Article

Pharmacotherapy as an Adjunct to Vitrectomy for Retinal Disease

Pharmacotherapy remains a critical component in the management of complex retinal disease.

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Since the introduction of vitrectomy, the realm of therapeutic interventions for retinal diseases has changed the approach to patients as well as the ability to stabilize retinal anatomy while recovering visual function. The advent of more efficient surgical platforms has begun a new era of retinal surgery. Novel approaches to retinal surgery have paved the way for advanced instruments and pharmacotherapy.1 In recent years, the armamentarium of intravitreal agents used as surgical adjuvants to microincisional vitrectomy surgery (MIVS) has evolved significantly. This evolution has led to effective procedures with higher success rates and faster restoration of vision.

The role of pars plana vitrectomy, most recently MIVS, in the diagnosis and treatment of retinal pathology, is undeniable. However, MIVS requires a great deal of skill and finesse, adequate knowledge of the techniques and ocular anatomy, and appropriate preoperative and postoperative management to achieve optimal results.

In our practice, preoperative management is individualized. Patients with systemic diseases that are prone to inflammation or patients with known intraocular inflammation often require pretreatment with anti-inflammatory agents to reduce the burden of severe postoperative inflammation that may affect surgical outcomes. For example, in patients with a history of uveitis requiring cataract surgery, there is a generalized consensus that intraocular inflammation should be clinically quiescent for at least 3 months prior to considering surgery.2 Vitrectomy, on the other hand, doesn’t follow the same rule. One possible explanation for this is that persistent inflammatory cells and mediators circulating in the vitreous gel could be removed with surgery and stop the cycle of persistent reactivation.3 Nevertheless, if the eye has active inflammation at the time of surgery, this may portend longer recovery times and potentially poorer anatomic and visual outcomes. Periocular steroid injections (40mg/mL), oral steroids (prednisone 1 mg/kg/d) with or without nonsteroidal anti-inflammatory drugs (ibuprofen 600 mg TID; indomethacin 75 mg TID) are now frequently given at the physician’s discretion. Protocols can vary but are typically delivered within 1 week of the elective procedure. Despite these measures, sometimes complete control of ocular inflammation can’t be achieved.

Diabetes remains the leading cause of blindness among working-age individuals in the United States. Complex proliferative diabetic retinopathy cases are the bread and butter of retina surgeons. Tractional complications in this subset of patients are sight-threatening. Twenty percent of the 70% of eyes with tractional alterations in the Diabetic Retinopathy Vitrectomy Study (DRVS) worsened after vitrectomy.4 Since the initial DRVS report, there has been a paradigm shift in surgical care led by improvements in visualization, instrumentation, fluidics, and pharmacotherapy. Earlier rather than later surgery is recommended in multiple occasions with promising visual results.5

The introduction of anti-vascular endothelial growth factors (anti-VEGF) once again revolutionized the field of retina. Vascular endothelial growth factor (VEGF) plays a key role in neovascularization.6 Angiogenesis in ocular disease can lead to a myriad of vascular changes in several retinal diseases including vein occlusions, diabetic retinopathy, wet macular degeneration, retinopathy of prematurity and radiation retinopathy, among others. In all these conditions, VEGF levels are dramatically elevated, enhancing ischemia and creating a vicious cycle leading to vascular leakage or neovascularization.7-8

Some concerns have been raised regarding risks of progression of tractional changes with the injection of anti-VEGF agents (“crunch phenomena”); however, the potential of improvement in surgical outcomes has clearly outweighed the risks. Preoperative injection of anti-VEGF, typically bevacizumab (Avastin; Genentech), has the ability to decrease intraoperative bleeding, allows easier dissection of thin and adherent fibrovascular membranes, and reduces the risk of postoperative hemorrhage. Once the patient is ready and has had the clearance for surgery, and the date has been selected, we perform the injection in standard fashion within 1 week of the surgery. With this protocol, we have not seen progression of tractional retinal detachment associated with anti-VEGF treatment.

