John Grigg

Axonal loss and myelin in early ON loss in postacute optic neuritis

To investigate the relation between retinal nerve fiber layer (RNFL) thickness and latency and amplitude of multifocal visual‐evoked potentials (mfVEPs) in the postacute stage of optic neuritis in patients with early or possible multiple sclerosis.

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.

CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes

Mutations of the calcium/calmodulin-dependent serine protein kinase (CASK) gene have recently been associated with X-linked mental retardation (XLMR) with microcephaly, optic atrophy and brainstem and cerebellar hypoplasia, as well as with an X-linked syndrome having some FG-like features. Our group has recently identified four male probands from 358 probable XLMR families with missense mutations (p.Y268H, p.P396S, p.D710G and p.W919R) in the CASK gene. Congenital nystagmus, a rare and striking feature, was present in two of these families. We screened a further 45 probands with either nystagmus or microcephaly and mental retardation (MR), and identified two further mutations, a missense mutation (p.Y728C) and a splice mutation (c.2521-2A>T) in two small families with nystagmus and MR. Detailed clinical examinations of all six families, including an ophthalmological review in four families, were undertaken to further characterise the phenotype. We report on the clinical features of 24 individuals, mostly male, from six families with CASK mutations. The phenotype was variable, ranging from non-syndromic mild MR to severe MR associated with microcephaly and dysmorphic facial features. Carrier females were variably affected. Congenital nystagmus was found in members of four of the families. Our findings reinforce the CASK gene as a relatively frequent cause of XLMR in females and males. We further define the phenotypic spectrum and demonstrate that affected males with missense mutations or in-frame deletions in CASK are frequently associated with congenital nystagmus and XLMR, a striking feature not previously reported.

Bevacizumab (Avastin) for the treatment of neovascular glaucoma

Herein three cases of angle closure secondary to neovascularization (elevated intraocular pressure in two of the cases) treated with the anti‐vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (Avastin) are reported. In all three cases there was rapid resolution of neovascularization and control of intraocular pressure. One patient with corneal anaesthesia from diabetes developed infectious keratitis, potentially as a consequence of inhibition of VEGF wound healing and neurotrophic functions. Avastin appears to have a promising role in the treatment of neovascular glaucoma but is not without potential local and systemic side‐effects.

Efficacy of Intravenous Tissue-Type Plasminogen Activator in Central Retinal Artery Occlusion Report From a Randomized, Controlled Trial

Background and Purpose— Central retinal artery occlusion is caused by a platelet-fibrin thrombus or embolic occlusion and is a stroke of the eye. Observational studies suggest that thrombolytics may restore ocular perfusion and visual function. We hypothesized that intravenous tissue-type plasminogen activator (tPA) administered within 24 hours of symptom onset might restore ocular perfusion and visual function. Methods— A placebo-controlled, randomized trial of intravenous tPA versus intravenous saline was performed in patients with clinically defined central retinal artery occlusion within 24 hours of symptom onset. tPA was administered at a total dose of 0.9 mg/kg, with 10% given as a 1-minute bolus and the remainder over 1 hour. An improvement of visual acuity of 3 lines or more was considered significant. Results— Twenty-five percent (2 of 8) of the tPA group experienced the primary outcome at 1 week after tPA versus none of the placebo group. One patient had an intracranial hemorrhage. The visual acuity improvement of these 2 patients was not sustained at 6 months. In both patients, tPA was administered within 6 hours of symptom onset. Conclusions— Although essentially a negative study, it does add to the evidence base of reperfusion in central retinal artery occlusion by showing that the time window for intervention is likely to be <6 hours. Reocclusion is a potential problem and may require adjuvant anticoagulation. Future studies should concentrate on determining the efficacy of thrombolytics in the <6-hour time window. Clinical Trial Registration— URL: http://www.anzctr.org.au. Unique identifier: 83102.

Multicystic Dysplastic Kidney and Variable Phenotype in a Family with a Novel Deletion Mutation of PAX2

The renal coloboma syndrome (OMIM 120330) is caused by mutations in the PAX2 gene. Typical findings in these patients include renal hypoplasia, renal insufficiency, vesicoureteric reflux, and optic disc coloboma. A family with a novel heterozygous 10-bp deletion in exon 2 of the PAX2 gene leading to a truncating mutation and variable phenotype across three generations is reported. The first presentation of multicystic dysplastic kidney in this syndrome is reported. The possibility that abnormal PAX2 protein in this case may cause a dominant negative effect also is discussed. The finding of multicystic dysplastic kidney in renal coloboma syndrome could suggest that PAX2 may play a role in early ureteric obstruction and subsequent renal maldevelopment.

