Su T, Zhu P-W, Li B, Shi W-Q, Lin Q, Yuan Q, Jiang N, Pei C-G, Shao Y. Gray matter volume alterations in patients with strabismus and amblyopia: voxel-based morphometry study. Sci Rep 2022;12(1):458.Abstract
This study proposes the use of the voxel-based morphometry (VBM) technique to investigate structural alterations of the cerebral cortex in patients with strabismus and amblyopia (SA). Sixteen patients with SA and sixteen healthy controls (HCs) underwent magnetic resonance imaging. Original whole brain images were analyzed using the VBM method. Pearson correlation analysis was performed to evaluate the relationship between mean gray matter volume (GMV) and clinical manifestations. Receiver operating characteristic (ROC) curve analysis was applied to classify the mean GMV values of the SA group and HCs. Compared with the HCs, GMV values in the SA group showed a significant difference in the right superior temporal gyrus, posterior and anterior lobes of the cerebellum, bilateral parahippocampal gyrus, and left anterior cingulate cortex. The mean GMV value in the right superior temporal gyrus, posterior and anterior lobes of the cerebellum, and bilateral parahippocampal gyrus were negatively correlated with the angle of strabismus. The ROC curve analysis of each cerebral region confirmed the accuracy of the area under the curve. Patients with SA have reduced GMV values in some brain regions. These findings might help to reveal the potential pathogenesis of SA and its relationship with the atrophy of specific regions of the brain.
VanderVeen DK, Allred EN, Wallace DK, Leviton A, Leviton A. Strabismus at Age 2 Years in Children Born Before 28 Weeks' Gestation: Antecedents and Correlates. J Child Neurol 2016;31(4):451-60.Abstract

Children born very preterm are at greater risk of ophthalmic morbidities, including strabismus, than children born at term. We evaluated perinatal factors associated with strabismus at age 2 years in a large population of infants delivered before 28 weeks' gestation. A total of 996 infants in the multicenter ELGAN (Extremely Low Gestational Age Newborn) study who had a retinal exam in infancy and a developmental assessment at 2 years corrected age are included. Their mothers were interviewed about the pregnancy, and both mother and newborn charts were reviewed. Certified examiners administered the Bayley Scales of Infant Development-II and performed an examination of ocular alignment. Time-oriented logistic regression risk models were created to evaluate the associations of characteristics and exposures with the development of strabismus. Overall, 14% (n = 141) of the children had strabismus at 2 years, and 80% of strabismic children had esotropia. Characteristics associated with strabismus were birth before 26 weeks' gestation, severe fetal growth restriction, and maternal history of aspirin ingestion. Associated postnatal factors included a SNAP-II (Score for Neonatal Acute Physiology) illness severity value ≥30, brain ventriculomegaly, type I retinopathy of prematurity, and ventilator-dependent severe bronchopulmonary dysplasia. Strabismus in very preterm populations is associated with a number of antenatal and postnatal antecedents as well as clinical and imaging correlates indicative of brain damage in these children. Routine ophthalmologic assessments in the early years can allow appropriate and timely interventions.

Wan MJ, Gilbert A, Kazlas M, Wu C, Mantagos IS, Hunter DG, Shah AS. The Effect of Botulinum Toxin Augmentation on Strabismus Surgery for Large-Angle Infantile Esotropia. Am J Ophthalmol 2018;189:160-165.Abstract
PURPOSE: To determine whether botulinum toxin augments the effect of strabismus surgery in pediatric patients with large-angle infantile esotropia. DESIGN: Retrospective, comparative, case series. METHODS: Setting: Tertiary-care pediatric hospital. STUDY POPULATION: Patients with large-angle infantile esotropia. INTERVENTION: Treatment with botulinum toxin-augmented bilateral medial rectus muscle recessions ("augmented-surgery group") or traditional bilateral medial rectus muscle recessions ("surgery-only group"). MAIN OUTCOME MEASURE: The effect of surgery on ocular alignment at 4 months, measured in prism diopters of change per mm of surgery (PD/mm). RESULTS: There were 14 patients in the augmented-surgery group and 16 patients in the surgery-only group. The mean effect on alignment was significantly greater in the augmented-surgery group compared to the surgery-only group at 4 months (5.7 ± 1.3 vs 4.0 ± 1.4 PD/mm, P = .002) and at 1 year (5.4 ± 1.2 vs 3.7 ± 1.2 PD/mm, P = .002). There was a partial loss of treatment effect between 4 months and 1 year in both groups, which was similar in magnitude (P = .57). On linear regression, there was a trend toward a positive correlation between botulinum toxin dose and treatment effect, but this was not statistically significant (P = .09). CONCLUSIONS: Botulinum toxin augments the surgical effect of medial rectus muscle recession. Botulinum toxin-augmented surgery may be an alternative to traditional options for large-angle infantile esotropia. A surgical dosing table is proposed for this technique.
