Surgery at the vitreoretinal interface: Current concepts and future prospects.

Within the last years histomorphological correlations and new histological preparation techniques such as flat mount preparations of the internal limiting membrane (ILM) helped us to improve our understanding of the complex pathology of vitreomacular diseases and refine our concepts of surgical interventions at the vitreoretinal interface, including the idea of the removal of relevant scaffolds for cellular proliferations such as the ILM.[12]

This was aligned not only by improvements of vitrectomy machines (increased cut rates, improved pumps, improved fluidics, etc.), but also a continuous miniaturization of the surgical instruments such as cutters, forceps, scissors from 20 gauge to 23 or 25 gauge, and even 27 gauge is experimental. In addition, improved illumination as well as viewing systems allow for a better visualization not only of the periphery of the retina. All these refinements greatly helped to reduce surgical trauma, facilitated surgical maneuvers and improved postoperative comfort for the patient. Thus, mechanical means of vitrectomy have constantly been optimized during the years.

Meanwhile, as pharmacotherapy of retinal diseases has become an essential standard in the field of medical retina, which is substantiated by many prospective clinical trials of different phases, new ideas, and concepts with regard to pharmacotherapy have also emerged in the field of vitreoretinal surgery and provide very promising new tools in the armamentarium of the vitreoretinal surgeon.

Chromodisscetion

The application of vital dyes to visualize transparent and sometimes barely visible target structures such as the ILM, epimacular membranes or vitreous has become very popular among vitreoretinal surgeons. “Chromodissection” made ILM peeling accessible even to the less experienced surgeon. Epimacular membranes can be stained using the anionic disazo dye trypan blue, which is commercially available in a concentration of 0.15% for that purpose. For ILM peeling, two other dye classes are currently predominantly used for ILM peeling: The cyanine dye indocyanine green (ICG) and the triarylmethane dye brilliant blue G (BBG). Due to tissue dye interactions and alterations of its collagen structure, the stained ILM can be peeled off more easily, and postulating that the dye used provides a high biocompatibility, with less damage to underlying retinal structures such as the nerve fibers and Muller cell endfeet. While the staining effect seen after ICG use appears more pronounced compared to BBG,[3] the latter seems to provide the better safety profile and is approved in many countries. Given this background, it seems that an ideal candidate dye would be a dye incorporating the excellent contrast provided by ICG and the high biocompatibility of brilliant blue (i.e. strongly absorbing at visible wavelengths, conveniently tissue binding, nontoxic, and physiologically degradable at a practical time scale). New molecules are under investigation, being adapted to the spectral sensitivity of the human eye and to the standard illumination used during surgery and providing improved absorption and fluorescent qualities, equal staining properties but a better safety profile compared to ICG.[4] Investigations also aim at enhancing the contrast by implying both a blue absorption color and an even stronger purple fluorescence color. Additionally, several other absorbent dyes have been subject of experimental in vivo and ex vivo experiments including among others methyl violet, crystal violet, eosin Y, Sudan black B, methylene blue, toluidine blue, light green, indigo carmine, fast green, Congo red, Evans blue, and bromophenol blue.

Furthermore, it becomes apparent that there are additional tissue dye interactions that need to be considered. It was shown very recently, that any dye, be it BBG or ICG, interferes with the biomechanical properties of the tissue. It could be demonstrated that both dyes increase the rigidity of the ILM and lens capsule significantly. This fact may very well explain the observation made during vitreoretinal surgery that the stained ILM can be peeled off easier and in larger fragments [Figure 1].[57]

Figure 1

Averages of all map-results of internal limiting membrane (ILM) are plotted with respect to the measured side (vitreal: Blue; retinal: Red), with error bars showing the standard error of the mean. Indicated P values hold a significance level of 5% and are calculated from a t-test. WT = control, BB = brilliant blue, BBL = brilliant blue and illumination, ICG = indocyanine green, ICGL = indocyanine green and illumination. Differences between control (WT) and BBL and ICGL were also significant both for the retinal as well as the vitreal surface

