Search

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.

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)

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)

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.

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.

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.

PURPOSE Optokinetic eye movements stabilize gaze by tracking motion of the visual scene during sustained movement of a creature's body. The purpose of this study was to describe vertical and horizontal optokinetic nystagmus (OKN) in nonhuman primates (NHPs) with normal binocular vision, and to compare their responses to NHPs with binocular maldevelopment induced by prism-rearing. METHODS Optical strabismus was created in infant macaques (n = 6) by fitting them with prism goggles. The goggles were removed after 3, 6, 9, or 12 weeks to determine the effects of increasing durations of binocular noncorrespondence. Infant NHPs (n = 2) reared wearing plano goggles served as controls. OKN was evoked by horizontal or vertical stripe motion. Eye movements were recorded by using binocular search coils. RESULTS NHPs reared in early infancy under conditions of binocular noncorrespondence for durations of 6 weeks or longer had horizontal OKN responses biased directionally in favor of nasalward motion. NHPs reared with prisms for any duration had vertical OKN responses more biased than normal NHPs in favor of upward motion. Diagonal "crosstalk" during horizontal or vertical OKN (vertical slow phases during horizontal stimulus motion, and vice versa) was present to some degree in all NHPs. However, crosstalk-upward during horizontal OKN and nasalward during vertical OKN-was most pronounced in NHPs reared with prism for durations long enough to induce a permanent esotropic strabismus (longer than 3 weeks). CONCLUSIONS With fusion maldevelopment, the OKN pathways retain a nasalward and upward bias. During forward locomotion, optic flow excites temporalward and downward visual motion in each eye. The OKN biases would act in counterbalance. The biases attenuate with emergence of fusion, but may persist and crosstalk when fusion is impeded.

To determine whether demographic or clinical factors are associated with the outcome of office-based nasolacrimal duct probing for the treatment of congenital nasolacrimal duct obstruction (NLDO).In two multicenter prospective studies, 384 eyes of 304 children aged 6 to15 months with NLDO underwent a nasolacrimal duct probing performed in the office using topical anesthesia. Treatment success, defined as no clinical signs of NLDO (epiphora, increased tear lake, or mucous discharge) and no reoperation, was assessed 1 month after probing in one study and 6 months after probing in the other study. Data from both studies were pooled to evaluate associations between baseline characteristics and treatment success.Office probing was successful in 75% of eyes overall (95% CI, 70%-80%). The procedure was less successful in eyes of children with bilateral NLDO compared with unilateral NLDO (63% vs 80%; relative risk = 0.78 [95% CI, 0.66-0.92]) and in eyes that had 2 or 3 clinical signs of NLDO compared with one (71% vs 83%; relative risk = 0.88 [95% CI, 0.81-0.96]). Treatment success did not appear to be related to age, specific clinical signs of NLDO, prior treatment, or research study.Performing nasolacrimal duct probing in the office successfully treats NLDO in the majority of cases in children aged 6 to15 months. The success rate is lower with bilateral disease or when more than one clinical sign of NLDO is present.

PURPOSE. Children with cerebral palsy (CP) tend to be either excluded from studies of strabismus repair or pooled with children who have other neurologic disorders. The authors limited this study to children with defined CP to determine the success or failure of restoring eye alignment and fusion. METHODS. An observational, cross-sectional, prospective study was conducted on a representative cohort of 50 children. CP severity ranged from Gross Motor Function Classification System (GMFCS) level 1 (least severe) to 5 (most severe). Mean age at entrance and surgery was 3.5 years, and mean follow-up was 4.1 years (minimum 1 year). RESULTS. The predominant form of strabismus was infantileonset: esotropia in 54%, exotropia in 26%, and dyskinesia in 10%. Sixty-six percent of esotropic children and 61% of exotropic children achieved optimal (microtropic) alignment after an average of 2 and 1.8 surgical procedures, respectively. The likelihood of optimal alignment was similar in children with mild (GMFCS level 1‐2) versus severe (GMFCS level 3‐5) CP (P 0.7; 2 ). Irrespective of GMFCS severity, 46% of children gained binocular fusion/stereopsis, but the quality of fusion gained was greater in children with mild CP (P 0.05). Earlier surgery was more likely to be successful (P 0.05). CONCLUSIONS. Restoration of binocular alignment and a degree of fusion is a realistic goal in the majority of strabismic CP children. Repair may be achieved in children at both the mild and the severe ends of the GMFCS spectrum, without undue concern about treatment futility or excessive reoperation. (Invest Ophthalmol Vis Sci. 2011;52:7664‐7671) DOI:10.1167/ iovs.10-6906

