Calcified Sclero-Choroidal Choristomas in Mosaic RASopathies: A Description of a New Imaging Sign.

PURPOSE: To evaluate the imaging and clinical features of unusual calcified lesions seen in the fundus of patients with mosaic RASopathy. DESIGN: Single-center retrospective observational study. SUBJECTS: Ten eyes with calcified fundus lesions in 7 patients with mosaic RASopathy. METHODS: The lesions were evaluated with fundus photography, oral fundus fluorescein angiography, B-scan ultrasonography, magnetic resonance imaging (MRI), and computed tomography (CT) scan where available. MAIN OUTCOME MEASURES: The imaging characteristics of calcified fundus lesions were assessed. RESULTS: We found 7 patients with mosaic RASopathies, 5 men and 2 women (3 with linear sebaceous nevus syndrome, 3 with oculoectodermal syndrome, and 1 with encephalocraniocutaneous lipomatosis) with molecular confirmation in 5 cases, all 5 having KRAS-pathogenic variants. Calcified fundus lesions were identified in 10 eyes (bilateral in 3 patients), appearing as slightly elevated, creamy-yellow lesions around or adjacent to the optic nerve, extending supero-nasally; all but 2 of these lesions involved both the choroid and sclera, with 2 of them only involving the sclera at the time of examination. One case developed a choroidal neovascular membrane necessitating intravitreal bevacizumab injections. All 7 patients had B-scan ultrasonography, and the lesion appeared as a hyperechogenic area with an acoustic shadow posteriorly despite reduced gain. Five patients had MRI, and where fundus lesions were present, there was a focal defect in the sclero-choroidal layer. Four patients had a CT scan, and all 4 showed calcifications affecting both the posteromedial sclero-choroid and adjacent medial rectus muscle. Two of these patients had normal eye movements, 1 had a unilateral fixed adducted eye and a vestigial fibrous medial rectus muscle seen in imaging and intraoperatively, and the fourth had marked exotropia with a right gaze deficit affecting both eyes. CONCLUSIONS: We propose that the lesions seen in this cohort are calcified sclero-choroidal choristomas and should be suspected in mosaic RASopathies when creamy-yellow lesions are seen in the fundus. If identified, the possibility of choroidal neovascularization should be considered during follow-up. In all cases where a CT scan was performed, a novel sign of sclero-muscular calcification involving the medial rectus muscle was seen. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Variable Phenotype of Congenital Corneal Opacities in Biallelic CYP1B1 Pathogenic Variants.

PURPOSE: The aim of this study is to describe the variable phenotype of congenital corneal opacities occurring in patients with biallelic CYP1B1 pathogenic variants. METHODS: A retrospective chart review was conducted to identify patients with congenital corneal opacities and CYP1B1 pathogenic variants seen at UPMC Children's Hospital of Pittsburgh. Ophthalmic examination, high-frequency ultrasound, anterior segment optical coherence tomography, histopathologic images, and details of genetic testing were reviewed. RESULTS: Three children were identified. All presented with raised intraocular pressure. Two patients showed bilateral limbus-to-limbus avascular corneal opacification that did not resolve with intraocular pressure control; 1 showed unilateral avascular corneal opacity with a crescent of clear cornea, iridocorneal adhesions, iridolenticular adhesions, and classical features of congenital glaucoma in the fellow eye (enlarged corneal diameter, Haab striae, and clearing of the corneal clouding with appropriate intraocular pressure control). The first 2 patients were visually rehabilitated with penetrating keratoplasty. Histopathology revealed distinct features: a variably keratinized epithelium; a thick but discontinuous Bowman-like layer with areas of disruption and abnormal cellularity; Descemet membrane, when observed, showed reduced endothelial cells; and no pathological changes of Haab striae were identified. Two patients had compound heterozygous pathogenic variants in CYP1B1 causing premature stop codons, whereas 1 was homozygous for a pathogenic missense variant. CONCLUSIONS: Congenital corneal opacities seen in biallelic CYP1B1 pathogenic variants have a variable phenotype. One is that commonly termed as Peters anomaly type 1 (with iridocorneal adhesions, with or without iridolenticular adhesions) and the other is a limbus-to-limbus opacity, termed CYP1B1 cytopathy. Clinicians should be aware of this phenotypic variability.

