Corneal Anomalies Research Articles

Prevalence, causes and factors associated with vision impairment in Limpopo province

Background: Epidemiological data on the prevalence, causes and risk factors associated with vision impairment (VI) is necessary to evaluate the effectiveness of eye care services.Aim: To determine the prevalence, causes and factors associated with VI among patients presenting to public hospitals of Limpopo province, South Africa.Setting: This study was conducted in public hospitals.Methods: A retrospective chart review of patients seen from April 2019 to March 2022 in 29 public hospitals was conducted. The following information was extracted: demographic information, medical history, visual acuity (VA), refractive and ophthalmoscopy findings.Results: Of the 1140 participants, 56.1% were women. Participants’ ages ranged from 5 to 94 years. The prevalence of VI was 61.5%. Most had moderate-severe VI (57.3%), followed by blindness (22.7%) and mild VI (20.0%). The leading causes of VI were uncorrected refractive error (URE) (28.1%), cataract (26.0%) and glaucoma (25.0%). The main causes of blindness were glaucoma (42.8%) and cataract (32.1%); while URE (7.5%), retinal anomalies (7.5%) and corneal anomalies (6.9%) accounted for almost equal proportions of blindness. Participants aged 50–64 years (odds ratio [OR]: 1.7; 95% confidence interval [CI]: 1.2–2.6); 65 years and older (OR: 6.6; 95% CI: 4.3–10.2); and those diagnosed with systemic hypertension (OR: 2.5; 95% CI: 1.9–3.2) and diabetes mellitus (OR: 2.9; 95% CI: 1.9–4.4) had increased risk of VI.Conclusion: The prevalence of VI in this population is relatively high. The main causes of VI are correctable, suggesting the need for improved measures to prevent avoidable VI.Contribution: The study addresses the gap in the province’s current prevalence, causes and factors related to VI.

Pediatric Ocular Health and Obstructive Sleep Apnea Syndrome: A Review.

Obstructive sleep apnea (OSA) affects neurobehavioral, cognitive, and cardiovascular aspects, particularly in children, by obstructing the upper airways during sleep. While its impact in adult ocular health is recognized, there is ongoing debate about OSA's relevance in pediatrics. This review explores the relationship between OSA and ocular health in children, focusing on the effects and potential improvements through treatment. A systematic search found 287 articles through PubMeD/MEDLINE, Scopus, Web of Science, and ScienceDirect; 94.4% were excluded. After careful selection, six English articles were included, addressing the effects of OSA on children's eyes. Three studies examined choroidal alterations, three explored retinal and optic nerve changes, and two analyzed ocular changes following otorhinolaryngological intervention. The immediate correlation in children is inconclusive, but age may be a contributing factor. Pediatric OSA patients exhibit corneal anomalies and increased optic nerve thickness, possibly due to intermittent hypoxia. OSA influences retinal vascular density in children, with increased density after treatment and reduced choroidal thickness in cases of adenotonsillar hypertrophy. This review emphasized OSA's significant impact on children's ocular health, revealing alterations in the optic nerve, choroid, retina, and cornea. While the direct correlation with the optic nerve is not always evident, OSA raises intraocular pressure and induces structural changes. Treatment holds promise, highlighting the need for regular monitoring to promptly address childhood OSA.

Iridocorneal endothelial syndrome with rare case of posterior inflammation

Iridocorneal endothelial (ICE) syndrome is a group of iris and corneal disorders. Its presentation is the mixture of iris and corneal anomalies which may lead to low vision or blindness due to secondary glaucoma or corneal decompensation. We report a case of ICE syndrome in one eye and primary angle closure suspect in the other eye, both eyes having controlled intraocular pressure but low vision due to pars planitis/intermediate uveitis with macular oedema and also evaluating more potential inflammatory causes.

The research progress on the molecular mechanism of corneal cross-linking in keratoconus treatment.