Latent nystagmus (LN) is the by-product of fusion maldevelopment in infancy. Because fusion maldevelopment--in the form of strabismus and amblyopia--is common, LN is a prevalent form of pathologic nystagmus encountered in clinical practice. It originates as an afferent visual pathway disorder. To unravel the mechanism for LN, we studied patients and nonhuman primates with maldeveloped fusion. These experiments have revealed that loss of binocular connections within striate cortex (area V1) in the first months of life is the necessary and sufficient cause of LN. The severity of LN increases systematically with longer durations of binocular decorrelation and greater losses of V1 connections. Decorrelation durations that exceed the equivalent of 2-3 months in human development result in an LN prevalence of 100%. No manipulation of brain stem 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 and left cerebral hemispheres have balanced binocular activity. Fusion maldevelopment in infancy causes unbalanced monocular activity. If input from one eye dominates and the other is suppressed, MSTd in one hemisphere becomes more active. Acting through downstream projections to the ipsilateral nucleus of the optic tract, the eyes are driven conjugately to that side. The unbalanced MSTd drive is evident as the nasalward gaze-holding bias of LN when viewing with either eye.

Purpose: Strabismus in human infants is linked strongly to nasotemporal asymmetries of smooth pursuit, but many features of this co-morbidity are unknown. The purpose of this study was to determine how the duration of early-onset strabismus (or timeliness of repair) affects the severity of pursuit asymmetries in a primate model. Methods: Binocular image decorrelation was imposed on infant macaques by fitting them with prism goggles on day 1 of life. The goggles were removed after 3 weeks ( n =2), 12 weeks ( n =2) or 24 weeks ( n =3), emulating surgical repair of strabismus in humans at 3, 12, and 24 months of age, respectively. Two control monkeys wore plano lenses. Several months after the goggles were removed, horizontal smooth pursuit was recorded using binocular search coils and a nasal-bias index (NBI) was calculated. Results: Each animal in the 12- and 24-week groups developed a constant, alternating esotropic strabismus and a nasotemporal asymmetry of pursuit when viewing with either eye. Spatial vision was normal (no amblyopia). The 3-week duration monkeys were indistinguishable from control animals; they had normal eye alignment and symmetric pursuit. In the 12- and 24-week monkeys, the longer the duration of binocular decorrelation, the greater the pursuit asymmetry: for 15°/s target motion, the NBI in the 12-week and 24-week animals was 16× and 22× greater respectively, than that in the 3-week animals (ANOVA, P =0.03). Conclusions: Binocular decorrelation in primates during an early period of fusion development causes permanent smooth pursuit asymmetries when the duration exceeds the equivalent of 3 months in human. These findings support the conclusion that early correction of infantile strabismus promotes normal development of cerebral gaze pathways.

Human infants at greatest risk for esotropia are those who suffer cerebral insults that could decorrelate signals from the 2 eyes during an early critical period of binocular, visuomotor development. The author reared normal infant monkeys, under conditions of binocular decorrelation, to determine if this alone was sufficient to cause esotropia and associated behavioral as well as neuroanatomic deficits.Binocular decorrelation was imposed using prism-goggles for durations of 3 to 24 weeks (in 6 experimental, 2 control monkeys). Behavioral recordings were obtained, followed by neuroanatomic analysis of ocular dominance columns and binocular, horizontal connections in the striate visual cortex (area V1).Concomitant, constant esotropia developed in each monkey exposed to decorrelation for a duration of 12 to 24 weeks. The severity of ocular motor signs (esotropia-angle; dissociated vertical deviation; latent nystagmus; pursuit/optokinetic tracking asymmetry; fusional vergence deficits), and the loss of V1 binocular connections, increased as a function of decorrelation duration. Stereopsis was deficient and motion visual evoked potentials were asymmetric. Monkeys exposed to decorrelation for 3 weeks showed transient esotropia but regained normal visuomotor behaviors and binocular V1 connections.Binocular decorrelation is a sufficient cause of infantile esotropia when imposed during a critical period of visuomotor development. The systematic relationship between severity of visuomotor sign, and severity of V1 connectivity deficit, provides a neuroanatomic mechanism for several of these signs. Restoration of binocular fusion and V1 connections, after short durations of decorrelation, helps explain the benefits of early repair in human strabismus.

