Matthew P. Simunovic

The cone dystrophies

The cone dystrophies are a heterogeneous group of inherited disorders that result in dysfunction of the cone photoreceptors and sometimes their post-receptoral pathways. The major clinical features of cone dystrophy are photophobia, reduced visual acuity and abnormal colour vision. Ganzfeld electroretinography shows reduced or absent cone responses. On the basis of their natural history, the cone dystrophies may be broadly divided into two groups: stationary and progressive cone dystrophies. The stationary cone dystrophies have received more attention, and subsequently our knowledge of their molecular genetic, psychophysical and clinical characteristics is better developed. Various methods of classification have been proposed for the progressive cone dystrophies, but none is entirely satisfactory, largely because the underlying disease mechanisms are poorly understood. Multidisciplinary studies involving clinical assessment, molecular genetics, electrophysiology and psychophysics should lead to an improved understanding of the pathogenesis of these disorders.

Visual Acuity after Retinal Gene Therapy for Choroideremia

In this study, the subfoveal injection of a gene-therapy vector carrying nonmutated CHM, the gene that, when mutated, causes a form of blindness called choroideremia, was followed by an improvement in visual acuity in two of six patients at 3.5 years after injection.

Autosomal dominant cone-rod retinal dystrophy (CORD6) from heterozygous mutation of GUCY2D, which encodes retinal guanylate cyclase

OBJECTIVE To describe the clinical features of autosomal dominant cone-rod retinal dystrophy (CRD) in a British family mapping to chromosome 17p12-p13 (CORD6), with a heterozygous mutation (Glu837Asp/ Arg838Ser) of GUCY2D. DESIGN A prospective, clinical family survey. PATIENTS Ten affected members of a family with autosomal dominant CRD. METHODS Full clinical examinations were undertaken. Selected affected family members underwent electrophysiologic evaluation, scotopic static perimetry, dark adaptometry, and color vision assessment. MAIN OUTCOME MEASURES Clinical appearance and electroretinographic responses. RESULTS Typical clinical and electroretinographic features of childhood-onset CRD were recorded. In addition, moderate myopia and pendular nystagmus were seen in affected individuals. Color vision assessment in the youngest affected individual showed no color discrimination on a tritan axis, but retention of significant red-green discrimination. Electronegative electroretinogram responses were seen on electrophysiology in the only young family member examined. CONCLUSIONS The phenotype associated with GUCY2D CRD is clinically distinct from that associated with other dominant CRD loci. Unusual electroretinographic responses may indicate that this mutation of GUCY2D is associated with early defects in photoreceptor synaptic transmission to second-order neurons.

Endophthalmitis following intravitreal injection versus endophthalmitis following cataract surgery: clinical features, causative organisms and post-treatment outcomes

Aims To describe and compare the causative organisms, clinical features and visual outcomes of endophthalmitis following intravitreal injection (IVI) to endophthalmitis following cataract surgery. Methods Patient population and setting: A retrospective case series of patients with acute endophthalmitis following either cataract surgery or IVI presenting to a tertiary referral centre—Sydney Eye Hospital—between 2007 and 2010. Main outcome measures: (1) identification of the causative organism; (2) time to presentation; (3) odds of improvement in visual acuity (VA) following treatment; (4) odds of final VA of counting fingers (CF) or less and (5) odds of enucleation. Results Of the 101 patients in our study, 48 had preceding cataract surgery and 53 had preceding IVI. There was an increased incidence of Streptococcus spp. endophthalmitis in post-IVI cases (24.53% vs 6.25%; OR 5.85; p=0.022). Endophthalmitis following IVI had increased likelihood of a final VA of CF or less (OR=6.0; p<0.01), decreased likelihood of any improvement in acuity following treatment (OR=0.13; p<0.01) and an increased likelihood of presenting within a week of the procedure (OR=3.93; p<0.01). Endophthalmitis caused by Streptococcus spp. was associated with increased likelihood of a final VA of CF or less (OR=10.2; p<0.01), decreased likelihood of any improvement in acuity following treatment (OR=0.06; p<0.01) and increased likelihood of enucleation (OR=17.11; p<0.01). Conclusions Endophthalmitis following IVI is associated with an increased incidence of Streptococcus spp. infection, earlier presentation and poorer visual outcomes when compared with endophthalmitis following cataract surgery.