Keratoconus (KC) is a corneal anomaly that is manifested in a limited cone-like bulge with corneal thinning. Many molecules in the cornea change during the development of KC, including various components of the extracellular matrix, cytokines, cell connection, and cell adhesion-related proteins. Several treatment options are available, with corneal cross-linking (CXL) being the treatment of choice for early KC. However, postoperative complications have been reported in some CXL patients, mainly caused by corneal epithelial resection. Despite the fact that some novel approaches have helped to reduce some of the initial post-operative issues, their effectiveness seems to be inferior to that of the original CXL. To keep effectiveness while avoiding these negative effects, it is necessary to study the mechanism of CXL in KC treatment at the molecular level. This article provides a review of the molecular mechanism of CXL in the treatment of KC from four aspects: enzyme activity, signal transduction pathway, corneal-related proteins, and other KC-related molecules, further confirming the feasibility of CXL treatment of KC, providing new ideas for improving CXL.

A novel homozygous ZNF469 variant causing brittle cornea syndrome is associated with corneal ectasias in heterozygous carriers.

To describe a family segregating a novel truncating ZNF469 homozygous mutation causing brittle cornea syndrome type 1 in a male patient and associated with corneal ectasia in his two heterozygous young children. A 49-year-old affected male and his 12- and 8-year-old, apparently healthy, siblings underwent phenotypic and genetic assessment. An Oculus Pentacam Scheimpflug topographer system was employed for keratometries and central corneal thickness measurements. Exome sequencing was performed in DNA from the index case with subsequent Sanger sequencing confirmation of the ZNF469 gene causal variant in his relatives. The index case had a history of bilateral keratoglobus, corneal perforations, bilateral hypoacusia, and skeletal anomalies. His two children exhibited topographic anomalies compatible with keratoconus suspects as well as mild skeletal anomalies. Genetic analysis identified a novel homozygous c.2340delC variant in the ZNF469 gene, which predicts a p.(Arg781Glufs*19) truncated protein. Sanger sequencing identified heterozygosity for the c.2340delC variant in DNA from both siblings. Our results expand the mutational spectrum associated with brittle cornea syndrome and provide the first demonstration of early corneal anomalies in subjects carrying monoallelic ZNF469 variants.

How the tophic problems and the rubbing eye behavior may aggravate the presence of keratoconus in trisomy 21

AbstractPurposeDown syndrome is a congenital anomaly caused by non‐dislocation of chromosome 21. Ocular features in trisomy 21 patients, such as changes in corneal collagen composition as well as thinning predisposing to keratoconus are well appreciated. We present a case of unilateral acute corneal hydrops in a young adult with trisomy 21, and the management to prevent corneal perforation yielding a successful visual outcome.MethodA 20‐year‐old man presented in our emergency department due to sudden visual loss and severe left ocular pain. Visual acuity was 20/200 in the right eye, and finger counting in the left. Anterior segment examination revealed pigmented endothelial cells and endothelial cell count reduced to 2583 CD/mm2 in the right eye, as well as a very large central corneal leukoma and corneal ectasia in the right eye. Corneal topography confirmed the presence of an acute corneal hydrops in the left eye as well as milder keratoconus in the right.ResultsApart from topical steroid drops, oral acetazolamide and timolol drops were used to reduce the intraocular pressure on a decompensated cornea with reduced endothelial cell count. Penetrating keratoplasty was eventually necessary. Due to intolerance and insufficient patient ability to use form‐stable contact lenses, a cross‐linking procedure was performed to stabilize the right eye. Both surgeries lead to best‐corrected acuity of 20/50 OU without a need for additional contact lens correction. Surface issues related to trisomy 21 were addressed using topical lubricants.ConclusionIn the presented case, preexisting keratoconus, worsened by frequent eye rubbing of abnormal collagen composition corneas, permits transmission of mechanical forces to thinner exposed tissue, leading to acute hydrops. The extensive corneal tissue damage that occurred with stromal scarring left necessitates keratoplasty to successfully restore vision. This case highlights the need for preventive ophthalmic examinations in patients of trisomy 21 to rule out the presence of keratoconus. The timely application of lubricants, as well as anti‐histamines and mast cell stabilizers could reduce the eye rubbing behavior that aggravates corneal anomalies in such mentally handicapped individuals. This may reduce progression and eventual need for surgical interventions.