PURPOSE. Infantile esotropia is linked strongly to latent fixation nystagmus (LN) in human infants, but many features of this comorbidity are unknown. The purpose of this study was to determine how the duration of early-onset strabismus (or timeliness of repair) affects the prevalence of LN in a primate model. METHODS. Optical strabismus was created in infant macaques by fitting them with prism goggles on day 1 of life. The goggles were removed after 3 (n = 2), 12 (n = 1) or 24 weeks (n = 3), emulating surgical repair of strabismus in humans at 3, 12, and 24 months of age, respectively. Eye movements were recorded by using binocular search coils. RESULTS. Each animal in the 12- and 24-week groups exhibited LN and manifest LN, normal spatial vision (no amblyopia), and constant esotropia. The 3-week duration monkeys had stable fixation (no LN) and normal alignment indistinguishable from control animals. In affected monkeys, the longer the duration of binocular decorrelation, the greater the LN: mean slow-phase eye velocity (SPEV) in the 24-week animals was three times greater than that in the 12-week monkey (P = 0.03); mean LN intensity in the 24-week monkeys was three times greater than that in the 12-week monkey (P = 0.03). CONCLUSIONS. Binocular decorrelation in primates during an early period of fusion development causes permanent gaze instability when the duration exceeds the equivalent of 3 months in humans. These findings support the conclusion that early correction of infantile strabismus promotes normal development of cerebral gaze-holding pathways.

Infantile nystagmus is a clinically and genetically heterogeneous eye movement disorder. Here we map and identify the genetic mutation underlying X-linked idiopathic infantile nystagmus (XL-IIN) segregating in two Caucasian-American families.Eye movements were recorded using binocular infrared digital video-oculography. Genomic DNA was prepared from blood or buccal-cells, and linkage analysis was performed using short tandem repeat (STR) and single nucleotide polymorphism (SNP) markers. Pedigree and haplotype data were managed using Cyrillic, and LOD scores calculated using MLINK. Mutation profiling of PCR-amplified exons was performed by dye-terminator cycle-sequencing and analyzed by automated capillary electrophoresis.Video-oculography of affected males recorded conjugate, horizontal, pendular nystagmus with increasing-velocity waveforms in primary gaze converting to jerk nystagmus in eccentric gaze. Linkage analysis detected significantly positive two-point LOD scores (Z) at markers DXS8078 (Z=4.82, recombination fraction [theta]=0) and DXS1047 (Z=3.87, theta=0). Haplotyping indicated that the IIN locus mapped to the physical interval DXS8057-(11.59 Mb)-rs6528335 on Xq25-q26. Sequencing of positional-candidate genes detected a c.425TG transversion in exon-6 of the gene for FERM domain containing-7 (FRMD7) that cosegregated with affected and carrier status. In addition, the same change was found to cosegregate with IIN in a genetically unrelated family but was not detected in 192 control individuals.The c.425TG change is predicted to result in the missense substitution of the phylogenetically conserved leucine at codon 142 for an arginine (p.L142R), and supports a causative role for FRMD7 mutations in the pathogenesis of XL-IIN.

