Acute Myopic Shift after a Single Dose of Acetazolamide: A Case Report and Review of the Literature.

We report the case of a 32-year-old male who presented with an acute myopic shift as a result of uveal effusion following a single administration of 250 mg acetazolamide. The drug was discontinued and following cycloplegia and topical steroid therapy, we observed progressive deepening of the anterior chamber, reopening of the iridocorneal angle, and complete resolution of the myopic shift after 5 days. A literature review since 1956 identified 23 cases, including ours, which developed a myopic shift after a median time of 24 h (3 - 24) following a median dose of 500 mg (125 - 1000) acetazolamide, with about a third complicated by angle closure ocular hypertension. This presumed idiosyncratic reaction can occur without prior drug exposure and independent of the phakic status. Treatment options include systematic drug withdrawal associated with cycloplegia, anti-glaucomatous agents, and/or corticosteroids. Full recovery is achieved within about 5 days (2 - 14). Given the widespread use of acetazolamide, awareness of this idiosyncratic reaction is crucial to avoid complications of acute angle-closure glaucoma.

PRESERFLO MicroShunt in Severe Myopia: A Case Report and Review of the Literature.

The PRESERFLO™ MicroShunt (MP; Santen Inc., Osaka, Japan) is a minimally invasive bleb surgery (MIBS) manufactured to treat primary open-angle glaucoma (POAG), with lower postoperative adverse effects than with conventional filtering surgeries. We describe here the case study of a 58-year-old woman who presented with bilateral severe myopia with bilateral advanced POAG and unreached target pressure under quadritherapy, who was successfully managed by PM surgery. A review of the literature completes our observation. At presentation, the patient had a spherical equivalent of - 7.50 RE and - 7.75 LE with an IOP of 22 mmHg right and left eye (RLE) under quadritherapy, and with severe bilateral visual field loss, including scotomas within the central 5°. The patient presented with systemic hypertension treated with an antihypertensive drug. Two selective laser trabeculoplasties (SLT), performed 3 months apart, were first tried on the LE, without any change in IOP at 2 months. After considering the high risk of postoperative complications, a PM operation was proposed, with a targeted IOP in the mid-fifteens RLE. The patient's eyes underwent PM surgery with mitomycin C (MMC) MMC0.2 mg/mL for 3 minutes without any complications. The LE required 2 consecutive needlings with 1 mL MMC0.2 mg/mL. At 24 months after surgery, the two eyes gave successful results without the need for any additional medical therapy, and with well-functioning conjunctival blebs. The PM was an effective alternative to the gold standard trabeculectomy in our severely myopic patient. A comparative study between conventional filtering operations and this MIBS in highly myopic patients would confirm our observation.

Genome-wide Association Studies of Retinal Vessel Tortuosity Identify Numerous Novel Loci Revealing Genes and Pathways Associated With Ocular and Cardiometabolic Diseases.

