Gene therapy for neovascular age-related macular degeneration by subretinal delivery of RGX-314: a phase 1/2a dose-escalation study.

BACKGROUND: Frequent anti-vascular endothelial growth factor A (VEGF-A) injections reduce the risk of rapid and severe vision loss in patients with neovascular age-related macular degeneration (nAMD); however, due to undertreatment, many patients lose vision over time. New treatments that provide sustained suppression of VEGF-A are needed. RGX-314 (currently known as ABBV-RGX-314) is an adeno-associated virus serotype 8 vector that expresses an anti-VEGF-A antigen-binding fragment, which provides potential for continuous VEGF-A suppression after a single subretinal injection. We report results on the safety and efficacy of subretinal injection of RGX-314 in patients with nAMD. METHODS: For this open-label, multiple-cohort, multicentre, phase 1/2a, dose-escalation study conducted at eight sites in the USA, we enrolled participants with nAMD aged 50-89 years who had previously been treated with anti-VEGF injections into five cohorts (with five different doses of RGX-314). To be eligible, participants had to have macular neovascularisation secondary to nAMD with subretinal or intraretinal fluid in the centre subfield, be pseudophakic (after cataract removal), and have a best-corrected visual acuity (BCVA) in the study eye between 20/63 and 20/400 for the first participant in each cohort and between 20/40 and 20/400 for others. Subretinal injection of RGX-314 was done without a pre-bleb by a wet-laboratory-trained vitreoretinal surgeon. Cohort 1 received 3 × 109 genome copies per eye, cohort 2 received 1 × 1010, and cohort 3 received 6 × 1010. Two additional dose cohorts (cohort 4: 1·6 × 1011; cohort 5: 2·5 × 1011) were added. Participants were seen 1 day and 1 week after administration of RGX-314, and then monthly for 2 years (up to week 106). The primary outcome was safety of RGX-314 delivered by subretinal injection up to week 26. This analysis includes all 42 patients enrolled in the study. This study is registered with ClinicalTrials.gov, NCT03066258. FINDINGS: Between May 12, 2017, and May 21, 2019, we screened 110 patients for eligibility and enrolled 68. 42 participants demonstrated the required anatomic response to intravitreal ranibizumab and then received a single RGX-314 injection (dose range 3 × 109 to 2·5 × 1011 genome copies per eye) and were followed up for 2 years. There were 20 serious adverse events in 13 participants, of which one was possibly related to RGX-314: pigmentary changes in the macula with severe vision reduction 12 months after injection of RGX-314 at a dose of 2·5 × 1011 genome copies per eye. Asymptomatic pigmentary changes were seen in the inferior retinal periphery several months after subretinal injection of RGX-314 most commonly at doses of 6 × 1010 genome copies per eye or higher. There were no clinically determined immune responses or inflammation beyond that expected following routine vitrectomy. Doses of 6 × 1010 genome copies or higher resulted in sustained concentrations of RGX-314 protein in aqueous humour and stable or improved BCVA and central retinal thickness with few or no supplemental anti-VEGF-A injections in most participants. INTERPRETATION: Subretinal delivery of RGX-314 was generally well tolerated with no clinically recognised immune responses. RGX-314 gene therapy provides a novel approach for sustained VEGF-A suppression in patients with nAMD that has potential to control exudation, maintain vision, and reduce treatment burden after a single administration. Results from this study informed the pivotal programme to evaluate RGX-314 in patients with nAMD. FUNDING: RegenxBio.

Long-term Follow-up of a Phase 1/2a Clinical Trial of a Stem Cell-Derived Bioengineered Retinal Pigment Epithelium Implant for Geographic Atrophy.

