Several factors prompt new approach to treating corneal diseases in patients. 

This article was reviewed by Jose Gomes, MD, PhD


	
	Antimicrobial resistance, epithelial toxicity resulting from frequently instilled fortified and toxic drugs, and lack of compliance with drug regimens are all problems associated with topical therapies.
	
	These three factors cry out for a new approach to treating 

 diseases, and collagen crosslinking (CXL) may be a new strategy, according to Jose Gomes, MD, PhD, professor of ophthalmology, Cornea and External Disease Service, Paulista Medical School/Federal University of Sao Paulo, Brazil. 

Photochemical CXL works by increasing the stiffness of the corneal tissue. Besides, CXL has the added benefit of a disinfectant effect that is achieved by combining ultraviolet A (UVA) plus riboflavin, he said.
	
	

Corneal collagen crosslinking imperative in paediatric keratoconus 

Photo-activated chromophore for keratitis (PACK) CXL may be considered the next therapeutic step in cases of confirmed infectious keratitis in which atimicrobial resistance rears its head.
	
	The technology has been used to treat non-infectious keratitis for years, and in 2016 started to be used to treat mild cases of infectious keratitis, Dr. Gomes pointed out. 


	In vitro and in vivo studies and clinical case series have reported the beneficial effects of PACK-CXL for infectious keratitis.

Dr. Gomes cited a pre-clinical study of the in vitro effect of riboflavin/UVA for treating bacterial and fungal isolates that reported that some gram-positive and gram-negative bacteria but not fungi are susceptible to CXL (Martins et al. 

CXL imperative in treatment of pediatric keratoconus 


	
	However, previous treatment with amphotericin B allowed riboflavin/UVA effectiveness against 

2010;51:3950-3953). The in vivo results of PACK-CXL also showed beneficial results in an animal model of fungal keratitis (Ãzdemir et al. 

In clinical studies, case series have reported that CXL helps in managing advanced microbial keratitis refractory to topical medical therapy (Shetty et al. 

 2014;98:1033-5).
	
	A combination of medical therapy and CXL or CXL alone can be efficacious, Dr. Gomes said. He also described a case of Pseudomonas keratitis treated with PACK-CXL at the Paulista Medical School, Sao Paulo. The case resolved well by day 18 after treatment with CXL.

CXL also was shown to reduce the time to resolution of suppurative fungal corneal ulcers, as reported recently (Basaiawmoit et al. 

“We in Brazil also found that some cases of fusarium keratitis responded well to CXL, especially when the fungal infection was more superficial in the corneal tissue,” Dr. Gomes said.
	
	

Doing justice to corneal irregularities 


	Another study of 40 cases with infectious keratitis showed that PACK-CXL was effective when the depth of the infection was shallow, and the success rate was higher for bacterial infections compared with fungal infections. 

An important finding was that riboflavin/UVA should not be applied in eyes with a previous herpes simplex infection. (Price et al. 

may be the pathogenic exception to the response to CXL. The in vitro results did not show a good response to 

This finding also was true for the in vivo model of infection. However, in the clinical setting, a few reported cases had contradictory results. In 2011, Khan et al. (

 2011;118:324-331) described the resolution of three cases of acanthamoeba infection following CXL. 
	
	

Estimating the total corneal power key in keratoconus patients 

In a multicenter, prospective, comparative study including eyes with infectious keratitis and corneal melting treated with PACK-CXL and antimicrobial therapy (21 eyes) or only antimicrobial therapy (19 eyes), Said et al. (

 2014;121:1377-82) found a complication rate of 21% in the control group, whereas there was no incidence of corneal perforation or recurrence of the infection in the PACK-CXL group. 

These results indicate that PACK-CXL may be an effective adjuvant therapy in the management of severe infectious keratitis associated with corneal melting.

A few meta-analyses are evaluating the efficacy of PACK-CXL. One of them that included 12 reports with a total of 104 eyes treated with CXL showed the same results as found previously and corroborated the results with bacterial infections and acanthamoeba cases more so than with fungal keratitis (Papaioannou et al. 

Hardware, software offer surgeons a window to cornea diagnosis 


	The period of 2018 to 2019 saw the introduction of accelerated CXL. As seen previously, cases of bacterial keratitis fared well. A new device (C-Eye Technology, EMAGine) that can be mounted onto the slit lamp is available and facilitates more focused treatment.

Rose Bengal plus 518-nanometer green light (rose Bengal photodynamic antimicrobial therapy) is another new wrinkle in CXL. With this technology, fungal and bacterial keratitis both responded well to CXL and more so than riboflavin (Amescua et al. 

Traversing the CXL pathway: Where do we go from here?

Dr. Gomes reported that researchers at the Paulista Medical School are conducting in vitro studies using PACK-CXL with 0.1% rose Bengal under green light-emitting diode irradiation and found complete growth inhibition of 


	
	When the technology was applied to clinical cases, the researchers achieved better results with fungal keratitis than the results previously achieved with riboflavin.

