The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade.

Age-related macular degeneration (AMD) is a complex neurodegenerative eye disease with behavioral and genetic etiology and is the leading cause of irreversible vision loss among elderly Caucasians. Functionally significant genetic variants in the alternative pathway of complement have been strongly linked to disease. More recently, a rare variant in the terminal pathway of complement has been associated with increased risk, Complement component 9 (C9) P167S. To assess the functional consequence of this variant, C9 levels were measured in two independent cohorts of AMD patients. In both cohorts, it was demonstrated that the P167S variant was associated with low C9 plasma levels. Further analysis showed that patients with advanced AMD had elevated sC5b-9 compared to those with non-advanced AMD, although this was not associated with the P167S polymorphism. Electron microscopy of membrane attack complexes (MACs) generated using recombinantly produced wild type or P167S C9 demonstrated identical MAC ring structures. In functional assays, the P167S variant displayed a higher propensity to polymerize and a small increase in its ability to induce hemolysis of sheep erythrocytes when added to C9-depleted serum. The demonstration that this C9 P167S AMD risk polymorphism displays increased polymerization and functional activity provides a rationale for the gene therapy trials of sCD59 to inhibit the terminal pathway of complement in AMD that are underway.

Real world outcomes of ocriplasmin use by members of the British and Eire Association of Vitreoretinal Surgeons.

PurposeTo describe a survey of the use of ocriplasmin by members of the British and Eire Association of VitreoRetinal Surgeons (BEAVRS) for VitreoMacular Traction (VMT) and Full Thickness Macular Hole (FTMH) and compare it to published MIVI TRUST trial data.MethodsAll 173 BEAVRS members were contacted by email in October 2014 requesting data on all cases treated with ocriplasmin up to that date. The total number of cases, FTMH closure rate, VMT release rate and the frequency of adverse events were recorded. Results were compared with trial data.Results48 members responded reporting results from 241 eyes. The respective BEAVRS and MIVI TRUST trial closure rates for small FTMHs were 42.1 and 58.3% (P=0.09) and for medium FTMH 12.7 and 36.7% (P=0.01). The respective VMT release rates were 34.1 and 37.4% (P=NS). Retinal detachment was observed in 3.3% of the BEAVRS cohort compared with 0.4% in MIVI TRUST. Reduction in visual acuity to <6/60 was observed in 5.8% of the BEAVRS cohort and 0.6% in MIVI TRUST. Other complications not reported in the MIVI TRUST trial included an increase in FTMH basal diameter following unsuccessful ocriplasmin use in 46.9% of BEAVRS cases and zonular instability at the time of subsequent phacoemulsification in 2.4%.ConclusionMacular hole closure rates were lower in the BEAVRS survey than published in the MIVI TRUST trial data. The incidence of adverse events was greater than previously reported. The reasons for these disparities are unknown but could include positive reporting bias inherent to retrospective surveys, treatment and population differences.

Predicting macular hole closure with ocriplasmin based on spectral domain optical coherence tomography.

PurposeTo assess the preoperative features of patients with idiopathic macular hole (IMH) and vitreomacular adhesion (VMA) treated with ocriplasmin (OCP) that can predict successful closure.MethodData were prospectively collected on all patients with IMH treated with OCP in three British ophthalmic centres. Several preoperative variables were recorded including the IMH base diameter (BD), minimum linear diameter (MLD), and VMA width measured on spectral domain optical coherence tomography. Several other IMH indices were derived including a 'width factor', defined as the BD minus the MLD in µm. The occurrence of VMA release and hole closure were used as the main outcome measures.ResultsThirty-three patients in total with IMH were treated with OCP. Two patients developed rhegmatogenous retinal detachment and were excluded. The mean age of the remaining 31 patients was 71 years, and 71% were female. VMA release occurred in 19 of the 31 (61%) patients and macular hole closure in 11 (35%). Width factor was the most predictive feature for closure on multivariate analysis. The deviance R(2) was 67% (P<0.001). An IMH with a width factor of <60 µm had a 95% certainty of closure, whereas if >290 µm then there was less than a 5% chance of closure. Neither VMA width nor MLD alone was associated with VMA release or closure.ConclusionsPatients with macular holes where the BD was close in size to the MLD had an improved probability of closure than holes with wider base configurations.

The design and validation of an optical coherence tomography-based classification system for focal vitreomacular traction.