OCT Angiography in Noninfectious Uveitis: A Description of Five Cases and Clinical Applications.

BACKGROUND: Optical coherence tomography angiography (OCTA) is a noninvasive imaging modality used to analyze the retinochoroidal vasculature and detect vascular flow. The resulting images can be segmented to view each vascular plexus individually. While fluorescein angiography is still the gold standard for the diagnosis of posterior uveitis, it has limitations, and can be replaced by OCTA in some cases. METHODS: This case series describes five patients with posterior noninfectious uveitis and their description by OCTA. RESULTS: Cases included lupus retinopathy (n = 1) for which OCTA showed ischemic maculopathy as areas of flow deficit at the superficial and deep capillary plexus; choroidal granulomas (n = 1) with a non-detectable flow signal in the choroid; active punctate inner choroiditis and multifocal choroiditis (n = 1) with OCTA that showed active inflammatory chorioretinal lesions as non-detectable flow signals in choriocapillaris and choroid; dense type 2 inflammatory secondary neovascularization (n = 1) associated with active choroiditis; and acute posterior multifocal placoid pigment epitheliopathy (APMPPE) (n = 1) without flow abnormalities at the superficial and deep retinal plexuses but non-detectable flow at the levels of the choriocapillaris and choroid. CONCLUSIONS: Ophthalmologists can use OCTA to identify inflammatory changes in retinal and choroidal vasculature, aiding in the diagnosis, management, and monitoring of posterior uveitis.

Technique for the Management of Extensive Ocular Surface Lipodermoid Involving the Cornea of Children.

PURPOSE: Ocular surface lipodermoids with corneal involvement may require surgical intervention; if deep, ocular surface reconstruction with lamellar corneal tissue or amniotic membrane may be needed. We describe a staged technique using autologous ipsilateral simple limbal epithelial transplantation. METHODS: After verifying sparing of Descemet membrane, the conjunctival portion of the lipodermoid was debulked in the first stage. Six weeks later, the corneal portion was excised, followed by autologous ipsilateral simple limbal epithelial transplantation to promote rapid reepithelialization of the residual stromal bed. Temporary tarsorrhaphy was used for patient comfort and to expedite ocular surface healing. RESULTS: Three eyes of 3 children with grade III large ocular surface lipodermoids that encroached the visual axis and hindered proper eyelid closure underwent surgery without complications. In all cases, the visual axis was cleared and eyelid closure was improved. At the last follow-up (mean 35.7 months, median 36.0 months), the bed of the original dermoid showed minimal haze in 1 case, while 2 eyes developed small pseudopterygium; best spectacle-corrected visual acuity improved from 20/200 to 20/70 in the first case, from fix and follow to 20/50 in the second case, and remained fix and follow in the last case, but this child had congenital hydrocephalus with severe developmental delay. CONCLUSIONS: This surgical technique is a promising option for children with grade III large ocular surface lipodermoids given its effectiveness in clearing the visual axis and in improving eyelid closure. Moreover, it does not require lamellar corneal transplantation or intervention to the fellow eye.

Melphalan toxicity following treatment of retinoblastoma identified by pattern electroretinogram.

PURPOSE: To describe a patient with retinoblastoma and subsequent maculopathy unrelated to the tumor but related to intra-arterial melphalan documented by pattern electroretinography. METHODS: Comprehensive ophthalmic evaluation, treatment with intra-arterial chemotherapy and subsequent follow-up including electroretinography to assess for macular dysfunction. RESULTS: A 3-year-old child was evaluated with electrophysiological investigations following treatment of unilateral Group D retinoblastoma with intra-arterial and intravitreal chemotherapy with melphalan. Pattern reversal visual evoked potential amplitude and P100 latency were normal in the left eye, but abnormal and delayed in the right eye. Pattern electroretinograms (pERGs) were abnormal on the right eye. Flash electroretinograms (fERGs) were normal on both eyes. Visual acuity dysfunction of 20/50 attributed to melphalan was seen on the right eye vs 20/40 on the left eye. CONCLUSION: Our case report demonstrates that pERG rather than fERG should be used to monitor baseline macular function and potential toxicity in children undergoing chemotherapy for retinoblastoma using skin electrodes when corneal electrodes are not tolerated.