PURPOSE: To report long-term results from a phase 1/2a clinical trial assessment of a scaffold-based human embryonic stem cell-derived retinal pigmented epithelium (RPE) implant in patients with advanced geographic atrophy (GA). DESIGN: A single-arm, open-label phase 1/2a clinical trial approved by the United States Food and Drug Administration. PARTICIPANTS: Patients were 69-85 years of age at the time of enrollment and were legally blind in the treated eye (best-corrected visual acuity [BCVA], ≤ 20/200) as a result of GA involving the fovea. METHODS: The clinical trial enrolled 16 patients, 15 of whom underwent implantation successfully. The implant was administered to the worse-seeing eye with the use of a custom subretinal insertion device. The companion nonimplanted eye served as the control. The primary endpoint was at 1 year; thereafter, patients were followed up at least yearly. MAIN OUTCOME MEASURES: Safety was the primary endpoint of the study. The occurrence and frequency of adverse events (AEs) were determined by scheduled eye examinations, including measurement of BCVA and intraocular pressure and multimodal imaging. Serum antibody titers were collected to monitor systemic humoral immune responses to the implanted cells. RESULTS: At a median follow-up of 3 years, fundus photography revealed no migration of the implant. No unanticipated, severe, implant-related AEs occurred, and the most common anticipated severe AE (severe retinal hemorrhage) was eliminated in the second cohort (9 patients) through improved intraoperative hemostasis. Nonsevere, transient retinal hemorrhages were noted either during or after surgery in all patients as anticipated for a subretinal surgical procedure. Throughout the median 3-year follow-up, results show that implanted eyes were more likely to improve by > 5 letters of BCVA and were less likely to worsen by > 5 letters compared with nonimplanted eyes. CONCLUSIONS: This report details the long-term follow-up of patients with GA to receive a scaffold-based stem cell-derived bioengineered RPE implant. Results show that the implant, at a median 3-year follow-up, is safe and well tolerated in patients with advanced dry age-related macular degeneration. The safety profile, along with the early indication of efficacy, warrants further clinical evaluation of this novel approach for the treatment of GA. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

SUPRACHOROIDAL SPACE INJECTION TECHNIQUE: Expert Panel Guidance.

PURPOSE: To develop professional guidelines for best practices for suprachoroidal space (SCS) injection, an innovative technique for retinal therapeutic delivery, based on current published evidence and clinical experience. METHODS: A panel of expert ophthalmologists reviewed current published evidence and clinical experience during a live working group meeting to define points of consensus and key clinical considerations to inform the development of guidelines for in-office SCS injection. RESULTS: Core consensus guidelines for in-office SCS injection were reached and reported by the expert panel. Current clinical evidence and physician experience supported SCS injection as a safe and effective method for delivering retinal and choroidal therapeutics. The panel established consensus on the rationale for SCS injection, including potential benefits relative to other intraocular delivery methods and current best practices in patient preparation, pre- and peri-injection management, SCS-specific injection techniques, and postinjection management and follow-up. CONCLUSION: These expert panel guidelines may support and promote standardization of SCS injection technique, with the goal of optimizing patient safety and outcomes. Some aspects of the procedure may reasonably be modified based on the clinical setting and physician judgment, as well as additional study.

The Relationship Between Choroidal Abnormalities and Visual Outcomes in Pediatric Patients With NF1-Associated Optic Pathway Gliomas.

BACKGROUND: Choroidal abnormalities (CAs) visualized on near-infrared reflectance (NIR) imaging are a new diagnostic criterion for neurofibromatosis type 1 (NF1), but the association between the presence of CAs and visual function remains unknown. This study evaluated the relationship between visual acuity (VA) with the presence, number, or total area of CAs visualized by NIR in children with NF1-associated optic pathway gliomas (NF1-OPGs). METHODS: Patients (<18 years) enrolled in a prospective longitudinal study of children with NF1-associated OPGs from 3 institutions were eligible if they had optical coherence tomography (OCT) of the macula (Heidelberg Spectralis) with ≥1 year of follow-up. The central 30° NIR images were reviewed by 2 neuro-ophthalmologists who manually calculated the number and total area of CAs. VA (logMAR) was measured using a standardized protocol. Cross-sectional associations of presence, number, and total area of CAs with VA, retinal nerve fiber layer thickness (RNFL), and ganglion cell-inner plexiform layer thickness were evaluated at the first and most recent visits using regression models. Intereye correlation was accounted for using generalized estimating equations. RESULTS: Eighty-two eyes of 41 children (56% female) were included. The mean ± SD age at the first OCT was 10.1 ± 3.3 years, with a mean follow-up of 20.4 ± 7.2 months. At study entry, CAs were present in 46% of eyes with a mean number of 2.1 ± 1.7 and a mean total area of 2.0 ± 1.7 mm 2 per eye. At the most recent follow-up, CAs were present in 48% of eyes with a mean number of 2.2 ± 1.8 lesions and a mean total area of 2.3 ± 2.1 mm 2 per eye. Neither VA nor OCT parameters at first and follow-up visits were associated with the presence, number, or total area of CAs (all P > 0.05). CONCLUSIONS: CAs are prevalent but not ubiquitous, in children with NF1-OPGs. Although CAs are a diagnostic criterion for NF1, their presence and size do not appear to be associated with visual function.

