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BACKGROUND Sporadic optic pathway/hypothalamic gliomas represent a unique entity within pediatric low-grade glioma. Despite favorable survival, location makes treatment difficult and local progression debilitating. This study is a longitudinal assessment of visual acuity (VA) among children treated within the last 2 decades. METHODS Clinical characteristics were abstracted for patients treated from 2000 to 2018 at Texas Children's Cancer Center in Houston. Ophthalmologic data taken at 3- to 6-month intervals were examined with age-appropriate VA metrics converted to the LogMAR (logarithm of the minimum angle of resolution) scale. Kaplan-Meier blindness-free survival (BFS) curves, calculated as time-to-bilateral functional blindness (LogMAR ≥0.8 in both eyes), were calculated for patients receiving early radiation therapy (RT; upfront or as first-line salvage treatment) or chemotherapy (CT) and evaluated using the log-rank test. RESULTS Thirty-eight patients with a median follow-up of 8.5 years (range, 2-17 years) were identified. Median age at diagnosis was 3 years (interquartile range

A 9-year-old girl presented with morning headaches associated with vomiting, gait ataxia, and facial and ocular motor nerve palsies. Her initial imaging was concerning for demyelinating disease. After extensive infectious and rheumatologic workup returned negative, she was treated twice with intravenous immunoglobulin and intravenous steroids with near-complete resolution each time. She returned, however, with worsening neurologic deficits and imaging revealing focal ischemic infarction in the brainstem as well as new-onset hydrocephalus. A multispecialty workup was initiated without conclusive diagnosis. A novel, noninvasive test for plasma cell-free DNA established a diagnosis of Cladophialophora bantiana that was confirmed and validated by a brain biopsy taken during a clinical decompensation. Treatment was initiated with systemic voriconazole and intraventricular amphotericin B.

Objective Congenital orbital fibrosis (COF) is a nonprogressive, unilateral, congenital process in which variable fibrosis is demonstrated in the orbit, resulting in restrictive strabismus, upper eyelid malposition, and axial displacement of the globe. We present 4 new pediatric cases of COF and discuss factors that impact visual development. We also describe a patient with local compressive optic neuropathy/edema who underwent optic nerve sheath fenestration (ONSF) for visual preservation. Design/Methods/Participants Literature review and retrospective case series. Results Four male COF patients (mean age of 11 months) were examined. Two patients presented with decreased ocular motility of the affected eye. Two patients presented with exophthalmos, and one presented with enophthalmos. Two patients presented with ptosis, and one presented with eyelid retraction. Two patients presented with optic nerve atrophy, and one presented with optic nerve edema. Magnetic resonance imaging demonstrated involvement of the superior, medial, and inferior rectus and superior oblique muscles in 3 patients and the lateral rectus and inferior oblique muscles in 2 patients. Three patients underwent orbitotomy. Histology was consistent with fibrosis. Three patients demonstrated amblyopia, and 2 responded to treatment. The patient with optic nerve edema underwent ONSF. At 4 months’ follow-up, the edema had resolved. Conclusions COF can present with either anterior or posterior globe displacement. Patients must undergo a complete ophthalmic evaluation to identify modifiable factors. Strabismus and ptosis should be addressed for optimal visual development. Amblyopia therapy should be instituted quickly. Patients who present with active optic nerve edema may benefit from ONSF for local compressive optic neuropathy.

