Visualization Agents for Vitreoretinal Surgery

Intraoperative dyes can be a useful adjunct, but what are the pros and cons? Surgeons share their insights.

ANDREW E. MATHIS, PhD, MEDICAL EDITOR

While the use of intraoperative dyes for peeling of the internal limiting membrane (ILM) during surgery for macular hole and epiretinal membrane (ERM) has been practiced by retinal physicians for a decade, disagreement over which dyes to use and how to use them persist. Each of the most widely used dyes — indocyanine green (ICG), triamcinolone acetonide and trypan blue — has its proponents, and a few dyes are being used for techniques beyond ERM and ILM peeling. Furthermore, the issue of possible toxicity connected to the use of some dyes remains.

INDOCYANINE GREEN

Indocyanine green is a fluorescent cyanine dye that binds to plasma protein, which keeps it localized in the blood vessels. Because of this property, ICG has been used in ophthalmology as an alternative angiographic dye to fluorescein since the 1950s.¹ In 2000, surgeons began using it as a stain in macular hole surgery.² Going on the assumption that macular holes are more likely to close if there have been deeper dissections, and because peeling the ILM results in such dissections,^3,18 ICG has been applied to the ILM to assist peeling by increasing visualization (Figure 1).

Figure 1. Membrane peel with ICG in macular hole surgery.

As of today, many surgeons have adopted the use of indocyanine green dye when performing ILM peeling. However, thanks to reports of possible toxicity, including damage to the retinal pigment epithelium,^4,15,23 when using ICG, many physicians are proceeding with caution.

"I don't use ICG because of the substantial basic and clinical literature demonstrating its dose-dependent toxicity to retinal and RPE cells," says Mark W. Johnson, professor of ophthalmology and visual sciences at the University of Michigan's Kellogg Eye Center.

Other ophthalmologists do use ICG but are still concerned. "I use ICG to visualize ILM in macular hole surgery," says Anat Loewenstein, MD, who practices at the Tel Aviv Sourasky Medical Center in Israel. "However, we have performed studies that support others in the literature showing in rabbits that ICG can be toxic to the rabbit retina. Therefore, we use the smallest amount possible."

Sebastian Wolf, MD, who performs retinal surgery at the Universit�tsspital in Bern, Switzerland, suggests that, when used in a fluid-filled eye, concerns about toxicity might be less relevant than when used in an air-filled eye. "I think ICG toxicity is related to concentration of the dye and the light source," Dr. Wolf says. "Using the visualization agents in a fluid-filled eye, as I do, might not be problematic. Nevertheless, I try to avoid direct contact of ICG to the RPE in macular holes."

TRIAMCINOLONE ACETONIDE

Of the dyes used in retinal surgery, triamcinolone acetonide is probably the best known, if only because of its applications throughout ophthalmology. A synthetic corticosteroid estimated to be eight times stronger than prednisolone,⁵ triamcinolone in injectable form (Kenalog, Bristol-Myers-Squibb) is FDA approved for use in several connective-tissue disorders and autoimmune pathologies. In ophthalmology, it has been used as an adjunct to anti-VEGF treatments in age-related macular degeneration and as an experimental agent in patients with diabetic macular edema and macular edema secondary to retinal vein occlusions.

Triamcinolone's use in visualization was discovered largely by accident; its water-insolubility caused it to be retained for longer periods in the vitreous, which would then have augmented visualization in postoperative examinations.⁶ Since then, triamcinolone has been used in anterior- segment surgery and pars plana vitrectomy to visualize the vitreous and minimize or eliminate loss of vitreous. More recently, it has been applied to the ILM for peeling during macular hole surgery (Figure 2).^7,16

Figure 2. Membrane peel after triamcinolone acetonide application.

One advantage of triamcinolone appears to be greater versatility. "I use triamcinolone for visualizing the vitreous in macular hole surgery to make sure I have a good posterior vitreous detachment, and sometimes in ERM peeling as well," Dr. Loewenstein says. Dr. Johnson also uses triamcinolone to ascertain PVD, noting, "I use it occasionally in any case, diabetic or otherwise, where intraoperative induction of PVD is not straightforward."

Even surgeons who do not normally use dyes will use triamcinolone to visualize the vitreous. For example, William F. Mieler, MD, who is professor and vice chair of the Department of Ophthalmology at the University of Illinois–Chicago, says, "On rare occasion, I employ triamcinolone to visualize the cortical vitreous."

Dr. Johnson uses triamcinolone in a similarly limited way. "While in the great majority of ILM peeling cases I use no visualization agents," he says, "I occasionally use triamcinolone when there are problems, such as media opacity, multifocal intraocular lenses or small anterior capsular opening, that limit visualization of fine detail and/or stereopsis." Dr. Johnson also uses triamcinolone in cases of myopic traction maculopathy in order to identify and remove the layer of cortical vitreous that sometimes remains following PVD.