Congenital corneal staphyloma in 8q21.11 microdeletion syndrome.

BACKGROUND: Although 8q21.11 microdeletion syndrome (8q21.11 DS) has been reported in association with congenital corneal opacities, reports of the clinicopathological features and management are scarce. METHODS: We reviewed medical records including ophthalmic evaluations, imaging, operative reports, and pathology reports of two unrelated patients referred to the Ophthalmology Clinic of UPMC Children's Hospital of Pittsburgh with a cytogenetic diagnosis of 8q21.11 DS. RESULTS: Ophthalmological evaluation of both children revealed bilateral enlarged, staphylomatous, and cloudy corneas with neovascularization. These findings were consistent with the diagnosis of congenital corneal staphyloma (CCS). In one patient, anterior segment optical coherence tomography and high-frequency ultrasound revealed materials consistent with lens remnants embedded in the cornea; this was confirmed by histopathology. In the second patient, lens was found to be adherent to the cornea during surgery. One eye underwent enucleation for corneal perforation secondary to elevated intraocular pressure. In the other eyes, treatment consisted of penetrating keratoplasty combined with vitrectomy. Ahmed tube was subsequently placed to control intraocular pressure. CONCLUSION: 8q21.11 microdeletion syndrome can be associated with bilateral CCS, likely related to a combination of anterior segment developmental anomalies and elevated intraocular pressure. Tectonic penetrating keratoplasty is necessary to prevent corneal perforation, together with a strict control of the intraocular pressure.

Ocular biodistribution of cysteamine delivered by a sustained release microsphere/thermoresponsive gel eyedrop.

The objective of the investigation was to determine the ocular biodistribution of cysteamine, a reducing agent used for treatment of cystine crystals in cystinosis, following topical administration of a sustained release formulation and traditional eyedrop formulation. To the right eye only, rabbits received a 50 µL drop of 0.44% cysteamine eyedrops at one drop per waking hour for 2, 6, 12, and 24 h. A second group received one 100 µL drop of a sustained release formulation containing encapsulated cysteamine microspheres suspended in a thermoresponsive gel. Upon serial sacrifice, ocular tissues from both eyes and plasma were obtained and quantified for cysteamine using LC-MS/MS. Cysteamine was detected in the cornea, aqueous humor and vitreous humor. Systemic plasma concentrations of cysteamine from treatment groups were below the limit of detection. As expected, 0.44% cysteamine eyedrops when administered hourly maintained drug concentrations within the cornea at a magnitude 5 times higher than a single dose of the sustained release formulation over 12 h. The sustained release formulation maintained cysteamine presentation across 12 h from a single drop. These studies demonstrate distribution of cysteamine to the eye following topical administration, including high drug uptake to the cornea and low systemic distribution.

Macular atrophy in JAG1-related Alagille syndrome: a case series.

BACKGROUND: : Alagille syndrome (AS) is a multisystem disorder associated with a range of ocular anomalies affecting the anterior and posterior segments. While chorioretinal abnormalities have been reported in Alagille Syndrome, identification of macular dystrophy and detailed clinical and electrophysiologic descriptions are scarce. MATERIALS AND METHODS: : A retrospective review was conducted to identify patients with a diagnosis of AS and retinal disease who were evaluated in the Division of Pediatric Ophthalmology, Strabismus, and Adult Motility at UPMC Children's Hospital of Pittsburgh. Criteria of AS included biopsy-proven bile duct hypoplasia, presence of major clinical features of AS, and molecular confirmation of the JAG1 gene. RESULTS: : This cohort included three patients, two females and one male, diagnosed with JAG1-Alagille syndrome. The diagnosis was made before 2 years of life in all patients. The mean follow-up period in our center was 8 years. All patients were found to have retinal pigmentary changes, macular atrophy, choroidal thinning, optic disc anomalies, and progressive decrease in vision. Marked retinal and macular dysfunction were found in electrophysiological studies. CONCLUSIONS: : Three patients with molecularly confirmed Alagille syndrome demonstrated unusual retinal and macular findings, with two showing progressive vision loss. Due to the rarity of retinal findings in AS and the observed progression of disease in our patients, clinical genetic testing for retinal dystrophies could be completed in two cases. These investigations failed to reveal a separate molecular cause for the observed retinal dystrophy, helping to confirm the association with JAG1-related AS.

