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To report long-term ophthalmic findings in Wolfram syndrome, including rates of visual decline, macular thinning, retinal nerve fiber layer (RNFL) thinning, and outer plexiform layer (OPL) lamination.Single-center, cohort study.A total of 38 participants were studied, who underwent a complete ophthalmic examination as well as optical coherence tomography imaging of the macula and nerve on an annual basis. Linear mixed-effects models for longitudinal data were used to examine both fixed and random effects related to visual acuity and optic nerve quadrants of RNFL and macula thickness.Participants completed a mean of 6.44 years of follow-up (range 2-10 years). Visual acuity declined over time in all participants, with a mean slope of 0.059 logMAR/y (95% CI = 0.07-0.05 logMAR/y), although nearly 25% of participants experienced more rapid visual decline. RNFL thickness decreased in superior, inferior, and nasal quadrants (β = -0.5 µm/y, -0.98 µm/y, -0.28 µm/y, respectively). OPL lamination was noted in 3 study participants, 2 of whom had autosomal dominant mutations.Our study describes the longest and largest natural history study of visual acuity decline and retinal morphometry in Wolfram syndrome to date. Results suggest that there are slower and faster progressing subgroups and that OPL lamination is present in some individuals with this disease.

To determine whether rates of strabismus and associated visuomotor deficits differed among children with different severities of periventricular leukomalacia (PVL).Retrospective, case-control study.Brain magnetic resonance images (MRI) obtained from 98 children aged ≥2 years were analyzed using a standardized scoring system: 67 of 98 had PVL (mean GA 31 weeks) and 31 of 98 did not have PVL (mean GA 29 weeks). Severity of PVL was scored as degree of damage to the posterior optic radiations and the splenium of the corpus callosum on MRI. Ophthalmologic examination data were collated to assess the prevalence of visuomotor deficits and the relationship to PVL severity (grades 1-3, mild to severe).Infantile strabismus was documented in 61% of children with mild, 74% with moderate, and 88% with severe PVL (esotropia: exotropia ratio 3.5:1). Associated ocular motor deficits also increased systematically with PVL severity: latent ("fusion maldevelopment") nystagmus (20%, 47%, and 40%, respectively), dissociated vertical deviation (13%, 28%, and 30%), and nasotemporal pursuit/optokinetic nystagmus asymmetry (23%, 38%, and 54%). Additionally, the prevalence of retrograde optic neuropathy increased with PVL severity (5%, 26%, and 38%). The prevalence of each of these signs was substantially lower in children who had no PVL.Children who suffer PVL are likely to develop the deficits of the infantile strabismus complex. The deficits tend to increase systematically as a function of PVL severity. These findings provide evidence that infantile strabismus is linked to perinatal damage to cerebral vergence and gaze pathways.

Purpose Children with high ametropia who have difficulties with spectacle or contact lens wear benefit from gains in visual function after intraocular collamer lens (ICL) surgery. Here we assess safety by reporting rates and case specifics of peri-operative and longer-term adverse events (AE).[LINE SEPARATOR] SETTING:: St. Louis Children's Hospital at Washington University Medical Center. Design Retrospective Case Series. Methods Clinical data were collated retrospectively for 95 special-needs children (160 eyes) implanted with a Visian ICL over the last 5 years. All surgeries were performed at St Louis Children's Hospital under brief general anesthesia. Follow-up was a mean 2.0 ±1.4 years (range 0.5-5.2). Results Average age at implantation was 9.3 ± 5.2 years (range 1.8-25) and mean pre-operative SEQRE was -11.2 ± 3.9 D (range - 4-22). Sixty-two children (65%) had a neurodevelopmental disorder. The minor AE rate was 2% (3 eyes), consisting of steroid-response ocular hypertension (OHT), which resolved with cessation of topical steroid drops. Endothelial cell loss averaged 8.1 % over 2 years, comparable to that reported in ICL implanted adults. The most common major AE (4%, 7 eyes) was post-operative pupillary block, requiring revision of the peripheral iridotomy. One child (0.6%, 1 eye) with self-injurious behavior required repair of a wound leak. One child (0.6%, 1 eye) with Down syndrome developed a cataract 2.8 years after ICL surgery. And one child (0.6%, 1 eye) with severe Autism Spectrum Disorder experienced traumatic retinal detachment 1.2 years after implantation. Conclusion The most common major AE among our Visian ICL cohort was pupillary block due to closure of the iridotomy. Overall, the AE rate was low in this higher risk, difficult-to-manage population of special-needs children.

This study aims to characterize the eye-related quality of life of children with neurodevelopmental and ocular disorders at baseline and after refractive surgery.Prospective interventional case series.We enrolled children and adolescents 5 to 18 of age with neurodevelopmental disorders undergoing refractive surgery (6 for pre-/postsurgical assessment and 14 for baseline analysis). Eye-related quality of life was measured using the Pediatric Eye Questionnaire (PedEyeQ). Baseline levels of adaptive functioning and social behaviors were measured using the Adaptive Behavioral Assessment System (ABAS-3) and Social Responsiveness Scale (SRS-2). We assessed the correlation between baseline PedEyeQ scores, number of ocular comorbidities, magnitude of refractive error, and ABAS-3 and SRS-2 scores.At baseline, 14 patients demonstrated decreased median eye-related quality of life (60/100) in 5 of 9 PedEyeQ domains, moderate deficiencies in social behaviors (SRS-2 median 71, range 49-90), and low adaptive functioning (ABAS-3 median percentile for age of 0.100). Baseline PedEyeQ scores did not correlate with magnitude of refractive error or adaptive functioning scores but did correlate with number of ocular comorbidities and social behavior scores. Six patients have undergone refractive surgery without complication. Postoperatively, 11 of 11 eyes were within ±1.5 diopters spherical equivalent. Four of 6 patients exhibited clinically significant improvements in PedEyeQ scores after surgery.Even in the presence of significant social and adaptive impairments, quality of life in children with neurodevelopmental disorders is decreased by ocular disorders. Refractive surgery is associated with clinically significant improvements in eye-related quality of life.