The impact of changes in gadolinium-enhancement on disease progression in children with neurofibromatosis type 1-associated optic pathway glioma: a retrospective analysis.

PURPOSE: There has been limited investigation of imaging features associated with visual acuity (VA) decline and initiation of treatment for patients with neurofibromatosis type 1 (NF1) and optic pathway glioma (OPG). METHODS: To evaluate the association of increased gadolinium enhancement with decline in VA, initiation of chemotherapy, and tumor growth, we performed a retrospective cohort study of children diagnosed with NF1-OPG between January 2006 to June 2016. Two cohorts were defined: a new diagnosis and a longitudinal cohort. Outcomes were examined at 1 and 2 years from initial diagnosis, and 1 and 2 years from initial increase in enhancement in the longitudinal cohort. RESULTS: Eighty patients were eligible; all 80 contributed to the new diagnosis cohort and 73 to the longitudinal cohort. Fifty-six patients (70%) demonstrated enhancing NF1-OPG at diagnosis. 39% of patients in the new diagnosis cohort and 45% of those in the longitudinal cohort developed increased enhancement during the study period. There was no significant association between increases in enhancement and VA decline in the newly diagnosed or longitudinal cohorts, as well as with initiation of treatment in the longitudinal cohort. Although there was an association of enhancement increase with treatment in the new diagnosis cohort, this association was not maintained when stratified by concurrent change in tumor size. CONCLUSION: Increased gadolinium-enhancement independent of a concurrent increase in tumor size on MRI should not be used as a marker of NF1-OPG progression and does not appear to be associated with visual decline or initiation of chemotherapy.

Frequency and Etiologies of Visual Disturbance After Cataract Surgery Identified in Neuro-Ophthalmology Clinics.

BACKGROUND: To identify the frequency and etiologies of visual disturbances after cataract surgery in patients referred to Neuro-ophthalmology. METHODS: This study is a retrospective chart review. Records of patients 18 years and older referred to neuro-ophthalmology clinics for new-onset visual disturbances within 6 months of cataract surgery were reviewed. Those with pre-existing neuro-ophthalmic disorders, combined intraocular procedures with cataract surgery, or inadequate follow-up were excluded. The main outcome measures were frequency and etiologies of visual disturbances after cataract surgery. Secondary analyses of a cohort of patients who had cataract surgery at our institution were performed to determine the frequency and etiology of visual disturbances after uneventful cataract surgery. RESULTS: One hundred seventy-three patients met the inclusion criteria (internal referral: 36/173, from outside surgeons: 137/173). Sixty-one percent (106/173) were newly diagnosed with neuro-ophthalmic etiologies, including 21% (36/173) with afferent and 40% (70/173) with efferent disorders. Thirty-six percent (62/173) of patients had non neuro-ophthalmic causes and 3% (5/173) had systemic conditions responsible for visual disturbances postoperatively. Decompensated strabismus causing diplopia was the most common neuro-ophthalmic diagnosis after cataract surgery (50%, 53/106). Of the 13,715 patients who had cataract surgery performed at our institution over a 9-year period, 20 of 36 patients referred for visual disturbances were identified with neuro-ophthalmic etiologies of which 85% (17/20) had postoperative diplopia. CONCLUSIONS: In our study, decompensated strabismus causing diplopia was the most common neuro-ophthalmic visual disturbance after cataract surgery. Detailed history and ocular alignment should be assessed before cataract surgery to identify patients with the risk.

Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation.

PURPOSE: Neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are genetically distinct tumor predisposition syndromes with overlapping phenotypes. We sought to update the diagnostic criteria for NF2 and SWN by incorporating recent advances in genetics, ophthalmology, neuropathology, and neuroimaging. METHODS: We used a multistep process, beginning with a Delphi method involving global disease experts and subsequently involving non-neurofibromatosis clinical experts, patients, and foundations/patient advocacy groups. RESULTS: We reached consensus on the minimal clinical and genetic criteria for diagnosing NF2 and SWN. These criteria incorporate mosaic forms of these conditions. In addition, we recommend updated nomenclature for these disorders to emphasize their phenotypic overlap and to minimize misdiagnosis with neurofibromatosis type 1. CONCLUSION: The updated criteria for NF2 and SWN incorporate clinical features and genetic testing, with a focus on using molecular data to differentiate the 2 conditions. It is likely that continued refinement of these new criteria will be necessary as investigators study the diagnostic properties of the revised criteria and identify new genes associated with SWN. In the revised nomenclature, the term "neurofibromatosis 2" has been retired to improve diagnostic specificity.

Relating Metopic Craniosynostosis Severity to Intracranial Pressure.

PURPOSE: A subset of patients with metopic craniosynostosis are noted to have elevated intracranial pressure (ICP). However, it is not known if the propensity for elevated ICP is influenced by the severity of metopic cranial dysmorphology. METHODS: Children with nonsyndromic single-suture metopic synostosis were prospectively enrolled and underwent optical coherence tomography to measure optic nerve head morphology. Preoperative head computed tomography scans were assessed for endocranial bifrontal angle as well as scaled metopic synostosis severity score (MSS) and cranial morphology deviation score determined by CranioRate, an automated severity classifier. RESULTS: Forty-seven subjects were enrolled between 2014 and 2019, at an average age of 8.5 months at preoperative computed tomography and 11.8 months at index procedure. Fourteen patients (29.7%) had elevated optical coherence tomography parameters suggestive of elevated ICP at the time of surgery. Ten patients (21.3%) had been diagnosed with developmental delay, eight of whom demonstrated elevated ICP. There were no significant associations between measures of metopic severity and ICP. Metopic synostosis severity score and endocranial bifrontal angle were inversely correlated, as expected ( r =-0.545, P <0.001). A negative correlation was noted between MSS and formally diagnosed developmental delay ( r =-0.387, P =0.008). Likewise, negative correlations between age at procedure and both MSS and cranial morphology deviation was observed ( r =-0.573, P <0.001 and r =-0.312, P =0.025, respectively). CONCLUSIONS: Increased metopic severity was not associated with elevated ICP at the time of surgery. Patients who underwent later surgical correction showed milder phenotypic dysmorphology with an increased incidence of developmental delay.

Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation.

PURPOSE: By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). METHODS: We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. RESULTS: We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. CONCLUSION: The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.

Optic Neuropathy in Charcot-Marie-Tooth Disease.

BACKGROUND: Charcot-Marie-Tooth disease Type 2A (CMT2A) presents with optic atrophy in a subset of patients, but the prevalence and severity of optic nerve involvement in relation to other CMT subtypes has not been explored. METHODS: Patients with genetically confirmed CMT2A (n = 5), CMT1A (n = 9) and CMTX1 (n = 10) underwent high- and low-contrast acuity testing using Sloan letter charts, and circumpapillary retinal nerve fiber layer (RNFL) and macular total retinal, RNFL, and ganglion cell layer/inner plexiform layer thickness was measured using spectral domain optical coherence tomography (OCT). We used age- and gender-adjusted linear regression to compare contrast acuity and retinal thickness between CMT groups. RESULTS: One of 5 patients with CMT2A had optic nerve atrophy (binocular high-contrast acuity equivalent 20/160, mean circumpapillary RNFL 47.5 µm). The other patients with CMT2A had normal high- and low-contrast acuity and retinal thickness, and there were no significant differences between patients with CMT2A, CMT1A, and CMTX1. CONCLUSIONS: Optic atrophy occurs in some patients with CMT2A, but in others, there is no discernible optic nerve involvement. This suggests that optic neuropathy is specific to certain MFN2 mutations in CMT2A and that low-contrast acuity or OCT is of limited value as a disease-wide biomarker.