Colour vision deficiency.

Colour vision deficiency is one of the commonest disorders of vision and can be divided into congenital and acquired forms. Congenital colour vision deficiency affects as many as 8% of males and 0.5% of females—the difference in prevalence reflects the fact that the commonest forms of congenital colour vision deficiency are inherited in an X-linked recessive manner. Until relatively recently, our understanding of the pathophysiological basis of colour vision deficiency largely rested on behavioural data; however, modern molecular genetic techniques have helped to elucidate its mechanisms.The current management of congenital colour vision deficiency lies chiefly in appropriate counselling (including career counselling). Although visual aids may be of benefit to those with colour vision deficiency when performing certain tasks, the evidence suggests that they do not enable wearers to obtain normal colour discrimination. In the future, gene therapy remains a possibility, with animal models demonstrating amelioration following treatment

Blue cone monochromatism: a phenotype and genotype assessment with evidence of progressive loss of cone function in older individuals

AbstractAimTo perform a detailed clinical and psychophysical assessment of the members of three British families affected with blue cone monochromatism (BCM), and to determine the molecular basis of disease in these families.MethodsAffected and unaffected members of three families with BCM were examined clinically and underwent electrophysiological and detailed psychophysical testing. Blood samples were taken for DNA extraction. The strategy for molecular analysis was to amplify the coding regions of the long wavelength-sensitive (L) and middle wavelength-sensitive (M) cone opsin genes and the upstream locus control region by polymerase chain reaction, and to examine these fragments for mutations by direct sequencing.ResultsWe have confirmed the reported finding of protan-like D-15 arrangements of patients with BCM. In addition, we have demonstrated that the Mollon–Reffin (MR) Minimal test is a useful colour-discrimination test to aid in the diagnosis of BCM. Affected males were shown to fail the protan and deutan axes, but retained good discrimination on the tritan axis of the MR test, a compelling evidence for residual colour vision in BCM. This residual tritan discrimination was also readily detected with HRR plates. In two families, psychophysical testing demonstrated evidence for progression of disease. In two pedigrees, BCM could be linked to unequal crossovers within the opsin gene array that resulted in a single 5′-L/M-3′ hybrid gene, with an inactivating Cys203Arg mutation. The causative mutations were not identified in the third family.ConclusionsThe MR test is a useful method of detecting BCM across a wide range of age groups; residual tritan colour discrimination is clearly demonstrated and allows BCM to be distinguished from rod monochromatism. BCM is usually classified as a stationary cone dysfunction syndrome; however, two of our families show evidence of progression. This is the first report of progression associated with a genotype consisting of a single 5′-L/M-3′ hybrid gene carrying an inactivating mutation. We have confirmed that the Cys203Arg inactivating mutation is a common sequence change in blue cone monochromats.

Cone dystrophy phenotype associated with a frameshift mutation (M280fsX291) in the α-subunit of cone specific transducin (GNAT2)

Aim: To describe the phenotype of a three generation consanguineous Pakistani family containing six individuals with autosomal recessive cone dystrophy caused by mutation in GNAT2. Methods: Five of the six affected individuals underwent an ophthalmological examination, electrodiagnostic testing, fundus photography, autofluorescence imaging, and detailed psychophysical testing. Results: All five examined patients had a history of nystagmus from infancy, photophobia, defective colour vision, and poor visual acuity. The nystagmus in three of the individuals had lessened with time. Fundus examination revealed an abnormal foveal appearance, without frank atrophy or pigmentation. Electroretinography (ERG) revealed absent ISCEV cone flicker ERGs with some preservation of responses to short wavelength stimulation. Rod ERGs showed no definite abnormality, but maximal (mixed rod-cone) response a-wave amplitudes were mildly subnormal. Rudimentary residual colour vision was detected in three individuals. There is clinical evidence of progressive visual acuity reduction in two older individuals. Conclusion: Mutation in the α-subunit of cone specific transducin (GNAT2) is characterised by an infantile onset cone dystrophy. Some affected individuals may show deterioration of visual acuity with time.