Before the development of quantitative models of extraocular biomechanics,1–3 it was believed sufficient to describe orbital anatomy by cadaveric measurements of extraocular muscle (EOM) origins and insertions. These descriptions inform classic concepts of EOM actions and most current strabismus surgery. Attempts to calculate binocular alignment from these first principles then made it obvious that EOM paths, the gaze dependence of paths, and the supporting orbital tissues, were critical to ocular motility. Radiography in monkeys4 and humans5 subsequently suggested that rectus EOM bellies have stable paths relative to the orbit, despite gaze changes. Miller first used magnetic resonance imaging (MRI) to demonstrate the stability of rectus EOM belly paths in humans and initiated the notion that pulleys influence rectus EOM paths.6 It has subsequently emerged that the rectus and inferior oblique EOMs of humans and monkeys do indeed have highly structured soft pulleys that regulate EOM pulling directions.7–10 The pulleys act as functional origins of the rectus EOMs.11 Rectus EOMs travel through their respective pulleys, which imply that the pulleys must lie along the EOM paths. Many cases of human incomitant cyclovertical strabismus are associated with displacement of one or more rectus EOM pulleys. “A” and “V” patterns of incomitance in strabismic patients consistently match those predicted by computational simulation based on measured pulley locations, suggesting that pulley heterotopy caused the strabismus.12,13 Extreme pulley heterotopy is associated with esotropia and hypotropia in axial high myopia, the “heavy-eye syndrome.”14–16 The most common forms of human strabismus are horizontal, concomitant eso- and exotropia. Concomitant strabismus means that the degree of misalignment is the same regardless of horizontal gaze direction, although “A” and “V” patterns of variation with vertical gaze are typically associated with the most common forms in humans.14 Infantile esotropia is particularly prevalent in humans and is often associated with a “V” pattern, in which the esodeviation increases in downward gaze.17 The possible contribution of pulley abnormalities to human concomitant strabismus is unknown, as it is difficult to study in children who typically cannot cooperate for adequate magnetic resonance imaging (MRI). Even if rectus pulleys were found to be abnormal in humans with horizontal concomitant strabismus, it would be impossible to know whether the abnormalities were the causes or effects of the strabismus. A primate model offers a solution to the conundrum. The visual and oculomotor systems of monkeys are considered good models of the human because of peripheral orbital and neuroanatomic similarities.18–20 Infantile esotropia occurs naturally in monkeys, and strabismus can be induced artificially by optical means or lid suturing. Investigation in monkeys also affords opportunity to study the accessory lateral rectus (ALR) muscle, which occurs variably in some species, and has been said to be a factor in the prevalence of natural simian esotropia.21 The present study used MRI and serial histology to determine whether any abnormalities of the horizontal rectus EOMs or their pulleys are associated, either as cause or effect, with horizontal concomitant strabismus in monkeys.

Introduction Recent studies of human infants have described a spectrum of early-onset esotropia, from small angle to large heterotropias. We report here a similar spectrum of early-onset esotropia in infant monkeys, with emphasis on the relationship between visuomotor deficits, central nervous system circuitry, and orbital anatomy. Methods Eye movements were recorded in macaque monkeys with natural, infantile-onset esotropia (n = 7) and in control monkeys (n = 2) to assess alignment, latent nystagmus, dissociated vertical deviation (DVD), and pursuit/optokinetic nystagmus (OKN) asymmetries. Acuity was measured by preferential-looking technique or spatial sweep visual-evoked potentials. Geniculo-striate pathways were then analyzed with neuroanatomic tracers and ocular dominance column labels. Extraocular muscles were examined by high-resolution magnetic resonance imaging (MRI) and anatomic sectioning of whole orbits. Results Esotropia ranged from 4 to 13.5° (7–24Δ) with fixation preference (if any) varying idiosyncratically (as in human). Severity of ocular motor dysfunction (ie, nystagmus velocity, DVD amplitude, pursuit-OKN nasal bias index) increased as the magnitude of esotropia angle. Animals with greater ocular motor deficits tended to have greater visual area V1 (striate cortex) neuroanatomic deficits, evident as fewer binocular horizontal connections in V1. Orbital MRI/anatomic analysis showed no difference in horizontal rectus cross-sectional areas, muscle paths, innervation densities, or cytoarchitecture compared with normal animals. Conclusions The infantile esotropia spectrum in nonhuman primates is remarkably similar to that reported in human infants. Concomitant esotropia in these primates cannot be ascribed to abnormalities of the extraocular muscles or orbit. These findings, combined with epidemiologic studies of humans, suggest that perturbations of cerebral binocular pathways in early development are the primary cause of the infantile esotropia syndrome.