Utility of Ultrasound and Optical Coherence Tomography in Differentiating Between Papilledema and Pseudopapilledema in Children.

BACKGROUND: Differentiating between papilledema and pseudopapilledema in children presenting with mild-to-moderate optic nerve head elevation is challenging. This study sought to determine which B-scan ultrasonography (BSUS) and optical coherence tomography (OCT) features, individually or in combination, are best able to differentiate between papilledema and pseudopapilledema in children. METHODS: Children presenting with optic nerve head elevation of unknown etiology were eligible if they underwent BSUS and OCT performed by the same investigator. The absolute optic nerve sheath diameter (in millimeter) along with the presence/absence of a hyperreflective nodule(s) at the optic nerve head (indicative of druse) from BSUS was determined. The average circumpapillary retinal nerve fiber layer (cpRNFL), diameter of Bruch membrane opening, maximum papillary height, and the presence/absence of hyper-/hyporeflective lesions at the optic nerve head were calculated. Sensitivity and specificity were calculated to evaluate which BSUS and OCT imaging features, individually and in combination, accurately classified children as having papilledema vs pseudopapilledema. RESULTS: One hundred eighty-one eyes from 94 children (mean age, 11.0 years; range, 3.2-17.9) were included; 36 eyes with papilledema and 145 eyes with pseudopapilledema. Among BSUS features, optic nerve sheath widening (>4.5 mm) demonstrated the best sensitivity (86%; 95% confidence interval [CI], 64%-96%) and specificity (88%; 95% CI, 79%-94%) for papilledema. Among OCT measures, cpRNFL thickness of ≥140 µm demonstrated the best sensitivity (83%; 95% CI, 66%-93%) and specificity (76%; 95% CI, 66%-84%) to identify papilledema. The presence of both optic nerve sheath widening (>4.5 mm) and cpRNFL thickness of ≥140 µm reduced the sensitivity (72%; 95% CI, 52%-86%) but increased specificity (95%; 95% CI, 88%-98%). CONCLUSION: BSUS (optic nerve sheath widening [>4.5 mm]) and OCT (cpRNFL thickness ≥140 µm), individually and collectively, have good diagnostic accuracy for differentiating between papilledema and pseudopapilledema. The presence of druse does not exclude the diagnosis of papilledema.

Utility of Spectral-Domain Optical Coherence Tomography in Differentiating Papilledema From Pseudopapilledema: A Prospective Longitudinal Study.

BACKGROUND: Prospective and longitudinal studies assessing the utility of spectral-domain optical coherence tomography (SD-OCT) to differentiate papilledema from pseudopapilledema are lacking. We studied the sensitivity and specificity of baseline and longitudinal changes in SD-OCT parameters with 3D segmentation software to distinguish between papilledema and pseudopapilledema in a cohort of patients referred for evaluation of undiagnosed optic disc elevation. METHODS: Fifty-two adult patients with optic disc elevation were enrolled in a prospective longitudinal study. A diagnosis of papilledema was made when there was a change in the appearance of the optic disc elevation on fundus photographs as noted by an independent observer at or before 6 months. The degree of optic disc elevation was graded using the Frisen scale and patients with mild optic disc elevation (Frisen grades 1 and 2) were separately analyzed. SD-OCT parameters including peripapillary retinal nerve fiber layer (pRNFL), total retinal thickness (TRT), paracentral ganglion cell layer-inner plexiform layer (GCL-IPL) thickness, and optic nerve head volume (ONHV) at baseline and within 6 months of follow-up were measured. RESULTS: Twenty-seven (52%) patients were diagnosed with papilledema and 25 (48%) with pseudopapilledema. Among patients with mild optic disc elevation (Frisen grades 1 and 2), baseline pRNFL (110.1 µm vs 151.3 µm) and change in pRNFL (ΔpRNFL) (7.3 µm vs 52.3 µm) were greater among those with papilledema. Baseline and absolute changes in TRT and ONHV were also significantly higher among patients with papilledema. The mean GCL-IPL thickness was similar at baseline, but there was a small reduction in GCL-IPL thickness among patients with papilledema. Receiver operator curves (ROCs) were generated; ΔpRNFL (0.93), ΔTRT (0.94), and ΔONHV (0.95) had the highest area under the curve (AUC). CONCLUSIONS: The mean baseline and absolute changes in SD-OCT measurements (pRFNL, TRT, and ONHV) were significantly greater among patients with papilledema, and remained significantly greater when patients with mild optic disc elevation were separately analyzed. ROCs demonstrated that ΔpRNFL, ΔTRT, and ΔONHV have the highest AUC and are best able to differentiate between papilledema and pseudopapilledema.