Safety of apraclonidine eye drops in diagnosis of Horner syndrome in an outpatient pediatric ophthalmology clinic.

PURPOSE: To describe the efficacy and systemic side effects of apraclonidine drops 0.5% in children clinically suspected of having Horner syndrome. METHODS: The medical records of patients with clinically suspected Horner syndrome who underwent testing with apraclonidine 0.5% eyedrops were reviewed retrospectively. The following data were retrieved from the record: allergic reactions, somnolence, shallow respiration, pallor, or excessive fussiness noted by the examiner or parents. RESULTS: A total of 46 patients presenting with anisocoria and tested with apraclonidine 0.5% were included. Of these, 15 had a positive result, with reversal of anisocoria. The mean age of patients was 3.2 years (median, 0.91; mode, 0.25 years). Twenty-four patients were ≤1 year of age; 19 were ≤6 months. No systemic side effects were noted during the examination or reported by parents in any patients. CONCLUSIONS: The use of topical apraclonidine eyedrops has been described as an effective test for Horner syndrome. However, concerns have been raised regarding the potential systemic side effects in children, especially those under the age of 6 months. In our cohort, no systemic side effects were reported, including in those under 6 months of age.

Somatic KRAS mutation affecting codon 146 in linear sebaceous nevus syndrome.

Linear Sebaceous Nevus Syndrome is a rare disorder that presents with nevus sebaceus in association with corneal dermoids, colobomas, choroidal osteomas, and arachnoid cysts. It is thought to represent a mosaic RASopathy. These are disorders characterized by postzygotic somatic mutation in genes involved in RAS/MAPK signaling pathway. In this report we describe two patients with linear sebaceous nevus syndrome found to have mutations in codon 146 of KRAS with evidence of mosaicism. This specific mutation has previously been reported in Oculoectodermal Syndrome and Encephalocraniocutaneous Lipomatosis, two other mosaic RASopathies with predominantly cerebrooculocutaneous manifestations. These findings suggest that, while initially classified as different syndromes, these disorders should be evaluated and managed as a spectrum of related disorders.

Novel clinical presentation of a CRX rod-cone dystrophy.

We describe a novel clinical presentation of a CRX rod-cone dystrophy in a single family. Two boys ages 6 and 12 years presented with clinical and optical coherence tomography features suggestive of X-linked retinoschisis, but with optic nerve swelling without increased intracranial pressure. One patient had an electronegative electroretinogram (ERG) and the other had rod-cone dysfunction. Neither had retinoschisin (RS1) gene mutations. Biological mother and sister presented with retinal pigment epithelium (RPE) changes and abnormal cone-rod ERG responses. On further testing, next generation sequencing with array comparative genomic hybridisation showed a deletion in exon 4 of the CRX gene. Cystoid maculopathy in young male children can be difficult to distinguish from RS1-associated schisis. Phenotypic variants within a family must prompt a thorough retinal dystrophy evaluation even with electronegative ERG in the presenting child. This novel phenotype for CRX presents with optic nerve swelling and cystoid maculopathy in men, and RPE changes in women.

Integrated Intraoperative Optical Coherence Tomography in Pediatric Glaucoma Surgery.

The advent of integrated intraoperative optical coherence tomography (i2OCT) has opened the door for safer and more complex surgeries in the retina and cornea. However, to limit its use to just two subspecialties within ophthalmology is an opportunity lost for many other subspecialties. Here, we describe the use of i2OCT in pediatric glaucoma surgery. It can be used to identify Schlemm's canal, Barkan's membrane, demonstrate the corneal pathology in Haab's striae, and iris hypoplasia in cases of Axenfeld-Rieger anomaly. It can help identify drainage blebs that are filtering and those that are not, and identify successful drainage tube flushing. It has also been used to identify a ligating suture effect on a drainage tube. We describe these scenarios in relation to training and augmenting surgical techniques.

Use of Integrated Intraoperative Ocular Coherence Tomography in Pediatric Cataract Surgery: Thinking outside the Box.

