Frank Billson

Monocular Axial Myopia Associated with Neonatal Eyelid Closure in Human Infants

We studied eight infants who developed unilateral axial myopia associated with neonatal eyelid closure. Clinical findings and ultrasonographic biometric measurements suggested that axial elongation of the eye may occur as a result of neonatal eyelid closure, a finding similar to that for experimental myopia produced in neonatal animals after eyelid fusion. Early treatment of eyelid occlusion in the neonate may prevent axial myopia and subsequent anisometropic amblyopia.

Deletion at 14q22-23 Indicates a Contiguous Gene Syndrome Comprising Anophthalmia, Pituitary Hypoplasia, and Ear Anomalies

Anophthalmia and pituitary gland hypoplasia are both debilitating conditions where the underlying genetic defect is unknown in the majority of cases. We identified a patient with bilateral anophthalmia and absence of the optic nerves, chiasm and tracts, as well as pituitary gland hypoplasia and ear anomalies with a de novo apparently balanced chromosomal translocation, 46,XY,t(3;14)(q28;q23.2). Translocation breakpoint analysis using FISH and high‐resolution microarray comparative genomic hybridization (CGH) has identified a 9.66 Mb deleted region on the long arm of chromosome 14 which includes the genes BMP4, OTX2, RTN1, SIX6, SIX1, and SIX4. Three other patients with interstitial deletions involving 14q22‐23 have been described, all with bilateral anophthalmia, pituitary abnormalities, ear anomalies, and a facial phenotype similar to our patient. OTX2 is involved in ocular developmental defects, and the severity of the ocular phenotype in our patient and the other 14q22‐23 deletion patients, suggests this genomic region harbors other gene/s involved in ocular development. BMP4 haploinsufficiency is predicted to contribute to the ocular phenotype on the basis of its expression pattern and observed murine mutant phenotypes. In addition, deletion of BMP4 and SIX6 is likely to contribute to the abnormal pituitary development, and SIX1 deletion may contribute to the ear and other craniofacial features. This indicates that contiguous gene deletion may contribute to the phenotypic features in the 14q22‐23 deletion patients.

The aetiology of perforating ocular injuries in children

Aims: To assess the aetiological factors associated with the occurrence of perforating ocular injuries in children in an urban setting and to assess the visual outcomes of such injuries. Methods: All cases of perforating ocular injury presenting to a single paediatric hospital (age less than 16 years) over a 17 year period were identified by a medical record search. All new cases of perforating ocular injury identified were included. All information was obtained retrospectively from the medical records. Results: There were 72 cases identified. The commonest causes of perforating ocular injury were sharp tools (knives/scissors) poked by the child into his/her own eye (17%), or objects thrown at the child (17%). Injuries were most likely to have occurred at home (58%). The age range for injuries was 8 months to 14 years 8 months. Perforating ocular injury was most frequent in the 3–6 year group (32%) followed by the 6–9 year group (25%). Males were more frequently involved than females (48–24). There was no correlation between the laterality of the eye, the time of day of the occurrence, or the day of the week of the occurrence. The final acuity achieved was better or equal to 6/12 in 36% and less than 6/60 in 31%. Injuries occurred more frequently on weekends than on weekdays. There were six enucleations (8%). Follow up was for an average period of 25 months. Conclusions: Penetrating ocular injury occurs most frequently in the home setting and mostly as the result of the use of sharp tools or by thrown objects. Prevention of penetrating ocular injury requires greater education of children and their carers especially on the potential dangers within the home.

Primary iris melanoma: diagnostic features and outcome of conservative surgical treatment

