Abigail T. Fahim

Acute Panretinal Structural and Functional Abnormalities After Intravitreous Ocriplasmin Injection

IMPORTANCE Ocriplasmin cleaves fibronectin and laminin, components of the vitreous gel, and is used as a pharmacologic treatment for vitreomacular traction. Laminin is also found throughout multiple retinal layers. Ocriplasmin injection may lead to acute panretinal dysfunction in some eyes, but the mechanism of this toxic reaction has not been described. OBSERVATIONS We evaluated a 63-year-old woman demonstrating acute panretinal dysfunction after intravitreous ocriplasmin injection for a small macular hole with vitreomacular adhesion. Findings included visual acuity loss, visual field constriction, pupillary abnormalities, attenuated retinal arteries, loss of outer retinal signals on spectral-domain optical coherence tomography, and severely reduced electroretinography responses. B-waves were reduced more than A-waves were, suggesting postreceptoral dysfunction and decreased photoreceptor activity. CONCLUSIONS AND RELEVANCE Retinal dysfunction associated with intravitreous ocriplasmin injection is not limited to the macular region and seems to involve the entire retina. Enzymatic cleavage of intraretinal laminin is a biologically plausible mechanism for acute ocriplasmin retinal toxic effects.

Allelic Heterogeneity and Genetic Modifier Loci Contribute to Clinical Variation in Males with X-Linked Retinitis Pigmentosa Due to RPGR Mutations

Mutations in RPGR account for over 70% of X-linked retinitis pigmentosa (XlRP), characterized by retinal degeneration and eventual blindness. The clinical consequences of RPGR mutations are highly varied, even among individuals with the same mutation: males demonstrate a wide range of clinical severity, and female carriers may or may not be affected. This study describes the phenotypic diversity in a cohort of 98 affected males from 56 families with RPGR mutations, and demonstrates the contribution of genetic factors (i.e., allelic heterogeneity and genetic modifiers) to this diversity. Patients were categorized as grade 1 (mild), 2 (moderate) or 3 (severe) according to specific clinical criteria. Patient DNAs were genotyped for coding SNPs in 4 candidate modifier genes with products known to interact with RPGR protein: RPGRIP1, RPGRIP1L, CEP290, and IQCB1. Family-based association testing was performed using PLINK. A wide range of clinical severity was observed both between and within families. Patients with mutations in exons 1–14 were more severely affected than those with ORF15 mutations, and patients with predicted null alleles were more severely affected than those predicted to make RPGR protein. Two SNPs showed association with severe disease: the minor allele (N) of I393N in IQCB1 (p = 0.044) and the common allele (R) of R744Q in RPGRIP1L (p = 0.049). These data demonstrate that allelic heterogeneity contributes to phenotypic diversity in XlRP and suggest that this may depend on the presence or absence of RPGR protein. In addition, common variants in 2 proteins known to interact with RPGR are associated with severe disease in this cohort.

Acute ocriplasmin retinopathy.

Ocriplasmin, a recombinant truncated form of the enzyme plasmin, was approved by the Food and Drug Administration in October 2012 as a first-in-class drug for the nonsurgical treatment of vitreomacular traction (VMT).1 The potential advantages of pharmacologic vitreolysis over surgical vitrectomy include the induction of a “clean” and complete PVD without vitreoschisis, greater ease, lower cost, avoidance of surgical risk, and faster visual rehabilitation, possibly with better visual outcomes. Many retina specialists were hopeful that ocriplasmin was the long-awaited silver bullet—a safe and effective vitreolytic agent that would fulfill the promise of this new treatment approach. Real-life experience with the drug, however, has raised serious safety concerns.