Mean Change in Refractive Status After Levator Muscle Resection in Patients of Simple Congenital Ptosis

Purpose: To determine the mean change in refractive status after Levator muscle resection in patients of simple congenital ptosis.
 Study Design: Quasi Experimental study.
 Place and Duration of Study: This study was carried out at Institute of Ophthalmology, King Edward Medical University, Mayo Hospital Lahore, from 2014 to 2015.
 Material & Methods: Fifty patients were selected under the age of 12 years with no sex predilection presenting with simple congenital ptosis of pupil sparing type. Patients with neurogenic, aponeurotic ptosis, mechanical ptosis, Blepharophimosis syndrome, patients with previous failed ptosis surgery and patients with corneal anomalies were excluded. After history and examination, Cycloplegic retinoscopy was done, which was repeated after surgical intervention. All interventions were done by a single ophthalmic surgeon. The patients were examined and discharged on the second post operative day. All data including preoperative and postoperative recordings of spherical and cylindrical values were collected on a self-designed proforma. Follow up period was extended to 3 months. At 3rd month cycloplegic retinoscopy was done and change in character of refractive status was analyzed. Mean change in refractive status was calculated by difference of preoperative and postoperative sphere and cylinder values.
 Results: Mean age of patients was 4.26 ± 3.78 years. Mean change in spherical value after treatment was 0.447 ± 0.339. This difference was statistically significant with p-value = 0.000. While mean change in cylindrical value after treatment was 0.640 ± 0.580. This difference in cylinder value after treatment was also statistically significant with p-value = 0.000.
 Conclusion: Levator muscle resection has a significant effect on refractive status of the patients with congenital ptosis.

Study and characterization of morphogeometric parameters to assist diagnosis of keratoconus

BackgroundIn case of significant imperfections on the cornea, data acquisition is difficult and a significant level of missing data could require the interpolation of important areas of the cornea, resulting in a very ambiguous model. The development of methods to define in vivo customised geometric properties of the cornea based only on real raw data is extremely useful to diagnose and assess the progression of diseases directly related to the corneal architecture. The present work tries to improve the prognostic of corneal ectasia creating a 3D customised model of the cornea and analysing different geometric variables from this model to determine which variables or combination of them could be defined as an indicator of susceptibility to develop keratoconus.MethodsA corneal geometric reconstruction was performed using zonal functions and retrospective Scheimpflug tomography data from 187 eyes of 187 patients. Morphology of healthy and keratoconic corneas was characterized by means of geometric variables. The performance of these variables as predictors of a new geometric marker was assessed and their correlations were analysed.ResultsThe more representative variable to classify the corneal anomalies related to keratoconus was posterior apex deviation (area under receiver operating characteristic curve > 0.899; p < 0.0001). However, the strongest correlations in both healthy and pathological corneas were provided by the metrics directly related to the thickness, as deviations of the anterior/posterior minimum thickness points.ConclusionsThe presented morphogeometric approach based on the analysis and custom geometric modelling of the cornea demonstrates to be useful for the characterization and diagnosis of keratoconus disease, stating that geometrical deformation is an effective marker of the ectatic disease’s progression.

Combined effects of interleukin-1β and cyclic stretching on metalloproteinase expression in corneal fibroblasts in vitro.

BackgroundCorneal tensile strain increases if the cornea becomes thin or if intraocular pressure increases. However, the effects of mechanical stress on extracellular matrix (ECM) remodelling in the corneal repair process and the corneal anomalies are unknown.MethodsIn this study, the combined effects of interleukin-1β (IL-1β) on matrix metalloproteinases (MMPs) in corneal fibroblasts under cyclic stretching were investigated in vitro. Cultured rabbit corneal fibroblasts were subjected to 5, 10 or 15 % cyclic equibiaxial stretching at 0.1 Hz for 36 h in the presence of IL-1β. Conditioned medium was harvested for the analysis of MMP2 and MMP9 protein production using the gelatin zymography and western blot techniques.Results and conclusionsCyclic equibiaxial stretching changed the cell morphology by increasing the contractility of F-actin fibres. IL-1β alone induced the expression of MMP9 and increased the production of MMP2, and 5 % stretching alone decreased the production of MMP2, which indicates that a low stretching magnitude can reduce ECM degradation. In the presence of IL-1β, 5 and 10 % stretching increased the production of MMP2, whereas 15 % stretching increased the production of MMP9. These results indicate that MMP expression is enhanced by cyclic mechanical stimulation in the presence of IL-1β, which is expected to contribute to corneal ECM degradation, leading to the development of post-refractive surgery keratectasia.

