The application of mitomycin C (MMC) after corneal cross-linking (CXL) does not prevent development of corneal haze after the procedure, but it does contribute to development of more corneal haze, according to Shady T. Awwad, MD, professor of clinical ophthalmology at the American University of Beirut Medical Center, in Lebanon.

The rationale for applying MMC after CXL has been the inhibition of incoming keratocytes following the procedure. However, abundant cytokine release from a surge in apoptosis due to the combination of CXL and MMC seems to be responsible for the development of more haze.

Awwad and colleagues reached this conclusion based on the results of a retrospective, single-center study of 72 patients (87 eyes with keratoconus) who underwent CXL from June 2013 to January 2015 at the American University of Beirut Medical Center. The same surgeon performed all CXL procedures using the Dresden protocol. MMC was applied at the end of each CXL procedure as part of the routine protocol from February 2015 to December 2015.

The results obtained from the patients treated with CXL alone was compared with the patients who underwent CXL and application of MMC. All patients were followed for 1 year and underwent periodic examinations during that period. The clinicians used Cirrus high-definition optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec AG) to monitor the stromal haze. Optical coherence tomography (OCT) sections of stromal haze were analyzed using a patented machine learning algorithm, developed and published by the authors, to automatically detect and objectively stage areas of stromal haze. The visual results were slightly better without MMC—but not significantly so—and the topographic results with/without MMC were significantly better compared with preoperatively.

According to Awwad, the overall anterior stromal haze was significantly (

 < .05 for all comparisons) greater at all postoperative time points (ie, at 1, 3, 6, and 12 months when MMC was applied compared with when CXL alone was performed). The mean gamma-decoded anterior stromal reflectivity on OCT scans was 26.0 ± 15.0 vs 14.8 ± 04.7 gray scale units at 1 month and 18.4 ± 9.3 vs 13.9 vs 4.4 at 12 months.

Analysis of the middle stromal reflectivity indicated that haze was significantly greater at the 12 month time point but did not reach significance at any time in the posterior stroma. The reflectivity of the anterior stromal haze area (which is selected by the software as displaying more haze than the surrounding area), calculated as the mean pixel intensity in a particular corneal region, was 33.1 ± 16.6 vs 23.2 ± 05.9 at 1 month and 27.1 ± 12.8 vs 20.6 ± 07.9 at 12 months for the CXL with MMC and the CXL groups, respectively (

Awwad concluded by raising another area for consideration, notably the implications of this study on simultaneous photorefractive keratectomy plus CXL candidates, where the value and potential risks of MMC should be critically appraised.

Awwad has no financial disclosures related to this content.

Articles

The application of mitomycin C after corneal cross-linking does not prevent development of corneal haze after the procedure, but it does contribute to development of more corneal haze.

MMC increases corneal haze after CXL

Thyroid eye disease (TED) is a rare autoimmune condition that is associated with Graves disease and is vision-threatening, making its identification all the more important, according to Gary Lelli, MD, vice chairman of ophthalmology at Weill Cornell Medical College in New York, New York.

Although this association is recognized, TED and Graves disease are 2 separate entities. “The TED component,” Lelli said, “can occur in up to 50% of patients with Graves disease, but also in hypothyroid and normal thyroid levels.”

In addition, TED occurs much more often in women—that is, as much as 5 times more often—and more in the fourth decade of life. A second peak can occur in older patients in their sixth decade of life.

In addition, smokers are much more likely to develop TED and have a longer period of inflammation from TED as well as a more severe disease course. The inflammation that develops in TED around the eye and eye socket can cause progressive changes, resulting in functional vision disorders, patient discomfort, and changes in patient appearance over relatively short periods of weeks to months, Lelli explained.

A menu of symptoms accompanies TED, such as severe dry eye, ocular redness and irritation, ocular bulging, eyelid retraction, and blurry vision. The characteristic inflammation associated with TED can impact the ocular muscles, resulting in diplopia and a detrimental effect on daily activities, such as reading and driving.

In the most severe cases, inflammation can cause compression of the optic nerve, resulting in visual loss. This most severe result can occur in approximately 2% to 5% of patients. Inflammation also can affect the normal fat behind the eyes and cause hypertrophy. This scenario is involved with ocular bulging. Swelling that is related to the fat hypertrophy also can be apparent in the lower and upper eyelids.

Lelli emphasized that an evaluation conducted by the appropriate specialist is the most important factor in diagnosing and managing this patient population. A history of any thyroid imbalance, especially a history of Graves disease, should signal an evaluation by an oculoplastic surgeon or a neuro-ophthalmologist.

Early treatment and putting a team of clinicians in place that includes—in addition to the oculoplastic surgeons and neuro-ophthalmologist—an endocrinologist, a strabismus specialist, and in some cases a psychiatrist or psychologist to assist with the emotional problems that accompany drastic changes in appearance are most beneficial, Lelli advised.