Purpose: To identify novel susceptibility loci for retinal vascular tortuosity, to better understand the molecular mechanisms modulating this trait, and reveal causal relationships with diseases and their risk factors. Design: Genome-wide Association Studies (GWAS) of vascular tortuosity of retinal arteries and veins followed by replication meta-analysis and Mendelian randomization (MR). Participants: We analyzed 116 639 fundus images of suitable quality from 63 662 participants from 3 cohorts, namely the UK Biobank (n = 62 751), the Swiss Kidney Project on Genes in Hypertension (n = 397), and OphtalmoLaus (n = 512). Methods: Using a fully automated retina image processing pipeline to annotate vessels and a deep learning algorithm to determine the vessel type, we computed the median arterial, venous and combined vessel tortuosity measured by the distance factor (the length of a vessel segment over its chord length), as well as by 6 alternative measures that integrate over vessel curvature. We then performed the largest GWAS of these traits to date and assessed gene set enrichment using the novel high-precision statistical method PascalX. Main Outcome Measure: We evaluated the genetic association of retinal tortuosity, measured by the distance factor. Results: Higher retinal tortuosity was significantly associated with higher incidence of angina, myocardial infarction, stroke, deep vein thrombosis, and hypertension. We identified 175 significantly associated genetic loci in the UK Biobank; 173 of these were novel and 4 replicated in our second, much smaller, metacohort. We estimated heritability at ∼25% using linkage disequilibrium score regression. Vessel type specific GWAS revealed 116 loci for arteries and 63 for veins. Genes with significant association signals included COL4A2, ACTN4, LGALS4, LGALS7, LGALS7B, TNS1, MAP4K1, EIF3K, CAPN12, ECH1, and SYNPO2. These tortuosity genes were overexpressed in arteries and heart muscle and linked to pathways related to the structural properties of the vasculature. We demonstrated that retinal tortuosity loci served pleiotropic functions as cardiometabolic disease variants and risk factors. Concordantly, MR revealed causal effects between tortuosity, body mass index, and low-density lipoprotein. Conclusions: Several alleles associated with retinal vessel tortuosity suggest a common genetic architecture of this trait with ocular diseases (glaucoma, myopia), cardiovascular diseases, and metabolic syndrome. Our results shed new light on the genetics of vascular diseases and their pathomechanisms and highlight how GWASs and heritability can be used to improve phenotype extraction from high-dimensional data, such as images. Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

[Corticosteroids and glaucoma]. / Corticostéroïdes et glaucome.

Corticosteroid use is a major risk factor in the development of glaucoma and its aggravation. This is due to the augmentation of the intraocular pressure (IOP) induced by the corticoids. This augmentation is different between individuals: we called it steroid responsiveness, for which multiple risk factors have been identified, the most important being personal or family history of primary open angle glaucoma. The secondary augmentation of IOP depends also on the type of preparation, the mode of administration, the dosage and the duration of the therapy. Prevention and management are essentials to avoid this adverse effect. Among the most important measures, there are the education of the patient and the practitioner, IOP follow-ups after the use of corticoids and IOP-lowering medications.

L'utilisation de corticostéroïdes est un facteur de risque majeur dans le développement du glaucome et de son aggravation, en raison de l'augmentation de la pression intraoculaire (PIO) induite. Cette augmentation est variable selon les individus : il s'agit de la corticosensibilité, pour laquelle de nombreux facteurs de risque ont été identifiés, les plus importants étant les antécédents personnels ou familiaux de glaucome. L'augmentation de la PIO varie également en fonction du type de corticostéroïde, du mode d'administration, du dosage et de la durée de la thérapie. Des moyens de prévention et de prise en charge efficaces sont essentiels afin de limiter cet effet indésirable. Parmi les plus importants, on trouve l'information préventive du patient et du médecin, le suivi de la PIO après l'introduction de corticostéroïdes et les traitements abaissant la PIO.

Intraocular Pressure Reduction after Femtolaser Assisted Cataract Surgery and Its Association with the Use of Ultrasound.

Background and Objectives: To quantify the change in intraocular pressure (IOP) after phacoemulsification in patients having undergone femtolaser assisted cataract surgery (FLACS), and study the influence of the use of ultrasound on this change. Setting: Jules-Gonin Eye Hospital, University Department of Ophthalmology, Lausanne, Switzerland. Materials and Methods: Interventional study. Methods: All consecutive cases operated with FLACS and with complete data for the studied parameters were selected for inclusion in the study. Data had been prospectively collected and was analysed retrospectively. Linear regression was performed to explore the association of change in IOP with time of measure, ultrasound use, sex, age, and duration of surgery. Results: There was a mean decrease in intraocular pressure of 2.5 mmHg (CI 95% -3.6; -1.4, p < 0.001) postoperatively. No association between the change in intraocular pressure and ultrasound time or effective phaco time was observed when the data were analyzed one at a time or in a multiple linear regression model. There was no association with sex, age, nuclear density, presence of pseudoexfoliation, duration of surgery, and time of ocular pressure measurement. Eyes with preoperative IOP ≥ 21 mmHg had a more significant IOP reduction after surgery (p < 0.0001) as did eyes with an anterior chamber depth <2.5 mm (p = 0.01). Conclusion: There was a decrease in intraocular pressure six months after FLACS in our study similar to that in the published literature for standard phacoemulsification. The use of ultrasound may not influence the size of the decrease, whereas the preoperative IOP and anterior chamber depth do. FLACS may be as valuable as standard phacoemulsification for cases where IOP reduction is needed postoperatively.

Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies.

Pre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non-syndromic retinitis pigmentosa (RP) are frequent findings. Here we report that defects in spliceosome-associated protein CWC27 are associated with a spectrum of disease phenotypes ranging from isolated RP to severe syndromic forms. By whole-exome sequencing, recessive protein-truncating mutations in CWC27 were found in seven unrelated families that show a range of clinical phenotypes, including retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurological defects. Remarkably, variable expressivity of the human phenotype can be recapitulated in Cwc27 mutant mouse models, with significant embryonic lethality and severe phenotypes in the complete knockout mice while mice with a partial loss-of-function allele mimic the isolated retinal degeneration phenotype. Our study describes a retinal dystrophy-related phenotype spectrum as well as its genetic etiology and highlights the complexity of the spliceosomal gene network.

Novel ADAM9 homozygous mutation in a consanguineous Egyptian family with severe cone-rod dystrophy and cataract.

OBJECTIVE: To genetically and phenotypically describe a new ADAM9 homozygous mutation in a consanguineous family from Egypt with autosomal recessive cone-rod dystrophy (arCRD), anterior polar and posterior subcapsular cataract. DESIGN, SETTING AND PARTICIPANTS: The parents and their six children were included. They underwent a complete ophthalmic examination with fundus photography and optical coherence tomography (OCT). INTERVENTION: DNA was extracted from peripheral blood from all family members. Screening for mutations in genes known to be implicated in retinal disorders was done with the IROme, an in-solution enrichment array, followed by high-throughput sequencing. Validation of the results was done by bidirectional Sanger sequencing of ADAM9 exon 14, including exon-intron junctions. Screening of normal controls was done by denaturing high-performance liquid chromatography. RESULTS: arCRD was diagnosed in the mother and two of her children. Bilateral anterior polar and posterior subcapsular cataract was observed in the mother and bilateral dot cataract was diagnosed in three of the four children not affected with arCRD, one of whom also had glaucoma. The characteristics of the arCRD were childhood-onset visual impairment, reorganisation of the retinal pigment epithelium with mid-periphery greyish-white discolouration, attenuated retinal vasculatur and optic disc pallor. A coloboma-like macular lesion was observed in one of the arCRD-affected children. IROme analysis identified a c.1396-2A>G homozygous mutation in the splice acceptor site of intron 13 of ADAM9. This mutation was homozygous in the two children affected by arCRD and in their affected mother. This mutation was heterozygous in the unaffected father and the four unaffected children. CONCLUSIONS AND RELEVANCE: We identified a novel autosomal recessive ADAM9 mutation causing arCRD in a consanguineous Egyptian family. The percentage of arCRD cases caused by mutation in ADAM9 remains to be determined. Few families are reported in the literature to date; hence extensive clinical descriptions of families with ADAM9 mutations are of significant importance.

Femtosecond-laser assisted cataract surgery: a review.

Introduced in 2008, the femtosecond laser is a promising new technological advance which plays an ever increasing role in cataract surgery where it automates the three main surgical steps: corneal incision, capsulotomy and lens fragmentation. The proven advantages over manual surgery are: a better quality of incision with reduced induced astigmatism; increased reliability and reproducibility of the capsulotomy with increased stability of the implanted lens; a reduction in the use of ultrasound. Regarding refractive results or safety, however, no prospective randomized study to date has shown significant superiority compared with standard manual technique. The significant extra cost generated by this laser, undertaken by the patient, is a limiting factor for both its use and study. This review outlines the potential benefits of femtosecond-laser-assisted cataract surgery due to the automation of key steps and the safety of this new technology.