The Artisan-Ophtec aphakic iris-enclaved anterior chamber intraocular lens (IOL) has been used to advantage in children and adults who lack capsular support for implantation of a standard posterior chamber IOL. However, even the most skilled anterior segment surgeon may encounter difficulties enclaving the IOL to the iris using the enclavation needle. We describe a simple, secure, rapid alternative method for enclaving the IOL that requires only two eye incisions: one at the corneal limbus and the other through the pars plana.

This review assesses the risk of a photic-induced seizure in a child during viewing of 3D (binocular 3 dimensional, stereoscopic) movies or games, either on standard video displays or when wearing a virtual reality (VR) headset. Studies published by pediatric epilepsy experts emphasize the low risk of 3D viewing even for children with known photosensitive epilepsy (PSE). The low incidence of PSE is noteworthy because the number of hours devoted to 2D or 3D screen viewing and/or VR headset use by children worldwide has increased markedly over the last decade. The medical literature does not support the notion that VR headset use poses a risk for PSE.

Low-dose and very low-dose intravitreal bevacizumab (IVB) have been reported to be successful in short-term treatment of type 1 retinopathy of prematurity (ROP), down to an initial dose of 0.004 mg. We now report 12-month outcomes for these infants.Masked, multicenter, dose de-escalation study.One hundred twenty prematurely born infants with type 1 ROP.A cohort of 120 infants with type 1 ROP in at least 1 eye from 2 sequential dose de-escalation studies of low-dose IVB (0.25 mg, 0.125 mg, 0.063 mg, and 0.031 mg) or very low-dose IVB (0.016 mg, 0.008 mg, 0.004 mg, and 0.002 mg) to the study eye; the fellow eye (if also type 1) received 1 dose level higher of IVB. After primary success or failure at 4 weeks, clinical management was at investigator discretion, including all additional treatment.Reactivation of severe ROP by 6 months corrected age, additional treatments, retinal and other ocular structural outcomes, and refractive error at 12 months corrected age.Sixty-two of 113 study eyes (55%) and 55 of 98 fellow eyes (56%) received additional treatment. Of the study eyes, 31 (27%) received additional ROP treatment, and 31 (27%) received prophylactic laser therapy for persistent avascular retina. No trend toward a higher risk of additional ROP treatment related to initial IVB doses was found. However, time to reactivation among study eyes was shorter in eyes that received very low-dose IVB (mean, 76.4 days) than in those that received low-dose IVB (mean, 85.7 days). At 12 months, poor retinal outcomes and anterior segment abnormalities both were uncommon (3% and 5%, respectively), optic atrophy was noted in 10%, median refraction was mildly myopic (-0.31 diopter), and strabismus was present in 29% of infants.Retinal structural outcomes were very good after low- and very low-dose IVB as initial treatment for type 1 ROP, although many eyes received additional treatment. The rate of reactivation of severe ROP was not associated with dose; however, a post hoc data-driven analysis suggested that reactivation was sooner with very low doses.

Pediatric optic neuritis (ON) is a rare disease that has not been well characterized. The Pediatric ON Prospective Outcomes Study (PON1) was the first prospective study to our knowledge aiming to evaluate visual acuity (VA) outcomes, including VA, recurrence risk, and final diagnosis 2 years after enrollment.Nonrandomized observational study at 23 pediatric ophthalmology or neuro-ophthalmology clinics in the United States and Canada.A total of 28 (64%) of 44 children initially enrolled in PON1 (age 3-16 years) who completed their 2-year study visit.Participants were treated at the investigator's discretion.Age-normal monocular high-contrast VA (HCVA). Secondary outcomes included low-contrast VA (LCVA), neuroimaging findings, and final diagnoses.A total of 28 participants completed the 2-year outcome with a median enrollment age of 10.3 years (range, 5-15); 46% were female, and 68% had unilateral ON at presentation. Final 2-year diagnoses included isolated ON (n = 11, 39%), myelin oligodendrocyte glycoprotein-associated demyelination (n = 8, 29%), multiple sclerosis (MS) (n = 4,14%), neuromyelitis optica spectrum disease (NMOSD) (n = 3, 11%), and acute disseminated encephalomyelitis (n = 2, 7%). Two participants (7%; 95% confidence interval [CI], 1-24) had subsequent recurrent ON (plus 1 participant who did not complete the 2-year visit); all had MS. Two other participants (7%) had a new episode in their unaffected eye. Mean presenting HCVA was 0.81 logarithm of the minimum angle of resolution (logMAR) (∼20/125), improving to 0.14 logMAR (∼20/25Despite poor VA at presentation, most children had marked improvement in VA by 6 months that was maintained over 2 years. Associated neurologic autoimmune diagnoses were common. Additional episodes of ON occurred in 5 (18%) of the participants (3 relapses and 2 new episodes).

BACKGROUNDWolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial.METHODSBased on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions.RESULTSDantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, β cell functions were not significantly improved, but there was a significant correlation between baseline β cell functions and change in β cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1β, TNF-α, and isoprostane, were elevated in subjects.CONCLUSIONThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT02829268FUNDINGNIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs.

BACKGROUND Wolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial. METHODS Based on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions. RESULTS Dantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, β cell functions were not significantly improved, but there was a significant correlation between baseline β cell functions and change in β cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1β, TNF-α, and isoprostane, were elevated in subjects. CONCLUSION This study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT02829268 FUNDING NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs.

