Detection of extrascleral extension in uveal melanoma with histopathological correlation.

PURPOSE: Uveal melanoma is the most common primary intraocular malignancy. Extrascleral extension (ESE) is rare, but associated with an increased rate of orbital recurrence and an overall poor prognosis. Clinical studies show low rates when compared with histological studies. Due to the prognostic importance of ESE, we sought to compare our clinical, intraoperative, and histological detection rates. DESIGN: A retrospective cross-sectional case series. METHODS: A list of eyes enucleated for uveal melanoma was compiled from the admissions records of the London Ocular Oncology Service during the 28-month period, i.e. January 2010-April 2012. The surgical and clinical notes of patients with histopathology proven ESE were reviewed to determine when it was first diagnosed or suspected. The subsequent management of these cases is discussed. RESULTS: A total of 16 out of 174 (9%) eyes had histologically proven ESE. Eight of 16 cases were detected preoperatively at clinical examination, including the use of ocular ultrasound, 3 of 16 were discovered intra-operatively, and 5 of 16 deemed microscopic ESE, were first detected on histological examination. Seven of 7 (100%) of cases with anterior ESE were detected clinically by slit lamp biomicroscopy, while only 1 out of 9 (11%) of cases with posterior ESE was detected preoperatively with ultrasound. CONCLUSIONS: Slit lamp biomicroscopy is sensitive for detecting anterior ESE. Most posterior ESE is microscopic, but macroscopic posterior ESE may also be missed by B-scan ocular ultrasound. Orbital surgeons should be suspicious of clinically undetected posterior ESE, and consider adjuvant orbital radiotherapy in cases with macroscopic ESE.

NODULAR POSTERIOR SCLERITIS: Clinico-Sonographic Characteristics and Proposed Diagnostic Criteria.

PURPOSE: To report the clinical and ultrasound features and outcomes of a series of nodular posterior scleritis. METHODS: Retrospective medical record review of 11 consecutive patients with nodular posterior scleritis. Patient demographics, ocular and systemic findings, ultrasound features, and final anatomical and visual outcomes were recorded. RESULTS: There were 9 females and 2 males (11 eyes) with mean age at presentation of 57 years (range, 30-84 years). Underlying systemic inflammatory disease was present in 73%. Symptoms included pain in 73% and blurred vision in 45%. A solitary amelanotic mass without the presence of lipofuscin was found in all cases. Associated ocular features included retinal pigment epithelial changes (67%), intraocular inflammation (55%), subretinal fluid (50%), macular edema (50%), and choroidal folds (30%). B-mode ultrasound showed a sclerochoroidal mass with high internal reflectivity (100%) of mean elevation of 4.1 mm. There was nodular thickening of the sclera (100%) and fluid in Tenon space or "T" sign (36%). A complete regression of the nodule after the treatment was observed only in 1 patient (11%) and partial regression in 4 patients (44%). CONCLUSION: Nodular posterior scleritis should be considered in the differential diagnosis of a single amelanotic choroidal mass showing high internal reflectivity on ultrasound B-scan. It can produce intraocular inflammation in 50% of the cases and may be painless in 25%. It has a high association with a systemic underlying disease.

The extended clinical phenotype of dome-shaped macula.

PURPOSE: To describe the phenotype, associations, and complications of dome-shaped macula (DSM) through the combination of spectral-domain optical coherence tomography (OCT) imaging and B-scan ultrasonography, when available. This retroprospective cohort study aims to gain further pathophysiological understanding in eyes with DSM. METHODS: Fifty-eight eyes of 36 patients were identified as having OCT features of DSM. Retinal and choroidal thicknesses were determined from enhanced depth imaging (EDI)-OCT image sets, with scleral thickness subsequently calculated by subtraction from the B-scan ultrasound-derived measurements of posterior coat thickness. RESULTS: DSM was associated with myopia in 81 % of eyes. The underlying clinical diagnosis was variable: central serous chorioretinopathy (CSCR)-like entity, choroidal neovascularization, and inherited retinal disorders. The subfoveal choroidal thickness of the nine highly myopic eyes with a CSCR-like phenotype was thicker than the 25 eyes without CSCR (p = 0.169). The mean subfoveal scleral thickness of the highly myopic eyes was 585 ± 196 µm, which was significantly different from those with a refractive error less than 6 diopters (1133 ± 290 µm) (P < 0.0001). CONCLUSIONS: This study highlights the novel observation of a thickened choroid when CSCR is present. In addition, we expand the associations of DSM to eyes with hypermetropia and acquired disease, and to those with inherited retinal dystrophies.

Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways.

Developmental ocular malformations, including anophthalmia-microphthalmia (AM), are heterogeneous disorders with frequent sporadic or non-Mendelian inheritance. Recurrent interstitial deletions of 14q22-q23 have been associated with AM, sometimes with poly/syndactyly and hypopituitarism. We identify two further cases of AM (one with associated pituitary anomalies) with a 14q22-q23 deletion. Using a positional candidate gene approach, we analyzed the BMP4 (Bone Morphogenetic Protein-4) gene and identified a frameshift mutation (c.226del2, p.S76fs104X) that segregated with AM, retinal dystrophy, myopia, brain anomalies, and polydactyly in a family and a nonconservative missense mutation (c.278A-->G, p.E93G) in a highly conserved base in another family. MR imaging and tractography in the c.226del2 proband revealed a primary brain developmental disorder affecting thalamostriatal and callosal pathways, also present in the affected grandmother. Using in situ hybridization in human embryos, we demonstrate expression of BMP4 in optic vesicle, developing retina and lens, pituitary region, and digits strongly supporting BMP4 as a causative gene for AM, pituitary, and poly/syndactyly. Because BMP4 interacts with HH signaling genes in animals, we evaluated gene expression in human embryos and demonstrate cotemporal and cospatial expression of BMP4 and HH signaling genes. We also identified four cases, some of whom had retinal dystrophy, with "low-penetrant" mutations in both BMP4 and HH signaling genes: SHH (Sonic Hedgehog) or PTCH1 (Patched). We propose that BMP4 is a major gene for AM and/or retinal dystrophy and brain anomalies and may be a candidate gene for myopia and poly/syndactyly. Our finding of low-penetrant variants in BMP4 and HH signaling partners is suggestive of an interaction between the two pathways in humans.

Central retinal vessel blood flow after surgical treatment for central retinal vein occlusion.

PURPOSE: The purpose of this study was to determine the effect of radial optic neurotomy and retinal endovascular surgery on retinal blood flow velocity in patients with central retinal vein occlusion. METHODS: A prospective interventional case series. RESULTS: Six patients with a central retinal vein occlusion of <12 months' duration were included. Three patients were treated with radial optic neurotomy and three with retinal endovascular surgery. Five patients had decreased central venous blood flow velocity compared with the fellow eye, and one patient had similar central venous blood flow in both eyes at baseline. All study eyes had decreased central venous blood flow velocity compared with the fellow eye at 24 weeks after treatment. Two patients had a further decrease in central venous blood flow during the study. Three patients had no minimal change in central venous blood flow, and 1 patient showed a minimal increase from 3 cm/s at baseline to 4 cm/s 24 weeks after surgery. CONCLUSION: Radial optic neurotomy and retinal endovascular surgery do not alter central retinal blood flow velocity. The place of these therapies in the treatment for central retinal vein occlusion should be questioned.

Detecting optic nerve head swelling on ultrasound and optical coherence tomography in children and young people: an observational study.

BACKGROUND: Following high-profile cases, referrals for evaluation of 'suspicious optic discs' to eye clinics in the UK have sharply increased, asking ophthalmologists to reliably distinguish between true and pseudopapilloedema. Optic nerve sheath dilatation (ONSD) on ocular ultrasound (US) is considered a reliable sign of true papilloedema, but this test is not widely available. Recently, anterior bowing of Bruch's membrane (BM) and increased retinal nerve fibre layer thickness on optical coherence tomography (OCT) have emerged as indicators of intracranial hypertension, and OCT is widely available. We aimed to evaluate safety and efficacy of the diagnostic workup in our service, with particular emphasis of diagnostic reliability of US and OCT. METHODS: Retrospective service evaluation/cohort study of children and young people younger than 16 years investigated for 'suspicious discs' over a 7-month period in 2016 at a single eye care provider in London, UK. 61 children and young people underwent clinical assessment, US scan and OCT. RESULTS: Of 61 cases, 3 had intracranial pathology. At presentation, only one had ONSD on US and anterior bowing of BM on OCT. Increased nerve fibre layer thickness in at least one of three relevant sectors was observed in two cases. All three cases of intracranial pathology, however, had significant points in their presenting or medical history. CONCLUSION: Ophthalmologists and optometrists must not rely on funduscopy and ocular imaging when assessing a child for possible intracranial disease; history and basic neurological assessment are critical in the diagnostic workup.

Analysis of Long-term Outcomes of Radiotherapy and Verteporfin Photodynamic Therapy for Circumscribed Choroidal Hemangioma.