Dr. Gomes concluded that these studies have shown that CXL can be considered an adjunct treatment for infectious keratitis, especially in cases that have been refractory to conventional therapy. 

“CXL is effective for both bacterial and some cases of more superficial fungal and acanthamoeba keratitis,” he said. “Fast CXL and new photoactivated chromophores such as rose Bengal can improve the results by making the procedure faster and safer.” 
	
	

Dr. Gomes is a consultant to Alcon, Allergan, Bausch + Lomb, Mundipharma, and Ofta Vision Health.

Articles

PACK-CXL researchers continue to clear hurdles of topical drugs

The use of a thermal pulsation device can prove to be an important component of routine practice for the treatment of the signs and symptoms of meibomian gland dysfunction.


	
	Affecting more than 30 million Americans,

is a chronic condition that, in addition to being highly prevalent in the elderly, is being diagnosed more consistently in younger patient populations. 

Multiple factors contribute to the increasing prevalence of 

, including increased screen time and dietary factors (e.g., low consumption of omega-3). Up to 86% of patients with dry eye show signs of the complex, multifactorial disorder known as meibomian gland dysfunction (MGD).

New techniques probed for managing dry eye disease 

In obstructive MGD patients, the meibomian glands located in the upper and lower eyelids are blocked.

 Reduced meibum secretion may result in changes to the composition of the tear film, leading to quicker tear evaporation, eye irritation, inflammation, and 

Recently, the American Society of Cataract and Refractive Surgery (ASCRS) published an algorithm for the preoperative diagnosis and treatment of OSD, including dry eye.

 using non-invasive techniques prior to any refractive surgery.

 is detected, delaying surgery until after the patient’s 

(including dry eye) is important from both a patient and a clinician perspective. 

By improving ocular surface health, symptomatic patients (and those who did not realize they were symptomatic in the first place) may notice less burning and/or irritation. Patients that suffer from symptoms or show signs of 

 may benefit from treatment, including refractive and 

surgical patients (patients receiving either a monofocal or an advanced technology intraocular lens [AT-IOL]).
	
	

Lab tear tests aid reimbursement, application of dry eye 

It is estimated that up to 34% of patients at a routine eyecare clinic may have 

Experience at Metrolina Eye Associates suggests that up to 80% of patients at a 

 practice can show objective signs or symptoms of dry eye, and in many instances, these symptoms may have been undetected for some time.

 Therefore, my practice of aggressively treating 

Clinicians today have an array of tools at their disposal to optimize pre-operative measurements for both 

, intraoperative aberrometry, and premium phacoemulsification platforms (Centurion Vision System, Alcon). 

Despite these technological advancements, the value of any tests conducted pre-operatively depends on having a healthy ocular surface, especially because dry eye causes fluctuating vision.


	
	With the recent, and uptake of AT-IOLs, accurate refractive readings going into 

 are critical to minimize the risk of implanting the wrong lens, avoid under- or over-correcting astigmatism, and maximizing vision potential. 
	
	


	In treating dry eye, the underlying disease mechanism must be considered; the eyelids are often identified as a cause of

, with many patients having MGD. 
	
	The current approach to addressing MGD at Metrolina Eye Associates involves thermal lid pulsation with a thermal pulsation system (iLUX, Alcon). 

 with clinically demonstrated results in reducing the signs and symptoms of MGD.

 The hallmarks of the system include its portability, rapid treatment for patients, and significant improvements in MGD symptoms.

Pulsing or probing for MGD: How current devices compare


	
	Typically, after an initial iLUX treatment, patients will experience objective improvements in Meibomian Gland Score, tear break-up time, and ocular surface disease index.

Taking the time to address MGD, in general routine eye care as well as prior to refractive or 

, may help refine cataract surgery pre-operative measurements and improve ocular health.

Patients who are satisfied with their pre-operative care are likely to bring repeat business and refer their family and friends.
	
	If a patient exhibits signs of MGD, it is important to take the time to explain the disease to them (including its chronic, progressive, and irreversible nature), outline their treatment options, and highlight that the thermal pulsation system addresses the root cause of MGD (i.e., clears blocked meibomian glands) and supports a holistic approach to reducing the signs and symptoms associated with MGD.
	
	Even though this conversation only requires two minutes of time, it garners trust from patients and helps to set reasonable expectations. 

At Metrolina Eye Associates, the vast majority of patients who have been treated with the thermal pulsation system have experienced a reduction in the signs and symptoms of MGD.
	
	

Top questions about MGD treatment answered

The thermal pulsation system was first implemented at Metrolina Eye Associates’ clinics approximately 1.5 years ago. Since that time, each clinic has been outfitted with one system and these devices have been used to treat thousands of patients with MGD. 