BackgroundWolfram syndrome is a rare endoplasmic reticulum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting endoplasmic reticulum calcium homeostasis, including dantrolene sodium, may be beneficial.MethodsBased on the results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, our group put together the first-ever clinical trial in pediatric and adult patients with Wolfram syndrome. An open-label phase 1b/2a trial design was chosen. The primary objective of the study was to assess the safety and tolerability of dantrolene sodium in adult and pediatric patients with Wolfram syndrome. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β-cell functions, visual acuity, quality of life measures related to vision, and neurological functions.ResultsThe results indicate that dantrolene sodium is well tolerated by patients with Wolfram syndrome. Although the study was small, a select few patients seemed to have improvements in β-cell function, which might correlate with a positive trend in other outcome measures, including visual acuity and neurological functions.ConclusionThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the endoplasmic reticulum for the treatment of Wolfram syndrome.Trial registrationClinicalTrials.gov Identifier NCT02829268Key PointsQuestionIs dantrolene sodium safe and effective for the treatment of adult and pediatric patients with Wolfram syndrome?FindingsThe results of this open-label clinical trial show that dantrolene sodium is well tolerated by patients with Wolfram syndrome. Although the study was small, a select few patients seemed to have improvements in β-cell function, which might correlate with a positive trend in other outcome measures, including visual acuity and neurological functions.MeaningDantrolene sodium is well tolerated by patients with Wolfram syndrome. Some patients may experience an increase in β cell function when taking dantrolene.ImportanceWolfram syndrome is a rare endoplasmic reticulum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, preclinical studies in cell and rodent models suggest that targeting endoplasmic reticulum calcium homeostasis, including dantrolene sodium, is an emerging therapeutic strategy.ObjectiveThe primary objective of the study was to assess the safety and tolerability of dantrolene sodium in adult and pediatric subjects with Wolfram syndrome. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β-cell functions, visual acuity, quality of life measures related to vision, and neurological functions.DesignOpen-label phase 1b/2a trial of dantrolene sodium over a 6-month treatment period.SettingSingle site, academic medical center.ParticipantsAdult and pediatric subjects with a genetically confirmed diagnosis of Wolfram syndrome.InterventionsAll subjects received increasing doses of dantrolene sodium.Main Outcomes and MeasuresThe safety and tolerability of dantrolene sodium administered orally at the upper end of therapeutic dose range for 6 months, and the efficacy of dantrolene sodium on residual pancreatic β-cell functions using a mixed-meal tolerance test, visual acuity using LogMar scores, quality of life measures related to vision using Visual Functioning Questionnaire – 25, and neurological functions using the Wolfram Unified Rating Scale (WURS) and standard neurological assessments.ResultsThe results indicate that dantrolene sodium is well tolerated by subjects with Wolfram syndrome. Although the study was small, a select few subjects seemed to have improvements in β-cell function, which might be correlated with a positive trend in visual acuity.Conclusions and RelevanceThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the endoplasmic reticulum for the treatment of Wolfram syndrome.Trial RegistrationRegistered with clinicaltrials.gov, NCT02829268, (https://clinicaltrials.gov/ct2/show/NCT02829268?term=NCT02829268&draw=2&rank=1)

Purpose To analyze outcomes in a large cohort of spectacle-aversive children with high myopia who were treated by implantation of the Ophtec-Artisan or Visian phakic intraocular lens (pIOL). Methods Outcome data were collated retrospectively in 78 children (115 eyes) implanted with the Ophtec-Artisan iris-enclaved anterior chamber pIOL and 91 children (154 eyes) implanted with the Visian ICL (intraocular collamer lens) sulcus pIOL. All children had difficulties with spectacle or contact lens wear. Mean age at surgery was 9.9 years; mean follow-up was 3.9 years (range, 0.6-14.1 years). Results A total of 248 of 269 eyes (92%) were corrected to within ± 0.5 D of their target value. Spherical correction averaged 12.3 ± 1.0 D. Refractive spherical regression was −0.04 D/year at last follow-up. Uncorrected distance visual acuity improved from an average logMAR 1.8 to 0.4; corrected distance visual acuity improved an average 0.3 logMAR. Of the treated children, 68% had a gain in binocular fusion. Neurobehavioral and/or visuomotor comorbidities were present in 87% of children. Five eyes (2%) developed retinal detachment an average 6 years after implantation. Nine eyes (3%) implanted with the Ophtec-Artisan pIOL required repositioning after trauma. Conclusions Implantation of pIOLs in children is an effective method for correcting high myopia in spectacle noncompliant children. Rates of myopic regression after pIOL surgery are substantially lower than those reported for children treated by excimer laser photorefractive keratectomy (PRK). The prevalence of major complications was relatively low in this high-risk population.

Purpose A subset of children with high anisometropia or isoametropia and neurobehavioral disorders have chronic difficulties with spectacle or contact lens wear. We report the results of refractive surgery in a series of these children treated using bilateral or unilateral intraocular collamer lens (Visian ICL) implantation for moderate to high myopia. Design Prospective nonrandomized cohort study. Methods Clinical course and outcome data were collated prospectively for 40 implanted eyes in 23 children (mean age 10.2 ± 5.3 years, range, 1.8–17 years). Myopia ranged from −3.0 to −14.5 diopters (D), mean −9.2 ± 3.5 D. Goal refraction was plano to +1 D. Correction was achieved by sulcus implantation of a Visian ICL (STAAR Surgical, Monrovia, California, USA) under general anesthesia. Mean follow-up was 15.1 months (range, 6–22 months). Results Thirty-five eyes (88%) were corrected to within ±1.0 D of goal refraction; the other 5 (12%) were corrected to within 1.5 D. Uncorrected distance visual acuity improved substantially in all eyes (from mean 20/1050 [logMAR 1.72] to mean 20/42 [logMAR 0.48]). Spherical regression at last follow-up was an average of +0.59 D. Visuomotor comorbidities (eg, amblyopia, nystagmus, foveopathy, optic neuropathy) accounted for residual postoperative subnormal visual acuity. Thirteen of the 23 children (57%) had a neurobehavioral disorder (eg, developmental delay/intellectual disability/mental retardation, Down syndrome, cerebral palsy, autism spectrum disorder). Eighty-five percent (11/13) of those children were reported to have enhanced visual awareness, attentiveness, or social interactions. Endothelial cell density was measureable in 6 cooperative children (10 eyes), showing an average 1% decline. Central corneal thickness, measured in all children, increased an average of 8 μm. Two children (8%) required unplanned return to the operating room on the first postoperative day to alleviate pupillary block caused by a nonpatent iridotomy. No other complications were encounterd. Conclusion Visian ICL implantation improves visual function in special needs children who have moderate to high myopia and difficulties wearing glasses or contact lenses.