Secondary glaucoma after paediatric cataract surgery

Aim: To determine the prevalence and risk factors associated with secondary glaucoma postcongenital cataract surgery. Methods: All children diagnosed as having congenital cataracts in a major children’s hospital between 1985 and 2005 were included in a retrospective case series. Medical records of 423 eyes among 283 patients who underwent cataract surgery with or without intraocular lens implantation at age ⩽16 for congenital cataract were reviewed. The main outcome measure was presence or absence of secondary glaucoma and time to glaucoma postsurgery. The following risk factors were evaluated: age at cataract surgery, presence of systemic anomalies, microcornea, persistent hyperplastic primary vitreous (PHPV), primary capsulotomy/anterior vitrectomy, primary intraocular lens implantation, secondary membrane surgery and duration of postoperative observation. Results: The statistical methods were the use of Kaplan–Meier survival analysis and Multivariate Cox hazards regression analysis. The mean follow-up was 6.3 (SD 5.0) years (median 4.6 years; range 0.5 to 20.3 years). Glaucoma developed in 36 of 234 patients (15.4%). Multivariate Cox proportional hazards regression analysis identified age less than 9 months at time of surgery (RR 2.9, 95% CI 1.3 to 7.7; p = 0.03), microcornea (RR 3.7, 95% CI 2.0 to 7.0; p<0.001), and follow-up time as important predictors of glaucoma. PHPV (RR 1.4, 95% CI 0.7 to 2.7; p = 0.41) and primary posterior capsulotomy/anterior vitrectomy (RR 2.2, 95% CI 0.9 to 5.5; p = 0.17) were not significantly associated with secondary glaucoma in the multivariate model. The mean time to glaucoma after congenital cataract surgery was 4.9 years (range 2 weeks to 16.8 years). Conclusion: Secondary glaucoma is an important sequela in patients who undergo surgery for congenital cataracts. It is imperative that these patients get lifelong surveillance, as glaucoma can occur years after the initial operation.

Short-term Safety and Efficacy of Intravitreal Triamcinolone Acetonide for Uveitic Macular Edema in Children

OBJECTIVES To evaluate the short-term safety and efficacy of intravitreal (IV) triamcinolone acetonide (TA) for treating pediatric cystoid macular edema (CME) secondary to noninfectious uveitis. METHODS A retrospective noncomparative interventional case series. The medical records of 15 consecutive children (16 eyes) with uveitic CME treated with IVTA (2 or 4 mg) were reviewed. Data collected included details of uveitis, CME, visual acuity, intraocular pressure, and cataract development. The median follow-up time was 16 months (range, 9-36 months). RESULTS Resolution of CME was achieved in all of the treated eyes. The median time taken for CME to resolve was 3 weeks (range, 1-24 weeks). The mean improvement of visual acuity after IVTA was 0.6 logarithm of the minimum angle of resolution. Following initial response to IVTA, CME relapsed in 5 eyes (31%) after a median time of 7 months (range, 3-13 months). The most common adverse effect was increased intraocular pressure, with an increase of more than 15 mm Hg in 5 eyes (31%). Steroid-induced cataract was observed in 6 of 11 phakic eyes (55%). CONCLUSIONS We found that IVTA is efficacious in the treatment of uveitic CME in children and results in CME resolution and visual acuity improvement. As in adults, treatment in children may be associated with elevated intraocular pressure and cataract.

Port-wine vascular malformations and glaucoma risk in Sturge-Weber syndrome

PURPOSE Treatment of the capillary vascular malformation (port-wine stain) in Sturge-Weber syndrome with the use of a laser is helpful cosmetically. However, concerns have been raised that laser obliteration of port-wine stains may result in ocular hypertension. The aim of this study was to review clinical features and management of ocular complications of SWS and assess the effects of dermatological laser treatment on the incidence of glaucoma or ocular hypertension. METHODS This retrospective cohort study was conducted in an institutional setting. All patients had involvement of the face. Patients who underwent skin laser to the port-wine vascular malformation were analyzed further. Ocular involvement, glaucoma, and skin laser treatment and the relationship to ocular hypertension/glaucoma were observed. RESULTS Forty-one Sturge-Weber syndrome patients with port-wine vascular malformation were analyzed. Glaucoma was observed in 24 patients (58.5%) at mean age of 2.9 years (range, 0.0-16.5). Of these, 18 (75.0%) were treated with medical therapy, and 10 (41.7%) required trabeculectomy, with 2 of these requiring Seton implant. Of the 41 patients, 28 (68.3%) underwent laser to face/forehead. Mean age of laser commencement was 5 years (range, 0.4-16.5). Thirteen did not undergo laser treatment. Fourteen of the 28 and 10 of the 13 developed ocular hypertension/glaucoma. CONCLUSIONS This retrospective review did not find evidence to suggest that laser treatment of port-wine vascular malformations causes glaucoma or that it can worsen a preexisting ocular hypertension or glaucoma. Statistical analysis was inconclusive.

Objective perimetry in glaucoma: recent advances with multifocal stimuli.

The introduction of multifocal stimulus recording has enhanced our ability to examine the human visual field with electrophysiologic techniques. We have adapted the multifocal pattern visual evoked potential (PVEP) to detect visual field loss. In glaucoma patients we sought to determine the extent to which the PVEP amplitudes correlate with perimetric thresholds. Multifocal pseudorandomly alternated pattern stimuli, which were cortically scaled in size, were presented with use of the VERIS-Scientific system. Bipolar occipital straddle electrode positions were used. The visual field up to 25 degrees of eccentricity was investigated. Forty-three glaucoma patients with reproducible visual field defects were tested. The bipolar PVEP corresponded well with Humphrey visual field defects, showing loss of signal in the scotoma area. For Humphrey quadrant threshold totals and PVEP quadrant amplitudes, the correlation coefficient was strong (r = 0.49, P < 0.0001). The multifocal PVEP demonstrates good correspondence with the topography of the visual field. This technique represents the first practical application of the multifocal PVEP to objective detection of visual field defects in glaucoma.