In children with vitreoretinopathies requiring surgery, preoperative injection of plasmin enzymes has been explored. The vitreous gel in children is formed and hyaloid adhesion is stronger, making for a more challenging surgery. Vitreolysis with these components weakens hyaloid attachments at the vitreoretinal interface and can significantly improve removal of the vitreous in younger populations.9 Unfortunately, the benefit of its use in children has not been clearly established.10-11

A wide array of pharmacological options are available at the time of surgery. Overall, the first choice in our facility is triamcinolone acetonide (TA), which we use in almost every case to ensure adequate vitreous removal. Additionally, TA used as an intravitreal adjunct at the conclusion of the surgical case has been shown to decrease postsurgical inflammation. After that, the choice of agent should be based on the diagnosis and the appearance of the retina intraoperatively. The current pharmacological landscape includes those described below.

STEROIDS

When Peyman et al12 described the visualization of vitreous with the off-label use of TA, vitrectomy surgery immediately benefited from enhanced identification and removal of the posterior hyaloid and vitreous remnants. Its efficacy highlighting residual cortical vitreous is of paramount importance in surgery and relies on the insoluble nature of the white crystals and its integration into loosely organized collagen matrices.13 Triamcinolone acetonide is also frequently used to allow distinction of preretinal membranes. There are 3 options:

  1. Triesence (Alcon) is a FDA-approved, preservative-free preparation of TA, for intraocular use. It comes in 1-mL vials at a concentration of 40mg/mL.
  2. Trivaris (Allergan) is a preservative-free gel for intravitreal injection that is a single-use syringe with 8 mg (80 mg/mL).
  3. Kenalog (Bristol-Myers Squibb) use is off-label. This presentation contains benzyl alcohol as preservative with a concentration of 40 mg/mL.

Figure 1. Triamcinolone acetonide injection to visualize vitreous at the beginning of the surgery (A). Triamcinolone acetonide injection at the conclusion of the vitrectomy (B).

Based on preferences, TA can be used undiluted or diluted with balanced salt solution at a ratio of approximately 1:4 during vitrectomy. Some of the advantages of TA compared to other agents used in chromovitrectomy (described later in the article) are the low cost, the lack of toxicity, and the fact that it is easier to remove from the eye because it coats the surface without binding to the underlying tissue.

Additionally, injecting 4 mg of TA intravitreally at the conclusion of the procedure can use the antipermeability and anti-inflammatory properties of the steroids to reduce macular edema and address potential hypotony.14

ANTI-VEGF

Current anti-VEGF agents have shown similar efficacy and safety profiles, although each agent must be individualized to the patient. These biologic agents target different receptors and isomers, resulting in regression of disease activity and neovessels.15 Thus, preoperative anti-VEGF can reduce bleeding from fibrovascular membranes, improving surgical outcomes while minimizing the risks. This is the rationale for pretreatment of complex proliferative retinal conditions.6 Bevacizumab is the most commonly used drug, and the most cost effective.6-8 At the end of a complex diabetic retinopathy case, another 1.25 mg/0.05 mL of bevacizumab may be injected into the eye.

CHROMOVITRECTOMY

Compounds such as indocyanine green (ICG; Akorn Pharmaceuticals), TA, trypan blue (TB) (MembraneBlue; DORC), brilliant blue (BB) (TissueBlue; DORC), and bromophenol blue have become popular to assist in visualization of epiretinal and internal limiting membranes, facilitating their removal. Evaluation of the safety of these drugs is controversial due to lack of standard methodology.

Indocyanine green, a water-soluble dye that binds to type IV collagen, is the most widely used in the United States. Before instillation in the eye, the 25-mg vial of ICG solution requires dilution in a 1:24 ratio with dextrose 5% in water. The dextrose solution allows adequate staining of the internal limiting membrane without air–fluid exchange.