Mutations in ALDH1A3 represent a frequent cause of microphthalmia/anophthalmia in consanguineous families.

Anophthalmia or microphthalmia (A/M), characterized by absent or small eye, can be unilateral or bilateral and represent developmental anomalies due to the mutations in several genes. Recently, mutations in aldehyde dehydrogenase family 1, member A3 (ALDH1A3) also known as retinaldehyde dehydrogenase 3, have been reported to cause A/M. Here, we screened a cohort of 75 patients with A/M and showed that mutations in ALDH1A3 occurred in six families. Based on this series, we estimate that mutations in ALDH1A3 represent a major cause of A/M in consanguineous families, and may be responsible for approximately 10% of the cases. Screening of this gene should be performed in a first line of investigation, together with SOX2.

Anterior uveitis and cataract after rubella vaccination: a case report of a 12-month-old girl.

Many reports associating uveitis after vaccination have been reported, including 2 cases after measles, mumps, and rubella (MMR) vaccine. We report the case of a 12-month-old girl who developed a unilateral anterior uveitis with rubeosis and cataract 3 months after an MMR vaccination at 9 months of age. Aqueous humor analysis showed the presence of more rubella-specific immunoglobulin G in the affected eye than in the unaffected one. This is the second report showing an association between MMR vaccine and anterior uveitis and the first supported by the presence of intraocular rubella antibodies.

New-generation multifocal intraocular lens for pediatric cataract.

BACKGROUND/AIMS: To evaluate multifocal intraocular lens (MIOL) implantation in children. METHODS: This is a retrospective study evaluating refractive, visual and safety results of MIOL in pediatric cataract surgery. Average follow-up was 25.73 ± 10.5 months. Surgery included 12 o'clock clear corneal incision, anterior capsulorhexis, lens material aspiration and MIOL implantation (SN6AD3; Alcon). RESULTS: We included 34 cataract eyes of 26 pediatric patients aged 2-15 years, of which 14 (54%) were unilateral. Best near visual acuity (BNVA) and best distance visual acuity (BDVA) improved significantly in 100% of eyes (p = 0.0001). BDVA was above 0.8 in 31.25% (5/16) of bilateral cases. Significant stereopsis improvement was observed postoperatively in bilateral cases only (p = 0.01). CONCLUSION: MIOL implantation is a safe alternative to monofocal pseudophakia for pediatric cataract with a very low complication rate. Significant BNVA, BDVA and stereopsis improvement can be achieved, particularly in bilateral cases. MESSAGE: This study shows significant BDVA, BNVA and stereopsis improvement, especially in bilateral cases, after MIOL implantation for pediatric cataracts.

ALDH1A3 loss of function causes bilateral anophthalmia/microphthalmia and hypoplasia of the optic nerve and optic chiasm.

The major active retinoid, all-trans retinoic acid, has long been recognized as critical for the development of several organs, including the eye. Mutations in STRA6, the gene encoding the cellular receptor for vitamin A, in patients with Matthew-Wood syndrome and anophthalmia/microphthalmia (A/M), have previously demonstrated the importance of retinol metabolism in human eye disease. We used homozygosity mapping combined with next-generation sequencing to interrogate patients with anophthalmia and microphthalmia for new causative genes. We used whole-exome and whole-genome sequencing to study a family with two affected brothers with bilateral A/M and a simplex case with bilateral anophthalmia and hypoplasia of the optic nerve and optic chiasm. Analysis of novel sequence variants revealed homozygosity for two nonsense mutations in ALDH1A3, c.568A>G, predicting p.Lys190*, in the familial cases, and c.1165A>T, predicting p.Lys389*, in the simplex case. Both mutations predict nonsense-mediated decay and complete loss of function. We performed antisense morpholino (MO) studies in Danio rerio to characterize the developmental effects of loss of Aldh1a3 function. MO-injected larvae showed a significant reduction in eye size, and aberrant axonal projections to the tectum were noted. We conclude that ALDH1A3 loss of function causes anophthalmia and aberrant eye development in humans and in animal model systems.