This review assesses the risk of a photic-induced seizure in a child during viewing of 3D (binocular 3 dimensional, stereoscopic) movies or games, either on standard video displays or when wearing a virtual reality (VR) headset. Studies published by pediatric epilepsy experts emphasize the low risk of 3D viewing even for children with known photosensitive epilepsy (PSE). The low incidence of PSE is noteworthy because the number of hours devoted to 2D or 3D screen viewing and/or VR headset use by children worldwide has increased markedly over the last decade. The medical literature does not support the notion that VR headset use poses a risk for PSE.

Wolfram syndrome is a rare, progressive neurodegenerative disorder characterized by juvenile-onset diabetes, optic nerve atrophy and mutation of the WFS1 gene. Calcium dyshomeostasis is a key mechanism underlying neuronal and pancreatic β-cell death and dysfunction in this endoplasmic reticulum (ER) disorder. Dantrolene sodium is an FDA-approved muscle relaxant that preserves ER calcium through inhibition of ryanodine receptor (RyR) activity. We therefore hypothesized that dantrolene could have therapeutic potential for Wolfram syndrome. Our preclinical studies showed that dantrolene improves β-cell and neuronal cell survival in mouse and induced pluripotent stem (iPS) cell models of Wolfram syndrome. To translate these findings to humans, we conducted the first clinical trial in 19 Wolfram syndrome patients through a 6-month phase 1b/2 study of dantrolene sodium with an optional extension phase up to 24-months (NCT02829268). The endpoints of this study were to assess: (1) dantrolene safety and tolerability in pediatric and adult Wolfram syndrome patients and (2) its effects on remaining β-cell, visual and neurologic functions and quality of life measures. Among pediatric subjects, dantrolene was well-tolerated at a daily dose of 0.5mg/kg in those < 50kg and 2mg/kg in those > 50kg. Adults tolerated dantrolene well at 50mg - 100mg daily. Common adverse events included mild fatigue, diarrhea, headache and hypoglycemia. A mild increase in 30-minute mixed-meal-stimulated C-peptide was observed in subjects after 6- and 12-months of dantrolene treatment. No significant changes were observed in visual or neurological functions or quality of life measures, although mild improvement in disease severity was noted by the Wolfram Unified Rating Scale. These findings suggest that dantrolene is safe for use in Wolfram syndrome at the specified doses and support further study of dantrolene in a randomized, placebo-controlled trial. Disclosure D. Abreu: None. T.S. Pearson: None. R.C. Bucelli: None. A. Simpson: None. C.M. Brown: None. K. Kries: None. H. Gu: None. S.I. Stone: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Speaker’s Bureau; Self; AbbVie Inc. L. Tychsen: None. G. Van Stavern: None. N.H. White: None. B.A. Marshall: None. T. Hershey: Research Support; Spouse/Partner; Sage Pharmaceuticals. F. Urano: Board Member; Self; Healthbeat. Research Support; Self; Aetas, Amylyx, JDRF, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Stock/Shareholder; Self; CytRx. Other Relationship; Self; Novus Biologicals. Funding National Institutes of Health (R21DK113487-02)

Purpose To assess the safety of VR 3D headset (virtual reality 3-dimensional binocular-stereoscopic near-eye display) use in young children. Product safety warnings that accompany VR headsets ban their use in children under age 13 years. Design Prospective, interventional, before-and-after study. Methods Recordings were obtained in 50 children (29 boys) aged 4-10 years (mean 7.2 ± 1.8 years). Minimum binocular corrected distance visual acuity (CDVA) was 20/50 (logarithm of the minimum angle of resolution [logMAR] 0.4) and stereoacuity 800 seconds of an arc or better. A Sony PlayStation VR headset was worn for 2 sequential play sessions (of 30 minutes each) of a first-person 3D flying game (Eagle Flight) requiring head movement to control flight direction (pitch, yaw, and roll axes). Baseline testing preceded VR exposure, and each VR session was followed by post-VR testing of binocular CDVA, refractive error, binocular eye alignment (strabismus), stereoacuity, and postural stability (imbalance). Visually induced motion sickness was probed using the Simulator Sickness Questionnaire modified for pediatric use (Peds SSQ). Visual-vestibulo-ocular reflex (V-VOR) adaptation was also tested pre- vs post-trial in 5 of the children. Safety was gauged as a decline or change from baseline in any visuomotor measure. Results Forty-six of 50 children (94%) completed both VR play sessions with no significant change from baseline in measures of binocular CDVA (P = .89), refractive error (P = .36), binocular eye alignment (P = .90), or stereoacuity (P = .45). Postural stability degraded an average 9% from baseline after 60 minutes of VR exposure (P = .06). Peds SSQ scores increased a mean 4.7%—comparing pretrial to post-trial—for each of 4 symptom categories: eye discomfort (P = .02), head/neck discomfort (P = .03), fatigue (P = .03), and motion sickness (P = .01). None of the children who finished both trial sessions (94%) asked to end the play, and the majority were disappointed when play was halted. V-VOR gain remained unaltered in the 5 children tested. Three children (6% of participants) discontinued the trial during the first 10 minutes of the first session of VR play, 2 girls (aged 5 and 6 years) and 1 boy (aged 7 years). The girls reported discomfort consistent with mild motion sickness; the boy said he was bored and the headset was uncomfortable. No child manifested aftereffects (“flashbacks”) in the days following the VR exposure. Conclusion Young children tolerate fully immersive 3D virtual reality game play without noteworthy effects on visuomotor functions. VR play did not induce significant post-VR postural instability or maladaption of the vestibulo-ocular reflex. The prevalence of discomfort and aftereffects may be less than that reported for adults.