Some reports linking poor visual outcomes to ICG toxicity to the retinal pigment epithelium (RPE) and optic nerve have been published.16,17 Other studies have also suggested that these adverse effects are dose dependent and that iso-osmolar preparations are not toxic.18 Indocyanine green is our chromovitrectomy agent of choice and, to this day, we have seen no cases of ICG linked phototoxicity. This can be achieved by minimizing contact time of the dye, minimizing light exposure by distancing the light pipe from the retinal surface, and incorporating targeted surgical planning that reduces total surgical time.

Trypan blue is a hydrophilic, water-soluble dye with high affinity for cellular elements, at a concentration of 0.15%. Trypan blue cannot cross living cell membranes; therefore, it stains epiretinal membranes better, which contain abundant dead glial cells, than the internal limiting membrane (ILM) or the vitreous, due to its hydrophilic nature. Trypan blue remains the staining agent of choice for the anterior-segment surgeon needing to stain the lens capsule. During surgery, the surgeon can apply it in 2 ways:19

  1. Performing an air fluid exchange before injecting TB at the standard concentration (0.15%); and
  2. As a 3:1 mixture of 0.15% TB to 10% glucose without an air–fluid exchange.

Trypan blue is approved by the FDA for intraocular use. When used at study concentrations, Gale et al found the component was not toxic to the RPE.20

Brilliant blue is an anionic triarylmethane dye. An iso-osmolar solution at a concentration of 0.025% is used. Several studies suggest great affinity for the ILM and lack of retinal toxicity which suggest a better safety profile that the ICG counterpart.21 It is commercially available and FDA approved in the United States for intraocular use.

Figure 2. Indocyanine green being injected to stain the internal limiting membrane.

Bromophenol blue is very similar to BB. With a concentration 0.13% to 0.2%, bromophenol blue doesn’t require air–fluid exchange. This compound exhibits great affinity for ILM and epiretinal membranes along with a good reported safety profile, making it possibly a better alternative than other dyes. It is currently used for vitreoretinal surgeries in Europe, but it is not FDA approved.22

METHOTREXATE

Methotrexate (MTX) has been successful at treating ocular inflammatory conditions with a good safety profile in adults and children. This antineoplastic (antimetabolite and anti-inflammatory) agent works as a folate antagonist inhibiting proliferation with antifibrotic properties. Several reports have proposed that methotrexate blocks the development of proliferative vitreoretinopathy.23,24

In vitreoretinal surgery, methotrexate has been used in 2 concentrations:

  1. Adding 40 mg of MTX to 500 mL balance saline solution infusion bottle. This infusion will be used during retinal surgery yielding approximately 400 µg of intravitreal MTX.23
  2. Injection of 250 µg of MTX at the end of the surgical procedure.24

An ongoing randomized, prospective clinical trial is currently evaluating a unique formulation of methotrexate to lower recurrent PVR in complex eyes undergoing vitrectomy surgery (NCT04136366).

TISSUE PLASMINOGEN ACTIVATOR

Subretinal hemorrhage is a vision-threatening complication associated with surgical procedures and clinical conditions, such as neovascular AMD, retinal macroaneurysms, and polypoidal vasculopathy. The prognosis is guarded in many of these cases, unless removal or displacement of the blood is performed in a timely manner. The best suggested time for drainage is 10 days to 15 days after the event, when the hemorrhagic clot has started to liquify. With the evolution of vitreoretinal surgery, tPA had been used alone or in combination with filtered air and anti-VEGF for the treatment of large subretinal hemorrhages in several clinical scenarios.25,26

Tissue plasminogen activator (tPA) is a serine protease found on endothelial cells involved in fibrinolysis. Though toxicity has been reported, it is not typically seen in doses less than 25 µg. Recombinant tPA (alteplase [Activase]; Boehringer Ingelheim/Genentech) is usually injected to the subretinal space a 41-gauge cannula at a concentration of 12.5 μg in 0.1 mL.27

GENE THERAPY

Voretigene neparvovec-rzyl (Luxturna; Spark Therapeutics) is the first directly administered gene therapy approved by the FDA targeting a genetic disease for treatment of patients with confirmed biallelic RPE65 mutation. A one-time Luxturna injection provides a working gene to act in lieu of the mutated RPE65 gene. Furthermore, the new protein has been shown to restore a functionally active visual cycle.