PURPOSE. Infantile strabismus in humans and the monkey is associated with maldevelopment of visual motion responsiveness, one manifestation of which is directionally asymmetric motion visual evoked potentials (motion VEPs). Early repair of strabismus in infant monkeys has been shown to restore normal development of motion responsiveness for pursuit and optokinetic eye movements (optokinetic nystagmus [OKN]). The purpose of this study was to determine how early versus delayed repair of strabismus influences the development or maldevelopment of motion VEPs. METHODS. Optical strabismus was created in infant macaques by fitting them with prism goggles on day 1 of life. The Early Repair group wore the goggles for a period of 3 weeks (the equivalent of 3 months before surgical repair in humans), whereas the Delayed Repair group wore the goggles for a period of 3 to 6 months (the equivalent of 12‐24 months before surgical repair in humans). Several months after the removal of the goggles, motion VEPs to horizontally oscillating grating stimuli were recorded during monocular viewing. An asymmetry index (AI) was measured for each animal by extracting an asymmetric (F1) and symmetric (F2) frequency component from the motion VEP. The AIs of the infant monkeys with Early versus Delayed Repair were also compared with that of a group of adult monkeys, who had unrepaired, natural strabismus. RESULTS. When tested with a 1-cyc/deg, 6-Hz stimulus, both control and Early Repair monkeys exhibited symmetric motion VEPs (AI 0.25). Mean AI was 0.15 0.09 in control and 0.16 0.13 in Early Repair monkeys. In contrast, both Delayed Repair and naturally strabismic monkeys had asymmetric motion VEP responses: AI 0.57 0.22 in the Delayed Repair and 0.49 0.17 in the naturally strabismic monkeys (P 0.01). Delayed Repair and naturally strabismic monkeys also had motion VEP asymmetries of equivalent magnitude when tested using stimuli at higher (3 cyc/deg/11 Hz) spatial‐temporal frequencies. The concordance between motion VEP symmetry and normal fusional vergence was significant (P 0.01). CONCLUSIONS. Early repair of optical strabismus in primates restores normal development of visual motion pathways in the cerebral cortex, measured as symmetric motion VEPs. Delayed repair causes permanent motion VEP maldevelopment. These results provide additional evidence that early strabismus repair is beneficial for brain development in infant primates. (Invest Ophthalmol Vis Sci. 2004;45:821‐ 827) DOI:10.1167/iovs.030564

PURPOSE To describe symmetric convergence eye movements evoked by disparity and/or accommodative cues in esotropic macaque monkeys, with the goal of determining whether these animals have the vergence deficits found in humans with esotropia. METHODS Physical far and near targets were used to evoke large (approximately 8 degrees) symmetric convergence eye movements in four adult macaque monkeys (two with strabismus, two normal), using positive-feedback rewards. One strabismic monkey had infantile-onset, small-angle esotropia (small-eso approximately 2 degrees) induced by alternating occlusion from birth to age 9 months. The other strabismic monkey had naturally occurring, large-angle (approximately 25 degrees) infantile-onset esotropia (large-eso). Visual acuity was normal in each eye as measured by spatial sweep visually evoked potentials (VEPs). Eye movements were recorded using magnetic search coils. RESULTS When viewing binocularly, both normal monkeys exhibited accurate, stereotyped symmetric convergence movements that achieved 87% to 96% of the required change in vergence angle by the end of the initial movement. In contrast, the small-eso monkey's convergence response when viewing binocularly was variable, strikingly asymmetric, usually accompanied by a disjunctive saccade, and subnormal, achieving only 56% of required vergence. The convergence response of the large-eso monkey was also asymmetric and weak, achieving 18% of the required vergence and employing conjugate saccades to refixate the near target. Monocular viewing (i.e., accommodative vergence) caused substantial reductions in both convergence amplitudes and velocities in the normal monkeys, but had a minor effect on the vergence behavior of the strabismic animals. CONCLUSIONS Monkeys with small- and large-angle infantile esotropia have striking maldevelopments of binocular (disparity-driven) convergence and use accommodative vergence and saccades to refixate near targets. Their vergence behavior resembles that in esotropic humans. The maldevelopment may be explained in large part by the paucity of binocular connections recently described in the visual cortex of esotropic macaques.

