Feasibility and Safety of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia (SANE-01): A Randomized, Double-blind, Placebo-controlled Phase Ib Clinical Trial.

OBJECTIVE: To test feasibility and safety of administering sildenafil in neonates with neonatal encephalopathy (NE), developing brain injury despite therapeutic hypothermia (TH). STUDY DESIGN: We performed a randomized, double-blind, placebo-controlled phase Ib clinical trial between 2016 and 2019 in neonates with moderate or severe NE, displaying brain injury on day-2 magnetic resonance imaging (MRI) despite TH. Neonates were randomized (2:1) to 7-day sildenafil or placebo (2 mg/kg/dose enterally every 12 hours, 14 doses). Outcomes included feasibility and safety (primary outcomes), pharmacokinetics (secondary), and day-30 neuroimaging and 18-month neurodevelopment assessments (exploratory). RESULTS: Of the 24 enrolled neonates, 8 were randomized to sildenafil and 3 to placebo. A mild decrease in blood pressure was reported in 2 of the 8 neonates after initial dose, but not with subsequent doses. Sildenafil plasma steady-state concentration was rapidly reached, but decreased after TH discontinuation. Twelve percent of neonates (1/8) neonates died in the sildenafil group and 0% (0/3) in the placebo group. Among surviving neonates, partial recovery of injury, fewer cystic lesions, and less brain volume loss on day-30 magnetic resonance imaging were noted in 71% (5/7) of the sildenafil group and in 0% (0/3) of the placebo group. The rate of death or survival to 18 months with severe neurodevelopmental impairment was 57% (4/7) in the sildenafil group and 100% (3/3) in the placebo group. CONCLUSIONS: Sildenafil was safe and well-absorbed in neonates with NE treated with TH. Optimal dosing needs to be established. Evaluation of a larger number of neonates through subsequent phases II and III trials is required to establish efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT02812433.

Ophthalmic diseases in meningitis within the pediatric population.

OBJECTIVE: Meningitis may lead to ophthalmic complications in pediatric populations. The visual aftermath in developed countries has been poorly studied. This study aims to highlight the potential ocular and neuro-ophthalmic sequela of meningitis in the pediatric population of a tertiary pediatric hospital. DESIGN: A retrospective chart review of all pediatric patients, between 2006 and 2015, diagnosed with meningitis at the Montreal Children's Hospital was conducted. Study approval was obtained by the Institutional Review Board of the McGill University Health Centre and adhered to the tenets of the Declaration of Helsinki. METHODS: Records of all pediatric meningitis patients were extracted and further refined by isolating all who received an ophthalmology consultation. Relevant demographic data, general medical information, ocular findings, and imaging results were extracted. The proportion of ocular abnormalities was calculated and analyzed. RESULTS: Seventy-two of 861 meningitis patients (8.4%) received an ophthalmology consultation. Forty-six patients met the inclusion criteria, and 31 of those (67.4%) demonstrated ocular abnormalities. Children presented most frequently with abnormalities involving visual acuity (8 of 32), extraocular movements and alignment (14 of 28), optic nerve (10 of 41), pupillary reactivity (4 of 35), and periorbital/orbital cellulitis (4 of 46). Older patients were more likely to have ophthalmologic findings. CONCLUSION: This chart review highlights the ocular abnormalities found in children who suffer from meningitis and present to a tertiary-care centre in a high sociodemographic index country. Complications may be lasting. Treating ophthalmologists should be cognizant of potential ocular abnormalities among meningitis patients. We advocate for increased awareness of this association among health care providers.

Natural History of Untreated Optic Neuritis Associated With Mild COVID-19 Infection.

This article describes a case of untreated optic neuritis occurring in the setting of coronavirus disease 2019 (COVID-19) infection and provides new insights into the natural history of this condition. A 29-year-old male patient with no known ocular or systemic disease presented with pain on extraocular movements and sudden loss of vision in the inferior visual field affecting the right eye. He had tested positive for COVID-19 six days prior after experiencing mild upper respiratory symptoms. On examination, visual acuity was 20/20, and color vision was normal. A relative afferent pupillary defect was observed in the right eye. Fundoscopy revealed mild optic disc edema in the same eye. Optical coherence tomography showed increased retinal nerve fiber layer thickness of the right optic nerve head and visual field testing revealed an inferonasal defect. Extensive laboratory and imaging investigations failed to reveal an underlying etiology, supporting a diagnosis of COVID-19-associated optic neuritis. The patient improved spontaneously without treatment. At the five-month follow-up, minor optic atrophy and a small residual visual field defect remained.

Subtle magnetic resonance imaging differences in tegmental pilocytic astrocytomas as a caution against attempting gross-total resection: illustrative cases.