AIMS To describe features influencing the management of primary iris melanoma and report the outcome of conservative surgical treatment of patients diagnosed with this condition in a tertiary referral academic setting over a 20 year period. METHODS Retrospective non-comparative case series of consecutive patients diagnosed with iris melanoma from 1980–2000 using medical records from the University of Sydney Department of Ophthalmology and NSW Cancer Registry RESULTS 51 cases were identified. The most common presentation was growth of a previously noted pigmented lesion. Initial management was either observation or local resection (two had enucleations) with iris reconstruction where possible (23.8%). The mean follow up was 8.7 years (range 1–17 years). Vision of 6/12 or better was maintained in the majority (78.6%) treated by local resection. Pupil reconstruction significantly reduced reported postoperative glare symptoms. Four patients had features suggestive of local recurrence and there was no documented metastatic disease or death from iris melanoma in this series. Histologically, the majority were spindle B cell melanomas. Clinical features including prominent tumour vascularity, rapid growth, and heterogeneous pigmentation were each significantly associated with an epithelioid cell component. Involvement of the iridocorneal angle was frequently associated with ciliary body invasion. CONCLUSIONS Management decisions for iris melanoma will depend on the clinical features. Mixed or epithelioid histology is more likely in the presence of two or more of the features of malignancy and may justify earlier intervention. When treatment is undertaken, local resection achieves long term tumour clearance with an acceptable morbidity. In resecting iris melanoma, careful assessment for iridocorneal angle involvement is important in treatment planning. Iris reconstruction has a useful role in reducing postoperative photophobia.

The Use of Two-Stage Molteno Implants in Developmental Glaucoma

Developmental glaucoma, which cannot be controlled by conventional techniques, poses a difficult problem. Twenty-three eyes of 18 patients with developmental glaucoma underwent a two-stage implantation of the double template Molteno valve with follow-up between 12 and 84 months. The final pressure with medication was less than 21 mm Hg in 78% of the cases. These results were obtained in four out of four eyes with primary congenital glaucoma, six out of eight eyes with secondary congenital glaucoma, and eight of 11 eyes in which glaucoma followed surgery for congenital cataract. We feel that two-stage implantation of Molteno valves has a place in the management of difficult developmental glaucomas and is a reasonable early option when glaucoma occurs following surgery for congenital cataract.

Systemic use of anti-inflammatory medications and age-related maculopathy: the Blue Mountains Eye Study

Purpose To assess whether an association exists between systemic use of anti-inflammatory medications at baseline and the prevalence or incidence of either late or early age-related maculopathy (ARM) in a population-based cohort. Methods 3654 participants of the Blue Mountains Eye Study baseline examination (1992–94) were followed during 1997–99. Use of anti-inflammatory medication was recorded during the baseline interview. After excluding 543 persons who died since baseline, 2334 (75% of the surviving participants) attended 5-year follow-up examinations. Retinal photographs taken during both examinations were graded using the Wisconsin Age-Related Maculopathy Grading System. Prevalence refers to the proportion of participants having ARM at baseline. Incidence refers to the proportion of participants without ARM at baseline who developed it over the 5-year period. Known ARM risk factors were adjusted for when assessing the relationship between use of anti-inflammatory medications and ARM. Results At baseline, 1010 (27.6%) of 3654 participants were current users of non-steroidal anti-inflammatory drugs (NSAIDs), 514 (14.1%) were past users and 1282 (35.1%) were ever users. The corresponding numbers of subjects reporting current, past or ever use of corticosteroids (including inhaled steroids) were 225 (6.2%), 519 (14.2) and 564 (15.4), respectively. Late ARM was present in 72 participants (2.0%) and early ARM was present in 171 participants (4.9%) at the baseline examination. During the follow-up period, 25 participants (1.1%) developed incident late ARM and 192 (8.7%) developed incident early ARM. After adjusting for age, sex, family history of ARM and smoking, no significant associations were evident for the use of NSAIDs or corticosteroids and the prevalence of either late or early ARM. There were also no associations found between use of these medications at baseline and the 5-year incidence of either late or early ARM. Conclusions No association was found between use of systemic anti-inflammatory medications and either the cross-sectional prevalence or longitudinal incidence of ARM in this population.

Serum levels of antioxidants and age-related macular degeneration

A number of reports have suggested that oxidative damage in the retina may contribute to the pathogenesis of Age-related macular degeneration (AMD). The present study was designed to investigate the hypothesis that serum levels of the antioxidants, Vitamin E and selenium are related to the pathogenesis of AMD. Fasting bloods were obtained from 80 patients with AMD and 86 controls. Assays for serum levels of Vitamin E, selenium, cholesterol and triglycerides were performed. Assessment of patients and controls was based upon eye examination, fundus photography and medical history. No significant difference was found in serum levels of Vitamin E between subjects and controls, however, there was a borderline association between AMD and both serum selenium levels and current smoking status. The results suggest that if oxidative damage is a factor in the pathogenesis of AMD, it is not reflected in serum levels of Vitamin E; further studies are required to clarify the possible relationship between serum selenium levels, smoking and AMD.