Binocular fusion is blending of corresponding images from each eye to form a single percept. Maldevelopment of fusion (binocular non-correspondence) in infancy causes a specific type of lifelong ocular instability: fusion maldevelopment nystagmus (FMN). Because fusion maldevelopment – in the form of strabismus and amblyopia – is common, FMN is the most prevalent pathologic nystagmus encountered in clinical practice. Experiments on nonhuman primates (NHP) with strabismus and amblyopia have revealed that loss of binocular connections within area V1 (striate cortex) in the first months of life is the necessary and sufficient cause of FMN. The severity of FMN increases with greater losses of V1 connections. No manipulation of brainstem motor pathways is required. The binocular maldevelopment originating in area V1 is passed on to downstream, extrastriate regions of cerebral cortex that drive conjugate gaze (notably MSTd). Conjugate gaze is stable when MSTd neurons of the right vs. left cerebral hemisphere have balanced, binocular activity. Fusion maldevelopment causes unbalanced, monocular activity. If input from one eye dominates and the other is suppressed, MSTd in one hemisphere becomes more active. Downstream projections to the ipsilateral nucleus of the optic tract (NOT) drive the eyes conjugately to that side. The unbalanced MSTd drive is evident as nasalward slow-phase nystagmus when viewing with either eye.

A 10-year-old boy was referred for a circumscribed choroidal hemangioma with underlying exudative detachment of the left eye. To avoid general anesthetics required for laser-based therapy in a child, we began a trial of oral propranolol. The patient's exudative detachment resolved, with resulting improvement in visual acuity, and remained quiescent for 3 years.

Background/aimsTo report alterations in visual acuity and visual pathway structure over an interval of 1–3 years in a cohort of children, adolescents and young adults who have Wolfram syndrome (WFS) and to describe the range of disease severity evident in patients with WFS whose ages differed by as much as 20 years at first examination.MethodsAnnual, prospective ophthalmological examinations were performed in conjunction with retinal nerve fibre layer (RNFL) analysis. Diffusion tensor MRI-derived fractional anisotropy was used to assess the microstructural integrity of the optic radiations (OR FA).ResultsMean age of the 23 patients with WFS in the study was 13.8 years (range 5–25 years). Mean log minimum angle resolution visual acuity was 0.66 (20/91). RNFL thickness was subnormal in even the youngest patients with WFS. Average RNFL thickness in patients with WFS was 57±8 µ or ~40% thinner than that measured in normal (94±10 µ) children and adolescents (PConclusionThe genetic mutation of WFS causes damage to both pregeniculate and postgeniculate regions of the visual pathway. The damage is progressive. The decline in visual pathway structure is accompanied by declines of visual function. Disease severity differs widely in individual patients and cannot be predicted from their age.

Diagnosing idiopathic intracranial hypertension (IIH), or pseudotumor cerebri, can be challenging in children. Diagnosis is based on lumbar puncture, opening pressures, and appearance of the optic disk. Misdiagnosis of papilledema, a typical finding, may lead to unnecessary treatments and procedures. We report 52 children over a 6-year period to better identify the true incidence of pseudopapilledema and other factors that may confound the diagnosis of IIH. A retrospective chart review approved by the Institutional Review Board was performed. Fifty-two children under the age of 21 referred to us based on suspected IIH or papilledema from 2007 to 2013 are included in this study. Patients were assessed by a pediatric ophthalmologist and a neurosurgeon. Fifty-two children were initially diagnosed with IIH and/or papilledema; 26 diagnoses were revised to pseudopapilledema after pediatric ophthalmological review. Out of those 26 patients with pseudopapilledema, 14 had undergone lumbar punctures, 19 had MRIs, 9 had CTs, and 12 were taking medications—these medications were discontinued upon revision of the diagnoses. The difference in the CSF opening pressure between children diagnosed with true IIH (32.7 cm H2O) and children diagnosed with pseudopapilledema (24.7 cm H2O) was statistically significant. IIH diagnosis is heavily reliant on the appearance of the optic disk. Pediatric ophthalmological assessment is essential to carefully examine the optic disk and prevent further unnecessary investigation and treatments. Close communication between pediatricians, ophthalmologists, and neurosurgeons can avoid invasive procedures for children who do have pseudopapilledema, and not IIH or associated papilledema.

Lymphocytic choriomeningitis virus is a rodent-borne arenavirus that can cause congenital infection affecting the developing central nervous system. When the infection occurs during pregnancy, the virus targets the fetal brain and retina, potentially causing ventriculomegaly, hydrocephalus, chorioretinitis, and neurodevelopmental abnormalities. It has been previously suggested that lymphocytic choriomeningitis virus be added to the list of congenital infections currently included in the TORCH acronym (toxoplasmosis, rubella, cytomegalovirus, herpes, and syphilis). We present 2 neonates with antenatally known ventriculomegaly that were diagnosed with congenital lymphocytic choriomeningitis virus infection after birth. In addition to ventriculomegaly, one had nonimmune hydrops fetalis and the other had intracranial hemorrhage. In view of the seroprevalence of lymphocytic choriomeningitis virus (4.7%-10%), our findings suggest that screening for congenital lymphocytic choriomeningitis virus infection should be considered in fetuses and newborns with ventriculomegaly as well as other abnormal neuroimaging findings such as intracranial hemorrhage.