MG-108 Agenesis of the corpus callosum and autism associated with zeb1 gene deletion – a case report

Background Agenesis of the corpus callosum (ACC) is a rare congenital anomaly presenting with partial or complete absence of the corpus callosum (CC). ACC could present as an isolated finding or a part of a genetic syndrome. A recent publication reported two cases of mal-development of CC in two unrelated individuals with posterior polymorphous corneal dystrophy (PPCD), an autosomal dominant inherited disorder of the corneal endothelium. Both cases presented novel deletions of the ZEB1 gene. *ZEB1 mutations are reported in approximately one third of PPCD patients. Objective To report a case of a child with ACC and de novo chromosome 10 deletion involving ZEB1 gene. Case report: a 12-year-old girl presented with facial dysmorphism, bilateral renal reflux, developmental delay, autism and ACC. She presented with normal growth parameters, continued to acquire new developmental skills with no regression episodes or seizures. Ophthalmological exam showed thinning of the retinal nerve fibre layer in the nasal aspect around the discs with relative sparing of the macular areas bilaterally. The rest of the ocular examination, including corneal exam was normal. Results Whole genome sequencing revealed heterozygous de novo deletion in chromosome 10p11.23- p11.22 (del:chr10:30814000–32892000) overlapping ZEB1 gene. Conclusion This is the third case reported of ZEB1 gene deletion in a patient with CC anomalies, and the first patient with no corneal anomalies but with autism. This finding might imply a broader phenotypic range for ZEB1 deletion than previously thought and add it to the possible causes of autism.

Capsid Mutated Adeno-Associated Virus Delivered to the Anterior Chamber Results in Efficient Transduction of Trabecular Meshwork in Mouse and Rat.

BackgroundAdeno associated virus (AAV) is well known for its ability to deliver transgenes to retina and to mediate improvements in animal models and patients with inherited retinal disease. Although the field is less advanced, there is growing interest in AAV’s ability to target cells of the anterior segment. The purpose of our study was to fully articulate a reliable and reproducible method for injecting the anterior chamber (AC) of mice and rats and to investigate the transduction profiles of AAV2- and AAV8-based capsid mutants containing self-complementary (sc) genomes in the anterior segment of the eye.Methodology/Principle FindingsAC injections were performed in C57BL/6 mice and Sprague Dawley rats. The cornea was punctured anterior of the iridocorneal angle. To seal the puncture site and to prevent reflux an air bubble was created in the AC. scAAVs expressing GFP were injected and transduction was evaluated by immunohistochemistry. Both parent serotype and capsid modifications affected expression. scAAV2- based vectors mediated efficient GFP-signal in the corneal endothelium, ciliary non-pigmented epithelium (NPE), iris and chamber angle including trabecular meshwork, with scAAV2(Y444F) and scAAV2(triple) being the most efficient.Conclusions/SignificanceThis is the first study to semi quantitatively evaluate transduction of anterior segment tissues following injection of capsid-mutated AAV vectors. scAAV2- based vectors transduced corneal endothelium, ciliary NPE, iris and trabecular meshwork more effectively than scAAV8-based vectors. Mutagenesis of surface-exposed tyrosine residues greatly enhanced transduction efficiency of scAAV2 in these tissues. The number of Y-F mutations was not directly proportional to transduction efficiency, however, suggesting that proteosomal avoidance alone may not be sufficient. These results are applicable to the development of targeted, gene-based strategies to investigate pathological processes of the anterior segment and may be applied toward the development of gene-based therapies for glaucoma and acquired or inherited corneal anomalies.