PURPOSE: To develop and validate a classification system for focal vitreomacular traction (VMT) with and without macular hole based on spectral domain optical coherence tomography (SD-OCT), intended to aid in decision-making and prognostication. METHODS: A panel of retinal specialists convened to develop this system. A literature review followed by discussion on a wide range of cases formed the basis for the proposed classification. Key features on OCT were identified and analysed for their utility in clinical practice. A final classification was devised based on two sequential, independent validation exercises to improve interobserver variability. RESULTS: This classification tool pertains to idiopathic focal VMT assessed by a horizontal line scan using SD-OCT. The system uses width (W), interface features (I), foveal shape (S), retinal pigment epithelial changes (P), elevation of vitreous attachment (E), and inner and outer retinal changes (R) to give the acronym WISPERR. Each category is scored hierarchically. Results from the second independent validation exercise indicated a high level of agreement between graders: intraclass correlation ranged from 0.84 to 0.99 for continuous variables and Fleiss' kappa values ranged from 0.76 to 0.95 for categorical variables. CONCLUSIONS: We present an OCT-based classification system for focal VMT that allows anatomical detail to be scrutinised and scored qualitatively and quantitatively using a simple, pragmatic algorithm, which may be of value in clinical practice as well as in future research studies.

Wide-field imaging and OCT vs clinical evaluation of patients referred from diabetic retinopathy screening.

PURPOSE: Compare wide-field Optomap imaging and optical coherence tomography (OCT) with clinical examination in diabetic retinopathy (DR). METHODS: Patients referred from Diabetic Eye Screening Programmes to three centres underwent dilated ophthalmoscopy and were assigned a DR grade. Wide-field colour imaging and OCT were then examined by the same clinician at that visit and a combined grade was assigned. Independent graders later reviewed the images and assigned an imaging-only grade. These three grades (clinical, combined, and imaging) were compared. The method that detected the highest grade of retinopathy, including neovascularisation, was determined. RESULTS: Two thousand and forty eyes of 1023 patients were assessed. Wide-field imaging compared with clinical examination had a sensitivity and specificity of 73% and 96%, respectively, for detecting proliferative DR, 84% and 69% for sight-threatening DR, and 64% and 90% for diabetic macular oedema. Imaging alone found 35 more eyes with new vessels (19% of eyes with new vessels) and the combined grade found 14 more eyes than clinical examination alone. CONCLUSIONS: Assessment of wide-field images and OCT alone detected more eyes with higher grades of DR compared with clinical examination alone or when combined with imaging in a clinical setting. The sensitivity was not higher as the techniques were not the same, with imaging alone being more sensitive. Wide-field imaging with OCT could be used to assess referrals from DR screening to determine management, to enhance the quality of assessment in clinics, and to follow-up patients whose DR is above the screening referral threshold but does not actually require treatment.

An analysis of the outcomes for patients with failed primary vitrectomy for rhegmatogenous retinal detachment.

PURPOSE: Our aim was to identify the timing of retinal redetachments and the prognosis for affected patients. METHODS: Retrospective review of electronic patient records and casenotes from two centres. Inclusion criteria were failed primary vitrectomy for rhegmatogenous retinal detachment during a 12-year period. Failure was defined as re- or persistent detachment of the retina prior to a further procedure or at final follow-up. RESULTS: The records of 133 cases of failed primary PPV for RRD were analysed. The mean age at time of primary surgery was 62.9 years, and mean follow-up was over 3 years from the date of primary surgery. In 72.9 % of cases, the redetachment was diagnosed within 2 months of the primary surgery. Eighty-five percent were diagnosed within 3 months, 89.5 % within 4 months, and 97.7 % within 6 months. For patients in whom the primary surgery had failed, the rates of attached retina at final follow-up were 80.5 %, or 68.8 % if PVR B/C were present at the time of primary surgery. The final follow-up success rates (attached retina with no tamponade) were 66.2 % for all patients, and 59.4 % for the subset with PVR B/C at the time of primary surgery respectively. Of the total, 33.8 % had one further vitreoretinal procedure, 30.8 % two more, 25.6 % three more, and 5.3 % had four or more. Visual outcome was better with final success (attached retina and no tamponade, p < 0.0001) and worse with PVR B/C evident on diagnosis of failed primary surgery (p < 0.0001). CONCLUSIONS: A short duration of follow-up can over-estimate surgeon success rates for retinal detachment repair. For patients in whom primary surgery has failed, the prognosis for ultimate success is markedly lower than for primary surgery, and most patients require two or more further procedures to achieve this.

Idiopathic vitreomacular traction and macular hole: a comprehensive review of pathophysiology, diagnosis, and treatment.