Unicoronal Craniosynostosis: Is There a Lateral Difference in Retinal Morphology?

BACKGROUND: Craniosynostosis is the premature fusion of cranial sutures in pediatric patients, which may lead to elevated intracranial pressure due to cerebro-cephalic disproportion between a growing brain and constricted skull. It is unknown whether this increased pressure is distributed equally throughout the cranial vault, or whether certain areas of the brain experience greater pressure at these regions of premature osseous fusion. METHODS: Optical coherence tomography (OCT) is a noninvasive modality for detecting elevated intracranial pressure. Optical coherence tomography was utilized to measure the peripapillary retinal nerve fiber layer (RNFL) thickness in patients undergoing surgical correction of craniosynostosis. Retinal nerve fiber layer in the eye ipsilateral to the unicoronal suture fusion was compared to the RNFL in the eye contralateral to the unicoronal suture fusion. RESULTS: During the study interval, 21 patients met inclusion criteria. Median age at operative intervention was 8.0 months, and 28.6% patients presented with left-sided unicoronal craniosynostosis, whereas 71.4% of patients presented with right-sided unicoronal craniosynostosis. Rather than universal increase on the affected side of coronal suture fusion, retinal nerve fiber layer thickness parameters showed a rotation phenomenon, such that the patterns of elevation had a 45° circumferential rotation in the direction of intorsion. CONCLUSIONS: The explanation for these results remains elusive, but they likely indicate either intracranial changes transmitted differentially to the peripapillary retina, or differing retinal morphology, between the ipsilateral and contralateral eyes in unicoronal craniosynostosis.

Outcomes After Transcervical Thymectomy for Ocular Myasthenia Gravis: A Retrospective Cohort Study With Inverse Probability Weighting.

BACKGROUND: The benefit of thymectomy in reducing requirement for corticosteroids, symptom severity, need for immunosuppression, and hospitalization rates in patients with seropositive generalized myasthenia has recently been established. It is unclear whether this benefit applies to patients with myasthenia and purely ocular manifestations (ocular myasthenia gravis [OMG]). METHODS: We conducted a retrospective single-center cohort study of patients with OMG. Patients were included if their diagnosis was confirmed by acetylcholine receptor or muscle-specific kinase antibodies, abnormal electrophysiology, or a positive edrophonium test and at least 1 year of clinical follow-up. At each visit, the presence and severity of ocular and generalized symptoms was ascertained using a 4-point scale. Prednisone dose, steroid-sparing agent use, and need for intravenous immunoglobulin or plasmapheresis were recorded. The effect of thymectomy on time-weighted prednisone dose and symptom severity score was assessed using linear regression models. To adjust for nonrandomization of thymectomy, we used inverse probability weighting using a propensity score model derived from the prethymectomy observation period for thymectomy patients and a 6-month lead-in period for nonthymectomy patients that incorporated age, sex, acetylcholine receptor antibody seropositivity, disease severity (as defined by both symptom severity and treatment requirement), and treating physician preferences. RESULTS: Eighty-two patients (30 with thymectomy and 52 nonthymectomy) were included. In unadjusted analyses, time-weighted daily prednisone dose was 2.9 mg higher with thymectomy compared with nonthymectomy (95% CI: 0.2-5.7), but after inverse probability weighting, this was no longer statistically significant (difference = 1.7 mg, 95% CI: -0.8 to 4.2). There was no statistically significant difference in symptom severity score (adjusted difference = 0.35, 95% CI: -0.02 to 0.72) or risk of generalization (P = 0.22). CONCLUSIONS: In this retrospective study that used statistical techniques to account for nonrandomization, no significant differences in prednisone dose or symptom severity after thymectomy in ocular myasthenia were demonstrated.

