Peter Stalmans

Enzymatic Vitreolysis with Ocriplasmin for Vitreomacular Traction and Macular Holes

BACKGROUND Vitreomacular adhesion can lead to pathologic traction and macular hole. The standard treatment for severe, symptomatic vitreomacular adhesion is vitrectomy. Ocriplasmin is a recombinant protease with activity against fibronectin and laminin, components of the vitreoretinal interface. METHODS We conducted two multicenter, randomized, double-blind, phase 3 clinical trials to compare a single intravitreal injection of ocriplasmin (125 μg) with a placebo injection in patients with symptomatic vitreomacular adhesion. The primary end point was resolution of vitreomacular adhesion at day 28. Secondary end points were total posterior vitreous detachment and nonsurgical closure of a macular hole at 28 days, avoidance of vitrectomy, and change in best-corrected visual acuity. RESULTS Overall, 652 eyes were treated: 464 with ocriplasmin and 188 with placebo. Vitreomacular adhesion resolved in 26.5% of ocriplasmin-injected eyes and in 10.1% of placebo-injected eyes (P<0.001). Total posterior vitreous detachment was more prevalent among the eyes treated with ocriplasmin than among those injected with placebo (13.4% vs. 3.7%, P<0.001). Nonsurgical closure of macular holes was achieved in 40.6% of ocriplasmin-injected eyes, as compared with 10.6% of placebo-injected eyes (P<0.001). The best-corrected visual acuity was more likely to improve by a gain of at least three lines on the eye chart with ocriplasmin than with placebo. Ocular adverse events (e.g., vitreous floaters, photopsia, or injection-related eye pain--all self-reported--or conjunctival hemorrhage) occurred in 68.4% of ocriplasmin-injected eyes and in 53.5% of placebo-injected eyes (P<0.001), and the incidence of serious ocular adverse events was similar in the two groups (P=0.26). CONCLUSIONS Intravitreal injection of the vitreolytic agent ocriplasmin resolved vitreomacular traction and closed macular holes in significantly more patients than did injection of placebo and was associated with a higher incidence of ocular adverse events, which were mainly transient. (Funded by ThromboGenics; ClinicalTrials.gov numbers, NCT00781859 and NCT00798317.).

The International Vitreomacular Traction Study Group Classification of Vitreomacular Adhesion, Traction, and Macular Hole

OBJECTIVE The International Vitreomacular Traction Study (IVTS) Group was convened to develop an optical coherence tomography (OCT)-based anatomic classification system for diseases of the vitreomacular interface (VMI). DESIGN The IVTS applied their clinical experience, after reviewing the relevant literature, to support the development of a strictly anatomic OCT-based classification system. PARTICIPANTS A panel of vitreoretinal disease experts was the foundation of the International Classification System. METHODS Before the meeting, panel participants were asked to review 11 articles and to complete 3 questionnaires. The articles were preselected based on searches for comprehensive reviews covering diseases of the VMI. Responses to questionnaires and the groups opinions on definitions specified in the literature were used to guide the discussion. MAIN OUTCOME MEASURES Optical coherence tomography-based anatomic definitions and classification of vitreomacular adhesion, vitreomacular traction (VMT), and macular hole. RESULTS Vitreomacular adhesion is defined as perifoveal vitreous separation with remaining vitreomacular attachment and unperturbed foveal morphologic features. It is an OCT finding that is almost always the result of normal vitreous aging, which may lead to pathologic conditions. Vitreomacular traction is characterized by anomalous posterior vitreous detachment accompanied by anatomic distortion of the fovea, which may include pseudocysts, macular schisis, cystoid macular edema, and subretinal fluid. Vitreomacular traction can be subclassified by the diameter of vitreous attachment to the macular surface as measured by OCT, with attachment of 1500 μm or less defined as focal and attachment of more than 1500 μm as broad. When associated with other macular disease, VMT is classified as concurrent. Full-thickness macular hole (FTMH) is defined as a foveal lesion with interruption of all retinal layers from the internal limiting membrane to the retinal pigment epithelium. Full-thickness macular hole is primary if caused by vitreous traction or secondary if directly the result of pathologic characteristics other than VMT. Full-thickness macular hole is subclassified by size of the hole as determined by OCT and the presence or absence of VMT. CONCLUSIONS This classification system will support systematic diagnosis and management by creating a clinically applicable system that is predictive of therapeutic outcomes and is useful for the execution and analysis of clinical studies.