The pathophysiology underlying pseudotumor cerebri syndrome (PTCS) is complex and not well understood. There are clear differences between PTCS in adults and pediatrics. Few and isolated case reports have suggested that adrenal function may be involved, yet no large cohort study has examined this relationship.We conducted a retrospective single-center study of children who presented with a diagnosis of PTCS and had cortisol testing measured between January 2010 and September 2019. We included all subjects meeting the revised PTCS diagnostic criteria after the chart review. Based on morning, random or 1-μg cosyntropin stimulated cortisol levels, adrenal functioning was classified as: (1) insufficient (peak cortisol16 μg/dL and AM cortisol5 μg/dL), (2) at risk (peak cortisol 16-20 μg/dL, AM cortisol 5-13 μg/dL, or random13 μg/dL), or (3) sufficient (peak cortisol20 μg/dL and AM or random cortisol13 μg/dL).A total of 398 individuals were reviewed, and 64 were included for analysis. Of these, 40.6% were men, of mixed race and ethnicity with a mean age of 10.5 (SD 4.7) years. Of these, 23% and 52% had insufficient or at-risk cortisol levels. The majority of those in the insufficient (70%) or at-risk (80%) groups were exposed to topical, nasal, or inhaled glucocorticoids but not systemic. Only 60% and 12% of those with PTCS with insufficient or at-risk cortisol testing, respectively, underwent definitive testing with a stimulation test.Glucocorticoid use and hypocortisolism are prevalent in PTCS and need consideration as a potential underlying cause. Most children had insufficient or at-risk cortisol levels, and many did not undergo further testing/workup. Children who present with PTCS, particularly young, males should be evaluated for adrenal insufficiency and its risk factors, including nonsystemic steroids. Prospective studies are necessary to further evaluate the effect of cortisol in relation to pediatric PTCS.

Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS) is an autosomal dominant neurodevelopmental disorder caused by loss-of-function variants in NR2F1 and characterized by visual impairment, developmental delay, and intellectual disability. Here we report 18 new cases, provide additional clinical information for 9 previously reported individuals, and review an additional 27 published cases to present a total of 54 patients. Among these are 22 individuals with point mutations or in-frame deletions in the DNA-binding domain (DBD), and 32 individuals with other types of variants including whole-gene deletions, nonsense and frameshift variants, and point mutations outside the DBD. We corroborate previously described clinical characteristics including developmental delay, intellectual disability, autism spectrum disorder diagnoses/features thereof, cognitive/behavioral anomalies, hypotonia, feeding difficulties, abnormal brain MRI findings, and seizures. We also confirm a vision phenotype that includes optic nerve hypoplasia, optic atrophy, and cortical visual impairment. Additionally, we expand the vision phenotype to include alacrima and manifest latent nystagmus (fusional maldevelopment), and we broaden the behavioral phenotypic spectrum to include a love of music, an unusually good long-term memory, sleep difficulties, a high pain tolerance, and touch sensitivity. Furthermore, we provide additional evidence for genotype-phenotype correlations, specifically supporting a more severe phenotype associated with DBD variants.

Importance Optic neuritis (ON) in children is uncommon. There are limited prospective data for visual acuity (VA) outcomes, associated diseases, and neuroimaging findings. Prospective data from a large sample would be useful for counseling families on treatment decisions and prognosis. Objective To prospectively study children with a first episode of ON, describe VA after 6 months, and ascertain the network's (Pediatric Eye Disease Investigator Group and Neuro-Ophthalmology Research Disease Investigator Consortium) ability to enroll pediatric patients with ON prospectively. Design, Setting, and Participants This nonrandomized cohort study was conducted from September 20, 2016, to July 20, 2018, at 23 sites in the United States and Canada in pediatric ophthalmology or neuro-ophthalmology clinics. A total of 44 children (aged 3-15 years) presented with a first episode of ON (visual loss, pain on eye movements, or both) within 2 weeks of symptom onset and at least 1 of the following in the affected eye: a distance high-contrast VA (HCVA) deficit of at least 0.2 logMAR below age-based norms, diminished color vision, abnormal visual field, or optic disc swelling. Exclusion criteria included preexisting ocular abnormalities or a previous episode of ON. Main Outcomes and Measures Primary outcomes were monocular HCVA and low-contrast VA at 6 months. Secondary outcomes were neuroimaging, associated diagnoses, and antibodies for neuromyelitis optica and myelin oligodendrocyte glycoprotein. Results A total of 44 children (mean age [SD], 10.2 [3.5] years; 26 boys [59%]; 23 White individuals [52%]; 54 eyes) were enrolled in the study. Sixteen patients (36%) had bilateral ON. Magnetic resonance imaging revealed white matter lesions in 23 children (52%). Of these children, 8 had myelin oligodendrocyte glycoprotein-associated demyelination (18%), 7 had acute disseminated encephalomyelitis (16%), 5 had multiple sclerosis (11%), and 3 had neuromyelitis optica (7%). The baseline mean HCVA was 0.95 logMAR (20/200), which improved by a mean 0.76 logMAR (95% CI, 0.54-0.99; range, -0.70 to 1.80) to 0.12 logMAR (20/25) at 6 months. The baseline mean distance low-contrast VA was 1.49 logMAR (20/640) and improved by a mean 0.72 logMAR (95% CI, 0.54-0.89; range, -0.20 to 1.50) to 0.73 logMAR (20/100) at 6 months. Baseline HCVA was worse in younger participants (aged