BILATERAL RING-SHAPED CORNEAL OPACITY: CASE REPORT AND REVIEW OF THE LITERATURE

Purpose: To describe a bilateral corneal ring-shaped opacity that does not resemble any known corneal degeneration, dystrophy or other disorder, that occurs without any associated ocular or systemic disease. Methods: Case report and review of literature. Results: The authors describe the clinical history and examination of an 80 year old man, with an asymptomatic ring-shaped corneal opacity, bilateral and symmetrical, in the deep stroma of the corneal mid-periphery. The surrounding corneal stroma was clear, and the tear film, epithelium and its basement membrane, Descemet's membrane and endothelium were normal. This rare corneal anomaly was discovered by chance and its etiology is unknown. Conclusions: These rings may result from deposits of unknown origin or possibly a rare corneal dystrophy.

Angle Kappa Measurements: Normal Values in Healthy Iranian Population Obtained With the Orbscan II.

Background:The angle kappa is important in proper centration of corneal ablation in keratorefractive surgery. Orbscan II device is widely used preoperatively in photoablation surgeries and can be used to measure the angle kappa.Objectives:This study aimed to determine the mean angle kappa and its intercepts in healthy young Iranian adults.Patients and Methods:In this cross-sectional study, orthotropic patients (age range, 18-35 years) who were referred to the Khatam Eye Hospital (Mashhad, Iran) were included. Exclusion criteria were as follows: history of any eye deviation or strabismus with or without orthoptic or surgical treatment; any intraocular, corneal, or keratorefractive surgery; contact lens use; any corneal anomaly; any ophthalmic or systemic drug consumption; and hyperopic spherical refraction > + 3.00 diopters (D), spherical refraction > -5.00 D, or cylindrical refraction > 2.00 D. All of the parameters were measured by the same operator through an Orbscan II device.Results:A total of 977 healthy participants who aged 18 to 45 years were included consecutively. The study population consisted of 614 females and 363 males. The average angle kappa was 5.00º ± 1.36º at 240.21º ± 97.17º in males and 4.97º ± 1.30º at 244.22º ± 94.39º in females (P = 0.63). The average horizontal (x-axis) angle kappa was -0.02º ± 0.49º, with a mean of -0.02º ± 0.50º in males and -0.02º ± 0.49º in females (P = 0.93). The average vertical (y-axis) angle kappa was -0.09º ± 0.32º, with a mean of -0.09º ± 0.33º in males and -0.09º ± 0.32º in females (P = 0.74).Conclusions:By using the normal angle kappa determined in this study, pseudodeviations can be identified more precisely in those who might undergo keratorefractive surgery.

Long‐term outcomes of penetrating keratoplasty in children

AbstractPurpose Outcomes of pediatric penetrating keratoplasties (PK) performed for various corneal anomalies in children.Methods Since 2000 56 PKs in children (6 months to 16 years) were performed. In infants group there were: 17 Peters Anomaly cases (24 eyes including 3 bilateral cases, 4 reoperations), 3 cases of sclerocornea. In older children surgeries were performed for 18 leucomas and 11 posttraumatic lesions. Follow up was at least 12 months. VA and graft transparency were analyzed.Results 59,2% of infant’s eyes had transparent corneas, VA ranged from 0.01 to 0.2. 19.2% of transplanted corneas were cloudy with blured vision. Other grafts were failed including one phthisis. In older children success rate with transparent cornea was achieved in 82,7% of cases. Mean VA was 0.3±0.12. Main complications were: immune rejection (11 eyes), stromal vascularisation (5 cases).Conclusion Keratoplasty is an effective procedure to safe vision in children.