[Femtocataract surgery: a promising future?]. / Femtolaser dans la chirurgie de la cataracte: un avenir prometteur.

Introduced in 2008, femtolaser is playing a more and more significant role in cataract surgery. This laser allows to perform three steps of the cataract surgery: the corneal incisions, the capsulotomy, and the lens fragmentation. The prooved advantages of the technique are a better quality of the incisions with a reduced induced astigmatism, a better reliability and reproducibility of the capsulotomy with a better stability of the implanted lens and a reduction of the use of ultrasounds which can negatively affect the cornea. To date, there is no prospective randomized study that has proven the superiority of this technique in terms of refractive results or safety compared to the standard manual technique. The significant extracost generated by the laser, which has to be undertaken by the patient, is a limiting factor for both its use and study.

RAX and anophthalmia in humans: evidence of brain anomalies.

PURPOSE: To report the clinical and genetic study of two families of Egyptian origin with clinical anophthalmia. To further determine the role of the retina and anterior neural fold homeobox gene (RAX) in anophthalmia and associated cerebral malformations. METHODS: Three patients with clinical anophthalmia and first-degree relatives from two consanguineous families of Egyptian origin underwent full ophthalmologic, general and neurologic examination, and blood tests. Cerebral magnetic resonance imaging (MRI) was performed in the index cases of both families. Genomic DNA was prepared from venous leukocytes, and direct sequencing of all the exons and intron-exon junctions of RAX was performed after PCR amplification. RESULTS: Clinical bilateral anophthalmia was observed in all three patients. General and neurologic examinations were normal; obesity and delay in psychomotor development were observed in the isolated case. Orbital MRI showed a hypoplastic orbit with present but rudimentary extraocular muscles and normal lacrimal glands. Cerebral MRI showed agenesis of the optic nerves, optic tracts, and optic chiasma. In the index case of family A, the absence of the frontal and sphenoidal sinuses was also noted. In the index case of family B, only the sphenoidal sinus was absent, and there was significant cortical atrophy. The three patients carried a novel homozygous c.543+3A>G mutation (IVS2+3A>G) in RAX. Parents were healthy heterozygous carriers. No mutations were detected in orthodenticle homeobox 2 (OTX2), ventral anterior homeobox 1 (VAX1), or sex determining region Y-box 2 (SOX2). CONCLUSIONS: This is the first report of a homozygous splicing RAX mutation associated with autosomal recessive bilateral anophthalmia. To our knowledge, only two isolated cases of anophthalmia, three null and one missense case affecting nuclear localization or the DNA-binding homeodomain, have been found to be caused by compound heterozygote RAX mutations. A novel missense RAX mutation was identified in three patients with bilateral anophthalmia and a distinct systemic and neurologic phenotype. The mutation potentially affects splicing of the last exon and is thought to result in a protein that has an aberrant homeodomain and no paired-tail domain. Functional consequences of this change still need to be characterized.

Phenotypic variability of retinocytomas: preregression and postregression growth patterns.