Diagnostic Fundus Autofluorescence Patterns in Achromatopsia

PURPOSE To describe the unique diagnostic fundus autofluorescence (FAF) patterns in patients with achromatopsia and the associated findings on optical coherence tomography (OCT). DESIGN Observational case series. METHODS We evaluated 10 patients with achromatopsia by means of best-corrected visual acuity (BCVA), ophthalmoscopy, Goldmann visual field, full-field electroretinography (ffERG), OCT, and FAF photography. FAF patterns were compared with patient age and foveal changes on OCT. RESULTS Patients fell into two dichotomous age groups at the time of evaluation: six patients ranged from 11 to 23 years of age, and 3 patients ranged from 52 to 63 years of age. All patients had severely reduced photopic ffERG responses, including those exhibiting preserved foveal structure on OCT. The younger patients had absent to mild foveal atrophy on OCT, and four of the six demonstrated foveal and parafoveal hyperfluorescence on FAF. In addition, a 7-month-old child with compound heterozygous mutations in CNGA3 demonstrated similar foveal hyperfluorescence. The older patients demonstrated advanced foveal atrophy and punched-out foveal hypofluorescence with discrete borders on FAF imaging corresponding to the area of outer retinal cavitation on OCT. CONCLUSIONS Foveal hyperfluorescence is an early sign of achromatopsia that can aid in clinical diagnosis. In our cohort, patients with achromatopsia demonstrated age-dependent changes in FAF, which are likely to be progressive and to correlate with foveal atrophy and cavitation on OCT. This finding may be useful in charting the natural course of the disease and in defining a therapeutic window for treatment.

Polymorphic variation of RPGRIP1L and IQCB1 as modifiers of X-linked retinitis pigmentosa caused by mutations in RPGR.

Mutations in retinitis pigmentosa GTPase regulator (RPGR) account for over 70% of X-linked retinitis pigmentosa (XlRP), characterized by retinal degeneration and eventual blindness. RPGR mutations demonstrate extreme phenotypic heterogeneity, even within the same family, suggesting a role for genetic modifiers in disease expression. This study aimed to categorize the clinical diversity in a cohort of 98 affected males from 56 families with RPGR mutations, and to test candidate modifier genes for association with disease severity. Ninety-eight affected males from 56 families were enrolled. Patients were categorized as mild, moderate, or severe according to specific clinical criteria. Patient DNA was genotyped for common coding SNPs in four candidate modifier genes known to interact with RPGR: RPGRIP1, RPGRIP1L, CEP290, and NPHP5. Family-based association testing was performed using PLINK (pngu.mgh.harvard.edu/purcell/plink/). A wide range of severity was observed between and within families. Two SNPs showed association with severe disease: the minor allele (N) of I393N in IQCB1 (p = 0.044) and the common allele (R) of R744Q in RPGRIP1L (p = 0.049).

Transgenic overexpression of a stable Plasminogen Activator Inhibitor-1 variant

INTRODUCTION Plasminogen Activator Inhibitor-1 (PAI-1) is a member of the Serine Protease Inhibitor (SERPIN) gene family and a key regulator of fibrinolysis. PAI-1 is unique among SERPINs in its spontaneous transition to a latent, inactive state, with a half-life of approximately 2 hours under physiologic conditions. The biologic importance of the PAI-1 transition to latency is unknown. This study aimed to engineer transgenic overexpression of a stable murine PAI-1 variant to examine the physiologic effects in vivo from delayed transition of PAI-1 to latency. MATERIALS AND METHODS Ten independent transgenic lines were generated with expression of a stable PAI-1 variant driven by the hybrid CMV/chicken beta-actin promoter. RESULTS Plasma PAI-1 levels in the transgenic founders ranged from 3.1+/-0.1 ng/mL to 1268.8+/-717.0 ng/mL. Quantitative PCR analysis in 3 transgenic lines demonstrated elevated PAI-1 mRNA in multiple tissues, with the highest increases observed in liver, brain, heart, and kidney. The fold-increase in PAI-1 mRNA over wild-type ranged from 2-fold to >2000-fold. Immunohistochemistry showed increased PAI-1 in liver, kidney, heart, spleen, and lung. Histologic examination of transgenic mice showed no evidence of thrombosis. The two founders with the highest plasma PAI-1 levels failed to produce any transgenic offspring that survived to weaning, although genotyping of expired pups revealed successful transmission of the transgene. CONCLUSION These results suggest that high expression of a stable variant of PAI-1 may be lethal in mice, while more moderate expression is generally well tolerated and produces no apparent thrombosis.