Deletions and duplications of developmental pathway genes in 5q31 contribute to abnormal phenotypes

Although copy number changes of 5q31 have been rarely reported, deletions have been associated with some common characteristics, such as short stature, failure to thrive, developmental delay (DD)/intellectual disability (ID), club feet, dislocated hips, and dysmorphic features. We report on three individuals with deletions and two individuals with duplications at 5q31, ranging from 3.6 Mb to 8.1 Mb and 830 kb to 3.4 Mb in size, respectively. All five copy number changes are apparently de novo and involve several genes that are important in developmental pathways, including PITX1, SMAD5, and WNT8A. The individuals with deletions have characteristic features including DD, short stature, club feet, cleft or high palate, dysmorphic features, and skeletal anomalies. Haploinsufficiency of PITX1, a transcription factor important for limb development, is likely the cause for the club feet, skeletal anomalies, and cleft/high palate, while additional genes, including SMAD5 and WNT8A, may also contribute to additional phenotypic features. Two patients with deletions also presented with corneal anomalies. To identify a causative gene for the corneal anomalies, we sequenced candidate genes in a family with apparent autosomal dominant keratoconus with suggestive linkage to 5q31, but no mutations in candidate genes were found. The duplications are smaller than the deletions, and the patients with duplications have nonspecific features. Although development is likely affected by increased dosage of the genes in the region, the developmental disruption appears less severe than that seen with deletion.

RAB23 mutation in a large family from Comoros Islands with Carpenter syndrome

We report here on a RAB23 mutation (c.86dupA) present in the homozygote state in four relatives of Comorian origin with Carpenter syndrome. All children presented with acrocephaly and polysyndactyly. However, intrafamilial variability was observed with variable severity of craniosynostosis ranging from cloverleaf skull to predominant involvement of the metopic ridge. All children also presented with a combination of brachydactyly with agenesis of the middle phalanges, syndactyly, broad thumbs, and postaxial polydactyly (2/4) in the hands, and preaxial polydactyly (3) and syndactyly (4) in the toes. Mental development was normal in all four children but the eldest one presented with impaired motor development as a result of orthopedic complications. Brain imaging showed hydrocephalus in 2/4 and additional features included genu valgum (2/4), abnormal genitalia (3/4), corneal anomaly (2/4), umbilical hernia (1/4), severe cyphoscoliosis (1), patent ductus arteriosus (1/4), and accessory spleen (1). In contrast to previous reports, growth was below average except for one patient and the eldest one became moderately overweight with time. We conclude from the report of this large unique family with four affected children that Carpenter syndrome is a genetically homogenous but a clinically variable condition.

Central Corneal Thickness, Anterior Chamber Depth, and Pupil Diameter Measurements Using Visante OCT, Orbscan, and Pentacam

To evaluate the agreement among three different optical methods in measuring anterior chamber depth (ACD), central corneal thickness (CCT), and pupil diameter. One hundred eyes of 50 healthy patients (25 men, 25 women) were enrolled in the study. Mean patient age was 25 years (range: 21 to 32 years). Exclusion criteria were history of any intraocular or corneal surgery, contact lens wear, corneal anomalies, and spherical refraction >5.00 diopters (D) or cylindrical refraction >2.00 D. All measurements were done by the same operator under mesopic light conditions and repeated using three different optical methods: Visante optical coherence tomography (OCT) (Carl Zeiss Meditec), Orbscan (Bausch & Lomb), and Pentacam (Oculus Optikgeräte GmbH). Mean CCT as measured by Visante OCT, Orbscan, and Pentacam was 529+/-30.5 microm, 554+/-32.7 microm, and 552+/-29.3 microm, respectively. Mean ACD values were 2.94+/-0.34 mm, 2.84+/-0.33 mm, and 2.98+/-0.33 mm, respectively. Mean pupil diameter measurements were 4.87+/-1.09 mm, 4.0+/-0.67 mm, and 3.05+/-0.59 mm, respectively. The Visante OCT measured CCT thinner and Orbscan measured ACD shallower than the other two methods. All three methods measured pupil diameters significantly different. This study found some statistically significant but clinically insignificant differences among the optical methods assessed. The differences are small and do not influence decisions for refractive surgery in clinical practice.