Background In autoimmune myasthenia gravis (MG), autoantibodies target the neuromuscular junction. Ocular myasthenia gravis (OMG) is localized, affecting only extraocular and/or levator palpebrae muscles. OMG presents across all ages, varying in presentation, treatment modalities, and outcomes. Recently, there have been advances in MG/OMG treatment; their utilization and effectiveness are an important part of optimal disease management. Methods We completed a retrospective chart review of children aged 18 years or younger with a confirmed diagnosis of OMG presenting from 2002 to 2019. Results Forty-two patients were included with mean age at presentation of 8.5 years (2 to 18 years). Twenty-one patients (50%) had positive antibodies; 90% had acetylcholine receptor antibodies. Ten patients developed generalized symptoms with mean time to generalization of 13.6 months. Multiple logistic regression showed that older age of onset was a trend predictive factor (P = 0.054; odds ratio 1.17) for generalized disease. All patients were treated with pyridostigmine. Immunomodulating agents included steroids (15), mycophenolate mofetil (four), and intravenous immunoglobulin (one). Three patients underwent thymectomy. Twenty patients reached minimal manifestation status, and 12 achieved remission. Gender, race, and positive antibody status were not statistically significant predictors for advanced immunosuppressive therapy. Conclusions We summarize one of the largest cohorts of pediatric patients with OMG who have undergone up-to-date diagnostic and therapeutic regimens. The predictors of outcome and treatment pathway for OMG patients suggested by this report may be further elucidated by future prospective studies.

Background: Idiopathic intracranial hypertension (IIH) is a condition of elevated intracranial pressure without identifiable secondary causes. The childhood incidence is 0.7 per 100,000 and increases with age, obesity, and female gender. Few case reports in the literature, and our own experience, suggest there may be an association between IIH and adrenal insufficiency (AI) but the real extent is unknown. Aim: To describe the prevalence of AI in children presenting with IIH to a large pediatric referral center. Methods: Retrospective chart review identified all children who presented with IHH and had cortisol measured between January 2010 and September 2019. Based on morning, random or 1 mcg ACTH stimulated cortisol levels, adrenal functioning was classified as: (1) deficient (peak cortisol 20 μg/dl, AM or random cortisol >13 μg/dl). Descriptive data present mean (+/- standard deviation), and chi-squared (χ 2) tests of differences are used to examine differences between the adrenal functioning groups. Results: Participants (N=64) were 40.6% male, of mixed ancestry (61% non-Hispanic white; 19% African-American, 16% Hispanic White and 5% Asian), with a mean age of 10.8 (4.8) years. Cortisol levels were obtained at an average of 0.6 (1.9) years after diagnosis of IIH; 23% and 52% of patients had insufficient or at risk cortisol levels. The majority of those in the insufficient (70%) or at risk (80%) groups were exposed to topical, nasal or inhaled corticosteroids, but not systemic. Only 60% and 12 % of those with IIH and insufficient or at risk cortisol testing, respectively, underwent definitive testing with a stimulation test. Adrenal function did not differ by age, race/ethnicity, zBMI, nor prolong exposure to steroids (> 2 weeks), time between IIH diagnosis and cortisol testing (all P>.05). Those in the deficient group were less likely to be female (33%) than those in the at risk (61%; χ 2=3.07, df=1, P=.001) or sufficient (81%; χ 2=7.30, df=1, P.05) Conclusions: Steroid use and AI are common in IIH and need consideration as a cause of IIH development. Appropriate diagnosis and treatment of AI in children who present with IIH may lead to its resolution, significantly impacting clinical outcomes of these children. In our cohort, the majority had AI or at risk cortisol levels, and many did not undergo further testing. All young children who present with IIH should be evaluated for steroid exposure, including non-systemic steroids, and undergo evaluation for AI. Caution should be utilized in pediatric providers prescribing these medications. More prospective studies are required to evaluate the effects of steroid use in relation to IIH development.