High- and Low-Contrast Letter Acuity Perception Matures With Age in Normally Sighted Children.

BACKGROUND: High-contrast visual acuity (HCVA) changes with age, yet little is known about pediatric-specific age- and sex-normative values for low-contrast letter acuity (LCLA). We define maturational changes in monocular and binocular HCVA and LCLA in childhood and adolescence. METHODS: Normally sighted youth (ages 5-20 years, without neurologic or ophthalmologic disease and best-corrected HCVA of 20/25 or better in each eye) were recruited. Mean monocular and binocular scores using Early Treatment Diabetic Retinopathy Study (for HCVA) and 2.5% and 1.25% Sloan (for LCLA) charts and the magnitude of binocular summation were calculated using 2-year bins. Relationships between scores and age were explored using scatterplots with Locally Weighted Scatterplot Smoothing (LOWESS) and analysis of variance that accounts for intereye correlation, followed by test of linear trend for age effect. RESULTS: Among 101 (202 eyes) healthy participants (mean age 13 years, 42% males), monocular and binocular scores varied by age, with highest mean scores achieved in the 13 to 14-year age group for both HCVA and LCLA. Between the ages of 5 and 14.9 years, monocular scores increased linearly with age (0.76 letter/year for HCVA, 1.11 letters/year for 2.5% LCLA, and 0.97 letter/year for 1.25% LCLA; all P < 0.0001). Binocular HCVA scores also increased with age between 5 and 14.9 years (0.71 letters/year, P < 0.0001). The magnitude of binocular summation for HCVA or LCLA did not change with age. CONCLUSIONS: HCVA and LCLA abilities mature into adolescence, peak between 13 and 14.9 years of age, and then plateau into adulthood. Evaluation of patients with visual deficits should consider age-expected normal visual acuity.

Current treatment of optic nerve gliomas.

PURPOSE OF REVIEW: Optic pathway gliomas are low-grade neoplasms that affect the precortical visual pathway of children and adolescents. They can affect the optic nerve, optic chiasm, optic tracts and radiations and can either be sporadic or associated with neurofibromatosis type one. Gliomas isolated to the optic nerve (ONG) represent a subgroup of optic pathway gliomas, and their treatment remains controversial. New developments in ONG treatment have emerged in recent years, and it is necessary for clinicians to have a current understanding of available therapies. RECENT FINDINGS: The current review of the literature covers the background of and recent developments in ONG treatment, with a focus on standard chemotherapy, new molecularly targeted therapies, radiation therapy and surgical resection and debulking. SUMMARY: Although standard chemotherapy remains the mainstay of ONG treatment, newer molecularly targeted therapies such as mitogen-activated protein kinase kinase inhibitors and bevacizumab represent a promising new treatment modality, and clinical studies are ongoing.

Orbital/Periorbital Plexiform Neurofibromas in Children with Neurofibromatosis Type 1: Multidisciplinary Recommendations for Care.

