARS-CoV-2 infection in pregnancy or at time of delivery to evaluate acute and mid-term multidisciplinary outcomes. METHODS: Infants were offered a multidisciplinary follow-up consisting of nasopharyngeal Polymerase Chain Reaction test at birth and at 48-72 h of life, auxological and ophthalmological assessments, and serologic testing. RESULTS: 791 women and their 791 children (52.3% males) were included. Most placentas (94.9%) had abnormal inflammatory findings. 171 (27.3%) and 36 (13.7%) children respectively had pathological TEOAEs in at least one ear and bilaterally, while only four of the 85 children that underwent ABR had pathological findings (4.7%). 64 children underwent fluorescein angiography, which resulted pathological only in 1 case (1.6%). Anti-SARS-CoV-2 IgGs were found in up to 60% of children tested at six months of age. Our findings showed no association between the maternal vaccination status or the presence of maternal symptoms during pregnancy and neonatal outcomes. CONCLUSIONS: Our study shows that the large majority of newborns exposed to SARS-CoV-2 infection in utero or during the first hours of life have optimal outcomes. Our previous report of abnormal ophthalmologic findings was not confirmed on a larger cohort, while further studies are needed to better characterize audiological outcomes. Further prospective, case-controlled studies are still needed.

Visual Function in Children with GNAO1-Related Encephalopathy.

BACKGROUND: GNAO1-related encephalopathies include a broad spectrum of developmental disorders caused by de novo heterozygous mutations in the GNAO1 gene, encoding the G (o) subunit α of G-proteins. These conditions are characterized by epilepsy, movement disorders and developmental impairment, in combination or as isolated features. OBJECTIVE: This study aimed at describing the profile of neurovisual competences in children with GNAO1 deficiency to better characterize the phenotype of the disease spectrum. METHODS: Four male and three female patients with confirmed genetic diagnosis underwent neurological examination, visual function assessment, and neurovisual and ophthalmological evaluation. Present clinical history of epilepsy and movement disorders, and neuroimaging findings were also evaluated. RESULTS: The assessment revealed two trends in visual development. Some aspects of visual function, such as discrimination and perception of distance, depth and volume, appeared to be impaired at all ages, with no sign of improvement. Other aspects, reliant on temporal lobe competences (ventral stream) and more related to object-face exploration, recognition and environmental control, appeared to be preserved and improved with age. SIGNIFICANCE: Visual function is often impaired, with patterns of visual impairment affecting the ventral stream less.

The role of retinal imaging in the management of abusive head trauma cases.

BACKGROUND: As retinal hemorrhage (RH) is the most frequent and reliable finding of abusive head trauma (AHT), an ophthalmology consultation should be systematically required in suspected cases. Full retinal examination through pharmacologically dilated pupil can detect the type and pattern of RHs, helping to distinguish abusive from non-abusive head trauma. METHODS: We performed a retrospective analysis of a case series of 6 infants (aged 0.6-10 months) with AHT who were admitted to the Emergency Department of Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome with severe intracranial hemorrhages. Children underwent full multidisciplinary assessment including dilated fundus examination, optical coherence tomography (OCT) and digital wide-field fundus photography (DWFFP - in our case RetCam). In our paper we report the clinical presentation, the ocular findings and outcome at discharge. RESULTS: The mean age at the hospital admission was 6.28 months. In all infants, intracranial hemorrhages were found. Preretinal and intraretinal hemorrhages were detected, collecting good-quality retinal images. CONCLUSIONS: Imaging of retinal hemorrhages represents a fundamental moment of AHT diagnosis and documentation. Although RetCam is the gold standard for the acquisition of retinal images in suspected cases, OCT is extremely valuable in forensic evaluation since it can detect even small macular hemorrhages. Therefore, the combination of RetCam and OCT imaging can give relevant hints for the diagnosis of AHT, allowing to evaluate the extent, spread and morphology of RHs.

Short- and mid-term multidisciplinary outcomes of newborns exposed to SARS-CoV-2 in utero or during the perinatal period: preliminary findings.