A 5-year-old boy had initial symptoms of behavioral changes, nausea, vomiting, headache, weight loss, and progressive vision failure. Brain MRI revealed abnormal signal intensity in both optic nerves, the optic chiasm, the right medial temporal lobe, and tissues surrounding the right supraclinoid internal carotid artery with associated leptomeningeal and spinal cord enhancement. After nondiagnostic dural and spinal arachnoid biopsies, a temporal lobe biopsy was diagnostic for a rare malignant peripheral nerve sheath tumor.

We report a case of surgical management of Crouzon syndrome with multisuture craniosynostosis presenting with increased intracranial pressure (ICP) manifesting with chronic papilledema without ventriculomegaly. A 12-month-old boy had complete resolution of papilledema after posterior cranial vault distraction followed by staged fronto-orbital advancement. Expansion of the cranial vault with posterior distraction osteogenesis posed an elegant treatment, obviating ventriculoperitoneal shunt placement for cerebrospinal fluid (CSF) diversion. Strategies for the management of elevated ICP without ventriculomegaly in craniosynostosis include CSF shunting and cranial vault expansion. Posterior calvarial vault distraction associated with resolved papilledema has not been previously reported. Addressing the craniocephalic disproportion for this child with chronic papilledema, without ventriculomegaly, allowed the possibility of shunt freedom.

We present a review of current strategies in the treatment of pediatric ocular myasthenia gravis (OMG). A critical appraisal was performed of the current literature available on OMG and the treatment options available for all age populations. From this data, we present the evidence surrounding therapeutic options for pediatric OMG and discuss treatment outcomes in the pediatric population. We also present gaps in the literature with regard to pediatric OMG and possibilities for future research. While there is data on the use of steroid-sparing immunosuppressive agents for myasthenia gravis (MG), as a whole it is more specific for the use in generalized juvenile myasthenia gravis (JMG) and more focused toward the adult population. In the currently available literature, there have been reports published on the use of steroid-sparing agents including azathioprine, cyclosporine, and mycophenolate mofetil. A recent open-label trial has provided evidence for the use of tacrolimus to improve symptoms of JMG including OMG that were refractory to prednisone. In addition to this, there has been evidence that thymectomy is effective in controlling pediatric OMG and shows a pattern toward preventing generalization of MG, reducing prednisone dosing, and increasing resolution of disease. There are other treatments used in the pediatric population of MG, including intravenous immunoglobulin (IVIG), plasmapheresis, and rituximab, but currently there are no reports on use in OMG. In the population of patients with pediatric OMG, a high percentage of patients are able to obtain stabilization of symptoms using only pyridostigmine or pyridostigmine in combination with oral prednisone. Rates of generalization of OMG range from 15 to 35%, with higher rates in the adolescent population, but approximately 25% of pediatric patients with OMG can have complete remission. For pediatric OMG patients with ophthalmologic manifestations that are refractory to pyridostigmine and prednisone, the use of steroid-sparing agents has been practiced more recently. In addition to this, thymectomy has been utilized in this population. In both of these instances, no pediatric randomized control trials have been performed to date.

ObjectiveMyelin oligodendrocyte glycoprotein–immunoglobulin G (MOG-IgG) associated disorder (MOGAD) often manifests with recurrent CNS demyelinating attacks. The optimal treatment for reducing relapses is unknown. To help determine the efficacy of long-term immunotherapy in preventing relapse in patients with MOGAD, we conducted a multicenter retrospective study to determine the rate of relapses on various treatments.MethodsWe determined the frequency of relapses in patients receiving various forms of long-term immunotherapy for MOGAD. Inclusion criteria were history of ≥1 CNS demyelinating attacks, MOG-IgG seropositivity, and immunotherapy for ≥6 months. Patients were reviewed for CNS demyelinating attacks before and during long-term immunotherapy.ResultsSeventy patients were included. The median age at initial CNS demyelinating attack was 29 years (range 3–61 years; 33% ConclusionThis large retrospective multicenter study of patients with MOGAD suggests that maintenance immunotherapy reduces recurrent CNS demyelinating attacks, with the lowest ARR being associated with maintenance IVIG therapy. Traditional MS disease-modifying agents appear to be ineffective. Prospective randomized controlled studies are required to validate these conclusions.