AIM: To describe the incidence of retinocytomas, their variability at presentation and their growth patterns both before and after regression. METHODS: Medical notes of the 525 patients of the Jules-Gonin Eye Hospital Retinoblastoma Clinic between 1964 and 2008 were reviewed and the charts of 36 patients with retinocytomas and/or phthisis bulbi were selected. RESULTS: The proportion of patients with retinocytomas and/or phthisis bulbi was 3.2%. The mean age at diagnosis was 28.7 ± 17 years. Five tumours presented a cystic pattern (5.8%). Evidence of aggressive exophytic disease prior to spontaneous regression was documented in two eyes, and of invasive endophytic disease (regressed vitreous seeding or internal limiting membrane disruption) in three eyes. Twenty patients were followed with a mean follow-up of 44 ± 60 months. Tumour growth was observed in 16% cases, benign cystic enlargement in 4% and malignant transformation in 12%. CONCLUSION: This large study of retinocytomas substantially expands the published features of retinocytoma by describing the cystic nature of some retinocytomas as well as clinical characteristics of the endophytic and exophytic preregression growth patterns. The authors report two different patterns of reactivation: benign cystic enlargement and malignant transformation with or without cystic growth. Higher than previously reported frequency of growth and possible life-threatening complications impose close lifetime follow-up of retinocytoma patients.

VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans.

Vax1 and Vax2 have been implicated in eye development and the closure of the choroid fissure in mice and zebrafish. We sequenced the coding exons of VAX1 and VAX2 in 70 patients with anophthalmia/microphthalmia (A/M). In VAX1, we observed homozygosity for two successive nucleotide substitutions c.453G>A and c.454C>A, predicting p.Arg152Ser, in a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate, and corpus callosum agenesis. This mutation affects an invariant residue in the homeodomain of VAX1 and was absent from 96 Egyptian controls. It is likely that the mutation results in a loss of function, as the mutation results in a phenotype similar to the Vax1 homozygous null mouse. We did not identify any mutations in VAX2. This is the first description of a phenotype associated with a VAX1 mutation in humans and establishes VAX1 as a new causative gene for A/M.

Mutations in the SPARC-related modular calcium-binding protein 1 gene, SMOC1, cause waardenburg anophthalmia syndrome.

Waardenburg anophthalmia syndrome, also known as microphthalmia with limb anomalies, ophthalmoacromelic syndrome, and anophthalmia-syndactyly, is a rare autosomal-recessive developmental disorder that has been mapped to 10p11.23. Here we show that this disease is heterogeneous by reporting on a consanguineous family, not linked to the 10p11.23 locus, whose two affected children have a homozygous mutation in SMOC1. Knockdown experiments of the zebrafish smoc1 revealed that smoc1 is important in eye development and that it is expressed in many organs, including brain and somites.

Modern cataract surgery for radiation-induced cataracts in retinoblastoma.

BACKGROUND: Surgery of radiation-induced cataracts in children with retinoblastoma (RB) is a challenge as early intervention is weighted against the need to delay surgery until complete tumour control is obtained. This study analyses the safety and functional results of such surgery. METHODS: In a retrospective, non-comparative, consecutive case series, we reviewed medical records of RB patients ≤ 14 y of age who underwent either external beam radiotherapy or plaque treatment and were operated for radiation-induced cataract between 1985 and 2008. RESULTS: In total, 21 eyes of 20 RB patients were included and 18 out of the 21 eyes had Reese-Ellsworth stage V or ABC classification group D/E RB. Median interval between last treatment for RB and cataract surgery was 21.5 months, range 3-164 months. Phacoaspiration was performed in 13 eyes (61%), extra-capsular cataract extraction in 8 (39%) and intraocular lens implantation in 19 eyes (90%). The majority of cases, 11/21 (52%), underwent posterior capsulorhexis or capsulotomy and 6/21 (28%) an anterior vitrectomy. Postoperative visual acuity was ≥ 20/200 in 13 eyes and < 20/200 in 5 eyes. Intraocular tumour recurrence was noted in three eyes. Mean postoperative follow up was 90 months ± 69 months. CONCLUSIONS: Modern cataract surgery, including clear cornea approach, lens aspiration with posterior capsulotomy, anterior vitrectomy and IOL implantation is a safe procedure for radiation-induced cataract as long as RB is controlled. The visual prognosis is limited by initial tumour involvement of the macula and by corneal complications of radiotherapy. We recommend a minimal interval of 9 months between completion of treatment of retinoblastoma and cataract surgery.