Posterior vitreous detachment (PVD) is a common phenomenon in the aging eye. However, this may be complicated by persistent symptomatic vitreomacular adhesions that exert tractional forces on the macula (vitreomacular traction; VMT). VMT itself may be associated with epiretinal membrane formation and the development of idiopathic macular holes (IMH). Such pathologies may cause visual disturbances, including metamorphopsia, photopsia, blurred vision, and decreased visual acuity, which impact an individual's quality of life. Technologies such as optical coherence tomography allow an increasingly more accurate visualisation of the macular anatomy, including quantification of macular hole characteristics, and this facilitates treatment decision-making. Pars plana vitrectomy remains the primary treatment option for many patients with VMT or IMH; for the latter, peeling of the inner limiting membrane (ILM) of the retina has shown improved outcomes when compared with no ILM peeling. The development of narrow-gauge transconjunctival vitrectomy systems has improved the rate of visual recovery following surgery. Ocriplasmin, by degrading laminin and fibronectin at the vitreoretinal interface, may allow induction of PVD in a non-invasive manner. Indeed, clinical studies have supported its use as an alternative to surgery in certain patient populations. However, further research is still needed with respect to greater understanding of the pathophysiology underlying the development of VMT and IMH.

Entry site treatment to prevent late recurrent postoperative vitreous cavity haemorrhage after vitrectomy for proliferative diabetic retinopathy.

AIMS: To assess the effectiveness of treatment to the inner sclerostomy sites at the time of vitrectomy for proliferative diabetic retinopathy (PDR) in reducing the incidence of late recurrent postoperative vitreous cavity haemorrhage (POVCH). METHOD: Retrospective study of a consecutive series of 82 eyes undergoing vitrectomy for PDR by a single surgeon treated with either cryotherapy or argon laser directly to the inner sclerostomy site at the completion of surgery (treatment group). These were compared with a previous consecutive series of 82 eyes operated on by the same surgeon who did not have inner sclerostomy site treatment (control group). The occurrence of any POVCH was recorded within the first 6 months of surgery. RESULTS: The composition of the two groups was similar in terms of age, indication for surgery and a variety of other preoperative factors. There were 64 patients in the control group and 65 in the treatment group. There was a significant reduction in the incidence of late recurrent POVCH in the treatment group. Late recurrent POVCH occurred in 12 (15%) eyes in the control group compared with five (6%) in the treatment group (p=0.03). The number of eyes requiring revision surgery within the first 6 months for late recurrent POVCH was four (5%) in the control group and two (2.5%) in the treatment group (p=0.31). CONCLUSION: This study suggests that inner sclerostomy site treatment is effective in reducing the occurrence of recurrent late POVCH in patients undergoing vitrectomy for PDR. A randomised controlled study is needed to clarify this.

Entry site neovascularization and vitreous cavity hemorrhage after diabetic vitrectomy. The predictive value of inner sclerostomy site ultrasonography.

OBJECTIVE: To assess the incidence of neovascularization of the inner sclerostomy wound and occurrence of postoperative vitreous cavity hemorrhage (POVCH) after vitrectomy for proliferative diabetic retinopathy (PDR). DESIGN: Consecutive prospective longitudinal clinical study. PARTICIPANTS: Seventy-three eyes (58 patients) undergoing primary vitrectomy for PDR. METHODS: Twenty-megahertz (MHz) high-resolution anterior segment ultrasonography was performed on all sclerostomy sites 2 months postoperatively and repeated at the time of any POVCH. The appearance of the inner sclerostomy wound was divided into 4 classes (normal, spheroidal, tent, and trapezoidal, representing entry site neovascularization). The occurrence, degree, and duration of POVCH and need for revision surgery with vitreous cavity washout (VCW) were recorded. Postoperative vitreous cavity hemorrhage was divided into 3 groups-namely, mild, moderate, and major. MAIN OUTCOME MEASURES: Inner sclerostomy wound appearance on ultrasonography, degree and timing of POVCH, and need for VCW. RESULTS: There were 15 eyes in total with POVCH (20%): one patient had a persistent POVCH that required VCW. Fourteen other eyes (19%) had recurrent POVCH. Four (28%) of these 14 eyes with recurrent POVCH were classified as mild and 3 (21%) moderate: all cleared spontaneously with no further intervention needed. None of these had a trapezoidal image. Seven of the 14 eyes with recurrent POVCH were classified as major. Five of these 7 eyes had a trapezoidal image at 2 months postoperatively, and 4 required VCW (5.5% of total no. of eyes in study). All patients with a trapezoidal image experienced some degree of recurrent vitreous cavity hemorrhage (P = 0.0000024). The odds ratio was approximately 330:1. There was a significant correlation between the severity of POVCH and entry site appearance on ultrasound. In the first year of follow-up, all patients requiring VCW after recurrent POVCH had a trapezoidal image present at 2 months postoperatively (P = 0.009). CONCLUSION: The appearance of a trapezoidal image on 20-MHz high-resolution anterior segment ultrasonography at a sclerostomy site after vitrectomy for PDR was highly correlated with the occurrence of nonclearing POVCH and need for VCW. Conversely, the absence of a trapezoidal image in patients with POVCH was associated with spontaneous hemorrhage clearance.