The advent of integrated intraoperative optical coherence tomography (i2OCT) has opened the door for safer and more complex surgeries in the retina and cornea. However, to limit its use to just two subspecialties within ophthalmology is an opportunity lost for many other subspecialties. Here, we describe the use of i2OCT in pediatric cataract surgery in circumstances that are not traditionally considered for i2OCT use. The specific circumstances include: evaluation and treatment of a child following cataract extraction with lens implantation who has failed two attempts at YAG capsulotomy; lysis of post-trauma keratolenticular adhesion in an opaque cornea; surgical removal of secondary lens epithelial cell proliferation after pediatric cataract extraction with lens implantation, and identification of posterior capsular openings and defects. In each case the use of i2OCT allowed the procedure to be completed safely and successfully or informed the surgeon, allowing modification of the surgical decision tree.

A sustained release cysteamine microsphere/thermoresponsive gel eyedrop for corneal cystinosis improves drug stability.

Cystinosis is a rare, metabolic, recessive genetic disease in which the intralysosomal accumulation of cystine leads to system wide organ and tissue damage. In the eye, cystine accumulates in the cornea as corneal cystine crystals and severely impacts vision. Corneal cystine crystals are treated with cysteamine eyedrops when administrated 6 to 12 times day and used within 1 week. The strict dosing regimen and poor stability are inconvenient and add to the burden of therapy. To reduce the dosing frequency and improve the stability, we present reformulation of cysteamine into a novel controlled release eyedrop. In this work, we characterize and evaluate a topical drug delivery system comprised of encapsulated cysteamine in polymer microspheres with a thermoresponsive gel carrier. Spray-dried encapsulation of cysteamine was performed. In vitro cysteamine release, stability, and ocular irritation and corneal permeation were evaluated. The data suggest that encapsulated cysteamine improves the stability to 7 weeks when compared with 1-week aqueous cysteamine eyedrops. Release studies from one drop of our system show that cysteamine release was present for 24 h and above the minimum cysteamine eyedrop amount (6 drops). Cysteamine from our system also resulted in negligible irritation and enhanced permeation when compared with traditional cysteamine eyedrops. In vivo studies were implemented to support ease of administration, tolerability, and retention for 24 h. These studies suggest that our controlled release delivery system may provide stable cysteamine from a safe, once daily gel eyedrop.

Developing a pediatric ophthalmology telemedicine program in the COVID-19 crisis.

PURPOSE: To describe our methodology for implementing synchronous telemedicine during the 2019 novel coronavirus (COVID-19) pandemic. METHODS: A retrospective review of outpatient records at a single children's hospital from March 21 to April 10, 2020, was carried out to determine the outcome of already-scheduled face-to-face outpatient appointments. The week leading up to the March 21, all appointments in the study period were categorized as follows: (1) requiring an in-person visit, (2) face-to-face visit that could be postponed, and (3) consultation required but could be virtual. Teams of administrators, schedulers, and ophthalmic technicians used defined scripts and standardized emails to communicate results of categorization to patients. Flowcharts were devised to schedule and implement telemedicine visits. Informational videos were made accessible on social media to prepare patients for the telemedicine experience. Simultaneously our children's hospital launched a pediatric on-demand e-consult service, the data analytics of which could be used to determine how many visits were eye related. RESULTS: A total of 237 virtual ophthalmology consult visits were offered during the study period: 212 were scheduled, and 206 were completed, of which 43 were with new patients and 163 with returning patients. Following the initial virtual visit, another was required on average in 4 weeks by 21 patients; in-person follow-up was required for 170 patients on average 4.6 months after the initial virtual visit. None needed review within 72 hours. The pediatric on-demand service completed 290 visits, of which 25 had eye complaints. CONCLUSIONS: With proper materials, technology, and staffing, a telemedicine strategy based on three patient categories can be rapidly implemented to provide continued patient care during pandemic conditions. In our study cohort, the scheduled clinic e-visits had a low no-show rate (3%), and 8% of the on-demand virtual access for pediatric care was eye related.

Development of Corneal Sensation With Remodeling of the Epithelium and the Palisades of Vogt After Corneal Neurotization.