PURPOSE: To determine the long-term therapeutic outcome for different treatments of circumscribed choroidal hemangioma (CCH). DESIGN: Retrospective observational study. SUBJECTS: Patients with newly diagnosed CCH. METHODS: Observation, verteporfin (Visudyne) photodynamic therapy (PDT), lens-sparing external beam radiotherapy (LS-EBRT), or plaque brachytherapy. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA) at baseline and throughout follow-up, tumor dimensions, and OCT central thickness (where available) at baseline and throughout follow-up were recorded. RESULTS: There were 60 treatment-naïve consecutive cases with CCH between January 2000 and June 2014; 42 (70%) received treatment. These were LS-EBRT (23/60 [38%]; mean follow-up, 45.5 months), PDT (16/60 [27%]; mean follow-up, 38 months), and plaque radiotherapy (3/60 [5%]; mean follow-up, 92 months). Macular location, mottled or orange pigment, and absence of drusen were significantly more frequent in the treatment group. In the LS-EBRT group, median thickness reduction on ultrasound B scan was 1.6 mm (mean ± standard deviation, 1.65±1.6; range, -6.5 to +0.7). The mean ± standard deviation BCVA gain was 0.22±0.34, with >3 Snellen lines in 48% of cases. Kaplan-Meier estimates were 80% for any gain and 40% for >3 Snellen lines gain at 5 years. In the PDT group, the median decrease in thickness was 0.95 mm (mean ± standard deviation, 1.0±0.8; range, -2.5 to +0.2). The mean ± standard deviation BCVA gain was at 0.3±0.51, with >3 Snellen lines in 30% of cases. Kaplan-Meier estimates were 93% for any gain and 68% for >3 Snellen lines at 5 years. Double versus single duration PDT had more favorable outcomes with a greater reduction in tumor thickness (P = 0.04), central retinal thickness (P = 0.02), and improvement in visual acuity (median, 0.33 vs -0.05). There was no difference in decrease in tumor thickness or BCVA gain between the LS-EBRT and PDT groups. With plaque brachytherapy, the mean decrease in thickness was 2.5 mm, but BCVA loss of >2 Snellen lines was noted in all 3 cases at the end of follow-up. Radiation complications developed in 10 of 23 cases (43.5%) from the LS-EBRT group and 2 of 3 cases (67%) from the plaque brachytherapy group. CONCLUSIONS: LS-EBRT is equivalent to PDT in CCH management for post-treatment BCVA and tumor thickness reduction. The risk of LS-EBRT and plaque brachytherapy was late radiation-related complications. Double duration PDT was more favorable than single duration.

Biometry and formula accuracy with intraocular lenses used for cataract surgery in extreme hyperopia.

PURPOSE: To audit intraocular lens (IOL) power predictions for cataract surgery in extreme hyperopia and to compare the accuracy across different biometry formulae and IOL types. DESIGN: A retrospective analysis of 76 eyes from 56 patients undergoing cataract surgery with IOLs ranging in power from 30 to 35 diopters (D). METHODS: Axial lengths, corneal powers and anterior chamber depths were measured with ultrasound or optical methods, and the IOLMaster (Carl Zeiss Meditech, Inc, Dublin, California, USA) software was used to predict the refractive outcome for each IOL used. Differences between the predicted and actual postoperative refraction were then analyzed for each formula. RESULTS: In practice, 55% of patients were within +/-1.0 D of the refraction predicted by their surgeon. In theory, the Haigis formula would have given the smallest mean refractive error (+0.51 +/- 0.12 D), followed by the Hoffer Q (-0.70 +/- 0.14 D), Holladay 1 (-1.11 +/- 0.13 D), and SRK/T formulae (-1.45 +/- 0.14 D). The Haigis formula overpredicted the lens power required, which would have generated a myopic result. The other formulae underpredicted the lens power required and would have generated a hyperopic result. There was a significant difference between lens designs: the Haigis was more accurate for open-loop, whereas the Hoffer Q was more accurate for plate-haptic lenses. The anterior chamber depth measurement could also be used to predict changes in intraocular pressure after surgery. CONCLUSION: This represents the largest published series to date of biometry predictions for cataract surgery in extreme hyperopia and confirms the Haigis formula to be the most accurate. A consistent difference between open-loop and plate-haptic lenses suggests that haptic design may influence the effective lens position in very small eyes. We further propose a simple formula to optimize the Haigis and Hoffer Q formulae in patients with extreme hyperopia.

Repeatability of swept-source optical coherence tomography retinal and choroidal thickness measurements in neovascular age-related macular degeneration.