Because TED has a variety of presentations, the first step is categorization of the patient regarding the disease stage, degree of inflammation, specific ocular symptoms, and presence of any aesthetic changes. Establishing this base of information then leads to determination of the appropriate treatment, Lelli said.

Treatment ranges from addressing symptoms with dry eye drops, for example; antioxidants to decrease the inflammation; oral or intravenous anti-inflammatories; and surgery to relieve ocular bulging, eyelid retraction, and diplopia. “There is a wide range of treatment options, but they hinge on assembling the right team of clinicians who can properly diagnose and categorize patients,” he said.

Although there currently is no cure for TED, Lelli reported that more targeted treatments for patients are in the offing.

“A lot of the disease and orbital inflammation occur at the level of the orbital fibroblasts, receptors that are targeted by the autoimmune process to create inflammation,” he said. “We have ways to target those, and more research is being done. We can make the disease substantially more tolerable for patients.”

The second TED awareness week was held this year, with a focus of disseminating more information about TED to patients and clinicians alike. A small percentage of patients with TED (ie, 5%-10%) have hypothyroidism, and a baseline examination is warranted.

The goal is to provide information to patients, ophthalmologists, and other eye care clinicians to raise their awareness of TED signs and symptoms in patients who have a history of thyroid disease, according to Lelli. A referral to an oculoplastic surgeon or neuro-ophthalmologist may catch the disease early in the process.

Lelli advises that clinicians who have patients with Graves disease or a thyroid condition should look for the signs and symptoms of TED. If a clinician is suspicious that a patient may have TED, speed is of the essence. An early evaluation by specialists can help get the patients on the right treatment path if warranted. Lelli also suggested the website, focusonted.com, to provide useful information about the disease for patients and doctors as well as specialists listed by ZIP code.

Lelli has no proprietary interest in any aspect of this report.

An evaluation conducted by the appropriate specialist is the most important factor in diagnosing and managing this patient population. 

Focusing on TED: Rare but devastating

To control pain and inflammation most effectively and responsibly for our cataract surgery patients, we must not only use the appropriate drugs but also ensure they are delivered in the most beneficial manner. We should be mindful of the implications of our pharmaceutical strategies and their impact on our patients.

The opioid crisis in this country may have taken a back seat to the COVID-19 pandemic in terms of headlines, but it certainly has not faded. If anything, it has worsened. Nearly 50,000 people in the United States died from opioid-involved overdoses in 2019, according to the National Institute on Drug Abuse.1 Around 21% to 29% of patients who are prescribed opioids for chronic pain misuse them, between 8% and 12% of people using an opioid for chronic pain develop an opioid use disorder, and an estimated 4% to 6% who misuse prescription opioids transition to heroin.

The chances of developing an opioid use disorder depends on factors, such as length of time one is prescribed opioids for acute pain and length of time that people continue taking the drug. In the United States, the total economic burden of prescription opioid misuse is estimated to be $78.5 billion a year, according to the Centers for Disease Control and Prevention.

It has been reported that opioid-naïve cataract surgery patients who receive an opioid prescription within 7 days of surgery are 1.6 times more likely to be using opioids long-term than those who are not prescribed an opioid following cataract surgery.

 Being older than 50 is a risk factor for chronic opioid use following surgery, therefore most cataract surgery patients are considered at greater risk of opioid dependency.

 It is clear that ophthalmologists, like other physicians, should seek to avoid prescribing opioids whenever possible.

Our cataract patients frequently struggle to adhere to complex postoperative drop regimens. We commonly prescribe 3 different agents—a nonsteroidal anti-inflammatory drug (nSAID), a steroid, and an antibiotic—and expect them to instill these drops as directed. This is a problem, as we know patients do not use their medications properly, with adherence being a major obstacle.

 In fact, 1 study showed that as many as 92% of patients do not correctly instill drops, being hindered by manual dexterity problems and other physical limitations.8 We surgeons seek to not only control pain and inflammation but also prevent it to ensure the best patient experience and optimal visual outcomes, particularly in the setting of premium IOLs.

Today we have the option of adopting delivery platforms that require no effort on the part of patients—this is a sea change in our strategies. One such option is preservative-free Dextenza, a dexamethasone 0.4-mg intracanalicular insert made of a resorbable polyethylene glycol–based hydrogel. The insert is placed within the canaliculus to provide a hands-free and tapered delivery of drug to the ocular surface. It can be inserted preoperatively or intraoperatively, and it takes just 1 minute to do. The highest concentration of dexamethasone is released during the first 2 weeks, and it slowly tapers over a period of about 1 month. The insert demonstrated a retention rate of 99% in the punctum at day 14 in the studies. Phase 3 studies showed there were no significant IOP spikes with the dexamethasone 0.4-mg intracanalicular insert compared with placebo.