BACKGROUND: Although surgery within the tegmentum of the midbrain is challenging, resection of tegmental pilocytic astrocytomas (PAs) is a standard treatment because this has been shown to outperform chemotherapy and radiotherapy in terms of long-term tumor control. Gross total resection (GTR) assisted by intraoperative neuroelectrophysiological monitoring can be achieved with a reasonable risk-to-benefit ratio, especially for well-circumscribed tumors, but careful scrutiny of magnetic resonance imaging (MRI) is critical to surgical decision making. The authors present two cases of tegmental PAs, which appeared grossly similar on MRI and were operated on via the same surgical approach using the same intraoperative adjuncts. OBSERVATIONS: The tumors had identical histopathological and molecular diagnoses but drastically different functional outcomes for the patients, with significant long-term complications for one of the children, which the authors believe was due to a slightly more invasive nature of this tumor. The authors demonstrate subtle preoperative MRI findings that might be potential clues to a more infiltrative nature of one PA versus another and present pathological findings supporting this argument. LESSONS: This report serves as a reminder that not all tegmental PAs can be managed by the same surgical approach. Subtle signs of infiltration may indicate that GTR should not be attempted.

PCDH12 variants are associated with basal ganglia anomalies and exudative vitreoretinopathy.

PCDH12 is a member of the non-clustered protocadherins that mediate cell-cell adhesion, playing crucial roles in many biological processes. Among these, PCDH12 promotes cell-cell interactions at inter-endothelial junctions, exerting essential functions in vascular homeostasis and angiogenesis. However, its exact role in eye vascular and brain development is not completely understood. To date, biallelic loss of function variants in PCDH12 have been associated with a neurodevelopmental disorder characterized by the typical neuroradiological findings of diencephalic-mesencephalic junction dysplasia and intracranial calcifications, whereas heterozygous variants have been recently linked to isolated brain calcifications in absence of cognitive impairment or other brain malformations. Recently, the phenotypic spectrum associated with PCDH12 deficiency has been expanded including cerebellar and eye abnormalities. Here, we report two female siblings harboring a novel frameshift homozygous variant (c.2169delT, p.(Val724TyrfsTer8)) in PCDH12. In addition to the typical diencephalic-mesencephalic junction dysplasia, brain MRI showed dysmorphic basal ganglia and thalamus that were reminiscent of a tubulin-like phenotype, mild cerebellar vermis hypoplasia and extensive prominence of perivascular spaces in both siblings. The oldest sister developed profound and progressive monocular visual loss and the eye exam revealed exudative vitreoretinopathy. Similar but milder eye changes were also noted in her younger sister. In summary, our report expands the clinical (brain and ocular) spectrum of PCDH12-related disorders and adds a further line of evidence underscoring the important role of PCDH12 in retinal vascular and brain development.

Congenital hypertrophy of the retinal pigment epithelium complicated by a choroidal neovascular membrane.

A 66-year-old woman presenting with a history of visual loss in her left eye was diagnosed with congenital hypertrophy of the retinal pigment epithelium accompanied by a choroidal neovascular membrane (CNVM) affecting the macula. Visual acuity improved after 2 treatments of verteporfin photodynamic therapy. Recurrent CNVM in the same eye 3 years later was stabilized and vision slowly improved with a series of intravitreal bevacizumab injections.

Feasibility and quality of nonmydriatic fundus photography in children.

PURPOSE: Ocular funduscopic examination is difficult in young children and is rarely attempted by nonophthalmologists. Our objective was to determine the feasibility of reliably obtaining high-quality nonmydriatic fundus photographs in children. METHODS: Nonmydriatic fundus photographs were obtained in both eyes of children seen in a pediatric ophthalmology clinic. Ease of fundus photography was recorded on a 10-point Likert scale (10 = very easy). Quality was graded from 1 to 5 (1, inadequate for any diagnostic purpose; 2, unable to exclude all emergent findings; 3, only able to exclude emergent findings; 4, not ideal, but still able to exclude subtle findings; and 5, ideal quality). The primary outcome measure was image quality by age. RESULTS: A total of 878 photographs of 212 children (median age, 6 years; range, 1-18 years) were included. Photographs of at least one eye were obtained in 190 children (89.6%) and in both eyes in 181 (85.3%). Median rating for ease of photography was 7. Photographs of some clinical value (grade ≥2) were obtained in 33% of children <3 years and 95% ≥3 years. High-quality photographs (grade 4 or 5) were obtained in both eyes in 7% of children <3 years, 57% of children ≥3 to <7 years, 85% of children ≥7 to <9 years, and 65% of children ≥9 years. The youngest patient with high-quality photographs in both eyes was 22 months. CONCLUSIONS: Nonmydriatic fundus photographs of adequate quality can be obtained in children over age 3 and in some children as young as 22 months.

A neovascularized epiretinal membrane in a patient with terson syndrome.

PURPOSE: We report on a patient with Terson syndrome in the left eye complicated by a neovascularized epiretinal membrane likely secondary to cocaine use. METHODS: Case report and literature review using the Medline database (1966-2007). RESULTS: A woman known for cocaine use was seen in the ophthalmology clinic for Terson syndrome in the left eye after subarachnoid hemorrhage. Ten months later, a neovascularized epiretinal membrane was noted in the left eye and confirmed with retinal angiography and optical coherence tomography. After vitrectomy, the neovascular membrane was sent for histopathological examination, revealing neovascular capillaries. CONCLUSION: Neovascularized epiretinal membranes have never been reported in Terson syndrome and in our patient this likely occurred due to an ischemic retinal environment created by cocaine use and decreased retinal perfusion after subarachnoid hemorrhage.

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.