BACKGROUND: The aim was to determine the intrasession repeatability of swept-source optical coherence tomography (SS-OCT)-derived retinal and choroidal thickness measurements in eyes with neovascular age-related macular degeneration (nAMD). METHODS: A prospective study consisting of patients with active nAMD enrolled in the Distance of Choroid Study at Moorfields Eye Hospital, London. Patients underwent three 12×9 mm macular raster scans using the deep range imaging (DRI) OCT-1 SS-OCT (Topcon) device in a single imaging session. Retinal and choroidal thicknesses were calculated for the ETDRS macular subfields. Repeatability was calculated according to methods described by Bland and Altman. RESULTS: 39 eyes of 39 patients with nAMD were included with a mean (±SD) age of 73.9 (±7.2) years. The mean (±SD) retinal thickness of the central macular subfield was 225.7 µm (±12.4 µm). The repeatability this subfield, expressed as a percentage of the mean central macular subfield thickness, was 23.2%. The percentage repeatability of the other macular subfields ranged from 13.2% to 28.7%. The intrasession coefficient of repeatability of choroidal thickness of the central macular subfield was 57.2 µm with a mean choroidal thickness (±SD) of 181 µm (±15.8 µm). CONCLUSIONS: This study suggests that a change >23.2% of retinal thickness and 57.2 µm choroidal thickness in the central macular subfield is required to distinguish true clinical change from measurement variability when using the DRI OCT-1 device to manage patients with nAMD.

Evidence of genetic heterogeneity in MRCS (microcornea, rod-cone dystrophy, cataract, and posterior staphyloma) syndrome.

PURPOSE: To present the detailed phenotype of a subject with MRCS (microcornea, retinal dystrophy, cataract, and posterior staphyloma) syndrome and to investigate the underlying molecular genetic basis. DESIGN: Interventional case report. METHODS: Clinical examination, electrophysiologic assessment, B-scan ultrasonography, and mutation screening of the gene VMD2. The protocol of the study was approved by the local ethics committee and informed consent was obtained. RESULTS: A 12-year-old boy was identified with bilateral microcornea, rod-cone dystrophy, congenital cataracts, and posterior staphylomata associated with high myopia (MRCS). Mutation screening failed to identify disease-causing sequence variants in VMD2, the gene associated with MRCS syndrome. All previous subjects have had pathogenic VMD2 sequence alterations. CONCLUSIONS: We present a further report of the MRCS syndrome and provide evidence in support of genetic heterogeneity in this phenotype.

Spectral-domain Optical Coherence Tomography Retinal and Choroidal Thickness Metric Repeatability in Age-related Macular Degeneration.

PURPOSE: To determine the intrasession repeatability of spectral-domain OCT (SDOCT)-derived macular retinal and choroidal metrics in patients with neovascular age-related macular degeneration (nAMD) in the Distance of Choroid Study (DOCS). DESIGN: Validity and reliability analysis. METHODS: Enrolled patients underwent repeated SDOCT imaging using the Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany). A single technician certified for clinical trials took 3 macular volume scans. Retinal thicknesses were calculated for each of the 9 Early Treatment Diabetic Retinopathy Study (ETDRS) macular subfields. Center point thickness and total macular volume were also included in the analysis. Manual subfoveal choroidal thickness measurements were made by a masked observer. RESULTS: A total of 40 eyes of 40 patients were included in this analysis (mean [± standard deviation] age: 74.1 [± 7.2] years, 60% male). The coefficient of repeatability (CR) of the central macular subfield was 30.6 µm (95% confidence interval [CI] 29.8-1.4 µm). The CR for the other macular subfields ranged from 7.0 µm to 38.2 µm. The CR for the total macular volume was 0.212 mm(3) (95% CI 0.206-0.217 mm(3)) and the CR for the center point was 47.5 µm (95% CI 46.2-48.7 µm). Images were also reviewed for the presence of segmentation error in the central macular subfield, and after exclusion of these eyes the revised CR for this subfield was 13.7 µm (95% CI 13.3-14.1 µm). The intrasession CR of subfoveal choroidal thickness was 34.7 µm (95% CI 33.7-35.7 µm). CONCLUSIONS: This study suggests that a change of greater than 31 µm in Spectralis SDOCT-derived retinal thickness measurement of the central macular subfield and 35 µm in subfoveal choroidal thickness is necessary to detect true clinical change associated with disease progression or improvement in nAMD with a revised figure of 14 µm for central macular retinal subfield thickness in the absence of segmentation error.

Biometry accuracy using zero- and negative-powered intraocular lenses.