Purpose Heterozygous mutations in the essential X-linked gene CASK associate with optic nerve hypoplasia (ONH) and other retinal disorders in girls. CASK+/- heterozygous knockout mice with mosaic CASK expression exhibit ONH with a loss of retinal ganglion cells (RGCs) but no changes in retinal morphology. It remains unclear if CASK deficiency selectively affects RGCs or also affects other retinal cells. Furthermore, it is not known if CASK expression in RGCs is critical for optic nerve (ON) development and maintenance. Methods The visual behavior of CASK+/- mice was assessed and electroretinography (ERG) was performed. Using a mouse line with a floxed CASK gene that expresses approximately 40% CASK globally in all cells (hypomorph) under hemizygous and homozygous conditions, we investigated effects of CASK reduction on the retina and ON. CASK then was completely deleted from RGCs to examine its cell-autonomous role. Finally, for the first time to our knowledge, we describe a hemizygous CASK missense mutation in a boy with ONH. Results CASK+/- heterozygous mutant mice display reduced visual contrast sensitivity, but ERG is indistinguishable from wildtype. CASK hypomorph mice exhibit ONH, but deletion of CASK from RGCs in this background does not exacerbate the condition. The boy with ONH harbors a missense mutation (p.Pro673Leu) that destabilizes CASK and weakens the crucial CASK-neurexin interaction. Conclusions Our results demonstrate that mosaic or global reduction in CASK expression and/or function disproportionately affects RGCs. CASK expression in RGCs does not appear critical for cell survival, indicating a noncell autonomous role for CASK in the development of ON.

Patients with craniosynostosis with subnormal vision due to papilledema and/or exposure-related corneal decompensation are well documented in the literature; however, there is only a single prior documented case of vision compromise secondary to anterior segment dysgenesis and glaucoma in this patient population. This report highlights a case of syndromic craniosynostosis with advanced corneal decompensation and anterior segment dysgenesis that was masked and ultimately delayed the diagnosis of congenital glaucoma.

PURPOSE Sporadic optic pathway/hypothalamic gliomas (OP/HGs) represent a unique entity within pediatric low-grade glioma. Despite favorable survival, the location makes treatment difficult and local progression debilitating. We conducted longitudinal assessment of visual acuity (VA) among patients treated in the modern era with chemotherapy (CT) or early radiotherapy (RT). METHODS Clinical characteristics were abstracted for patients treated over a 15-year period (2000–2015) at a single institution. Comprehensive ophthalmologic data taken at three to six-month intervals was examined with age-appropriate VA metrics converted to LogMAR scale. Kaplan-Meir “blindness-free survival” (BFS) curves were calculated as time to bilateral functional blindness (i.e. LogMAR ≥ 0.8 in both eyes), stratified by treatment and compared using log-rank test. RESULTS Thirty-six patients with median follow-up of 7.6 years (range: 2–17) were identified. Median age at diagnosis was 2.5 years (IQR: CONCLUSIONS In a contemporary cohort, early RT, defined as initial or 1st line salvage therapy for OP/HGs manifested in superior VA. Children undergoing CT are at highest risk of functional blindness following five years of treatment.

Isolated amyloid deposition in an extraocular muscle is a rare event but can be a presenting feature of systemic amyloidosis. A 67-year-old woman with an acquired exotropia and hypertropia was found to have unilateral diffuse extraocular muscle enlargement on magnetic resonance imaging. Owing to the progressive nature of her strabismus and the negative laboratory testing for thyroid disease, she underwent an extraocular muscle biopsy that revealed amyloid deposition. Further workup demonstrated a monoclonal gammopathy consistent with systemic amyloidosis. This case demonstrates the need to consider amyloidosis in the differential diagnosis of patients presenting with an atypical acquired strabismus. We review other reports of isolated amyloid deposition in extraocular muscles and its association with systemic amyloidosis, emphasizing the importance of the ophthalmologist in the early recognition of this disease to prevent irreversible, life-threatening end organ damage.