Certainly, if there was a concern, the insert can be easily explanted. Regarding pain and inflammation in the phase 3 studies, a significantly greater proportion of eyes in the dexamethasone 0.4-mg intracanalicular insert group had an absence of ocular pain and an absence of anterior chamber cells, compared with the placebo group.

Many surgeons have found they can go completely dropless by combining Dextenza with intracameral moxifloxacin—particularly if they also use intraoperative ketorolac and phenylephrine (Omidria; Omeros). The nSAID lasts for 2 to 3 days, which is adequate for a significant number of patients. In my practice, I have moved to using just 1 postoperative drop for 3 to 4 weeks: once-daily bromfenac (Prolensa; Bausch + Lomb).

Eric Donnenfeld, MD, and I conducted a study comparing the 3-drop regimen with a dropless or near dropless strategy in 56 patients and found that patients overwhelmingly favored the latter regimen (96%). There was no significant difference in patient-reported pain or inflammation as seen on optical coherence tomography, no IOP concerns, and it was less expensive. In other words, the dropless or near dropless approach checked every box.

Although the benefits of sustained-release dexamethasone go well beyond their eliminating need for opioid medications after cataract surgery, avoiding opioids is still a strong and important reason surgeons should consider embracing use of the insert. As a specialty, we need to remain sensitive to the use of narcotics as well as opportunities we have to proactively reduce pain. The amount of effort it takes to incorporate dropless or near dropless cataract surgery into surgeons’ practice is well worth the numerous benefits they and their patients will reap.

Hovanesian is in private practice at Harvard Eye Associates in Laguna Hills, California, and is a clinical instructor at Jules Stein Eye Institute at the University of California, Los Angeles. Find him online @DrHovanesian. Hovanesian is a consultant for Ocular Therapeutix, EyePoint Pharmaceuticals, Omeros, and several other manufacturers of ophthalmic drugs and devices.

1. Opioid overdose crisis. National Institute on Drug Abuse. Accessed October 29, 2021. https://www.drugabuse.gov/drug-topics/opioids/opioid-overdose-crisis

2. Donnenfeld ED, Shojaei RD. Effect of intracameral phenylephrine and ketorolac 1.0%/0.3% on intraoperative pain and opioid use during cataract surgery. 

. 2019;13:2143-2150. doi:10.2147/OPTH.S229515

3. Okeke CO, Quigley HA, Jampel HD, et al. Adherence with topical glaucoma medication monitored electronically the Travatan Dosing Aid study. 

 2009;116(2):191-199. doi:10.1016/j.ophtha.2008.09.004

4. Richter A, Anton SF, Koch P, Dennett SL. The impact of reducing dose frequency on health outcomes. 

2003;25(8):2307-2306. doi:10.1016/s0149-2918(03)80222-9

5. Tsai T, Robin AL, Smith JP 3rd. An evaluation of how glaucoma patients use topical medications: a pilot study. 

6. Robin AL, Novack GD, Covert DW, Crockett RS, Marcic TS. Adherence in glaucoma: objective measurements of once-daily and adjunctive medication use. 

. 2007;144(4):533-540. doi:10.1016/j.ajo.2007.06.012

7. Jones J, Francis P. Ophthalmic utility of topical bromfenac, a twice-daily nonsteroidal anti-inflammatory agent. 

. 2009;10(14):2379-2385. doi:10.1517/14656560903188425

8. An JA, Kasner O, Samek DA, Lévesque V. Evaluation of eyedrop administration by inexperienced patients after cataract surgery. 

. 2014;40(11):1857-1861. doi:10.1016/j.jcrs.2014.02.037

9. Tyson SL, Bafna S, Gira JP, et al; Dextenza Study group. Multicenter randomized phase 3 study of a sustained-release intracanalicular dexamethasone insert for treatment of ocular inflammation and pain after cataract surgery. 

. 2019;45(2):204-212. doi:10.1016/j.jcrs.2018.09.023

10. Walters T, Bafna S, Vold S, et al. Efficacy and safety of sustained release dexamethasone for the treatment of ocular pain and inflammation after cataract surgery: results from two phase 3 studies

 2016;7:1000572. doi:10.4172/2155-9570.1000572

Donnenfeld E, Hovanesian J, Hummel C, Quintero J. Dropless punctal plug dexamethasone, intracameral ketorolac and moxifloxacin compared to conventional topical therapy in cataract surgery. Presented at: ASCRS 2020 Virtual Annual Meeting; May 16-17, 2020.

Ophthalmology Times: January 2022

MMC increases corneal haze after CXL

Focusing on TED: Rare but devastating

Removing burden of adherence, opioids from patients

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