The long-term outcomes of newborns exposed to SARS-CoV-2 infection in utero or during the first hours of life are still unknown. We performed a single-center, prospective, observational study of newborns born from mothers with microbiologically confirmed SARS-CoV-2 infection in pregnancy or at time of delivery. Infants were offered a multidisciplinary follow-up consisting of nasopharyngeal Polymerase Chain Reaction test at birth and at 48-72 h of life, auxological growth and neurological development, serologic testing, and audiological and ophthalmological assessments. One-hundred ninety-eight mothers and 199 newborns were enrolled. Of the 199 newborns, 171 underwent nasopharyngeal swab, four (2.3%) and two (1.15%) children tested positive at birth and 48-72 h of life, respectively. None had SARS-CoV-2 related symptoms. Auxologic and neurologic development were normal in all children during follow-up. Nine out of 59 infants had SARS-CoV-2 IgG at 3 months of life, which was associated with a positive nasopharyngeal swab at birth (P = 0.04). Twenty seven out of 143 (18.8%) newborns had pathologic transitory evoked otoacoustic emissions at birth, although 14/27 repeated after 1 month were normal. Audiological evaluation was completed with Auditory Brainstem Response between the third and sixth month of life in 34 children, showing in all normal hearing threshold. The ophthalmological evaluation found retinal vascular anomalies in 3/20 (15%) children, immature visual acuity in 5/20 (25%) children, and reduced distance attention in 6/20 cases (30%). CONCLUSIONS: Our study showed that the neonatal and mid-term multidisciplinary outcomes of newborns exposed to SARS-CoV-2 infection in utero or during the first hours of life are mostly positive, with the exception of ophthalmologic findings which, in a preliminary cohort, were abnormal in about 15% of cases. Further prospective, longitudinal studies are needed to better understand the clinical outcomes of children exposed to SARS-CoV-2 in utero and in the early postnatal life. WHAT IS KNOWN: • In utero mother-to-child transmission of SARS-CoV-2 has been documented by several independent studies. • Neonatal COVID-19 is a systemic disease that can be severe, although rarely. WHAT IS NEW: • Newborns exposed in utero to SARS-CoV-2 have mostly a normal auxological, audiological, and neurological development during the first months of life. • Fundus fluorescein angiography revealed that up to 5% of newborns exposed in utero to SARS-CoV2 can show retinal and choroidal abnormalities, including peripheral hypofluorescence of the choroid and increased vascular tortuosity.

Visual Function and Ophthalmological Findings in CHARGE Syndrome: Revision of Literature, Definition of a New Clinical Spectrum and Genotype Phenotype Correlation.

CHARGE syndrome (CS) is a rare genetic disease causing multiple anatomical defects and sensory impairment. Visual function is usually reported by caregivers and has never been described with a structured behavioral assessment. Our primary objective was to describe ocular abnormalities, visual function and genotype-ocular-phenotype correlation in CS. A prospective monocentric cohort study was performed on 14 children with CS carrying pathogenic CHD7 variants. All children underwent ophthalmological evaluation and structured behavioral assessment of visual function. The VISIOCHARGE questionnaire was administered to parents. Colobomas were present in 93% of patients. Genotype-phenotype correlation documented mitigated features in a subset of patients with intronic pathogenic variants predicted to affect transcript processing, and severe features in patients with frameshift/nonsense variants predicting protein truncation at the N-terminus. Abnormal visual function was present in all subjects, with different degrees of impairment. A significant correlation was found between visual function and age at assessment (p-value = 0.025). The present data are the first to characterize visual function in CS patients. They suggest that hypomorphic variants might be associated with milder features, and that visual function appears to be related to age. While studies with larger cohorts are required for confirmation, our data indicate that experience appears to influence everyday use of visual function more than ocular abnormalities do.

Early angiographic signs of retinopathy of prematurity requiring treatment.