The adeno-associated viral-vector-based gene therapy’s efficacy may depend on several factors, including the surgical delivery to the subretinal space. One of the purposes of the delicate procedure is to minimize retinal trauma while maximizing viral transduction of cells. The injection is performed with a 41-gauge blunt-tipped subretinal cannula connected to the viscous fluid control port of the vitrectomy system.28

POSTOPERATIVE PHARMACOTHERAPY

At the end of the surgical procedure, the decision of injecting subtenon steroids is not standard. Invariably, antibiotic and anti-inflammatory agents (usually a steroid) are injected subconjunctivally. Following postoperative management, we tend to prescribe a short or long course of oral steroids if the condition is more proinflammatory or if the patient has other risk factors. In retinal detachment surgeries, protocols may differ, but acetazolamide used 250 mg twice daily for the first 3 days would assist in faster resorption of the subretinal fluid and less worry about intraocular pressure spikes.

DISCUSSION

Pharmacotherapy preoperatively, intraoperatively, and postoperatively remains a critical component in the management of complex retinal disease. Improvements in surgical platforms, vitrectomy probes, and intraoperative visualization have broadened the reach of the vitreoretinal surgeon. Understanding and incorporating pharmacologic treatment strategies requires a focus on each individual surgeon’s preference and experience. Ultimately, the surgeon’s goal is enhancing visual and anatomic outcomes while minimizing risk. Ongoing strides in pharmacotherapy, including suprachoroidal drug delivery, extended release devices, viral vector delivery, and novel therapeutics, will rapidly impact clinical practices to the benefit of patients. RP