Two groups of visually impaired children now benefit from refractive surgery and stand to further benefit with future advances. These children have difficulties with spectacle-wear and are unsuitable for contact lens-wear. The majority are neurologically normal and have anisometropic amblyopia. They are treated by advanced surface ablation using the excimer laser (photorefractive keratectomy or laser-assisted subepithelial keratomilieusis). Surface ablation is safe in children; the drawback is the high rate of pediatric refractive regression (more pronounced for myopia > 10.0 D, and hyperopia > 4.5 D). Ametropia beyond this range may be treated using phakic intraocular lens implantation or clear lens extraction, with or without implantation of a posterior chamber intraocular lens (refractive lens exchange). The minority are neurobehaviorally impaired children (e.g., cerebral palsy, autism, Angelman syndrome, Down syndrome and mental retardation) with high bilateral ametropia. Spectacle noncompliance releg...

Purpose A subset of children with high ametropia and neurobehavioral disorders have chronic difficulties with spectacle or contact lens wear. We report the results of refractive surgery in a series of these children treated using bilateral or unilateral phakic intraocular lenses (IOLs) for ametropia >10 D. Methods Clinical course and outcome data were collated prospectively in a group of 12 children (mean age, 10.1 years; range, 4-17 years) with neurobehavioral disorders exacerbated by poor compliance with spectacles. Myopia in 18 eyes ranged from −10.0 to −22.75 D (mean, −15.2 D) and in 2 hyperopic eyes from +10.25 to +10.75 (mean, +10.5 D). Goal refraction was approximately 0 to +1 D. Correction was achieved by implantation of an iris-enclaved phakic IOL under general anesthesia. Mean follow-up was 9.1 months (range, 3-15 months). Results Myopia correction averaged 14.5 D and hyperopia correction 9.4 D. Eighty-six percent of eyes (17/20 eyes) were corrected to within ± 1 D of emmetropia and the remaining 14% (3 eyes) to within ± 2 D. Uncorrected visual acuity improved substantially in all 20 eyes (60-fold; from a mean of 20/3400 to a mean of 20/57). Ocular comorbidities in each child accounted for residual postoperative, subnormal visual acuity (eg, amblyopia, nystagmus, albinism, regressed retinopathy of prematurity). Visual functions (measured using a 23-item validated survey) improved. One eye required IOL exchange; no other clinically significant complications have been encountered. Conclusions Phakic IOL implantation improves visual function substantially in neurobehaviorally impaired children who have high ametropia and difficulties wearing glasses.

Objective: To determine how the duration of infantile strabismus influences the development of horizontal connections in V1. Methods: Six infant macaques were fitted with prisms, which were removed after 3 weeks (wks.), 3 months (mos.), or 6 mos. Two control monkeys wore plano lenses. The number of horizontal connections was determined using neuroanatomic techniques. Results: The 3-wks animal had equal number of monocular (51%) and binocular (49%) connections. In the 6-mos. animal, however, monocular connections (76%) were three times more abundant than binocular (24%) connections (p < 0.001). Conclusions: Longer duration of infantile strabismus causes greater deficit of binocular connections. Early correction of infantile strabismus is supported.

Can ophthalmologists repair defects of visual cortex circuitry in infants who have esotropia? The answer to this question encompasses both sensory and motor behaviors because the clinical hallmarks of the disorder are stereoblindness and absence of motor fusion, which manifests as convergently deviated eyes. Functional recovery of sensory and motor fusion in infantile esotropia was a consuming interest, if not career-defining passion, of Marshall Parks. The purpose of this work is to pay tribute to Parks' legacy by showing how human and animal studies, conducted largely during the last 25 years, support both his clinical insights and treatment philosophy.

Purpose: We sought to determine whether laser subepithelial keratomileusis (LASEK) and photorefractive keratectomy (PRK) are effective methods for correcting amblyopiogenic refractive errors in children. Methods: Thirty-six eyes in 35 amblyopic children, who ranged in age from 4 to 16 years (mean, 8.4 years), received treatment for large magnitude ametropia. Seventy-two percent (25/35) of the children had a neurobehavioral disorder and/or were noncompliant with spectacle or contact lens wear. Myopia ranged from −3.25 to −24.25 D (mean, −11.48 D); one patient had hyperopia of +5.87 D. Correction was tailored to match the refractive error of the nonamblyopic eye. VISX Star S2/S3 excimer lasers were used in manual or auto-tracking modes, and corneal centration was achieved using brief, general anesthesia. Mean follow-up was 29.2 months (range, 4–42 months). Results: Myopia correction averaged −8.95 ± 2.89 D (range, −3.25 to −15.50). Eighty-nine percent (31 children) were corrected to within ± 1.00 D of goal refraction and the remaining 11% to within 2.0 D of the goal (most were undercorrected). Acuity improved postoperatively in 97%; by 1 optotype line in 37% and by 2 or more in 60%. No child lost acuity. Binocularity improved in 69% (24/35) and remained the same in 31%. Corneal haze measured grade 0–1 in 78%, grade 2 in 14%, and grade 3–4 in 8%. Myopic regression exceeding ≅ 1.0 D/year (0.08 D/month) occurred in 50% (18/36) of eyes treated. No substantial differences were observed in PRK- (n = 18) versus LASEK- (n = 17) treated children. Conclusions: Laser refractive surgery is effective for correcting anisometropic myopia in amblyopic children. Recurrence of myopia is common. Further study is indicated to determine long-term stability and safety of the procedure in this population.