Wan MJ, AlShaker S, Hunter DG. Use of Botulinum Toxin in Ophthalmology. Handb Exp Pharmacol 2021;263:147-160.Abstract
Botulinum toxin is an important treatment for many conditions in ophthalmology, including strabismus, nystagmus, blepharospasm, hemifacial spasm, spastic and congenital entropion, corneal exposure, and persistent epithelial defects. The mechanism of action of botulinum toxin for both strabismus and nystagmus is the neuromuscular blockade and transient paralysis of extraocular muscles, but when botulinum toxin is used for some forms of strabismus, a single injection can convey indefinite benefits. There are two unique mechanisms of action that account for the long-term effect on ocular alignment: (1) the disruption of a balanced system of agonist-antagonist extraocular muscles and (2) the reestablishment of central control of alignment by the binocular visual system. For other ocular conditions, botulinum toxin acts through transient paralysis of periocular muscles. Botulinum toxin is a powerful tool in ophthalmology, achieving its therapeutic effects by direct neuromuscular blockade of extraocular and periocular muscles and by unique mechanisms related to the underlying structure and function of the visual system.
White E, Walsh L. The impact of occlusion therapy and predictors on amblyopia dose-response relationship. Strabismus 2022;30(2):78-89.Abstract
This study aimed to calculate the dose-response relationship and predictors of visual acuity (VA) improvement following occlusion therapy at the IWK Health Center Eye Clinic and to add to amblyopia therapy dose-response relationship literature. A retrospective chart review was performed, considering patients who reached an occlusion therapy outcome at the IWK Eye Clinic between 2012 and 2019. The treatment outcome was defined as equal VA or stable VA for three consecutive clinical visits despite reported compliance. Subjective patching hours from parental reports, not prescribed hours, were used for statistical analyses. One hundred and thirty-four patients (66 females and 68 males) ages 2-11 years were included. Results showed a dose-response relationship of 224 hours/0.1logMAR increase in VA and total dose of 1344 hours for full-time occlusion and 504 hours for part-time occlusion was required to reach outcome VA. The fastest VA improvement occurred with younger age at treatment initiation, during the first 4 weeks of treatment, and in patients with strabismic and/or severe amblyopia. Classification of amblyopia, age, VA chart, initial distance VA (amblyopic eye), and treatment dose predicted the hour dose-response relationship. Dose-response relationship was faster in younger participants, in participants with strabismic and severe amblyopia, and during the first month of occlusion. Additionally, by creating a GLM model of dose-response relationship, relationship calculations can be performed. Therefore, an estimated timeline can be developed to allow allocation of clinical resources and to prepare patients for the treatment duration required and possibly increase treatment compliance.
Whitman MC. Axonal Growth Abnormalities Underlying Ocular Cranial Nerve Disorders. Annu Rev Vis Sci 2021;7:827-850.Abstract
Abnormalities in cranial motor nerve development cause paralytic strabismus syndromes, collectively referred to as congenital cranial dysinnervation disorders, in which patients cannot fully move their eyes. These disorders can arise through one of two mechanisms: (a) defective motor neuron specification, usually by loss of a transcription factor necessary for brainstem patterning, or (b) axon growth and guidance abnormalities of the oculomotor, trochlear, and abducens nerves. This review focuses on our current understanding of axon guidance mechanisms in the cranial motor nerves and how disease-causing mutations disrupt axon targeting. Abnormalities of axon growth and guidance are often limited to a single nerve or subdivision, even when the causative gene is ubiquitously expressed. Additionally, when one nerve is absent, its normal target muscles attract other motor neurons. Study of these disorders highlights the complexities of axon guidance and how each population of neurons uses a unique but overlapping set of axon guidance pathways.
Whitman MC, Di Gioia SA, Chan W-M, Gelber A, Pratt BM, Bell JL, Collins TE, Knowles JA, Armoskus C, Pato M, Pato C, Shaaban S, Staffieri S, MacKinnon S, Maconachie GDE, Elder JE, Traboulsi EI, Gottlob I, Mackey DA, Hunter DG, Engle EC, Engle EC. Recurrent Rare Copy Number Variants Increase Risk for Esotropia. Invest Ophthalmol Vis Sci 2020;61(10):22.Abstract
Purpose: To determine whether rare copy number variants (CNVs) increase risk for comitant esotropia. Methods: CNVs were identified in 1614 Caucasian individuals with comitant esotropia and 3922 Caucasian controls from Illumina SNP genotyping using two Hidden Markov model (HMM) algorithms, PennCNV and QuantiSNP, which call CNVs based on logR ratio and B allele frequency. Deletions and duplications greater than 10 kb were included. Common CNVs were excluded. Association testing was performed with 1 million permutations in PLINK. Significant CNVs were confirmed with digital droplet polymerase chain reaction (ddPCR). Whole genome sequencing was performed to determine insertion location and breakpoints. Results: Esotropia patients have similar rates and proportions of CNVs compared with controls but greater total length and average size of both deletions and duplications. Three recurrent rare duplications significantly (P = 1 × 10-6) increase the risk of esotropia: chromosome 2p11.2 (hg19, 2:87428677-87965359), spanning one long noncoding RNA (lncRNA) and two microRNAs (OR 14.16; 95% confidence interval [CI] 5.4-38.1); chromosome 4p15.2 (hg19, 4:25554332-25577184), spanning one lncRNA (OR 11.1; 95% CI 4.6-25.2); chromosome 10q11.22 (hg19, 10:47049547-47703870) spanning seven protein-coding genes, one lncRNA, and four pseudogenes (OR 8.96; 95% CI 5.4-14.9). Overall, 114 cases (7%) and only 28 controls (0.7%) had one of the three rare duplications. No case nor control had more than one of these three duplications. Conclusions: Rare CNVs are a source of genetic variation that contribute to the genetic risk for comitant esotropia, which is likely polygenic. Future research into the functional consequences of these recurrent duplications may shed light on the pathophysiology of esotropia.