Peripheral fundus findings in X-linked retinoschisis

Background/aims Vitreous haemorrhage (VH) and retinal detachment (RD) cause a precipitous decline in vision in a subset of patients with X-linked retinoschisis (XLRS), an otherwise a slowly progressive condition. This study aims to report the frequency of macular and peripheral retinal findings in a large cohort of patients with XLRS and to determine whether peripheral retinal findings are associated with VH and RD. Methods A retrospective observational case series was performed in 65 patients with XLRS with a pathogenic variant in retinoschisin 1. Chart review included examination notes, fundus photographs and optical coherence tomography (OCT). Fisher exact tests and univariable logistic regression analysis were used to determine the association between peripheral retinal findings (including retinoschisis, metallic sheen, vascular sheathing, pigmentary changes, white spiculations and vitreous veils) and complications (including VH and RD). Results Seven eyes (8%) showed normal macular structure on OCT. Peripheral retinoschisis was significantly associated with both VH and RD. Out of 10 eyes with complications, 9 (90%) had peripheral retinoschisis, compared with 33 out of 116 eyes (28%) without complications (p=0.0014). In addition, each additional peripheral finding increased the odds of RD by a factor of 4.06 (95% CI 1.58 to 10.39, p=0.028). There were no complications in the 28 eyes with a normal periphery (p=0.84) or in the 35 eyes with metallic sheen (p=0.42). Conclusion The data suggest that patients with peripheral retinoschisis are at increased risk for VH and RD. Furthermore, patients with additional peripheral retinal findings together with peripheral schisis may carry additional risk for RD.

Double hyperautofluorescent ring on fundus autofluorescence in ABCA4

ABSTRACT We report an unusual phenotype in a child with a clinical diagnosis of recessive Stargardt disease (STGD1) and two pathogenic variants in the ABCA4 gene. Typically, the diagnosis of early-onset STGD1 is challenging because children may present with a variety of fundus changes and a variable rate of progression. At the time of his initial visit, the 6-year-old boy presented with 20/200 OD (right eye) and 20/150 OS (left eye), symmetrical mild foveal atrophy without flecks on fundus exam, and foveal hypoautofluorescence surrounded by a homogeneous hyperautofluorescent background on wide-field fundus autofluorescence. Over 4 years of follow-up, the retinal atrophy continued to progress, resulting in two well-defined and concentric hyperautofluorescent rings: one ring located at the posterior pole and the other located around the peripapillary region. Visual acuity also deteriorated to counting fingers at 4ft OD and 20/500 OS. To the best of our knowledge, this phenotype has not been previously described with the ABCA4 gene.

Bullous X linked retinoschisis: clinical features and prognosis

Background/Aims A subset of patients with X linked retinoschisis (XLRS) have bullous schisis cavities in the peripheral retina. This study describes the characteristics and prognosis of the bullous form of XLRS. Methods A retrospective case series was performed of nine patients with molecularly proven bullous XLRS seen at a single tertiary centre. Results All cases of bullous peripheral schisis were bilateral, with one unilateral case at presentation which developed into bilateral bullous schisis over time. The mean age of onset was 1.9 years (range: 1 month–7 years, SD: 2.1 years) and at clinical diagnosis was 5.9 years (range: 1 month–27 years, SD: 9.0 years). Mean follow-up was 11 years (range: 6 months–36 years, SD: 10.8 years). Strabismus was the most common presentation (n=7). Other presenting complaints included decreased vision, floaters and an irregularly shaped pupil. The most frequently associated ocular features were strabismus (100%), vitreous haemorrhage (4/18 eyes, 22%), nystagmus (2/9, 22%) and persistent fetal vasculature (1/18, 6%). Localised tractional detachment was seen in 2/18 (11%) eyes, total detachment that underwent surgical repair in 1/18 (6%) and pigmented demarcation lines in a further 22% of the eyes. There was one eye with exudative retinal detachment. Conclusion In XLRS, bullous schisis may be congenital or develop soon after birth and most commonly presents with strabismus. Cases may be complicated by some form of retinal detachment, which may be tractional or a Coats-like exudative detachment.

Comparison of ophthalmic training in 6 English-speaking countries

OBJECTIVE To compare key characteristics of ophthalmology training programs in 6 different English-speaking countries: Australia, New Zealand, Canada, Ireland, the United Kingdom, and the United States. PARTICIPANTS Seven ophthalmologists with personal knowledge of all 6 systems contributed. METHODS The main features examined were career pathway, duration of training, surgical training, governing bodies, and examination structure. Data were collected from the literature, online resources, and personal experience. RESULTS Several differences were highlighted, including length of training (ranging from 4 to 9 years after medical school), number of surgical procedures such as cataracts (ranging from minimum 86 to approximately 600), and structure of fellowship training. CONCLUSIONS As trainees increasingly seek international experience to enhance their knowledge and skills, the similarities and differences between training programs in different countries have become more relevant. Some of these differences may reflect differing needs of different patient populations and different healthcare delivery systems across the globe. However, these differences should also prompt educators to more carefully scrutinize their own training system and search for potential improvements.