PURPOSE: To audit the accuracy of biometry using the SRK/T formula when negative- or zero-powered intraocular lenses (IOLs) are predicted and to compare the results between A-scan, B-scan, and optical methods of biometry. SETTING: Moorfields Eye Hospital, London, United Kingdom. METHODS: This retrospective analysis comprised 78 eyes of 54 patients having cataract surgery with zero- or negative-powered IOLs. Axial lengths were measured with A-scan, B-scan, applanation, or optical methods. Differences between SRK/T-predicted and actual postoperative refraction were analyzed for 75 eyes having cataract surgery. Ocular comorbidity, visual acuity, and biometry readings were also compared. RESULTS: Forty-one percent of 75 patients analyzed were within +/-1.00 diopter (D) of the predicted refraction, although there was a significant tendency toward a hyperopic overcorrection by 1.14 D (95% confidence interval, 0.89-1.39 D). This overcorrection error was consistent across all 3 biometry methods used to estimate axial length and increased with the use of stronger (more negative) IOLs. CONCLUSION: Surgeons should be aware of the tendency for negative-powered lenses to overcorrect and lead to a hyperopic outcome when using the SRK/T biometry formula in highly myopic eyes. A weaker-powered negative IOL is recommended to aim for a more myopic postoperative outcome by about 1.00 to 2.00 D.

Evaluation of iris and iridociliary body lesions with anterior segment optical coherence tomography versus ultrasound B-scan.

AIMS: To compare anterior segment optical coherence tomography (AS-OCT) with ultrasound B-scan (USB) in evaluating iris and iridociliary body lesions. METHODS: Image features and resolution comparison between AS-OCT and USB in 126 patients (126 eyes) presenting with iris or iridociliary body lesion. Bland-Altman plots were generated to assess the level of agreement between the two techniques. RESULTS: The three most common diagnoses were iris naevi (62 (49.2%)), iris pigment epithelial cysts (23 (18.3%)) and iris melanoma (11 (8.7%)). Image feature comparison for USB was better than AS-OCT in visualising all tumour margins (81 (64.3%) vs 59 (46.8%)), posterior tumour margin (54 (42.9%) vs 16 (12.7%)) and producing less posterior shadowing (121 (96%) vs 43 (34.1%)). Image resolution comparison revealed USB to be slightly better for resolving the overall tumour (45 (35.7%) vs 43 (34.1%)) and posterior tumour surface (70 (55.6%) vs 32 (25.4%)) but AS-OCT was better for resolving the anterior (62 (49.2%) vs 4 (3.2%)) and lateral tumour surface (62 (49.2%) vs 31 (24.6%)). Comparing the three most common diagnoses, USB was better for visualising iris pigment epithelial cysts (12 (52.2%) vs 2 (8.7%)) and iris melanoma (7 (63.6%) vs 1 (9.1%)) but AS-OCT was better (28 (45.2%) vs 15 (24.2%)) for visualising iris naevi. Bland-Altman plots showed good agreement between the two techniques for lesions smaller than 3 mm in base and 2 mm in elevation. CONCLUSIONS: AS-OCT is superior to USB for imaging small lesions pertaining to the anterior iris but USB is better for imaging larger iris lesions with posterior or ciliary body extension.

Association of CHRDL1 mutations and variants with X-linked megalocornea, Neuhäuser syndrome and central corneal thickness.

We describe novel CHRDL1 mutations in ten families with X-linked megalocornea (MGC1). Our mutation-positive cohort enabled us to establish ultrasonography as a reliable clinical diagnostic tool to distinguish between MGC1 and primary congenital glaucoma (PCG). Megalocornea is also a feature of Neuhäuser or megalocornea-mental retardation (MMR) syndrome, a rare condition of unknown etiology. In a male patient diagnosed with MMR, we performed targeted and whole exome sequencing (WES) and identified a novel missense mutation in CHRDL1 that accounts for his MGC1 phenotype but not his non-ocular features. This finding suggests that MMR syndrome, in some cases, may be di- or multigenic. MGC1 patients have reduced central corneal thickness (CCT); however no X-linked loci have been associated with CCT, possibly because the majority of genome-wide association studies (GWAS) overlook the X-chromosome. We therefore explored whether variants on the X-chromosome are associated with CCT. We found rs149956316, in intron 6 of CHRDL1, to be the most significantly associated single nucleotide polymorphism (SNP) (p = 6.81×10(-6)) on the X-chromosome. However, this association was not replicated in a smaller subset of whole genome sequenced samples. This study highlights the importance of including X-chromosome SNP data in GWAS to identify potential loci associated with quantitative traits or disease risk.