CONTROVERSIES IN CARE

The Role of Indocyanine Green in Macular Hole Surgery

EDITED BY MICHAEL COLUCCIELLO, MD

In 1991, Kelly and Wendel reported that pars plana vitrectomy with identification and removal of adherent posterior vitreous cortex (with its associated vitreoretinal traction) followed by injection of long-acting gas in the posterior segment and facedown positioning may close an idiopathic macular hole and improve vision in the involved eye.¹ Several different modifications and refinements have occurred since then, generally resulting in an improvement in anatomical and functional outcomes.

The internal limiting membrane may harbor myofibroblasts that contract and contribute to macular hole enlargement.² Removal of the ILM around the hole (“peeling”) has been shown to improve success in idiopathic hole closure.³ Anatomical closure usually translates into improved functional outcome.

Unfortunately, it is often difficult to assess completeness of the ILM peel. Incomplete peeling, or increased operative time to achieve a peel as the surgeon attempts to identify a surgical plane, may result in poor functional outcome due to postoperative persistent macular hole, macular edema, retinal pigment epithelial changes and small scotomas.

Indocyanine green dye stains the ILM, which allows the surgeon to identify all ILM, enabling a complete, efficient peel. However, concerns have been raised over the possibility of RPE and retinal toxicity and induction of apoptosis as a result of the exposure to ICG, especially with higher ICG concentrations and contact times.^4,5

Other vital dyes have been used; surgeons have voiced concerns over their potential toxicity as well. A recent study showed RPE morphological changes in cultured RPE cells with exposure to ICG, infracyanine green and brilliant blue G, and changes in RPE cell membrane permeability and mitochondrial membrane potential with exposure to ICG, patent blue, trypan blue and bromphenol blue.⁶

These concerns have led to controversy in the field: should ICG (or another vital dye) be used in macular hole surgery, or in peeling of epiretinal membranes in general? Are these dyes necessary in macular surgery at all? Drs. John Thompson and Steve Charles discuss their viewpoints.

REFERENCES

1. Kelly NE, Wendel RT. Vitreous surgery for idiopathic macular holes. Results of a pilot study. Arch Ophthalmol. 1991;109:654-659.
2. Yooh HS, Brooks HL Jr, Capone A Jr, et al. Ultrastructural features of tissue removed during idiopathic macular hole surgery. Am J Ophthalmol. 1996;122:67-75.
3. Mester V, Kuhn F. Internal limiting membrane removal in the management of full-thickness macular holes. Am J Ophthalmol. 2000;1:769-777.
4. Yam H F, Kwok AK, Chan KP, et al. Effect of indocyanine green and illumination on gene expression in human pigment epithelial cells. Invest Ophthalmol Vis Sci. 2003;44:370-377.
5. Enaida H, Sakamoto T, Hisatomi T, et al. Morphological and functional damage of the retina caused by intravitreous indocyanine green in rat eyes. Graefes Arch Clin Exp Ophthalmol. 2002;240:209-213.
6. Morales MC, Freire V, Asumendi A, et al. Comparative effects of six intraocular vital dyes on retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. [Epub ahead of print]

NO STAINING FOR ILM REMOVAL

STEVE CHARLES, MD

Many papers have been published concerning the retinal and RPE toxicity of ICG.^1-7 I have personally seen at least 15 macular hole patients operated on by other surgeons using ICG with poor vision and obvious RPE changes seen on autofluorescence. It is my impression from reviewing many published series of macular hole surgery cases that, although closure rates average about 90%, visual outcomes are significantly worse than those in my practice without using ICG. Many surgeons who use ICG protect the RPE by injecting viscoelastic in the macular hole. This would not be done if ICG didn't have a toxicity issue.

There is substantial discussion about pH, osmolarity, concentration, exposure time and diluent suggesting that sufficient safety studies have not been done and many surgeons have observed toxicity. Mixing errors are common in the operating room setting, adding additional risk.⁸

Noncontact wide-angle viewing (BIOM or EIBOS) is a significant factor driving ICG staining of the ILM because of reduced axial and lateral resolution compared to using a plano contact lens. Similarly, wide-angle illumination using a chandelier or Tornambe Torpedo illumination specular, focal and retroillumination make ILM visualization more difficult, also driving ICG use.

