Release of experimental retinal vein occlusions by direct intraluminal injection of ocriplasmin

Purpose Retinal vein occlusions (RVO) are a major cause of vision loss in people aged 50years and older. Current therapeutic options limit the consequences of RVO but do not eliminate the cause. Cannulation of the involved vessel and removal of the clot may provide a more permanent solution with a less demanding follow-up. However, cannulation of smaller retinal veins remains challenging. This paper explores the use of ocriplasmin (recombinant plasmin without its kringles) to clear RVO, using a robotic micromanipulator. Methods Branch RVO were induced in a porcine model with rose bengal followed by 532nm endolaser to the superior venous branch of the optic nerve. The vein was cannulated proximal to the occlusion or beyond the first branching vessel from the obstruction. The vein was infused with a physiologic citric acid buffer solution (CAM) or CAM/ocriplasmin. The time of cannulation, number of attempts, and the ability to release the thrombus were recorded. Results Cannulation and infusion was possible in all the cases. The use of a micromanipulator allowed for a consistent cannulation of the retinal vein and positional stability allowed the vein to remain cannulated for up to 20min. In none of the attempts (5/5) with CAM did the thrombus dissolve, despite repeat infusion/relaxation cycles. In 7/7 injections of CAM/ocriplasmin near to the point of obstruction, the clot started to dissolve within a few minutes of injection. An infusion, attempted beyond the first venous branch point proximal to the clot, was unsuccessful in 2/3 attempts. Conclusions Ocriplasmin is effective in resolving RVO if injected close to the site of occlusion with the use of a micromanipulator

Relative value of clinical variables, bicycle ergometry, rest radionuclide ventriculography and 24 hour ambulatory electrocardiographic monitoring at discharge to predict 1 year survival after myocardial infarction

The relative value of predischarge clinical variables, bicycle ergometry, radionuclide ventriculography and 24 hour ambulatory electrocardiographic monitoring for predicting survival during the first year in 351 hospital survivors of acute myocardial infarction was assessed. Discriminant function analysis showed that in patients eligible for stress testing the extent of blood pressure increase during exercise slightly improved the predictive accuracy beyond that of simple clinical variables (history of previous myocardial infarction, persistent heart failure after the acute phase of infarction and use of digitalis at discharge), whereas radionuclide ventriculography and 24 hour electrocardiographic monitoring did not. The predictive value for mortality was 12% with clinical variables alone and 15% with the stress test added. Radionuclide ventriculography and 24 hour electrocardiographic monitoring were slightly additive to clinical information in the whole group of patients independent of the eligibility for stress testing (predictive value for mortality 24% with clinical variables alone and 26% with radionuclide ejection fraction and 24 hour electrocardiographic monitoring added). It is concluded that the appropriate use of simple clinical variables and stress testing is sufficient for risk stratification in postinfarction patients, whereas radionuclide ventriculography and 24 hour electrocardiographic monitoring should be limited to patients not eligible for stress testing

Design schematic of the micromanipulator.

<p>Shown are the the various axes of rotation and degrees of freedom (DOF). The parallelogram mechanism kinematically constrains the instrument pivot to the entry point into the eye.</p

Green epifluorescence (A 20X, B 10X) and H&E stain (C: 20X, D:10X) of a laser induced vascular occlusion.

<p>The eye was collected within 2 hours of the occlusion. Epifluorescence in the green channel confirms the presence of fibrin while the remainder of the thrombus is composed of a network of platelets and erythrocytes and inflammatory cells.</p

Hematoxylin-eosin stain (A-5x, B-10X) of an occluded vessel.

<p>Damage to the surrounding retina and underlying choroid is clearly visible following laser extending beyond the limits of the vascular wall. However, the vascular lumen is occluded with limited damage to the vessel wall. Extensive choroidal hemorrhage indicates that considerable damage was also induced in the choroidal circulation.</p

SLO image (left) and corresponding OCT image of the retina pre and post induction of a vein occlusion.

<p>OCT showing the site of a venous occlusion. A- prior to the induction of a thrombus. B- shortly after the creation of a venous occlusion, the outer diameter of the vein increases in size. An area of hyperfluorescence appears in the upper portion of the vascular lumen corresponding to the area of fibrin deposition within the thrombus (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162037#pone.0162037.g007" target="_blank">Fig 7</a>). In the lower portion, the area of hypofluorescence corresponds to a dense meshwork of erythrocytes, platelets and inflammatory cells. An associated serous detachment is also present, often appearing within 30 minutes of the induction of the occlusion. In panel C, 14 days after the induction of the thrombus, there is still retinal inflammation present as witnessed by hyper reflective dots in the retina and the vitreous. A partial posterior vitreous detachment is present containing a number of inflammatory cells and residual debris. The area around the vein is thinned as the outer retinal layers are reduced in size.</p