
This article was reviewed by Nancy J. Newman, MD

The developer of a gene therapy for patients with Leber hereditary optic neuropathy (LHON) caused by a mutation in the 

 gene applied for European marketing authorization of the therapy in September 2020. 

According to the company, GenSight, LUMEVOQ (GS010; lenadogene nolparvovec) targets LHON by specifically targeting the 

 mitochondrial gene mutation, which is the most common cause of the disease.

Investigators evaluated LUMEVOQ in the RESCUE and REVERSE trials. The 2 studies found that in 76% of the patients in the RESCUE study and 71% of those in the REVERSE study, there was a “rate of clinically meaningful improvement from a nadir of at least 0.3 [logarithm of the minimum angle of resolution],” which translates to at least 3 lines of Snellen visual acuity, GenSight reported.



Gene therapy zeroes in on LHON treatment 

These findings are especially important considering the nature of LHON, a genetic disease that affects patients bilaterally. Spontaneous recovery of LHON is rare in those with a mutation in the ND4 gene. 

For patients who experience visual loss when they are age 15 years or older, the percentage who have some visual recovery is only 11.3%, according to a recent meta-analysis published in the 

The challenge for physicians has been to estimate the rate of visual recovery given the small numbers of affected patients, which usually ranges from about 800 to 1200 new cases annually in the United States and Europe.

The investigators, led by Nancy J. Newman, MD, pointed out that visual prognosis associated with LHON is generally poor, with most patients’ visual acuity worsening to at least 20/200. 

In addition, there are few treatments for LHON, and clinical trials are hampered because there is little information about the natural history of vision loss and recovery. In light of this information gap, researchers conducted a meta-analysis with the hope of expanding the body of information about LHON with this mutation.

Newman is from the departments of ophthalmology, neurology, and neurological surgery at the Emory School of Medicine in Atlanta, Georgia.



Research shows promising results for LHON gene therapy 


Investigators were able to identify 12 retrospective studies and 3 prospective studies that, in total, provided visual function information on 695 patients with LHON caused by the m.11778G>A mutation. 

Of these patients, the investigators found that “100 (14.4%) … were reported to have ‘recovered’ some vision, although definitions of ‘recovery’ varied among studies.”

When they considered the age at which the vision loss began and those who were at least 15 years of age, the investigators noted “meaningful visual recovery occurred in 23 of 204 (11.3%) patients. 

A younger age at onset, especially less than 12 years, portends a better visual prognosis and a different natural history of visual loss progression and recovery than in adults.”

Gene panel offers expanded diagnostic capability of inherited retinal diseases


The key findings of the meta-analysis, which provided an actual picture of the course of visual function in these patients, were as follows. 

The classic presentation of LHON in which patients with the m.11778G>A mutation have a severe loss of vision with rare or poor recovery from the nadir is true for most of the patients.

According to the team of investigators, among the patients aged 15 years and older, the percentage of patients who experience meaningful visual recovery “likely occurs in less than 20% of patients, irrespective of how recovery is defined, and ultimate visual acuities of better than 20/200 are rare.”



The investigators noted the importance of future prospective studies with enough genotypically homogeneous untreated patients with LHON.



Ocular gene therapy offers hope for inherited retinal disease

The studies that would yield the best information are those that the patients are stratified by age, enrolled immediately upon becoming symptomatic, and then followed regularly for a sufficiently long time during which they undergo consistent measures of visual function with standard definitions of visual improvement to clarify the natural order of the disease.

GenSight pointed out that the findings of the meta-analysis lend weight to the findings of the trials in which LUMEVOQ was evaluated. 



Newman is a consultant for GenSight, Santhera Pharmaceuticals, and Stealth BioTherapeutics, and reported receiving research support from GenSight and Santhera Pharmaceuticals.


1. Newman NJ, Carelli V, Taiel M, Yu-Wai-Man P. Visual outcomes in Leber hereditary optic neuropathy patients with the m.11778G>A (MTND4) mitochondrial DNA mutation. 

Articles

A new gene therapy for this patient population targets the ND4 gene mutation.

Leber hereditary optic neuropathy: Outlining disease’s natural course


This article was reviewed by Yusen Huang, MD



Adding cefuroxime to the irrigating solution used during cataract surgery appears to be a safe and effective method for reducing the risk of postoperative endophthalmitis, according to researchers who reported their experience with this technique in a recently published retrospective study.

The investigation included 61,299 eyes. Of the total cohort, 15,948 eyes were operated on between January 1, 2012, and December 31, 2014, using plain balanced salt solution (BSS) as the irrigating solution (control group), and 45,351 eyes underwent cataract surgery between January 1, 2015, and December 31, 2019, using irrigating solution that contained cefuroxime 1500 µg/mL. 



 Eliminating risk of endophthalmitis during intravitreal injections for patients wearing masks



The mixture was prepared by withdrawing 10 mL BSS from the irrigating solution and injecting it into a vial of cefuroxime 750 mg. The reconstituted solution was injected back into the BSS container.

The rate of endophthalmitis was significantly decreased after the transition to intraoperative irrigation with cefuroxime. Endophthalmitis occurred in 11 eyes (0.07%) in the group that did not receive intraoperative cefuroxime and in 5 eyes (0.01%) when cefuroxime was used in the irrigating solution (

 < .01). 

