Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss and blindness in people aged ≥50 years in the United States today.¹ Diabetic macular edema (DME) is the leading cause of vision loss in people aged ≤50 years. The treatment for both these conditions is the same: intravitreal injection (IVI). Although the pipeline for innovation in treatment is deep, IVI procedures are going to be the mainstay for the foreseeable future.

An analogy that I often use to describe macular damage that requires initiating IVI treatment to patients is that of a lawn. When the lawn is brown or has >50% of brown patches, intensive treatment is required to get it optimized: fertilizers and frequent watering. However, once we’ve gotten the lawn as green as we can, our job is not done; regular watering for maintenance is necessary to avoid regression. The same is true for both treatment-warranted wet AMD and DME: more intensive IVI treatment initially and then, similar to the optimized lawn, therapy typically continues indefinitely every 4 to 12 weeks to avoid regression. I explain to the patient that regression is vision loss to the level they were at presentation or worse.

INTRAVITREAL INJECTIONS

Intravitreal injection is now the most commonly performed intraocular procedure in ophthalmology.² Every time we perform this treatment, we extend patients’ visual function — as well as their independence — but the procedure comes with a tradeoff. Post-procedure pain and discomfort are relatively common after IVI. Because the retina doesn’t have any nerves, this discomfort can mainly be attributed to the injection site and the ocular surface.

The pretreatment protocol of anesthetic, speculum, and betadine prep irritates the ocular surface, and the injection causes trauma to an already irritated eye. Povidone-iodine (PI) is well established as an effective agent for sterilizing the operative field to reduce the risk of infective endophthalmitis, and more than 99% of retinal specialists use PI before IVI.³ Clinical studies show that PI adversely affects the tear film, decreases the epithelial integrity of the cornea, causes significant ocular surface disease (OSD)-like symptoms, and increases patient complaints about discomfort.⁴

This discomfort is typically attributed to chemical sensitivity to PI on the ocular surface, especially when concentrations of 5% to 10% are used.^1,5 PI is more acidic than the tear layer, and the free iodine that it releases is associated with corneal epithelial cell damage,⁶ corneal endothelial cell apoptosis, and reduction of corneal epithelium barrier function.⁷ Although a topical anesthetic is also administered to reduce injection-associated discomfort, studies have demonstrated that topical ocular anesthetics can also cause temporary corneal epithelial breakdown.^8,9

REPEATED EXPOSURE TO POVIDONE-IODINE

Although PI is necessary for preparation of an aseptic field, there is also a need for managing the symptoms caused by repeated exposure to PI, as well as topical anesthetic and trauma from the IVI itself. Because patients require multiple treatments over many years, there is a compounding effect of repeated traumatic insult from IVI to the ocular surface.

Some patients have OSD symptoms (blepharitis, dry eye, poor blink) that are exacerbated by IVI treatments, while others have no prior history of OSD and develop it as a result of repeated IVI. Patients who experience OSD-related discomfort resulting from, or exacerbated by, IVI are more likely to delay or miss injection appointments, and this leads to undertreatment of disease and worse visual outcomes over time. Thus, being proactive in response to reports of pain or other recovery concerns following IVI helps facilitate the best possible outcome for the patient, both subjectively and objectively.

CARING FOR THE OCULAR SURFACE

It is not uncommon for significant corneal epithelial issues to emerge within the first 24 hours after IVI. When my patients first complained of discomfort and prolonged recovery after receiving dozens of IVI, I tried several things related to the IVI procedure, such as pledget anesthesia, subconjunctival anesthesia, and 0.1% aqueous chlorhexidine, none of which worked. I had some success with dilute betadine (2%) and patching the eye for 12 hours to 24 hours following IVI. However, patients largely hate pressure patching after every IVI.

It appeared that these patients had become sensitized to the injections and were dreading them as much or more than initial IVI. As I questioned them about this, most had the same complaints: discomfort, irritation, and blurry vision that lasted for more than just a few hours (as it had with earlier injections). Now, they said, the blurry vision lasted for 1 or 2 days and was getting worse after each subsequent IVI, causing anxiety about the procedure the day preceding their appointment. What was perhaps a minor 2-hour to half-day inconvenience was transforming into a 3-day to 4-day tribulation.