When adopting the thermal pulsation system as part of standard MGD management practice, only minor hurdles were encountered, including ensuring the device was always charged and that enough sterile tips were consistently on-hand. Treatments take less than 10 minutes 

There is a spectrum of eye care professionals whose patients may exhibit the signs and symptoms of MGD and could benefit from treatment with the thermal pulsation system.
	
	I urge other eye care professionals to take the time and initiative to identify MGD and consider adopting the use of a thermal lid pulsation device as an important component of routine practice. 
	
	Addressing MGD is important not only to reduce the signs and symptoms of MGD, but also to optimize cataract surgery pre-operative measurements, patient comfort, and overall ocular health.


	Indication: The iLUX® Device is indicated for the application of localized heat and pressure therapy in adult patients with chronic disease of the eyelids, including Meibomian Gland Dysfunction (MGD), also known as evaporative dry eye.
	
	


	Do NOT use the iLUX® Device in patients with the following conditions: Patients whose pupils have been pharmaceutically dilated; patients who have undergone ocular surgery within prior 12 months; patients with ocular injury or trauma, chemical burns, or limbal stem cell deficiency (within prior 3 months); patients with active ocular herpes zoster or simplex of eye or eyelid or a history of these within prior 3 months; patients with cicatricial lid margin disease; patients with active ocular infection, active ocular inflammation or history of chronic, recurrent ocular inflammation within prior 3 months; patients with an ocular surface abnormality that may compromise corneal integrity; patients with lid surface abnormalities that affect lid function in either eye; patients with aphakia; or patients with permanent makeup or tattoos on their eyelids.
	
	


	Federal law restricts this device to sale by or on the order of a licensed healthcare practitioner.
	
	The Disposable may not fit all eyes, such as eyes with small palpebral fornices. Use of the iLUX® device is NOT recommended in patients with the following conditions: moderate to severe allergic, vernal or giant papillary conjunctivitis; severe eyelid inflammation; systemic disease conditions that cause dry eye; in patients who are taking medications known to cause dryness; or patients with punctal plugs.
	
	


	Potential adverse effects may include eyelid/eye pain requiring discontinuation of the treatment procedure, eyelid irritation or inflammation, temporary reddening of the skin, ocular surface irritation or inflammation (e.g., corneal abrasion, conjunctive edema or conjunctival injection (hyperemia)), and ocular symptoms (e.g., burning, stinging, tearing, itching, discharge, redness, foreign body sensation, visual disturbance, sensitivity to light).
	
	

Please refer to the User Manual for a complete list of contraindications, instructions for use, warnings and precautions for the iLUX® Device.

Dr. Mac is a consultant and/or speaker for Alcon, Allergan, Kala Therapeutics, NovaBay, Sun Pharmaceuticals; and an investor with Ellex, Tear Film Innovations/TearClear/Equinox/Corneagen/RxSight (investor), and Visionary Venture Group.

Lemp MA, Crews LA, Bron AJ, Foulks GN, Sullivan BD (2012) Distribution of aqueous-deficient and evaporative dry eye in a clinic-based patient cohort: a retrospective study. 

Baudouin C, Messmer EM, Aragona P, Geerling G, Akova YA et al. (2016) Revisiting the vicious circle of dry eye disease: a focus on the pathophysiology of meibomian gland dysfunction. 

Starr CE, Gupta PK, Farid M, Beckman KA, Chan CC et al. (2019) An algorithm for the preoperative diagnosis and treatment of ocular surface disorders. 

Trattler WB, Majmudar PA, Donnenfeld ED, McDonald MB, Stonecipher KG et al. (2017) The Prospective Health Assessment of Cataract Patients’ Ocular Surface (PHACO) study: the effect of dry eye. 

[No authors listed] (2007) The epidemiology of dry eye diease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop.

Lin PY, Tsai SY, Cheng CY, Liu JH, Chou P et al. (2003) Prevalence of dry eye among an elderly Chinese population in Taiwan: the Shihpai Eye Study. 

Gupta PK, Drinkwater OJ, VanDusen KW, Brissette AR, Starr CE (2018) Prevalence of ocular surface dysfunction in patients presenting for cataract surgery evaluation. 

FDA US (2016). iLux Premarket Approval Notification. Available online at: 

https://www.accessdata.fda.gov/cdrh_docs/pdf17/K172645.pdf

U.S. National Library of Medicine (Web Page) Comparison Between iLux and LipiFlow in the Treatment of Meibomian Gland Dysfunction. Updated May 30, 2019. Available online at: 

https://clinicaltrials.gov/ct2/show/NCT03055832

Chhadva P, Goldhardt R, Galor A (2017) Meibomian Gland Disease: The Role of Gland Dysfunction in Dry Eye Disease.

The use of a thermal lid pulsation device can prove to be an important component of routine practice for the treatment of the signs and symptoms of meibomian gland dysfunction.

Ophthalmology Times: April 15, 2020

PACK-CXL researchers continue to clear hurdles of topical drugs

Addressing MGD with thermal pulsation system