REFERENCES

  1. Bhagat N, Zarbin M. Recent innovations in medical and surgical retina. Asia Pac J Ophthalmol. 2015;4(3):171-179.
  2. Hooper PL, Rao NA, Smith RE. Cataract extraction in uveitis patients. Surv Ophthalmol. 1990;35(2):120-144.
  3. Scott RA, Haynes RJ, Orr GM, Cooling RJ, Pavesio CE, Charteris DG. Vitreous surgery in the management of chronic endogenous posterior uveitis. Eye (Lond). 2003;17(2):221-227.
  4. Diabetic Retinopathy Vitrectomy Study Research Group. Two-year course of visual acuity in severe proliferative diabetic retinopathy with conventional management. Diabetic Retinopathy Vitrectomy Study Report #1. Ophthalmology. 1985;92(4):492-502.
  5. Mason JO, Colagross CT, Haleman T, et al. Visual outcome and risk factors for light perception and no light perception vision after vitrectomy for diabetic retinopathy. Am J Ophthalmol. 2005;140(2):231-235.
  6. Castillo-Velazquez J, Aleman I, Rush SW, Rush RB. Bevacizumab before diabetic vitrectomy : a clinical trial assessing 3 dosing amounts. Ophthalmol Retina. 2018;2(10):1010-1020.
  7. Zhao X, Xia S, Chen Y. Antivascular endothelial growth factor agents pretreatment before vitrectomy for complicated proliferative diabetic retinopathy: A meta-analysis of randomized controlled trials. Br J Ophthalmol. 2018;102(8):1077-1085.
  8. Eric L, Ross BA, Hutton DW, et al; Diabetic Retinopathy Clinical Research Network. Cost-effectiveness of aflibercept, bevacizumab, and ranibizumab for diabetic macular edema treatment: analysis from the diabetic retinopathy clinical research network comparative effectiveness trial. JAMA Ophthalmol. 2016;134(8):888-896.
  9. Trese MT. Enzymatic vitreous surgery. Semin Ophthalmol. 2000;15(2)116-121.
  10. Wong SC, Capone A. Microplasmin (Ocriplasmin) in pediatric vitreoretinal surgery: update and review. Retina. 2013;33(2)339-348.
  11. Turgut B, Demir T, Catak O. The recommendations for pediatric vitreoretinal surgery. Adv Ophthalmol Vis Syst. 2019;9(6)142-145.
  12. Peyman GA, Cheema R, Conway MD, Fang T. Triamcinolone acetonide as an aid to visualization of the vitreous and the posterior hyaloids during pars plana vitrectomy. Retina. 2000;20(5):554-555.
  13. Enaida H, Hata Y, Ueno A, et al. Possible benefits of triamcinolone-assisted pars plana vitrectomy for retinal diseases. Retina. 2003;23(6):764-770.
  14. Floman N, Zor U. Mechanism of steroid action in ocular inflammation: inhibition of prostaglandin production. Invest Ophthalmol Vis Sci. 1977;16(1):69-73.
  15. Penn JS, Madan A, Caldwell RB, Bartoli M, Caldwell RW, Hartnett ME. Vascular endothelial growth factor in eye disease. Prog Retin Eye Res. 2008;27(4)331-371.
  16. Ikagawa H, Yoneda M, Iwaki M, et al. Chemical toxicity of indocyanine green damages retinal pigment epithelium. Invest Ophthalmol Vis Sci. 2005;46(7)2531-2539.
  17. Rodrigues EB, Meyer CH, Kroll P. Chromovitrectomy: a new field in vitreoretinal surgery. Graefes Arch Clin Exp Ophthalmol. 2005;243(4):291-293.
  18. Kiilgaard JF, Nissen MH, la Cour M. An isotonic preparation of 1 mg/ml indocyanine green is not toxic to hyperconfluent ARPE19 cells, even after prolonged exposure. Acta Ophthalmol Scand. 2006;84(1):42-46.
  19. Lee KL, Dean S, Guest S. A comparison of outcomes after indocyanine green and trypan blue assisted internal limiting membrane peeling during macular hole surgery. Br J Ophthalmol. 2005;89(4):420-424.
  20. Gale JS, Proulx AA, Gonder JR, Mao AJ, Hutnik CM. Comparison of the in vitro toxicity of indocyanine green to that of trypan blue in human retinal pigment epithelium cell cultures. Am J Ophthalmol. 2004;138(1):64-69.
  21. Enaida H, Hisatomi T, Hata Y, et al. Brilliant blue G selectively stains the internal limiting membrane/brilliant blue G-assisted membrane peeling. Retina. 2006;26(6):631-636.
  22. Balaiya S, Brar VS, Murthy RK, Chalam KV. Comparative in vitro safety analysis of dyes for chromovitrectomy. Retina. 2011;31(6):1128-1136.
  23. Sadaka A, Sisk RA, Osher JM, Duncan MK, Riemann CD. Intravitreal methotrexate infusion for proliferative vitreoretinopathy. Clin Ophthalmol. 2016;10:1811-1817.
  24. Falavarjani KG, Modarres M, Hadavandkhani A, Moghaddam AK. Intra-silicone oil injection of methotrexate at the end of vitrectomy for advanced proliferative diabetic retinopathy. Eye (Lond). 2015;29(9):1199-1203.
  25. Maturi R. Subretinal tissue plasminogen activator (TPA) injection for the treatment of acute subretinal hemorrhages associated with age-related macular degeneration. Invest Ophthalmol Vis Sci. 2004;45(13):3137.
  26. Kamei M, Estafanous M, Lewis H. Tissue plasminogen activator in the treatment of vitreoretinal diseases. Semin Ophthalmol. 2000;15(1):44-50.
  27. Ping F, Hai-Ying J, Qi Zhang, Xin Li Pei-Quan Z. Tissue plasminogen activator-assisted vitrectomy in the early treatment of acute massive suprachoroidal hemorrhage complicating cataract surgery. Int J Ophthalmol. 2018;11(1):170-171.
  28. Davis J, Gregori NZ, MacLaren RE, Lam BL. Surgical technique for subretinal gene therapy in humans with inherited retinal degeneration. Retina. 2019;39:S2-S8.