TOPIC: Children and adults with neurofibromatosis type 1 (NF1), a common autosomal dominant condition, manifest a variety of ophthalmologic conditions. Plexiform neurofibromas (PNs) involving the eyelid, orbit, periorbital, and facial structures (orbital-periorbital plexiform neurofibroma [OPPN]) can result in significant visual loss in children. Equally important, OPPNs can cause significant alteration in physical appearance secondary to proptosis, ptosis, and facial disfigurement, leading to social embarrassment and decreased self-esteem. CLINICAL RELEVANCE: Although NF1 is a relatively common disease in which routine ophthalmologic examinations are required, no formal recommendations for clinical care of children with OPPNs exist. Although medical and surgical interventions have been reported, there are no agreed-on criteria for when OPPNs require therapy and which treatment produces the best outcome. METHODS: Because a multidisciplinary team of specialists (oculofacial plastics, pediatric ophthalmology, neuro-ophthalmology, medical genetics, and neuro-oncology) direct management decisions, the absence of a uniform outcome measure that represents visual or aesthetic sequelae complicates the design of evidence-based studies and feasible clinical trials. RESULTS: In September 2013, a multidisciplinary task force, composed of pediatric practitioners from tertiary care centers experienced in caring for children with OPPN, was convened to address the lack of clinical care guidelines for children with OPPN. CONCLUSIONS: This consensus statement provides recommendations for ophthalmologic monitoring, outlines treatment indications and forthcoming biologic therapy, and discusses challenges to performing clinical trials in this complicated condition.

TREATMENT OF VITREOMACULAR TRACTION WITH INTRAVITREAL PERFLUOROPROPANE (C3F8) INJECTION.

PURPOSE: To assess the posterior vitreous release rates following a single, office-based intravitreal injection of expansile gas in treating vitreomacular traction. METHODS: Thirty eyes of 29 consecutive patients with symptomatic vitreomacular traction received a single, office-based intravitreal injection of up to 0.3 mL of 100% perfluoropropane (C3F8). RESULTS: Overall, vitreomacular traction release occurred in 25 of 30 eyes by the final follow-up visit (83% final release rate); furthermore, 90% (9 of 10 eyes) with diabetes mellitus released, 83% (5 of 6 eyes) with concurrent epiretinal membrane released, and 83% (5 of 6 eyes) previously treated with ocriplasmin released. Vitreomacular traction release occurred overnight in some patients and was documented on spectral domain optical coherence tomography at an average of 13 days (range, 1-62 days). The phakic release rate was 89% (16 of 18 eyes) versus a 75% pseudophakic release rate (9 of 12 eyes) (P = 0.3173). Ellipsoid zone changes on spectral domain optical coherence tomography occurred in 1 of 30 gas-treated eyes. One patient developed pupillary block. CONCLUSION: Office-based intravitreal injection of C3F8 offers an inexpensive and effective treatment for vitreomacular traction, including for patients who underwent previous ocriplasmin administration and in patients with diabetes mellitus or epiretinal membrane.

SYSTEMIC PHARMACOKINETICS AND PHARMACODYNAMICS OF INTRAVITREAL AFLIBERCEPT, BEVACIZUMAB, AND RANIBIZUMAB.

PURPOSE: To evaluate the systemic pharmacokinetics (PKs) of aflibercept, bevacizumab, and ranibizumab in patients with neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), or retinal vein occlusion (RVO). METHODS: Prospective, open-label, nonrandomized clinical trial of patients with AMD, DME, or RVO who were antivascular endothelial growth factor (VEGF) naïve or had not received anti-VEGF for ≥4 months. Patients received 3 monthly intravitreal injections of aflibercept 2.0 mg, bevacizumab 1.25 mg, or ranibizumab (0.5 mg for AMD/RVO, 0.3 mg for DME). The main outcome measures were serum PKs and plasma free-VEGF concentrations after the first and third injections. RESULTS: A total of 151 patients were included. In AMD/DME/RVO, systemic exposure to each drug was highest with bevacizumab, then aflibercept, and lowest with ranibizumab. Ranibizumab cleared from the bloodstream more quickly than bevacizumab or aflibercept. Aflibercept treatment resulted in the greatest reductions in plasma free-VEGF relative to baseline levels, whereas ranibizumab treatment resulted in the smallest decreases in plasma free-VEGF. CONCLUSION: The three anti-VEGF treatments examined in this analysis demonstrated notable differences in systemic PKs. Generally, the reduction in plasma free-VEGF levels correlated with elevated levels of circulating anti-VEGF agents, with the reduction in free-VEGF levels greatest with aflibercept and least with ranibizumab.