Purpose To present a case of visually significant retinal injury due to internal limiting membrane (ILM) peeling using ILM forceps alone. Methods Case report. Results A 60-year-old woman who underwent ILM peeling for an epiretinal membrane presented with linear central scotomata. Peeling had been initiated and performed with ILM forceps alone, without the use of other surgical instruments. Fundus examination and spectral domain optical coherence tomography imaging confirmed the presence of several discrete areas of inner and outer retinal injury in the macula, which corresponded to her scotomata. Conclusion This is a case of visually significant retinal injury due to ILM peeling that was performed with ILM forceps alone. Improper peeling technique can transmit injurious forces to the retina. Surgeons must be mindful of the biomechanical forces involved in ILM peeling to minimize traction on the retina.

Objective Visual abnormalities are common among children with posterior fossa tumors, resulting from disruption of ocular afferent and efferent systems due to the tumor or surgery. This study describes the visual complications and outcomes associated with these tumors. Methods Clinical and radiographic data of patients who underwent index surgery for resection of posterior fossa tumor from 2007 to 2016 were reviewed. Descriptive statistics, univariate, and multivariate regression were performed to assess factors contributing to visual acuity and postoperative strabismus. Results There were 182 patients who underwent posterior fossa craniotomy for neoplasm were included. Ophthalmologic symptoms were the fourth most common presenting complaint; initial ophthalmologic examination was abnormal in 40% of patients. Evaluation of visual acuity demonstrated a good outcome in 88% of patients following treatment. The most common postoperative oculomotor finding was esotropia (29%) which resolved spontaneously in more than half of patients. A good outcome was obtained in all patients who underwent surgery for esotropia. Hypertropia was noted in 14% of the cohort and less than half resolved spontaneously; less than half undergoing strabismus surgery for hypertropia had a good outcome. Multivariate analysis confirmed the association between cerebellar mutism and postoperative esotropia and hypertropia. Clinically significant pathological nystagmus was seen in 8% of the cohort. Conclusions Our results indicate a good visual outcome in the majority of pediatric patients undergoing resection of posterior fossa tumors. Ophthalmologic complications should be appropriately evaluated and addressed to allow for the best possible vision to survivors of posterior fossa tumors.

Congenital craniofacial anomalies are secondary to skull or soft tissue maldevelopment. Congenital skull developmental abnormalities may occur due to premature fusion of the calvarial or skull base sutures, termed craniosynostosis. Craniosynostosis can be further divided into syndromic and nonsyndromic. Syndromic craniosynostosis often involves more than one calvarial suture and has a genetic etiology, while nonsyndromic craniosynostosis often involves a single isolated suture and has no genetic etiology. Soft tissue maldevelopment can be divided into clefting and branchial arch disorders. Sequelae to the ophthalmic and visual system may occur in patients with congenital craniofacial anomalies. These sequelae may include ptosis, exorbitism, tear drainage abnormalities, corneal exposure, corneal infection, strabismus, abnormal extraocular muscles, papilledema, optic atrophy and decreased vision secondary to high refractive errors, amblyopia, and optic nerve disease.