PURPOSE: Neurotrophic keratopathy (NK) produces persistent epithelial erosion which is hard to treat effectively. Recently, corneal neurotization surgery has produced reinnervation of the cornea with resolving neurotrophic keratopathy. We hypothesized that the generation of corneal epithelial nerves after neurotization surgery would not only restore the integrity of corneal epithelium but also produce a change in the configuration of the palisades of Vogt (POV), which houses the corneal epithelial stem cells. METHODS: We assessed a patient with unilateral congenital corneal anesthesia with optical coherence tomography pre-neurotization and post-neurotization. RESULTS: Over the course of 2 years, the patient gained corneal epithelial sensation and corneal and limbal epithelium was restored to normal thickness with corresponding changes in the POV. CONCLUSIONS: The intimate relationship between epithelium and sensory nerves of the cornea has been well documented; however, changes in the corneal epithelial stem cell niche in conjunction with development of innervation have not previously been reported. Considering the architecture of the corneal nerves in conjunction with the architecture of the POV may assist in developing treatments that can support the regeneration and maintenance of epithelium during nerve regeneration.

Serial, Visually-Evoked Potentials for the Assessment of Visual Function in Patients with Craniosynostosis.

This study aimed to evaluate the effect of craniofacial surgical intervention on the visual pathway's function by comparing pre- to post-operative patterned, visually-evoked potentials (pVEP). A retrospective review was conducted on craniosynostosis patients who had pre- and post-craniofacial surgery pVEP testing. The pVEP measured grade in terms of amplitude latency and morphology of the waveforms. The pre- and post-operative results were compared. The study identified 63 patients (mean age at preoperative pVEP of 16.9 months). Preoperatively, 33 patients (52.4%) had abnormal pVEP. Nine patients had evidence of intracranial hypertension, and of those, eight (88.9%) had abnormal pVEP. Within 6 months postoperatively, 24 of 33 patients (72.7%) with abnormal preoperative pVEP developed normal postoperative pVEP, while all 30 patients with normal preoperative VEP maintained their normal results postoperatively. Significant improvements in pVEP latency in patients with broad or delayed latency waveforms was evident for subjects with preoperative grades 2-4 (grade 2, p = 0.015; grade 3, p = 0.029; grade 4; p = 0.007), while significant postoperative increase in amplitude was significant for patients with abnormally low amplitude grade 3 and 5 waveforms (grade 3, p = 0.011; grade 5, p = 0.029). Serial pVEP testing represents a useful tool for the early detection of visual pathway dysfunction and follow up visual pathway function in craniosynostosis. Surgical intervention for craniosynostosis can result in the reversal of preoperative pVEP abnormalities seen in these patients, resulting in the normalization of the pVEP waveform, amplitude and latency, depending on the preoperative pVEP abnormality.

Serial Visual Evoked Potentials in Patients with Craniosynostosis and Invasive Intracranial Pressure Monitoring.

This study aimed to detect the ability of pattern visual evoked potentials to detect visual pathway dysfunction in a cohort of patients with craniosynostosis who also had invasive intracranial pressure measurement. A retrospective review was conducted on craniosynostosis patients who had invasive intracranial pressure measurement and at least one pattern visual evoked potentials test. Reversal pattern visual evoked potentials were performed with both eyes open. Thirteen patients met the inclusion criteria (mean age at intracranial pressure measurement, 5.7 years). Seven patients had raised intracranial pressure, and of these, five (71.4 percent) had abnormal or deteriorated pattern visual evoked potentials parameters on serial testing, whereas all patients (100 percent) with normal intracranial pressure had normal pattern visual evoked potentials amplitude and latency. Four of the five patients (80 percent) with raised intracranial pressure and abnormal pattern visual evoked potentials did not show evidence of papilledema. The mean latency in patients with raised intracranial pressure (118.7 msec) was longer than in those with normal intracranial pressure (108.1 msec), although it did not reach statistical significance (p = 0.09), whereas the mean amplitude in patients with raised intracranial pressure (12.4 µV) was significantly lower than in patients with normal intracranial pressure (23.3 µV) (p = 0.03). The authors' results showed that serial pattern visual evoked potentials testing was able to detect visual pathway dysfunction resulting from raised intracranial pressure in five of seven craniosynostosis patients, and of these five patients, 80 percent had no evidence of papilledema, demonstrating the utility of serial pattern visual evoked potentials in follow-up of the visual function in craniosynostosis patients. CLINICAL QUESTION/LEVEL OF EVIDENCE:: Diagnostic, II.