Introduction: Suppression is a major sensorial abnormality in humans and monkeys with infantile strabismus. We previously reported evidence of metabolic suppression in the visual cortex of strabismic macaques, using the mitochondrial enzyme cytochrome oxidase as an anatomic label. The purpose of this study was to further elucidate alterations in cortical metabolic activity, with or without amblyopia. Materials and methods: Six macaque monkeys were used in the experiments (four strabismic and two control). Three of the strabismic monkeys had naturally occurring, infantile strabismus (two esotropic, one exotropic). The fourth strabismic monkey had infantile microesotropia induced by alternating monocular occlusion in the first months of life. Ocular motor behaviors and visual acuity were tested after infancy in each animal, and development of stereopsis was recorded during infancy in one strabismic and one control monkey. Ocular dominance columns (ODCs) of the striate visual cortex (area V1) were labeled using cytochrome oxidase (CO) histochemistry alone, or CO in conjunction with an anterograde tracer ([H 3 ]proline or WGA-HRP) injected into one eye. Results: Each of the strabismic monkeys showed inequalities of metabolic activity in ODCs of opposite ocularity, visible as rows of lighter CO staining, corresponding to ODCs of lower metabolic activity, alternating with rows of darker CO staining, corresponding to ODCs of higher metabolic activity. In monkeys who had infantile strabismus and unilateral amblyopia, lower metabolic activity was found in (suppressed) ODCs driven by the nondominant eye in each hemisphere. In monkeys who had infantile esotropia and alternating fixation (no amblyopia), metabolic activity was lower in ODCs driven by the ipsilateral eye in each hemisphere. The suppression included a monocular core zone at the center of ODCs and binocular border zones at the boundaries of ODCs. This suppression was not evident in the monocular lamina of the LGN, indicating an intracortical rather than subcortical mechanism. Conclusion: Suppression of metabolic activity in ODCs of V1 differs depending upon whether infantile strabismus is alternating or occurs in conjunction with unilateral amblyopia. Our findings reinforce the principle that unrepaired strabismus promotes abnormal competition in V1, observable as interocular suppression of ODCs.

Extraocular muscle tenotomy has been reported to damp congenital nystagmus in an achiasmatic sheepdog. We performed extraocular muscle tenotomy to evaluate its effects on congenital nystagmus in primates.Magnetic search coil eye movement recordings were used to document the presence of horizontal congenital nystagmus in 2 adult macaque monkeys that also had naturally occurring infantile strabismus. Extraocular muscle tenotomy was performed by operating on all 4 horizontal recti, surgically detaching the muscles from the globe and suturing them back to their original insertions without resection or recession. Eye movement recordings were repeated 4 months after the procedure, comparing the waveform, amplitude, retinal slip velocity, and intensity (frequency x amplitude) of the nystagmus before and after tenotomy. Visual acuity was also measured before and after surgery in 1 animal.Preoperatively, a disconjugate, pendular nystagmus was evident in 1 monkey, and the other had a conjugate pendular-jerk nystagmus damped by convergence. After tenotomy, nystagmus mean amplitude decreased 18% to 52% in 1 monkey but increased 14% in the other (t test, P.002). Retinal slip velocity and nystagmus intensity increased in both monkeys. After tenotomy, mean velocity increased 22% to 218%, while mean intensity increased 40% to 208% (t test, P.002). Visual acuity measured after tenotomy decreased an average of 20% ( approximately 2.0 cycles per degree) in each eye. Tenotomy had no noteworthy effects on eye alignment or other aspects of visual behavior other than the congenital nystagmus.Nystagmus velocity and intensity increased after extraocular muscle tenotomy in 2 monkeys. Further studies are required to establish the clinical value of this procedure as a treatment for various subtypes of congenital nystagmus in humans.

To describe current methodology used to: a) train alert adult macaque monkeys to perform visual fixation tasks, b) implant binocular magnetic scleral search coils and attach a head restraint, and c) precisely record their fixation and pursuit eye movements.Animals are trained to sit in a primate chair and manipulate a lever. The animal turns on a laser spot (1 degree of arc) by pulling the lever. The spot dims after a variable, randomized period of time (luminance decrement 30-80%) and if the monkey releases the lever within 150-500 msec of dimming, a small bolus of juice is squirted via a servo into the monkey's mouth as a reward. The small size of the spot, the difficulty of detecting the dimming, and the short reaction time required for reward act in concert to assure attentive foveal fixation. After training, a search coil is implanted subconjunctivally in each eye and a polycarbonate head restraint device is attached to the skull. With the animal at the center of magnetic field coils, eye position is then calibrated precisely by requiring the animal to perform the dimming task at known positions of gaze. Fixation, vergence and pursuit eye movements are recorded by rewarding the animal for positioning the fovea of the eye within a small fixation 'window' encompassing the position of a stationary or moving target. A cover test of binocular eye alignment is performed by having the animal view through liquid crystal shutters that can be switched instantaneously from transparent to opaque. These methods have been used to train and to record eye movements in over 20 monkeys, and a representative sample of our experience in eight animals is reported in the Results.Normal monkeys, and monkeys who had strabismus or amblyopia, required an average of 53 days to learn to fixate steadily for a minimum of 5 sec with a dimming-detection performance of at least 75% correct. Implanted coils provided good signals for durations ranging from 4 months to longer than 3 years (average greater than 1 year) before signs of breakage or extrusion. Head restraints under daily use have lasted an average of 11 months (range 5 months to greater than 2 years) before spontaneous detachment.The training and surgical techniques described provide an efficient, straightforward method for recording precise binocular eye movements in awake monkeys.