Syphilitic retinitis and uveitis in HIV-positive adults

Background:  The incidence of new infection with syphilis is increasing, particularly in men who have sex with men, with HIV co‐infection common. There has been a corresponding increase in ophthalmic manifestations that can be varied in presentation.

ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY FOR PROLIFERATIVE DIABETIC RETINOPATHY: A Systematic Review and Meta-Analysis.

Purpose: To systematically review and perform meta-analysis on the available randomized controlled trial data for anti-vascular endothelial growth factor (anti-VEGF) agents in the management of proliferative diabetic retinopathy and its complications. Methods: The authors identified randomized controlled trials using anti-VEGF agents, either as stand-alone therapy or combined with other interventions, in the management of proliferative diabetic retinopathy. The primary outcome measures were change in best-corrected visual acuity and (in the context of vitrectomy) duration of surgery and postoperative vitreous hemorrhage. Secondary outcomes were change in central retinal thickness and (in the context of vitrectomy) intraoperative variables suggestive of complex surgery (retinal breaks, intraoperative bleeding, and endodiathermy applications). The quality of evidence for all outcomes was appraised using the GRADE criteria. Results: Twenty-two studies involving 1,397 subjects met the criteria for inclusion in this study. One study compared intravitreal ranibizumab with saline, one compared intravitreal pegaptanib to pan-retinal photocoagulation (PRP), one compared intravitreal bevacizumab to PRP, 3 compared combined intravitreal ranibizumab/PRP to PRP, 5 compared combined intravitreal bevacizumab/PRP to PRP alone, and 11 compared combined intravitreal bevacizumab/PPV to PPV alone. When used in conjunction with PRP, there is a high-quality evidence to suggest that intravitreal ranibizumab is associated with superior visual acuity and central retinal thickness outcomes at 3 months to 4 months. In the context of PPV, there is moderate quality evidence to suggest that preoperative intravitreal bevacizumab results in a significant reduction in the duration of surgery, fewer retinal breaks, less intraoperative bleeding, and fewer endodiathermy applications. Although there is evidence to suggest occurrence of early postoperative vitreous hemorrhage is reduced, the quality of evidence in support of this finding is low. Conclusion: The use of anti-VEGF agents before PRP results in superior functional and structural outcomes at 3 months to 4 months. The use of anti-VEGF agents before PPV results in decreased duration of surgery, fewer breaks, and less intra-operative bleeding. Although there is evidence for a decreased incidence of early postoperative vitreous hemorrhage, the quality of evidence is low. The available data therefore support the use of anti-VEGF agents as adjuncts to PRP and PPV in patients with complicated proliferative diabetic retinopathy primarily as a means of facilitating, and potentially minimizing the iatrogenic damage resulting from, these procedures.

Vitrectomy for diabetic macular edema: a systematic review and meta-analysis

OBJECTIVE To systematically review, and perform meta-analysis on, the available data regarding the efficacy of vitrectomy for diabetic macular edema. DESIGN Systematic review and meta-analysis of published randomized controlled trial data. METHODS We searched PubMed and the Cochrane database for randomized, controlled trials investigating vitrectomy for diabetic macular edema. Structural (foveal thickness) and functional (visual acuity) outcomes were used as the primary outcome measures. RESULTS Eleven studies met the criteria for inclusion in this review: these studies were heterogenous in their experimental and control interventions, follow-up period, and eligibility criteria. Seven studies compared vitrectomy with the natural history of diabetic maculopathy, with laser, or with intravitreal corticosteroid injection. Four studies compared vitrectomy with internal limiting membrane peeling to vitrectomy alone. One of the latter 4 studies was the only to investigate vitrectomy in patients with vitreomacular traction. Meta-analysis suggests a structural, and possibly functional, superiority of vitrectomy over observation at 6 months. Vitrectomy also appears superior to laser in terms of structural, but not functional, outcomes at 6 months. At 12 months, vitrectomy offers no structural benefit and a trend toward inferior functional outcomes when compared with laser. CONCLUSIONS There is little evidence to support vitrectomy as an intervention for diabetic macular edema in the absence of epiretinal membrane or vitreomacular traction. Although vitrectomy appears to be superior to laser in its effects on retinal structure at 6 months, no such benefit has been proved at 12 months. Furthermore, there is no evidence to suggest a superiority of vitrectomy over laser in terms of functional outcomes.