However, because of the known side effects of any steroid, surgeons exercise extra caution when using triamcinolone.¹⁹ Dr. Johnson elaborates, "I try to avoid triamcinolone in macular hole cases out of concern that triamcin olone particles that become trapped in the base of the hole could theoretically reduce chances for hole closure. When I do use triamcinolone, I make every effort to remove it completely." Also of concern, his group demonstrated in an animal model several years ago that intravitreal triamcinolone increases susceptibility to endophthalmitis, presumably by severely depressing local immune function. "And, of course," Dr. Johnson adds, "there are the persistent problems with intraocular pressure pursuant to using any steroid." Dr. Mieler also notes that when employing triamcinolone, he monitors the postoperative IOP.

TRYPAN BLUE AND BRILLIANT BLUE

Shortly after the onset of use of ICG for ILM peeling, reports of the use of trypan blue intraoperatively for epiretinal membrane began to appear (Figure 3).⁸ Oddly, trypan blue, which had previously been used to stain the anterior capsule during phacoemulsification, had already been shown to be cytotoxic.^9,10 However, several studies have been conducted on possible toxic effects of trypan blue on the retina, and the results have been inconclusive.

Figure 3. Partially peeled internal limiting membrane stained with Membrane Blue in a case of macular hole.

Dr. Johnson is one of the surgeons who expresses concern, saying, "I have been hesitant to use trypan blue, pending additional information regarding its safety." Still, many of these same surgeons are routinely using trypan blue, with several opting for a 0.15% formulation called Membrane Blue by Dutch Ophthalmic USA (Exeter, NH). "I use Membrane Blue for ERM peeling," says Dr. Loewenstein, for instance, "unless it is very thick and nicely visualized." Another advantage of trypan blue is that it is useful for more procedures than ERM peel. "I use Membrane Blue for staining of proliferative vitreoretinopathy membrane, albeit rarely," Dr. Wolf says.

One possible way to ameliorate toxicity concerns of trypan blue that has been investigated is the application of whole blood to the ILM before the application of dye. A 2009 study conducted in Taiwan tested a method whereby whole blood was applied to macular holes in fluid-filled eyes.¹¹ Trypan blue was then applied only on the exposed tissue, which was then removed. Twenty-two of the patients needed only a single surgery to close their macular holes, and mean visual acuity improved from 20/140 to 20/62.

An alternative to trypan blue that has emerged is brilliant blue G (Figure 4), which, despite its derivation from coal tar, began life as textile dye. Marketed for retina as Brilliant Peel (Fluoron GmbH, Ulm, Germany), one of the immediate advantages of BBG is that it underwent preclinical testing in animals before being used in humans, thanks to its later introduction. And, while it has shown limited toxicity in higher doses, it has not been shown to be harmful in limited use.^12,17,22

Figure 4. Membrane peel after staining with brilliant blue G.

Besides replacing trypan blue for many surgeons, BBG can serve as an alternative to ICG as well. "ICG is better for staining the ILM than brilliant blue," Dr. Wolf says, "but since ICG may have some toxicity on the RPE, I therefore use brilliant blue in macular holes."

THE FUTURE OF DYES

Several other intraocular dyes are either under investigation or in limited use at some surgical centers already. These include three new blue dyes (patent blue V, Chicago blue and bromphenol blue), green SF, and rhodulinblau-basic, among others.^20,21 It has also been suggested that dyes that may have toxic side effects but may be more effective than others in aiding visualization be combined with more stable dyes; ICG has been combined with both trypan blue and triamcinolone to this end.^13,14

Of course, some surgeons resist using dyes at all. One retinal physician who was interviewed for this article said, "I personally do not use intraoperative dyes and do not think they are needed for the experienced surgeon. They may of benefit to new surgeons as a learning tool, but once one has enough experience, these adjuncts are not needed. Why use something if it is not needed or could be potentially toxic to the retina?"

For those surgeons who use such dyes, however, there is a view to the future of what visualization agents may offer. "I would love to have an agent that is perfectly safe and that reliably stains the ILM without risk," Dr. Johnson says. "I would also make use of an agent that quickly, reliably and safely could identify patches of remnant vitreous cortex on the retinal surface after PVD. Removal of such vitreous remnants in a variety of cases might reduce the incidence of ERM formation."

LIVE AND LET DYE

For now, that agent does not yet exist, but with growing attention being paid to visualization dyes and, thus, extensive research being done on toxicity, it appears certain that new dyes with minimal risk factors and maximum efficacy will be developed. In the meantime, the dyes of choice of various vitreoretinal surgeons remain as reliable, if somewhat controversial, adjuncts. Given the multitude of options, and the diversity of opinions in the surgical community, a live and let live — or live and let dye, if you will — approach is the prevailing wisdom. Surgeons would do well to investigate the visualization agents independently and arrive at their own conclusions about applicability for the surgical protocols they employ. RP

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