Microplasmin intravitreal administration in patients with vitreomacular traction scheduled for vitrectomy: the MIVI I trial

PURPOSE To evaluate the safety and preliminary efficacy of 4 doses and several exposure times of intravitreal microplasmin given before pars plana vitrectomy for vitreomacular traction maculopathy. DESIGN A multicenter, prospective, uncontrolled, dose-escalation, phase I/II clinical trial. PARTICIPANTS Sixty patients enrolled into 6 successive cohorts. INTERVENTION A single intravitreal injection of microplasmin at 1 of 4 doses (25, 50, 75, or 125 microg in 100 microl) administered either 1 to 2 hours, 24 hours, or 7 days before planned pars plana vitrectomy. MAIN OUTCOME MEASURES For safety, a complete ophthalmologic examination, fundus photography, fluorescein angiography, Humphrey visual fields, and electrophysiology; for efficacy, posterior vitreous detachment (PVD) induction as assessed by B-scan ultrasound and ease of PVD induction at the time of vitrectomy. RESULTS The use of microplasmin led to a progressively higher incidence of PVD induction on ultrasonography with increasing time exposure. A PVD before surgery was observed with 25 microg microplasmin in 0, 2, and 5 patients with increasing exposures (2 hours, 24 hours, 7 days). With increasing dose, a PVD before surgery was observed by ultrasound as follows: 25 microg, 0; 50 microg, 1; 75 microg, 2; 125 microg, 3. However, at surgery, with a 125-microg dose, these patients had a discontinuous layer of vitreous present on the retinal surface resulting from the induction of an anomalous PVD in the form of vitreoschisis. One retinal detachment developed shortly after administration of microplasmin. Two developed after surgery. There were no other safety concerns. CONCLUSIONS Results from this initial clinical trial evaluating intravitreal microplasmin show the drug to be well tolerated and capable of inducing a pharmacologic PVD in some patients. These results warrant evaluation of microplasmin in larger, controlled trials.

Autologous peripheral retinal pigment epithelium translocation in patients with subfoveal neovascular membranes

Aim: To evaluate the possibility of translocating autologous peripheral retinal pigment epithelial (RPE) cells and enhance their adhesion to improve functional outcome after choroidal neovascular membrane extraction in patients with subfoveal neovascular membranes. Methods: A prospective, non-controlled surgical study in eight consecutive patients operated between February and July 2001 with final data monitoring in July 2002. All patients had mixed subfoveal membranes of 2–4 disc diameters. Functional tests included Snellen vision and central fixation testing. During vitrectomy, after the extraction of the neovascular complex, 8×104–16×104 RPE cells were removed from the periphery and translocated under the macula following the submacular injection of 2 μg of poly-l-lysine to promote adhesion of the cells. Results: With a follow up ranging from 3 months to 16 months, a pigmented area was seen in the extraction bed of the neovascular membrane in only one patient. Fixation was at the edge of the extraction bed in three patients. Vision remained the same in five patients and deteriorated in three (all with retinal detachment). Retinal detachment due to proliferative vitreoretinopathy occurred in three patients. Conclusions: The translocation of autologous peripheral RPE cells after membrane extraction was technically possible in a sterile manner, but was associated with a high proliferative vitreoretinopathy rate and in the present series had no measurable positive effect on functional outcome.

Trypan blue staining in vitreoretinal surgery

PURPOSE To evaluate the efficacy of trypan blue for staining the internal limiting membrane (ILM) and epiretinal membranes (ERM) in vitreoretinal surgery. DESIGN Prospective noncomparative case series. PARTICIPANTS Fifty eyes of 50 patients with macular pucker (n = 22), macular hole (n = 18), or a combination (n = 2), proliferative vitreoretinopathy (n = 5), or diabetic retinopathy (n = 3). METHODS Trypan blue 0.2% was used to stain the ILM or ERM during vitreoretinal surgery. MAIN OUTCOME MEASURES The intraoperative visibility of the membranes was scored as poor, moderate, good, or excellent. RESULTS The application of trypan blue onto the ILM or the ERM resulted in a useful bluish staining, facilitating the identification, delineation, and removal of the membranes in all surgeries. No residual staining or adverse effects related to the dye were observed. CONCLUSIONS Trypan blue stains both ILM and ERM and might be an useful tool in vitreoretinal surgery.

Efficacy of Intravitreal Ocriplasmin for Treatment of Vitreomacular Adhesion: Subgroup Analyses from Two Randomized Trials

PURPOSE To evaluate the efficacy of a single intravitreal injection of ocriplasmin 125 μg across relevant subpopulations of patients with symptomatic vitreomacular adhesion (VMA)/vitreomacular traction (VMT), including when associated with macular hole. DESIGN Two multicenter, randomized, placebo-controlled, double-masked, 6-month studies. PARTICIPANTS A total of 652 randomized patients (464 receiving ocriplasmin; 188 receiving placebo). METHODS A single intravitreal injection of ocriplasmin 125 μg or placebo in the study eye. MAIN OUTCOME MEASURES Prespecified subgroup analyses were conducted to evaluate the effects on the proportion of patients with nonsurgical resolution of focal VMA at day 28, nonsurgical full-thickness macular hole (FTMH) closure at month 6, and categoric improvement in best-corrected visual acuity (BCVA) at month 6. RESULTS Resolution of VMA at day 28 was achieved more often in younger patients (<65 years), eyes without epiretinal membrane, eyes with FTMH, phakic eyes, and eyes with a focal VMA ≤ 1500 μm. Eyes with FTMH width ≤ 250 μm were more likely to achieve nonsurgical FTMH closure. Categoric ≥ 2-line and ≥ 3-line improvement in BCVA occurred more often in younger patients (<65 years) and in patients with a lower baseline BCVA (<65 letters). Treatment differences in favor of ocriplasmin were generally observed across each subgroup of subpopulations studied. CONCLUSIONS Subgroup analyses confirmed the positive effect of ocriplasmin across relevant subpopulations.