REGENERATIVE TECHNOLOGY

I began considering the use of regenerative technology in the form of amniotic membrane tissue (AMT) to help these patients (Figure 1). I shared my thoughts with the late Paul Tornambe, MD, who was my partner and colleague at the time. We gathered a small group of AMD patients whom I suspected would benefit most from this treatment. These were patients who had already received up to 30 IVI with no problems but then began complaining of worsening injection-associated pain and increased stress and anxiety at the thought of returning for future IVI appointments. They were also patients who had functional vision in only 1 eye, and continued treatment was the only hope of maintaining not just their vision but their ability to drive, work, and maintain their independence.

Our aim was to improve the ocular surface by reversing damage done by the IVI prep and the procedure itself, and thereby improve the patients’ comfort and reduce their anxiety about returning for future IVI appointments. After some back and forth, Dr. Tornambe and I finally agreed that if we could achieve a 30% improvement based on a subjective scale measuring improved comfort and reduced anxiety, treatment with Prokera AMT (Bio-Tissue) (Figure 2) could be considered a worthwhile intervention. We began with a small pilot study of 12 eyes, which we planned to follow for 3 months.

Our results were encouraging at month 3. After an average of 2 IVI procedures following placement of a Prokera, patients reported approximately 62% improvement in ocular surface symptoms. This was more than double our threshold signal for this to be a potentially viable option in treating IVI patients with recalcitrant pain and discomfort. We followed these 12 subjects for 9 months and learned that 2 patients requested that Prokera be reapapplied due to the previous beneficial effects: 1 patient at month 5.5, and the other at month 8.5. Overall, the beneficial effects of Prokera lasted for 5 months after placement before beginning to decline.

Encouraged by our initial results, we enlarged our cohort size to 40 and are following them in a prospective observational fashion. We hope to present results of this study in the near future.

AMNIOTIC MEMBRANE TISSUE

Amniotic membrane tissue is a vital tool for the treatment of a variety of ocular surface conditions. Amniotic membrane tissue acts as a bandage that protects damaged tissue and as a disease-modifying therapy that promotes regenerative wound healing.^10-12 The 2 types of AMT that are available for ophthalmic purposes are cryopreserved and dehydrated. Cryopreserved AMT (CAM) is kept refrigerated until shortly before use. Dehydrated AMT (DAM) is stored at room temperature and rehydrated just before use.

The cryopreservation process allows retention of heavy chain (HC) peptides covalently conjugated with high molecular weight hyaluronic acid (HA). The HC-HA is noncovalently complexed with pentraxin-3 (PTX3) and forms HC-HA/PTX3, the biologic matrix that is responsible for CAM’s anti-inflammatory and regenerative healing properties. Hyaluronic acid and PTX3 are involved in tissue repair and regeneration.^10,13 It is important to note that HC-HA/PTX3 is not found in DAM,¹⁴ because dehydrating AMT causes disruption or cleaving of the high-molecular-weight HA from the HC peptides. While there are many manufacturers of DAM, there is only 1 manufacturer of CAM.

ANTI-INFLAMMATORY PROPERTIES OF CRYOPRESERVED AMNIOTIC MEMBRANE

Cryopreserved amniotic membrane is used to treat eye diseases such as keratitis, corneal scars, chemical burns, corneal defects, partial limbal stem-cell deficiency, and many other ocular surface diseases with inflammation. Due to its anti-inflammatory and proregenerative actions, CAM promotes epithelial cell adhesion and growth, and it accelerates the recovery of the ocular surface.¹⁴ So, introducing it to the IVI paradigm made sense in our study.

I offer CAM to patients who complain of pain and discomfort that is progressively worsening after a history of at least 20 successful IVI. Patients have been so buoyed by the addition of CAM to their IVI regimen that I am no longer concerned about them delaying or skipping injection appointments. In many instances, they contact my clinic to let us know that they are ready for another CAM application when they begin to feel some OSD irritation beginning to return. They are often so pleased by the effect of the AMT that family members who accompany these patients to their appointments — and do not receive IVI — have expressed interest in having a CAM placed in their eyes.

CONCLUSION

Intravitreal injection is becoming increasingly common. Although physicians do their best to put patients at ease and make the experience as pleasant as possible, IVI ultimately causes trauma to the eye to preserve vision. Over time, the secondary effects of repeated IVI procedures manifest in a significant minority of patients; now, retina specialists have something in their armamentarium to offer them. More study needs to be undertaken to prove the efficacy and benefits of Prokera, but using this technology could help not only reverse the damage caused in the effort to save vision but also make for a more satisfied patient and physician. RP

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