The availability of different dyes with selective staining properties allows for variable operative techniques and sequential “chromodissection” of the tissue. In theory, one could stain the vitreous using triamcinolone and stain epimacular membranes using trypan blue, followed by ILM staining using brilliant blue. In epimacular membrane surgery, where the vitreous is detached already in most cases, a reasonable approach is to peel the epimacular membrane without adjuncts first, and then visualize the ILM and peel areas where ILM can be detected.[6] In macular hole surgery, the ILM can be stained without prior removal of epimacular tissue.

Pharmacologic Vitreolysis

Posterior vitreous detachment (PVD) is a progressive physiological process, involving both syneresis (liquefaction) and synchisis (separation). However, spontaneous PVD is very often incomplete and remnants of the vitreous adhere firmly either to areas in the periphery of the retina or to the macular area as seen in several tractive maculopathies including macular holes or vitreomacular traction syndromes. In addition, focal abnormal vitreoretinal adhesions may also be implicated in certain types of diabetic macular edema and exsudative age-related macular degeneration.

Our present therapeutic approach in these tractional maculopathies is to relieve tractional forces surgically by mechanical means inducing a more or less complete PVD using suction exerted by the vitrectomy probe, followed by a removal of remnants of vitreous collagen fibers and cellular proliferations and the ILM using an endgripping forceps. However, it may be hypothesized that direct manipulation in the area of the macula and the removal of the ILM itself somehow have an impact on function in the macular area or interfere with the morphological integrity of the retinal layers, especially when being removed with the aid of visualizing agents. Therefore, although ILM peeling appears safe from a clinical point of view, it may not be the optimum treatment option with regard to the best possible functional results.

Given this background, leaving the ILM in place and cleaving the vitreoretinal interface at the vitreal side of the ILM suing a pharmacological liquefaction of the vitreous gel and simultaneous enzymatic separation of vitreous fibrils from the inner aspect of the ILM may result in a resolution of focal vitreomacular adhesions and represent an alternative approach to treat traction related retinal and macular diseases. This pharmacologic induction of a PVD, if achieved early in the course of retinal or macular diseases, may have also a potential as a prophylactic treatment against advanced stages of potentially sight threatening conditions such as diabetic retinopathy or AMD. A variety of intravitreally applied enzymes has been investigated in animal studies so far and some of them have even progressed to clinical trials in humans. Based on the present published data microplasmin seems to be the most promising substance. Microplasmin represents a recombinant protein that contains the catalytic domain of human plasmin and nonspecific serine protease cleaving a variety of glycoproteins such as fibronectin, laminin, fibrin, and thrombospondin, which are involved in the adherence of the vitreous cortex to the ILM. Experimentally, microplasmin has been shown to increase vitreous diffusion coefficients in vitro using the noninvasive technique of dynamic light scattering and caused simultaneous vitreolysis and posterior vitreous separation in ex vivo and in vivo animal eye models in an apparent dose- and time-dependent fashion without morphological alterations in the retina. In a human, double-masked, Phase II trial[8] a nonsurgical resolution of vitreomacular adhesion was observed in 44% of patients after a single injection with 125 μg. If this dose was repeated up to three times, adhesion release was observed in 58% of patients 28 days after the final injection. Another placebo-controlled, double-masked, dose-ranging phase II clinical trial[9] observed that an injection of 125 μg microplasmin was associated with a greater likelihood of induction and progression of PVD than placebo injection 7 days prior vitrectomy. A most recent study on 652 eyes using a single intravitreal injection of 125 μg showed a resolution of vitreomacular traction and closure of macular holes in significantly more patients than did injection of placebo although the treatment was associated with a higher incidence of transient ocular adverse events [Table 1].[10]

Table 1

Effect of the treatment using ocriplasmin