MACULAR ATROPHY AND PHENOTYPIC VARIABILITY IN AUTOSOMAL DOMINANT STARGARDT-LIKE MACULAR DYSTROPHY DUE TO PROM1 MUTATION.

PURPOSE: To describe the phenotypic variability and rates of progression of atrophy in patients with PROM1 -associated macular dystrophy. METHODS: Patients in this retrospective, longitudinal case series from a tertiary center had clinical examination and multimodal imaging performed. Areas of retinal pigment epithelium and ellipsoid zone loss over time by optical coherence tomography were calculated by two independent graders. RESULTS: Fifteen patients from five kindreds with an Arg373Cys mutation in PROM1 were studied. The average age was 39 years, and 80% were women. The visual acuity was 20/40 at presentation and 20/57 at last follow-up (average 4.8 years). Three distinct macular phenotypes were observed: 1) central geographic atrophy (13%), 2) multifocal geographic atrophy (20%), and 3) bull's eye maculopathy (67%). The overall rate of atrophy progression was 0.36 mm 2 /year, but the average rate of atrophy progression varied by macular phenotype: 1.08 mm 2 /year for central geographic atrophy, 0.53 mm 2 /year for multifocal geographic atrophy, and 0.23 mm 2 /year for bull's eye maculopathy. CONCLUSION: Patients with PROM1 -associated macular dystrophy demonstrate distinct phenotypes, with bull's eye maculopathy being the most common. The average rate of atrophy progression may be similar to reported rates for ABCA4 -related Stargardt disease and less than age-related macular degeneration. These results provide important measures for following treatment response in future gene and stem cell-based therapies.

Stargardt disease masquerades.

PURPOSE OF REVIEW: Stargardt disease is the most common inherited macular dystrophy but has a wide clinical spectrum, and several inherited macular dystrophies have phenotypic similarities that can make clinical diagnosis challenging. This review seeks to highlight key clinical and multimodal imaging features to aid clinicians in accurate diagnosis. RECENT FINDINGS: Multimodal imaging has provided additional information to aid in the diagnosis of Stargardt disease and its masquerades. These data from multimodal imaging are important to correlate with findings from clinical examination to help support the clinical diagnosis or guide molecular investigations. SUMMARY: This review highlights the key similarities and differences, in history, clinical examination and multimodal imaging, to help distinguish between Stargardt disease and other macular dystrophies. These findings can help direct a focused molecular analysis for accurate diagnosis, which is critical in the era of gene and stem cell therapies.

Attaining functional levels of visual acuity after vitrectomy for retinal detachment secondary to proliferative diabetic retinopathy.

Most patients needing diabetic tractional retinal detachment (TRD) surgery are working-age adults that drive and participate in other vision-dependent activities of daily living. We sought to determine the proportion of patients that achieve functional visual acuity (VA) based on the World Health Organization (WHO) definition of 'low vision' (≤ 20/80) and US driving standards (≥ 20/40) after vitrectomy for diabetic TRD. In this 10-year retrospective review, consecutive patients who underwent primary vitrectomy for TRD from proliferative diabetic retinopathy were studied. 240 eyes in 203 patients met criteria for analysis (38 eyes were lost to follow up at 3 months; 68 at 12 months; 146 at 60 months). While most patients (nearly 80%) having TRD surgery had low vision pre-op, almost half attained VA that was > 20/80 five years post-op. Those most likely to achieve significant visual improvement (p < 0.0001) had concomitant vitreous hemorrhage pre-op. Only 6% of eyes met the US minimum driving standard before surgery based on VA compared to 28% after vitrectomy however this study did not examine visual fields which could warrant additional assessment depending on local requirements. In summary, significant gains in visual acuity are seen after vitrectomy for diabetic TRD that can result in functional improvement in activities of daily living.

Ocular Hypertension Following Intravitreal Antivascular Endothelial Growth Factor Therapy: Review of the Literature and Possible Role of Nitric Oxide.

PURPOSE: To review the literature regarding ocular hypertension following intravitreal antivascular endothelial growth factor therapy, and to propose a novel mechanism for the development of ocular hypertension as a result of such therapy. METHODS: The PubMed database was used to identify publications by using combinations of the search terms, "glaucoma," "ocular hypertension," "pegaptanib," "bevacizumab," "ranibizumab," "aflibercept," "anti-vascular endothelial growth factor," intraocular pressure," and "intravitreal." The reference lists of these publications were also reviewed for relevant articles. RESULTS: Numerous articles have been published describing ocular hypertension, either immediate-term/short-term or delayed/sustained, following intravitreal antivascular endothelial growth factor therapy. Ocular hypertension has been reported following intravitreal pegaptanib, bevacizumab, and ranibizumab, and aflibercept. On the basis of the fact that vascular endothelial growth factor, normally present as a vascular modulating and reparative growth factor, is known to upregulate endothelial nitric oxide (NO) synthase, and that NO has been shown to decrease intraocular pressure in both normal and glaucomatous human and animal eyes, we propose a novel mechanism for sustained ocular hypertension following intravitreal antivascular endothelial growth factor therapy. We propose that such intravitreal therapy may lead to decreased NO in the anterior segment, which then leads to trabecular meshwork constriction, decreased outflow facility, and increased intraocular pressure. CONCLUSIONS: Sustained ocular hypertension following the intravitreal administration of antivascular endothelial growth factor agents is a potentially serious side effect that has not been adequately explained. Further investigation is necessary to determine the role of NO in the mediation of this adverse effect.

High intraocular pressure following anti-vascular endothelial growth factor therapy: proposed pathophysiology due to altered nitric oxide metabolism.

The nitric oxide (NO) pathway and its physiological significance on relaxing smooth muscle and endothelial cells throughout the body is well outlined and understood. Components of this pathway have been located in the ocular anterior and posterior chambers, and they have been connected with vascular, retinal, and trabecular meshwork normal physiology. Nitric oxide has been shown to increase anterior chamber aqueous outflow via reduction in trabeculocyte size and smooth muscle contractility, and Schlemm's canal vasodilation. Anti-vascular endothelial growth factor (VEGF) therapy has been shown to disrupt the normal nitric oxide signaling pathway, producing systemic arterial hypertension following systemically administered anti-VEGF in oncology by exactly that mechanism. Intravitreal anti-VEGF therapy is now considered a standard of care in several retinal diseases. Sustained elevated intraocular pressure (IOP) has been described as a potential adverse effect of therapy that appears related to the number of injections, and it can be produced by any of the various anti-VEGF compounds. We propose a novel mechanism responsible for the increase in IOPs following prolonged intravitreal anti-VEGF therapy. This mechanism postulates a rise in IOP due to a decrease in aqueous outflow from relatively decreased levels of available nitric oxide in the anterior chamber because of anti-VEGF inhibition of nitric oxide synthase. This article outlines the novel mechanism, which provides a likely explanation for this consequence, along with offering therapeutic targets for future research and treatment.