SUMMARY Motion perception was tested by requiring adult subjects to view gratings that remained stationary but reversed in contrast several times per second. Subjects viewed monocularly and judged whether the gratings were stationary, or moving in one direction, in successive 3s trials. Subjects who had early-onset strabismus most frequently perceived vertically oriented gratings to be moving nasalward, and horizontally oriented gratings to be moving up or down. Norma! subjects and subjects who had late-onset strabismus most frequently perceived the gratings to be stationary. The asymmetries of motion perception in early-onset strabismus imply that the visual motion neurons of cerebral cortex develop properly only if they receive normal binocular input during infancy. RESUME Biais de la perception du mouvement reviles par des grilles-inverses chez les sujets avec un strabisme a debut precoce La perception du mouvement a ete explorec en demandant a des sujets adultes d'observer des grilles demeurant stationnaires mais inversees en contraste plusieurs fois par seconde. Les sujets en vision monoculaire jugeaient si les grilles etaient stationnaires ou se deplacaient dans une direction, dans essais successifs de trois secondes. Les sujets presentant un strabisme a debut precoce percevaient plus frequemment un deplacement nasal des grilles a orientation verticale et un desplacement vers le haut ou le bas des grilles horizontales. Les sujets normaux ou a strabisme tardif percevaient plus frequemment les grilles commc stationnaires. Les asymetries de la perception du mouvement dans le strabisme a debut precoce impliquent que les neurones visuocorticaux de la perception du mouvement ne se developpent correctement que s'ils beneficient d'une entree binoculaire normale durant la petite enfance. ZUSAMMENFASSUNG Storungen der Bewegungswahrnelmumg, nachgewiesen durch Rasterumkehr, bei Patienlen mil fruh beginnendem Nystagmus Zur Beurteilung der Bewegungswahrnehmung wurden erwachsene Probanden aufgefordert. Raster, die stationar blieben, sich aber mehrere Male pro Sekunde umkehrten, zu bcobachten. Die Probanden sahen mit einem Auge und beurteilten in aufeinanderfolgenden 3s Versuchen, ob das Raster stationar blieb oder sich in einer Richtung bewegte. Patienten mit fruh beginnendem Strabismus sahen sehr haufig vertikal ausgerichtete Raster sich nasalwarts bewegen und horizontal ausgerichtcte Raster sich auf- oder abbewegen. Gesunde Personen und Probanden mit spat beginnendem Strabismus sahen die Raster fast immer stationar. Die Asymmetrien der Bewegungswahrnehmung beim fruh beginneden Nystagmus besagen, das die visuellen Motoneurone des cerebralen Cortex sich nur normal entwickeln, wenn sie im Kindesalter normale binokulare Stimulationen crhalten. RESUMEN Sesos de percepcion motora revelados por medio de parrillas reversibles en personas que tenian un estrabismo desde la infancia Se exploro la percepcion de movimiento, pidiendo a adultos que observaran emparrillados que permanecian estacionarios, pero revertidos varias veces por segundo. Los individuos veian monocularmentc y opinaban sobre si los emparrillados eran estacionarios o se movian en una direccion en ensayos succesivos cada tres segundos. Los individuos que habian tenido un inicio precoz de estrabismo percibian con mayor frecuencia los emparrillados orientados verticalmente, como moviendose en direccion a la nariz, y los orientados horizontalmente como moviendose hacia arriba y abajo. Los individuos normales y aquellos con estrabismo de aparicion tardia percibian con mayor frecuencia los emparrillados como estacionados. Las asimetrias en la percepcion del movimiento en el estrabismo de inicio precoz implican que las neuronas visuales motoras del cortex cerebral, solo se desarrollan adecuadamente si reciben informacion binocular normal durante el periodo de la lactancia.

Several skeletal muscles are composed of multiple neuromuscular compartments that can be controlled individually by corresponding motor neuron pools.1–3 The transversus abdominis is composed of distinct regions that contract differentially.3 Similarly, the human cricothyroid muscle has three bellies with distinct functions innervated by separate motor nerve branches.3 The triceps brachii is composed of multiple fascicles that may be considered as distinct muscles with completely independent motoneuron subnucleus innervation.4 There exist more extraocular muscle (EOM) fibers and motor neurons than apparently required by conventionally recognized mechanisms of ocular motility.5,6 Could this be because individual EOMs are compartmentalized to implement multiple functions? One such example is the active pulley hypothesis that proposes that orbital layers of EOMs insert in connective tissue rings, called pulleys, through which pass the global layer fibers that in turn insert on the sclera to rotate the eye. Consequently, during EOM contraction, shifts in pulley positions influence EOM pulling directions.7–10 This laminar aspect of compartmentalization is evident in all oculorotary EOMs. Peng et al.11 traced the intramuscular arborization of the abducens nerve (CN6) within the lateral rectus (LR) muscles of two macaque monkeys and two humans, demonstrating that CN6 bifurcates externally to the EOM into two major trunks whose arborizations remain segregated into superior versus inferior zones throughout the EOM's length. Based on this finding, Peng et al.11 proposed that selective neural control of the two LR zones could execute significant torsional and vertical actions that are not classically recognized. This neuroanatomical finding of Peng et al.11 is consistent with the LR's dual-headed origin in the deep orbit.12,13 Some aspects of the LR are unique among EOMs, however, so that compartmentalization of LR innervation might be a developmental artifact rather than neural control strategy. Older studies of EOM embryology claimed that the LR originates from two different myotomes.14,15 More recent studies in birds demonstrate that the LR arises from somitomeres 4 and 5,16,17 and that CN6 arises from both rhombomeres 5 and 6.16 Separation of CN6 into two parallel nerve trunks is not rare. Indeed, 8–15% of CN6 in humans are split in this way.18–21 The LR can also exhibit longitudinal splitting, most prominently in congenital disorders of cranial nerve development such as processes involving the EOM or cranial nerve development such as congenital fibrosis of the extraocular muscles type 1,22 congenital oculomotor palsy,23 congenital trochlear palsy,23 and Duane syndrome.24–26 The possibility of selective activation of compartments requires topographical projection of motor nerves within segregated EOM regions. If selective control of rectus EOM compartments is a general neural strategy, evidence of compartmentalization should be evident in the intramuscular innervation of other rectus EOMs besides the LR. This study aimed at confirming, in additional specimens, Peng et al.'s report of compartmentalized LR innervation11 and extending study by tridimensional reconstruction of nerve arborizations, to the inferior (IR), medial (MR), and superior rectus (SR) muscles of humans and monkeys.