Detailed Ophthalmologic Evaluation of 43 Individuals withPAX6Mutations

Heterozygous mutations of the PAX6 gene cause a variety of ocular malformations, the best known being aniridia (absence of the iris). Mutation analyses and detailed clinical evaluations were performed in 43 individuals with aniridia or closely related ocular anomalies, to investigate whether phenotype correlates with mutation type. Case notes and medical records were reviewed and patients were reexamined when necessary. Denaturing high-performance liquid chromatography (DHPLC) analysis and sequencing of the PAX6 coding region was performed in individuals whose mutation was unknown. The most common PAX6 mutations identified were premature termination mutations, amino acid substitutions, and C-terminal extensions. Six novel mutations are reported. Mutations that inactivate one copy of the gene typically caused a severe phenotype including foveal hypoplasia, marked iris anomalies, and severe visual impairment. Missense mutations, all affecting invariant amino acids in the paired domain, caused milder phenotypes in this cohort, with a lower incidence of foveal hypoplasia and less severe visual loss. C-terminal extension mutations caused relatively severe anomalies and marked reduction in vision. Two C-terminal extension cases had a unilateral exudative retinopathy, resembling Coats' disease, which has not previously been reported in association with PAX6 mutation. PAX6 mutations cause panocular malformations that vary considerably in pattern and severity. In our cohort, iris hypoplasia, nystagmus, and foveal hypoplasia were most common, with cataracts, corneal anomalies, and high refractive errors also frequently observed. In this cohort, loss-of-function and C-terminal extension mutations were found to cause more severe phenotypes than missense mutations.

Corneal Molecular and Cellular Biology Update for the Refractive Surgeon

To review clinically relevant progress in understanding cellular and molecular interactions in the cornea that relate to refractive surgical outcomes in patients. Recent published literature focused on femtosecond LASIK and surface ablation procedures, such as photorefractive keratectomy, was reviewed and correlated with clinical results of surgery. The femtosecond laser has a direct necrotic effect on stromal keratocytes, resulting in the release of cellular components that are chemotactic to bone marrow-derived inflammatory cells. Developments of the femtosecond laser led to lower energy delivery to the stroma and altered laser ablation profiles that decrease epithelial damage during the side-cut, and have markedly improved femtosecond LASIK to the point that the overall early postoperative healing response is indistinguishable from microkeratome LASIK. New studies have directly demonstrated the importance of surface irregularity and resulting structural and functional defects in the epithelial basement membrane, in the generation and persistence of anterior stromal myofibroblasts and haze following surface ablation procedures. These defects augment penetration of epithelium-derived TGF-beta, which is a critical modulator of myofibroblast development in the stroma. Studies on the mechanism of action of mitomycin C treatment to prevent haze have confirmed that the most powerful effect is on stromal cell proliferation and, therefore, decreased population of the anterior stroma with myofibroblast progenitor cells. An undesirable long-term effect of mitomycin C is diminished anterior stromal keratocyte density due to diminished keratocyte re-population. This raises concerns regarding future corneal anomalies in treated corneas. Basic research studies of refractive procedures provide important insights into the effects of wound healing on surgical outcomes.

FGF19 is a target for FOXC1 regulation in ciliary body-derived cells

The forkhead C1 (FOXC1) transcription factor is involved in the development and regulation of several organs, including the eye, where FOXC1 alterations cause iris, trabecular meshwork and corneal anomalies. Using nickel agarose chromatin enrichment with human anterior segment cells, we previously identified the fibroblast growth factor 19 (FGF19) locus as a gene potentially regulated by FOXC1. Here, we demonstrate that FGF19 is a direct target of FOXC1 in the eye. FOXC1 positively regulates FGF19 expression in corneal and periocular mesenchymal cells in cell culture and in zebrafish embryos. Through the FGFR4 tyrosine kinase, FGF19 promotes MAPK phosphorylation in the developing and mature cornea. During development, loss of either FOXC1 or FGF19 results in complementary, but distinct, anterior segment dysgeneses. This study reveals an important role for FOXC1 in the direct regulation of the FGF19-FGFR4-MAPK pathway to promote both the development and maintenance of anterior segment structures within the eye.