BACKGROUND/OBJECTIVES: Fluorescein angiography (FA) has been a pivotal tool to study the pathophysiology of retinopathy of prematurity (ROP) in vivo. We examined the course of ROP using FA in order to assess the predictive value of angiographic features. SUBJECTS/METHODS: This is an observational retrospective cohort multi-center study of eyes screened for ROP with binocular indirect ophthalmoscope and with FA. All infants undergoing screening examination for ROP who had retinal vasculature limited to Zone I and posterior Zone II vascularization underwent FA between 31 and 34 weeks postmenstrual age. RetCam fundus imaging and video digital fluorescein angiography were performed in the neonatal intensive care units. Masked grading of the FA images was retrospectively conducted by two ROP expert ophthalmologists. Ten criteria that describe retinovascular and choroidal features on FA were used to assess their predictive value for development of treatment-requiring ROP. RESULTS: A total of 98 eyes of 56 patients were included for this study. FAs of eyes of premature infants show a wide range of features either at the junction between the vascular and avascular retina and posteriorly to that. Among the angiographic features evaluated, leakage, shunts and hyperfluorescent lesions at the junction between vascular and avascular zone were predictive of the development of treatment-requiring ROP (p < 0.05), but findings in the posterior vascularized retina were not. CONCLUSIONS: FA can add to our understanding of the evolution of vascular abnormalities in the course of ROP and can help predict which eyes will go on to treatment.

Cortical Visual Impairment in CDKL5 Deficiency Disorder.

BACKGROUND: CDKL5 deficiency disorder (CDD) is a developmental encephalopathy caused by pathogenic variants in the gene cyclin-dependent kinase-like 5. Cerebral visual impairment (CVI) is frequent in patients with CDD. In addition to being recognized as a specific feature of the pathology, it has been suggested that visual impairment may correlate with neurodevelopmental outcome and epilepsy severity, but no systematic behavioral visual assessment has been performed. The aim of our study was to evaluate clinical and electrophysiological profile of CVI in patients with CDD, to correlate various aspects of visual function to neurodevelopmental and epileptic features. METHODS: The study included all patients with CDD from the National Pathology Registry. All patients underwent neurological examination, a disease-specific functional assessment, structured clinical evaluation of visual functions, including pattern reversal visual evoked potential (VEP), and a detailed monitoring of epileptic features, including video-EEG. RESULTS: All the 11 patients recorded in the CDKL5 national registry, 10 females and one male, age range of 1.5 to 24 years (mean 9, SD 7.7, median 6.5), were enrolled. Visual function is impaired in all patients; in particular, visual fields, visual acuity, contrast sensitivity, and stereopsis were consistently abnormal whereas other aspects, such as fixing and tracking, were relatively preserved. Pattern reversal VEP was abnormal in nearly 80% of our patients. No correlation was found among CVI severity, age, level of psychomotor development, EEG abnormalities, and pathology stages even if an overall less abnormal EEG pattern was more often associated with better visual results. CONCLUSION: In conclusion, CVI can be considered as a major feature of CDD with a diffuse involvement in several behavioral and electrophysiological aspects. Larger cohorts will help to better clarify the possible prognostic role of EEG severity in predicting both visual and developmental abnormalities.

Conserved regression patterns of retinopathy of prematurity after intravitreal ranibizumab: A class effect.

PURPOSE: To determine if fluorescein angiographic (FA) findings after intravitreal ranibizumab (IVR) for retinopathy of prematurity (ROP) conform to a class effect previously described with bevacizumab. METHODS: Single-center retrospective case series of all infants treated with 0.2 mg (0.02 mL) IVR for Type 1 ROP from July 2016 to November 2018. FA were obtained at 40, 52, 62, and 72 weeks of postmenstrual age (PMA) using wide-angle photography. FA images were analyzed and the peripheral avascular areas measured with ImageJ using a reference disc diameter (DD). Based on the extent of the avascular area and tortuosity of the retinal vessels all eyes were classified into four categories: complete vascular maturity (vascularization within 2 DD of the ora serrata), VAA (avascular area >2 DD of the ora serrata), VAT (avascular area >2 DD of the ora serrata and posterior tortuosity), and reactivation (recurrence of stage disease). RESULTS: About 13 infants were enrolled and 24 eyes were available in this study. None of the eyes reached complete vascular maturity at an average PMA of 60 weeks, 7 (29%) eyes presented with VAA, 8 (33%) with VAT, and 9 (37.5%) reactivated. The reactivated eyes presented with the largest area of peripheral ischemia, followed by the VAT and then the VAA groups (p = 0.02). CONCLUSION: IVR conforms to the previously described regression patterns following intravitreal bevacizumab for ROP indicative of a class effect. Follow-up using FA might help to optimize the management of these infants after injection of the drug.

Risdiplam treatment has not led to retinal toxicity in patients with spinal muscular atrophy.

