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Kazuaki Kadonosono, MD, FASRS

In Japan, there isn’t an organized fellowship program in order to become a retina specialist as there is in the United States. When I graduated from Yokohama City University Medical School in 1988, I was fascinated with the ophthalmology ward. However, I wasn’t given the opportunity to do retinal surgery for quite a long time, as is commonplace in Japan. I was mostly engaged in anterior segment surgery such as phacoemulsification, but also started to research retinal pathology in the laboratory of anatomy (Figure 1).

One day when I encountered an interesting paper in the library, titled “Ultrastructural features of tissue removed during idiopathic macular hole surgery” from researchers at Emory University,1 I recognized the importance of the internal limiting membrane (ILM) in macular hole surgery. After returning to the laboratory, I first examined the similarity of histopathology between the ILM and the anterior capsular membrane of the lens. I soon moved on to examining the utility of indocyanine green (ICG) dye, previously used in cataract surgery, in improving ILM visualization. I'll never forget the first patient who underwent successful ILM removal with ICG, resulting in significant improvement in her visual acuity. She came into my office beaming with happiness.

I started using ICG dye with a concentration of 0.06% along with viscoelastic material for macular hole surgery (Figure 2A),2 a method that was adopted by the ophthalmology community and has been widely used now for over 2 decades (Figure 2B). When I discovered this surgical technique, I knew it was important to minimize the adverse effects of the ICG dye. I decided on that concentration and mixture with viscoelastic after several experimental trials. I have not experienced any surgical complications related to ICG personally; however, there have been animal studies noting the potential for ICG toxicity if used in high concentrations.3 ICG is currently widely used off-label.

Many researchers subsequently focused on finding other dyes that would be as effective as ICG while having no theoretical toxicity to retinal cells. Brilliant Blue G (BBG) was eventually accepted from several candidates as another appropriate dye for staining the ILM.4 This dye had previously been used in the laboratory to stain proteins in cells. BBG has recently become commercially available for clinical use with a concentration of 0.25 mg/ml. Generally, BBG has been found to be safe, although there have been occasional reports of potential toxicity, which may be confounded by other factors such as light toxicity.5 The staining quality, however, may not be as profound as with ICG.6 Trypan blue (TB) has also been investigated as a possible vital dye.7

ILM staining has become an important part of macular surgery, and this procedure has been coined chromovitrectomy (Figure 3). In the future, digital technology using AI algorithms will likely assist in chromovitrectomy, allowing surgeons to reduce the amount of dye used and minimize surgical complications. Perhaps in the future, digital staining without dye may also become a reality in macular surgery.

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References

1) Yooh HS, Brooks HL Jr, Capone A Jr,L'Hernault NL, Grossniklaus HE. Ultrastructural features oftissue removed during idiopathic macular hole surgery. Am J Ophthalmol 1996;122(1):67-75.doi:10.1016/s0002-9394(14)71965-8

2) Kadonosono K, Itoh N,Uchio E, Nakamura S, Ohno S. Staining of internal limitingmembrane in macular hole surgery. Arch Ophthalmol2000;118(8):1116-1118. doi:10.1001/archopht.118.8.1116

3) Maia M, Margalit E,Lakhanpal R, et al. Effects ofintravitreal indocyanine green injections in rabbits. Retina 2004;24(1):69-79.doi:10.1097/00006982-200402000-00011

4) Enaida H, Hisatomi T,Goto Y, et al. Preclinicalinvestigation of internal limiting membrane staining and peeling usingintravitreal brilliant blue G. Retina. 2006;26(6):623-630. doi:10.1097/01.iae.0000236470.71443.7c

5) Soni A, ParameswarappaDC, Tyagi M, et al. Brilliant blue Gtoxicity in macular hole surgeries: a report on combined phototoxicity anddye-induced macular damage. Semin Ophthalmol. 2022;37(1):117-122.doi:10.1080/08820538.2021.1928717

6) Kadonosono K, Arakawa A, Inoue M, et al.Internal limiting membrane contrast after staining with indocyanine green andbrilliant blue G during macular surgery. Retina. 2013;33(4):812-817.doi:10.1097/IAE.0b013e3182807629

7) Teba FA, Mohr A, Eckardt C, et al. Trypanblue staining in vitreoretinal surgery. Ophthalmology. 2003;110(12):2409-2412.doi:10.1016/s0161-6420(03)00716-4

(Milestone essay published 2023)