A 7-year-old girl presented with decreased vision in both eyes for 1 month. Examination showed visual acuity of 20/50 and 20/60, no afferent pupillary defect, cecocentral scotomas, and bilateral optic disc edema with extensive peripapillary and macular exudates. Magnetic resonance imaging showed multiple cortical and subcortical white matter lesions. Both the laboratory workup and the systemic examination were unrevealing. However, on follow-up, the patient showed episodic elevations of blood pressure as high as 240/160. Further workup revealed elevated urine catecholamines and a right supra-adrenal mass proven to be a pheochromocytoma by histopathologic analysis. The paroxysmal hypertension resolved, and the visual acuity, visual fields, fundus exam, and neuroimaging improved. The patient was lost to follow-up until age 18 when she developed shortness of breath and was found to have multiple pulmonary metastases identified as pheochromocytoma by biopsy. Genetic testing identified a 3p25-26 (c.482 G>A) VHL gene chromosomal mutation consistent with von Hippel–Lindau disease genotype. Multiple peripheral retinal vascular dilations and small retinal capillary hemangioblastomas were also found. This case highlights the importance of recognizing the lability of blood pressure often seen with pheochromocytomas, which may mask the underlying cause of hypertensive papillopathy and retinopathy, a diagnosis of low clinical suspicion in the pediatric population. The case also underscores the importance of thorough systemic workup, including genotyping to detect conditions where pheochromocytoma may be the presenting sign of the disease, such as multiple endocrine neoplasia 2A and 2B, von Hippel–Lindau disease, von Recklinghausen disease, tuberous sclerosis, and Sturge–Weber syndrome.

Reverse thermal gels have numerous biomedical implications, as they undergo physical gelation upon temperature increases and can incorporate biomolecules to promote tissue repair. Such a material is developed for the sustained release of bevacizumab (Avastin), a drug used to treat age-related macular degeneration. The polymer, poly(ethylene glycol)-poly-(serinol hexamethylene urethane) (ESHU), forms a physical gel when heated to 37 °C and shows good cytocompatibility with ocular cells. ESHU is capable of sustaining bevacizumab release over 17 weeks in vitro, and the release kinetics can be altered by changing the drug dose and the ESHU concentration. These results suggest that ESHU is biologically safe, and suitable for ocular drug delivery.

Cone-rod dystrophy (CRD) is a progressive degenerative disorder predominantly of retinal cones with varying patterns of inheritance.

Best vitelliform macular dystrophy (BVMD) due to to abnormal processing of photoreceptor outer segments and lipofuscin accumulation in RPE cells.

Leber congenital amaurosis is a group of early-onset retinal dystrophies characterized by severe vision loss, nystagmus, and retinal dysfunction demonstrated with severely abnormal ERG.

Congenital stationary night blindness (CNSB) is a clinically and genetic diverse group of nonprogressive retinal disorders that is characterized by stable poor vision in low light (night blindness). CNSB can be classified either functionally by electrophysiology or fundus phenotypes. ERG can distinguish a “complete” form or CNSB type 1 with absent rod function, from an “incomplete” form or CNSB type 2 with reduced rod and cone function. Phenotypically, CNSB can have a normal appearing fundus or an abnormal fundus (includes Oguchi’s disease and fundus albipunctatus).

Proper movement of the vertebrate eye requires the formation of precisely patterned axonal connections linking cranial somatic motoneurons, located at defined positions in the ventral midbrain and hindbrain, with extraocular muscles. The aim of this research was to assess the relative contributions of intrinsic, population-specific properties and extrinsic, outgrowth site-specific cues during the early stages of abducens and oculomotor nerve development in avian embryos. This was accomplished by surgically transposing midbrain and caudal hindbrain segments, which had been pre-labeled by electroporation with an EGFP construct. Graft-derived EGFP+ oculomotor axons entering a hindbrain microenvironment often mimicked an abducens initial pathway and coursed cranially. Similarly, some EGFP+ abducens axons entering a midbrain microenvironment mimicked an oculomotor initial pathway and coursed ventrally. Many but not all of these axons subsequently projected to extraocular muscles that they would not normally innervate. Strikingly, EGFP+ axons also took initial paths atypical for their new location. Upon exiting from a hindbrain position, most EGFP+ oculomotor axons actually coursed ventrally and joined host branchiomotor nerves, whose neurons share molecular features with oculomotor neurons. Similarly, upon exiting from a midbrain position, some EGFP+ abducens axons turned caudally, elongated parallel to the brainstem, and contacted the lateral rectus muscle, their originally correct target. These data reveal an interplay between intrinsic properties that are unique to oculomotor and abducens populations and shared ability to recognize and respond to extrinsic directional cues. The former play a prominent role in initial pathway choices, whereas the latter appear more instructive during subsequent directional choices.