Picks, diamond-dusted membrane scrapers and MVR blades damage the retinal surface. Their use is based on finding the outer margin or making an “edge” in the ILM (or epimacular membranes), an unnecessary step with end-grasping Alcon 23/25G DSP ILM forceps. Forceps with a platform longer than 125 μm are not suitable for end-grasping ILM peeling because of lack of apposition at the tips. I have watched several highly experienced surgeons using ICG and picks or scrapers make posterior retinal breaks while performing live surgery for a large audience. I have never made a pos terior retinal break with my end-grasping forceps technique, which doesn't require ICG.

I have reviewed several cases said to have light toxicity from excessive xenon light levels performed by other surgeons. The common thread was use of ICG; the dye is an efficient light absorber, exacerbating light toxicity in addition to producing chemical toxicity.

SUMMARY

Surgeons who use ICG often state that they haven't observed toxicity; it is critical to recall that the probability of an event is 3/N; small series coupled with observer bias and subtle changes can create the false impression that ICG toxicity is not a significant issue. Use of flat plano contact lenses, end-gripping peeling technique with Alcon ILM DSP forceps without picks or membrane or equivalent obviates the need for ICG; why take the risk?

REFERENCES

1. Narayanan R, Kenney MC, Kamjoo S, et al. Toxicity of Indocyanine Green (ICG) in combination with light on human retinal pigment epithelial cells and rat neurosensory retinal cells. Curr Eye Res. 2005;30:471-478.
2. Engelbrecht, NE, Freeman, J Sternberg, et al. Retinal pigment epithelial changes after macular hole surgery with indocyanine green-assisted internal limiting membrane peeling,. Am J Ophthalmol. 2002;133:89-94.
3. Farah ME, Maia M, Rodrigues EB. Dyes in ocular surgery: principles for use in chromovitrectomy. Am J Ophthalmol. 2009;148:332-340.
4. von Jagow B, Höing A, Gandorfer A, et al. Functional outcome of indocyanine green-assisted macular surgery: 7-year follow-up. Retina. 2009;29:1249-1256.
5. Rodrigues EB, Meyer CH, Farah ME, et al. Intravitreal staining of the internal limiting membrane using indocyanine green in the treatment of macular holes. Opthalmologica. 2005;219:251-262.
6. Haritoglou C, Gandorfer A, Gass CA, et al. Indocyanine green-assisted peeling of the internal limiting membrane in macular hole surgery affects visual outcome: a clinicopathologic correlation. Am J Ophthalmol. 2002;134:836-841.
7. Tadayoni R, Paques M, Girmens JF, et al. Persistence of fundus fluorescence after use of indocyanine green for macular surgery. Ophthalmology. 2003;110:604-608.
8. Narvaez J, Wessels IF, Mattheis JK, et al. Intravitreal antibiotics: accuracy of dilution by pharmacists, ophthalmologists, and ophthalmic assistants, using three protocols. Ophthalmic Surg. 1992;23:265-268.

ICG IS SAFE FOR MACULAR HOLE SURGERY

JOHN THOMPSON, MD

The literature strongly supports the desirability of removing internal limiting membrane to help improve the success of macular hole surgery. Indocyanine green is a very useful tool for vitreoretinal surgeons to help identify and remove the ILM.

Like many other tools commonly used by vitreoretinal surgeons — such as fiberoptic endoilluminators, intraocular gases and intravitreal antibiotics — ICG can cause intra-ocular damage if used improperly. Appropriate use of ICG allows the surgeon to reap the benefits of rapid and complete ILM removal without toxicity. The first report of ICG toxicity¹ alerted vitreoretinal surgeons to this possibility and techniques have evolved such that ICG toxicity should no longer be a concern.

Some of the reports of toxicity do not clearly prove that ICG was the culprit. Endoilluminator phototoxicity and mechanical damage to the retina during ILM removal may have been the cause of RPE and nerve fiber layer damage rather than ICG use.

More recent publications have confirmed the safety of ICG for macular hole surgery, including several large non-randomized studies^2-5 and one randomized clinical trial.⁶ The advantages of ICG staining of the ILM are readily apparent. It is true that ILM can be removed relatively easily in some eyes without staining ILM. This technique of peeling ILM with forceps alone works adequately in patients with darker RPE pigmentation. It is more challenging to remove ILM completely in eyes with high myopia, blonde fundus or media opacities.