OBJECTIVE: Evaluation of ophthalmologic safety with focus on retinal safety in patients with spinal muscular atrophy (SMA) treated with risdiplam (EVRYSDI®), a survival of motor neuron 2 splicing modifier associated with retinal toxicity in monkeys. Risdiplam was approved recently for the treatment of patients with SMA, aged ≥ 2 months in the United States, and is currently under Health Authority review in the EU. METHODS: Subjects included patients with SMA aged 2 months-60 years enrolled in the FIREFISH, SUNFISH, and JEWELFISH clinical trials for risdiplam. Ophthalmologic assessments, including functional assessments (age-appropriate visual acuity and visual field) and imaging (spectral domain optical coherence tomography [SD-OCT], fundus photography, and fundus autofluorescence [FAF]), were conducted at baseline and every 2-6 months depending on study and assessment. SD-OCT, FAF, fundus photography, and threshold perimetry were evaluated by an independent, masked reading center. Adverse events (AEs) were reported throughout the study. RESULTS: A total of 245 patients receiving risdiplam were assessed. Comprehensive, high-quality, ophthalmologic monitoring assessing retinal structure and visual function showed no retinal structural or functional changes. In the youngest patients, SD-OCT findings of normal retinal maturation were observed. AEs involving eye disorders were not suggestive of risdiplam-induced toxicity and resolved with ongoing treatment. INTERPRETATION: Extensive ophthalmologic monitoring conducted in studies in patients with SMA confirmed that risdiplam does not induce ophthalmologic toxicity in pediatric or adult patients with SMA at the therapeutic dose. These results suggest that safety ophthalmologic monitoring is not needed in patients receiving risdiplam, as also reflected in the United States Prescribing Information for risdiplam.

Familial Exudative Vitreoretinopathy With Neurodevelopmental Delay and Hypoplasia of the Corpus Callosum.

A 2-year-old child was referred to the authors' pediatric retina service for bilateral retinal folds, strabismus, and psychomotor retardation, as well as marked thinning of the corpus callosum. Family history was unremarkable and genetic testing revealed a previously undescribed mutation in the LRP5 gene. Widefield fundus photography, fluorescein angiography, and spectral-domain optical coherence tomography were used to image the retinal fundus. The authors' case suggests a correlation between LRP5 and neurological development, since its variants may lead to a syndromic condition characterized by FEVR-like abnormalities along with neurodevelopmental delay and hypoplasia of the corpus callosum. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:588-591.].

Early visual and neuro-development in preterm infants with and without retinopathy.

BACKGROUND: Retinopathy of prematurity (ROP) is often associated with visual impairment and multiple developmental disabilities. AIMS: As most of the previous studies include infants with brain lesions, that can determine visual impairment per se, a cohort of low neurological risk preterm infants without ROP and with various degree of severity of ROP was assessed in order to establish visual and neurodevelopmental outcome. STUDY DESIGN: Preterm infants born at <31 weeks gestation, without major brain lesions, underwent visual function assessment at 1 year corrected age and neurodevelopmental assessment at 2 years corrected age. SUBJECTS: One hundred and five infants were included in the study: 42 infants did not develop ROP, 7 reached stage 1 in zone 2 ROP, 37 reached prethreshold (untreated) type 2 ROP. The remaining 19 infants were classified as type 1 ROP. OUTCOME MEASURES: Visual function (including fixing, tracking, visual acuity, visual field, attention at distance and nystagmus) were assessed at 12 months corrected age and Griffiths Scales at 2 years corrected age. RESULTS: The severity of ROP was strongly correlated (p < 0.001) with both visual function at 1 year and neurodevelopment at 2 years. Similarly, the presence of nystagmus was also strongly correlated with visual and neurodevelopmental sequelae. CONCLUSIONS: Infants with no or milder retinopathy showed normal visual function at 1 year and neurodevelopment at 2 years. Infants who underwent treatment more frequently showed abnormal results on several aspects of visual function. Presence of nystagmus appeared to increase the risk for abnormal visual function and neurodevelopmental outcome.

Functional and Morphologic Findings at Four Years After Intravitreal Bevacizumab or Laser for Type 1 ROP.