During normal vertebrate development, Hoxd10 and Hoxd11 are expressed by differentiating motoneurons in restricted patterns along the rostrocaudal axis of the lumbosacral (LS) spinal cord. To assess the roles of these genes in the attainment of motoneuron subtypes characteristic of LS subdomains, we examined subtype complement after overexpression of Hoxd10 or Hoxd11 in the embryonic chick LS cord and in a Hoxd10 loss-of-function mouse embryo. Data presented here provide evidence that Hoxd10 defines the position of the lateral motor column (LMC) as a whole and, in rostral LS segments, specifically promotes the development of motoneurons of the lateral subdivision of the lateral motor column (LMCl). In contrast, Hoxd11 appears to impart a caudal and medial LMC (LMCm) identity to some motoneurons and molecular profiles suggestive of a suppression of LMC development in others. We also provide evidence that Hoxd11 suppresses the expression of Hoxd10 and the retinoic acid synthetic enzyme, retinaldehyde dehydrogenase 2 (RALDH2). In a normal chick embryo, Hoxd10 and RALDH2 are expressed throughout the LS region at early stages of motoneuron differentiation but their levels decline in Hoxd11-expressing caudal LS segments that ultimately contain few LMCl motoneurons. We hypothesize that one of the roles played by Hoxd11 is to modulate Hoxd10 and local retinoic acid levels and thus, perhaps define the caudal boundaries of the LMC and its subtype complement.

Hox genes encode anterior-posterior identity during central nervous system development. Few studies have examined Hox gene function at lumbosacral (LS) levels of the spinal cord, where there is extensive information on normal development. Hoxd10 is expressed at high levels in the embryonic LS cord but not the thoracic cord. To test the hypothesis that restricted expression of Hoxd10 contributes to the attainment of an LS identity, and specifically an LS motoneuron identity, Hoxd10 was ectopically expressed in thoracic segments in chick embryos by means of in ovo electroporation. Regional motoneuron identity was assessed after the normal period of motoneuron differentiation. Subsets of motoneurons in transfected thoracic segments developed a molecular profile normally shown by LS motoneurons, including Lim 1 and RALDH2 expression. In addition, motoneurons in posterior thoracic segments showed novel axon projections to two muscles in the anterodorsal limb, the sartorius and anterior iliotibialis muscles. At thoracic levels, we also found a decrease in motoneuron numbers and a reduction in gonad size. These last findings suggest that early and high levels of Hox expression impeded motoneuron development and neural-mesodermal interactions. Despite these adverse effects, our data indicate that Hoxd10 expression is sufficient to induce LS motoneuron identity and axon trajectories characteristic of motoneurons in the LS region.

PURPOSE We assessed the in vivo release profile of bevacizumab from and biocompatibility of poly(ethylene glycol)-poly-(serinol hexamethylene urethane), or ESHU, a thermoresponsive hydrogel administered intravitreally for drug delivery. METHODS The technical feasibility of injection was assessed quantitatively via mechanical testing. For in vivo studies, New Zealand White rabbit eyes were injected intravitreally with 0.05 mL of either: ESHU dissolved in 25 mg/mL bevacizumab, ESHU dissolved in PBS, or 25 mg/mL bevacizumab. Clinical examination included IOP measurements and examination with indirect ophthalmoscopy for signs of inflammation. Additionally, eyes were examined histologically following euthanasia. To quantify bevacizumab release, aqueous humor samples were obtained via anterior chamber paracentesis and ELISA was used to determine the concentration of drug weekly. In vitro cytotoxicity testing also was performed using bovine corneal endothelial cells. RESULTS The ESHU was injected easily through a 31-gauge needle, was well tolerated in vivo, and caused minimal cell death in vitro when compared to other common materials, such as silicone oil. The long-term presence of the gel did not affect IOP, and there was no evidence of inflammation histologically or through indirect observation. The ESHU sustained the release of bevacizumab for over 9 weeks and maintained a drug concentration that averaged 4.7 times higher than eyes receiving bolus bevacizumab injections. CONCLUSIONS To our knowledge, this is the first report demonstrating sustained bevacizumab release in vivo from an intravitreally injected hydrogel formulation, suggesting that this delivery system may be a promising candidate for ocular drug delivery.