The consistency of the ILM itself also determines the ease of removal. In some eyes, the ILM seems thicker and can be removed entirely around the macula in two or three pieces while in other eyes the ILM is very friable and tears easily, causing the surgeon to have to remove the ILM in numerous fragments. This is where ICG staining of the ILM is especially helpful. The ability to rapidly visualize exactly where the ILM has been removed allows the surgeon to identify and grasp the elevated edge of the ILM with forceps to continue ILM removal. It is a humbling experience to attempt to remove ILM in one of these difficult cases without ICG, then stain the ILM and see the residual pieces of ILM that were thought to have already been removed.

The more important issue is how ICG can be used safely. The following techniques allow ICG to be used with minimal risk to peel ILM in eyes with macular holes.

First, the ICG mixture must be of a low concentration containing no ICG crystal precipitates. ICG powder is relatively insoluble so constituting and diluting it in a busy operating room may result in inadequate mixing. It is essential to filter the ICG through a microfilter to prevent crystals of ICG from being injected into the eye.

I now prefer to use premixed 0.1% ICG purchased from a compounding pharmacy. This product is single-use and has a reliable concentration of ICG with no particulate matter. I then perform a fluid-air exchange anterior to the disc when the vitrectomy is complete. The fluid within the macular hole should not be aspirated, as this viscous fluid helps to prevent the ICG from diffusing into the macular hole. Then one to two drops of ICG are dripped on the surface of the macula. The small puddle of ICG is kept centered on the macular hole.

The ILM becomes adequately stained in 30 to 60 seconds. Then the eye is refilled with fluid and the ICG is diluted and lavaged from the eye. The vitreous fluid should not still be stained with ICG when the ILM is removed as this decreases visibility of the green-stained ILM. Then the end-gripping forceps (such as those designed by Eckardt) are used to grasp the ILM about one disc diameter from the macular hole edge, and it is removed in a circular motion around the macula. It is only necessary to remove the ILM for about two to three disc diameters around the macular hole.

This technique of staining the ILM with ICG allows the ILM to be removed reasonably rapidly; this in turn reduces the risk of phototoxicity from the fiber-optic endo-illuminators. In most eyes, this technique only stains the ILM within the temporal arcades; minimal ICG is left in the eye at the end of the case.

Alternatives to ICG such as triamcinolone can be used to define where the ILM has been removed, but the triamcinolone does not stain the ILM so the edges of ILM are not visible as with ICG. Trypan blue does not stain the ILM sufficiently well in my experience. Brilliant blue G shows some promise to stain the ILM but is not currently available for use in the United States. Appropriate use of ICG allows it to be used as an important tool to make the ILM re moval more rapid and complete.

REFERENCES

1. Engelbrecht NE, Freeman J, Sternberg P, et al. Retinal pigment epithelial changes after macular hole surgery with indocyanine green-assisted internal limiting membrane peeling. Am J Ophthalmol. 2002;133:89-94.
2. Sheidow TG, Blinder KJ, Holekamp N, et al. Outcome results in macular hole surgery: an evaluation of internal limiting membrane peeling with and without indocyanine green. Ophthalmology. 2003;110:1697-1701.
3. Mavrofrides E, Smiddy WE, Kitchens JW, et al. Indocyanine green-assisted internal limiting membrane peeling for macular holes: toxicity? Retina. 2006;26:637-644.
4. Kumagai K, Furukawa M, Ogino N, et al. Long-term outcomes of internal limiting membrane peeling with and without indocyanine green in macular hole surgery. Retina. 2006;26:613-617.
5. Schaal S, Barr CC. Management of macular holes: a comparison of 1-year outcomes of 3 surgical techniques. Retina. 2009;29:1091-1096.
6. Christensen UC, Kroyer K, Sander B, et al. Value of internal limiting membrane peeling in surgery idiopathic macular hole stage 2 and 3: a randomized clinical trial. Br J Ophthalmol. 2009;93:1005-1015.

IN CLOSING

One reason why our specialty is so enjoyable is that we can have stimulating discussions regarding issues that can be approached effectively via many different, constantly evolving paths. The issues surrounding chromovitrectomy illustrate this. We are fortunate to have two leaders in our specialty, Drs. Thompson and Charles, summarize their stance regarding the issue of staining the macular internal limiting membrane with indocyanine green in this edition of Retinal Physician. RP