Oct-based interpretation of the vitreomacular interface and indications for pharmacologic vitreolysis.

Purpose: To review the role of optical coherence tomography (OCT) in diagnosis and management of vitreomacular disease and the impact of OCT on potential uses of ocriplasmin, a new pharmacologic vitreolysis agent recently approved by the U.S. Food and Drug Administration for the treatment of symptomatic vitreomacular adhesion. Methods: Analysis of current literature regarding OCT in diagnosis and management of vitreomacular interface disease. Results: Posterior vitreous detachment is typically a nonpathologic age-related event. Anomalous posterior vitreous detachment emerges when the vitreous cortex fails to cleanly detach from the macula, optic nerve, or other adherent sites. Focal vitreomacular adhesion is a nonpathologic anatomical designation associated with perifoveal posterior vitreous detachment but normal retinal morphology on OCT. Vitreomacular traction is a pathologic consequence of persistent vitreous attachment with structural disturbance of the macular retina visible on OCT. Full-thickness macular holes are foveal defects continuous through all retinal layers to the retinal pigment epithelium. Vitreomacular traction and macular hole with focal vitreomacular adhesion are indications for pharmacologic vitreolysis. Conclusion: Noninvasive high-resolution OCT imaging has transformed the understanding of vitreomacular interface disease. Careful evaluation of the vitreomacular interface with OCT has increased in importance with the introduction of ocriplasmin for vitreomacular adhesion associated with symptomatic anatomical retinal changes.

Oximetry in glaucoma: correlation of metabolic change with structural and functional damage

Purpose:  To determine whether retinal vessel oxygen saturation in patients with glaucoma is associated with structural optic disc and retinal nerve fibre layer (RNFL) changes and visual field (VF) defects.

Trypan blue not toxic for retinal pigment epithelium in vitro.

PURPOSE To investigate whether trypan blue has a toxic effect on cultured retinal pigment epithelial (retinal pigment epithelium) cells. DESIGN Experimental study with a direct live/dead cell staining technique using fluorescent dyes. METHODS Cultured human retinal pigment epithelium cells were exposed for 5 minutes to various concentrations of trypan blue (0.06%, 0.15%, 0.30%), and cell viability was confocally measured. RESULTS No increased cell death was found in cultures incubated in any of the trypan blue concentrations used. CONCLUSION These findings indicate that a short exposure of trypan blue does not have a toxic effect on cultured retinal pigment epithelium cells.

Anatomical and visual outcome of macular hole surgery with infracyanine green-assisted peeling of the internal limiting membrane, endodrainage, and silicone oil tamponade

PURPOSE To evaluate the anatomical and visual outcome in macular hole patients who underwent surgery with infracyanine green-assisted internal limiting membrane peeling. DESIGN A prospective case series with 51 consecutive eyes of 49 patients with idiopathic, iatrogenic, or traumatic Stage 2, 3, or 4 macular holes. METHODS After removing the vitreous, in all eyes infracyanine green-assisted removal of the internal limiting membrane was performed. Patients older than 65 years of age underwent a simultaneous phacoemulsification. At the end of surgery, a silicone oil tamponade was used in all cases, and all patients were asked to position face down for 24 hours. Optical coherence tomography was performed preoperatively and postoperatively to determine the macular hole stage/size and the anatomical closure rate, respectively. RESULTS The mean follow-up time was 9.8 months (range, 6-26 months). The overall median duration between the first symptoms and the surgery was 5 months. The overall anatomical success rate after one surgery was 92% (47 eyes), while that of chronic and nonchronic ones was 72.3% and 97.5%, respectively. The median preoperative visual acuity was 20/160 (range, 20/30 to counting fingers) and increased to 20/50 (range, 20/20 to 20/400) postoperatively. The mean increase in visual acuity was 3.7 lines (range, -4 to 10 lines). Of all 51 operated-on eyes, 26 (51%) eyes had a final visual acuity of 20/50 or better. CONCLUSIONS These findings indicate that infracyanine green-assisted removal of the retinal internal limiting membrane appears to induce a high incidence of anatomical closure, with good visual outcome.