BACKGROUND AND OBJECTIVE: To compare morphologic and functional status at age 4 years for patients treated in one eye with laser photocoagulation and the other eye with intravitreal bevacizumab (IVB) injection for Type 1 retinopathy of prematurity (ROP). PATIENTS AND METHODS: In this single-center, randomized, controlled trial, best-corrected visual acuity (BCVA) in logMAR was obtained along with spherical equivalent refraction (SER), fluorescein angiography (FA), optical coherent tomography (OCT), and OCT angiography (OCTA). RESULTS: Eighteen babies (36 eyes) were selected for this study. BCVA and SER were similar in the two groups, but six patients had anisometropia of 4 diopters or more. IVB-treated eyes tended to have thinner foveal thickness than laser-treated eyes (mean difference: -5.33 pixels; 95% confidence interval, -9.62 to -1.05). CONCLUSION: Although the differences found here are minimal between the IVB-treated and laser-treated groups, further long-term evaluation of not only FA, but also OCT and OCTA, are needed in larger studies. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:180-186.].

Follow-up to Age 4 Years of Treatment of Type 1 Retinopathy of Prematurity Intravitreal Bevacizumab Injection versus Laser: Fluorescein Angiographic Findings.

PURPOSE: To compare structural outcome at age 4 years of eyes treated with intravitreal injection of bevacizumab with fellow eyes treated with conventional laser photoablation in type 1 retinopathy of prematurity (ROP). DESIGN: Single, randomized, controlled trial. PARTICIPANTS: All inborn babies with type 1 zone 1 ROP at the Neonatal Intensive Care Unit of the Catholic University, Rome, from September 1, 2009, to March 31, 2012. METHODS: In 21 infants (42 eyes), 1 eye was randomized to receive an intravitreal injection of 0.5 mg bevacizumab; the fellow eye underwent conventional laser photoablation. Digital retinal imaging and fluorescein angiography (FA) were performed at an average of 4 years after treatment in follow-up after these studies performed at treatment and 9 months. MAIN OUTCOME MEASURES: Fluorescein angiograms were examined by 2 experts to document retinal and choroidal findings. RESULTS: Among the 20 bevacizumab-treated eyes available at 4 years of age, all showed abnormalities at the periphery (avascular area, vessel leakage, shunts, abnormal vessel branching, and tangles) or the posterior pole (hyperfluorescent lesions, absence of foveal avascular zone). These lesions were not observed in the majority of the lasered eyes. Among the 19 laser-treated eyes, leakage was noted in 1 eye, shunts and tangles were noted in 3 eyes, and macular abnormalities were noted in 3 eyes. CONCLUSIONS: Fluorescein angiography has shown potentially serious and long-term ocular effects that are present more commonly after treatment with bevacizumab for acute-phase ROP than after laser.

Intravitreal bevacizumab versus laser treatment in type 1 retinopathy of prematurity: report on fluorescein angiographic findings.

PURPOSE: To compare the structural outcome at 9 months of eyes treated with intravitreal injection of bevacizumab with fellow eyes treated with conventional laser photoablation in zone I type 1 retinopathy of prematurity (ROP). DESIGN: Single randomized controlled trial. PARTICIPANTS: All inborn babies with type 1 zone I ROP at a single institution were included in the study. One eye was randomized to receive an intravitreal injection of 0.5 mg bevacizumab; the fellow eye received conventional laser photoablation. METHODS: Digital fundus photographs and fluorescein angiography (FA) using the RetCam (Clarity Medical Systems Inc., Pleasanton, CA) were performed before treatment and 9 months after treatment. MAIN OUTCOME MEASURES: Presence of retinal and choroidal abnormalities on FA at 9 months. RESULTS: Thirteen infants were enrolled; 1 died 3 months after birth. One laser-treated eye progressed to stage 5 retinal detachment. The remaining 23 eyes had favorable structural results at the 9-month follow-up and provided FA results. At 9 months of age, all eyes treated with a bevacizumab injection were noted to have abnormalities at the periphery (large avascular area, abnormal branching, shunt) or the posterior pole (hyperfluorescent lesion, absence of foveal avascular zone). These posterior and peripheral lesions were not observed in the majority of the lasered eyes. CONCLUSIONS: This study documents significant vascular and macular abnormalities of eyes in the bevacizumab group. Long-lasting implications of these abnormalities for visual function of the child need to be studied.