Review Article: Optic Nerve Hypoplasia: A Review

Optic nerve hypoplasia is a developmental anomaly of the retina and optic nerves in which there is a reduction in the number of ganglion cells in the retina and of their centripetal fibers projecting through the optic nerve to the lateral geniculate body. The condition may be unilateral or bilateral and is frequently misdiagnosed as optic atrophy. In about 25% of cases, bilateral optic nerve hypoplasia is associated with a variety of cerebral malformations of which the commonest single disturbance is absence of the septum pellucidum (septo-optic dysplasia). Cerebral malformations and their endocrine accompaniments are also seen, though less frequently, in unilateral hypoplasia. The endocrine disturbances that may accompany optic nerve hypoplasia include growth hormone deficiency, adrenal insufficiency, hypothyroidism, and disturbances of antidiuretic hormone production. Precocious puberty and hypogonadism have also been observed. The prognosis of optic nerve hypoplasia depends upon the severity of the changes in the optic nerves and especially the degree of associated cerebral malformation. The finding of optic nerve hypoplasia should lead to thorough ophthalmologic, neurologic, and endocrinologic evaluation of the patient. (J Child Neurol 1986;1:181-188)

Sporadic and Familial Congenital Cataracts: Mutational Spectrum and New Diagnoses Using Next‐Generation Sequencing

Congenital cataracts are a significant cause of lifelong visual loss. They may be isolated or associated with microcornea, microphthalmia, anterior segment dysgenesis (ASD) and glaucoma, and there can be syndromic associations. Genetic diagnosis is challenging due to marked genetic heterogeneity. In this study, next‐generation sequencing (NGS) of 32 cataract‐associated genes was undertaken in 46 apparently nonsyndromic congenital cataract probands, around half sporadic and half familial cases. We identified pathogenic variants in 70% of cases, and over 68% of these were novel. In almost two‐thirds (20/33) of these cases, this resulted in new information about the diagnosis and/or inheritance pattern. This included identification of: new syndromic diagnoses due to NHS or BCOR mutations; complex ocular phenotypes due to PAX6 mutations; de novo autosomal‐dominant or X‐linked mutations in sporadic cases; and mutations in two separate cataract genes in one family. Variants were found in the crystallin and gap junction genes, including the first report of severe microphthalmia and sclerocornea associated with a novel GJA8 mutation. Mutations were also found in rarely reported genes including MAF, VIM, MIP, and BFSP1. Targeted NGS in presumed nonsyndromic congenital cataract patients provided significant diagnostic information in both familial and sporadic cases.

Human uveal melanoma expresses NG2 immunoreactivity

Background/aims: NG2 is the rat homologue of the human melanoma proteoglycan (HMP), also known as the high molecular weight melanoma associated antigen. Most cutaneous melanomas, as well as glioblastomas, chondrosarcomas, and some leukaemias express NG2 immunoreactivity, recognised using monoclonal antibody (mAb) 9.2.27. This antibody has also been used for molecular targeting in targeted α therapy for melanoma. The purpose of this study was to evaluate the expression of NG2 immunoreactivity in human uveal melanoma and normal ocular tissue using mAb 9.2.27. Methods: Enucleated eyes from 26 patients with choroidal or ciliary body melanoma (n=26) were available as paraffin sections, and stained with haematoxylin and eosin to assess for tumour cell type and histopathology. Additional slides were investigated for NG2 immunoreactivity using mAb 9.2.27 and alkaline phosphatase anti-alkaline phosphatase (APAAP) immunostaining. Two independent observers graded immunostaining using a semiquantitative scale from 0 (negative) to 3 (strong). Results: Immunostaining for mAb 9.2.27 could not be graded in 7/26 cases with dense pigmentation of the tumour. For the remaining cases, grade 2 (moderate) or more immunostaining was seen in 18/19 tumours (95%). The retina, retinal pigment epithelium (RPE), and choroid displayed weak immunostaining (grade 0.5–1.5) in the majority of melanoma affected eyes. Normal retina and choroid (n=5) appeared negative for mAb 9.2.27. Optic nerve axon bundles in both control and melanoma affected eyes displayed moderate immunostaining. Conclusion: In the present study, the majority of human uveal melanomas expressed NG2 immunoreactivity, as detected using mAb 9.2.27. This antibody may be a suitable candidate for radioimmunotherapy to target ocular melanoma.