Purpose To describe an ophthalmic phenotype in children at relatively early stages of Wolfram syndrome. Methods Quantitative ophthalmic testing of visual acuity, color vision, automated visual field sensitivity, optic nerve pallor and cupping, and retinal nerve fiber layer (RNFL) thickness assessed by optical coherence tomography (OCT) was performed in 18 subjects 5-25 years of age. Subjects were also examined for presence or absence of afferent pupillary defects, cataracts, nystagmus, and strabismus. Results Subnormal visual acuity was detected in 89% of subjects, color vision deficits in 94%, visual field defects in 100%, optic disk pallor in 94%, abnormally large optic nerve cup:disk ratio in 33%, thinned RNFL in 100%, afferent pupillary defects in 61%, cataracts in 22%, nystagmus in 39%, and strabismus in 39% of subjects. RNFL thinning ( P P = 0.01), strabismus ( P = 0.04), and nystagmus ( P = 0.04) were associated with more severe disease using the Wolfram United Rating Scale. Conclusions Children and adolescents with Wolfram syndrome have multiple ophthalmic markers that correlate with overall disease severity. RNFL thickness measured by OCT may be the most reliable early marker.

Background: Anomalous retinal correspondence (ARC) is a neural adaptation to eye misalignment in which non-corresponding retinal points are linked in the visual cortex to provide binocular fusion. ARC within the striate cortex would require that horizontal neurons link right-eye and left-eye ocular dominance columns (ODCs) separated by a distance in the cortex proportional to the angle of strabismus. Two hypothetical mechanisms are possible: (1) The ODCs can be linked by axons of horizontal neurons that project monosynaptically from a right-eye to a left-eye ODC. The further apart the ODCs, the longer the axons; hence, axon length should be greater in subjects with strabismus than in healthy subjects (elongated axon, monosynaptic hypothesis). In this case, the clinical probability of developing ARC should be independent of the angle of strabismus, until an upper-limit angle of strabismus is reached equally to the maximal length of axons available to link nonadjacent ODCs, at which point an abrupt decline of ARC probability should be evident. (2) Alternatively, ODCs can be linked by a chain of horizontal neurons, the number of which increases as the distance among ODCs increases; axon length in subjects with strabismus would be expected to be the same as in healthy subjects (normal axon, polysynaptic hypothesis). In this case, the greater the angle of strabismus, the more horizontal neurons and synapses required for linkage, and the greater the probability of signal degradation. Thus, the clinical probability of developing ARC through a polysynaptic mechanism should be inversely proportional to the angle of strabismus. The purpose of this study was to test these 2 hypotheses neuroanatomically in primates and clinically in children. Methods: For the neuroanatomic portion of the study, biotinylated dextran amine was injected into ODCs of area V1 to label individual neurons. The length of the horizontal axons from these neurons was then compared in strabismic and normal monkeys. In the clinical portion of the study, the medical records of 192 children with strabismus were reviewed retrospectively. The angle of strabismus (prism cover test) and the presence of ARC (Bagolini striated lenses, Worth/Polaroid 4-dot) were recorded. Plots of the presence of ARC as a function of the angle of strabismus were obtained. Results: There was no significant difference in axon length between healthy (7. 02 ± 0. 83 mm) and strabismic monkeys (6. 60 ± 1. 07 mm) ( P = .16). In children with strabismus, ARC decreased as the angle of strabismus increased ( P Conclusions: The visual cortex adapts to strabismus by combining information from paired ODCs of opposite ocularity that, because of the eye misalignment, are nonadjacent and separated by abnormally long distances across the striate cortex. The cortex appears to achieve the linkage, not by elongating neuronal axons, but by using chains of neurons that have normal-length axons. The visual cortex is most successful stochastically at achieving this linkage (ie, developing ARC) when the gap that must be bridged is no greater than 4° to 5° (8–10 PD), or the retinotopic distance in the foveal visual field is spanned by 2 normal V1 neurons. (J AAPOS 2000;4:168–74)

Background: The probability of visual recovery in tumor-related optic neuropathy usually correlates with the severity and duration of optic pathway compromise. Recovery of visual acuity to normal levels is unexpected after profound loss of vision extending for a period of weeks and months. Methods: A 9-year-old girl who had neurosurgical resection of a craniopharyngioma compressing the optic chiasm and optic tract was followed up serially with neuroimaging and clinical examinations over a 6-year period. Results: Within 3 months of the diagnosis of craniopharyngioma, the girl's vision was reduced to no-light-perception blindness when she viewed with the more involved eye. The blindness correlated with an amaurotic (ie, >3.6 log unit) relative afferent pupillary defect and an absence of any response when tested with visual field perimetry. After more than a year of total blindness and cessation of all neurosurgical and radiation therapy, visual acuity recovered to a normal level (20/25), the afferent pupillary defect improved, and sensitivity in a portion of the temporal hemivisual field was restored. In the follow-up that has extended for 5 years from the time of recovery, stability of the restored vision has been documented. Conclusion: Children who have tumor-related loss of vision due to damage to the anterior visual pathways may be capable of recovery after intervals of blindness that would be considered irreversible in adults. The mechanism of the recovery in our patient may have been decompression-related restoration of axoplasmic flow, followed by gradual remyelination of visual fibers, which allowed reorganization of connections to the lateral geniculate nucleus to optimize synaptic transmission. (J AAPOS 1999;3:366-71)

Purpose: To determine how the duration of infantile strabismus influences the eventual eye alignment. Methods: Six infant macaques were fitted with prisms, which were removed after 3 weeks (wks.), 3 months (mos.), or 6 mos. Two control monkeys wore plano lenses. Eye alignment was measured using search coils. Results: Longer duration of infantile strabismus is correlated with a more severe misalignment. The strabismus in the 6-mos. group was 96% greater than that in the 3-mos. group, which, in turn, was 25 times greater than that in the 3-wks group (p < 0.05). Conclusions: Longer duration of infantile strabismus causes larger-angle esotropia. Early correction of infantile strabismus is supported.