Intraocular pressure (IOP) measurements in children are frequently performed under halothane-nitrous oxide anesthesia; however, anesthesia face masks may limit access to the eyes, and tracheal intubation is associated with transient increases in IOP. Use of the laryngeal mask airway (LMA) permits the maintenance of a patent airway without the need for laryngoscopy and tracheal intubation. In a randomized study of 41 children, we compared the IOP, hemoglobin oxygen saturation, and hemodynamic responses to the insertion of an LMA or tracheal tube during a standardized steady-state anesthetic technique consisting of 1 MAC halothane and 66% nitrous oxide. Baseline measurements of IOP, hemoglobin oxygen saturation, heart rate, and arterial blood pressure were recorded and repeated within 15-30 s after insertion of the airway device and at 1-min intervals for 5 min. Insertion of the LMA required significantly less time (26 +/- 16 vs 39 +/- 17 s [mean +/- SD]) and was associated with higher hemoglobin oxygen saturation values compared with the tracheal intubation. The LMA did not increase IOP, heart rate, or arterial blood pressure above baseline values. In contrast, tracheal intubation was associated with significant increases of IOP, heart rate, and arterial blood pressure. We concluded that the laryngeal mask offers advantages over tracheal intubation and the face mask for airway management in patients undergoing IOP measurements.

PURPOSE. Cerebral palsy (CP) is a permanent, nonprogressive disorder of movement and posture due to a lesion of the fetal or infant brain. The goal was to determine whether children with different severities of CP, as defined using the Gross Motor Function Classification System (GMFCS), had different degrees or types of visual dysfunction. METHODS. An observational, cross-sectional‐design study was conducted by using neurologic and masked ophthalmic measurements on a representative cohort of 50 children with CP. Mean age was 5.6 years (range, 2‐19.5 years); mean gestational age was 31 weeks. RESULTS. The likelihood of debilitating visual deficits was greater in children with higher GMFCS scores, independent of gestational age. Children with level 5 disease (most severe) were at greatest risk for high myopia, absence of binocular fusion, dyskinetic strabismus, severe gaze dysfunction, and optic neuropathy or cerebral visual impairment (CVI). These deficits were rare or absent in children with the mildest disease, level 1. When categorized by anatomic or physiologic CP subtype, diplegic and spastic children were more often hyperopic and esotropic, but had the highest prevalence of fusion and stereopsis. In contrast, children with quadriplegic and mixed CP (dyskinetic, athetoid, hypotonic, and ataxic) more often had high myopia, CVI, dyskinetic strabismus, and gaze dysfunction. CONCLUSIONS. Visual deficits differ in children who have mild versus severe CP. Children with GMFCS level 1 to 2 have sensorimotor deficits resembling those of neurologically normal children with strabismus and amblyopia; children at level 3 to 5 have more severe deficits, not observed in neurologically normal children. (Invest Ophthalmol Vis Sci. 2008;49: 572‐580) DOI:10.1167/iovs.07-0525