Cultures were positive for bacteria in 4 of the 11 cases in the control group and in 1 of the 5 eyes in the intraoperative cefuroxime group (

 > .05). No safety issues were associated with intraoperative cefuroxime irrigation.

Discussing the research, Yusen Huang, MD, PhD, of the Shandong Eye Institute, Shandong First Medical University and Shandong Academy of Medical Sciences in Qingdao, People’s Republic of China, pointed out that although intracameral antibiotics are already widely accepted as a method for endophthalmitis prophylaxis in patients undergoing cataract surgery, the optimal choice of prophylactic routes and antibiotics is controversial.

“In European countries, commercial cefuroxime formulation (Aprokam) has been widely used, and the dose administered is the same as in the European Society of Cataract and Refractive Surgeons’ (ESCRS’) randomized prospective study demonstrating its efficacy,” Huang said. 

Surgeons have been reluctant to adopt intracameral cefuroxime because it is off label and carries potential risks.



Research: Similar endophthalmitis rates for generic, branded topical antibiotics 


“In our study, the manner of cefuroxime preparation was modified so that it involved only a 1-step process. This makes it simpler, saves resources, and could reduce the potential risks of both preparation errors and contamination,” Huang pointed out. “Although the intracameral concentration achieved with our approach is estimated to be 1500 µg/mL, or only about 45% of the ESCRS recommendation, we found that it reduced the rate of postcataract surgery endophthalmitis by about sevenfold.”

Furthermore, Huang explained that “during the last 2 years in our hospital where more than 25,000 cases of cataract surgery have been performed using intraoperative cefuroxime irrigation, not a single patient developed endophthalmitis. 

It should be noted, however, that this method is not recommended for use in patients with a history of vitrectomy, [considering] the potential for rapid posterior segment diffusion of the antibiotic and potential macular toxicity.”

AAO live: Drop-free prophylaxis regimen before cataract surgery lowers treatment burden with caveats

Although adding cefuroxime to the irrigating solution is still an off-label use of the medication, the authors suggested that it represents a good option for countries with no licensed product for intracameral use of endophthalmitis prophylaxis and particularly in developing regions where the risks for both endophthalmitis and a poor outcome may be higher given a variety of contributory factors.

Throughout the entire study period, all patients received the same preoperative antisepsis with application of topical povidone-iodine. 

In addition, all patients started using topical levofloxacin 0.5% solution preoperatively and continued it postoperatively, along with a topical steroid and topical nonsteroidal anti-inflammatory drug.



Minimize inflammation after cataract surgery


Postoperative follow-up visits were scheduled at 1 and 4 days, 4 weeks, and 12 weeks, but patients were instructed to seek care if they developed pain, redness, or loss of vision. 

The analyzed outcome was onset of acute-onset endophthalmitis, which was diagnosed if a patient presented within 6 weeks of surgery with eye pain, anterior chamber reaction or flare, hypopyon, and/or vitritis with causes for intraocular inflammation other than endophthalmitis excluded.

The 16 cases of endophthalmitis recorded during the 9-year study period developed at a median of 7.56 days after cataract surgery (range, 1-21 days). 

None of the cases occurred in a patient who had an intraoperative complication or was noted to have incision leakage at the time endophthalmitis was identified.



Perioperative medications can eliminate postoperative drops after cataract surgery

Isolates from the culture-positive cases of endophthalmitis in the control group included 

 was identified as the causative pathogen in the culture-positive case of endophthalmitis among patients who received intraoperative cefuroxime, and the organism was found susceptible to cefuroxime.



1. Ma X, Zie L, Huang Y. Intraoperative irrigation prophylasix for acute-onset endophthalmitis after phacoemulsication surgery. 

Findings from retrospective study support intraoperative cefuroxime irrigation.  


Investigators focus on preventing postcataract surgery endophthalmitis

Any time we perform ocular surgery—whether 

, oculoplastic, or any other ocular procedure—we want to set the patient up for success. 

Part of that is addressing any potential sources of infection, inflammation, and ocular surface disease that could complicate the postoperative course. It is common to see patients with meibomian gland dysfunction (MGD), dry eye disease (DED), and blepharitis.

For long-term efficacy, therapeutic choices are focused on the underlying cause or causes of the problem. 



Considering Demodex infestation and cataract surgery

 was 1 potential cause that we tended to overlook or ignore, because there was little we could do to address the specific problem of 

 mite infestation. 

Now we are beginning to understand the role of 

 in blepharitis and inflammatory DED, and the treatment outlook has markedly improved.


 is the presence of collarettes, or cylindrical dandruff, at the base of the eyelashes.

 

These waxy collarettes are the waste material of 

 mites living inside the hair follicles. When you regularly look for collarettes, you’ll likely be surprised at how common 

About 84% of people 60 years or older have 

 infestation, as do 100% of patients 70 years or older.

 overpopulation as well, particularly those with MGD and keratitis.

 

The higher incidence in older populations is not well understood. We hypothesize that the natural defenses and skin barrier function may be compromised with age, allowing 

 to gain the upper hand, but we do not know for certain.



Drop shows effectiveness for Demodex blepharitis in phase 2a stud

 can have a spectrum of manifestations, from asymptomatic infestation to significant blepharitis inflammation. 

Generally, significant 

 infestation results in significant inflammation. Patients have classic dry eye and blepharitis symptoms, including dry or gritty feeling, foreign body sensation and fluctuating vision. 

Because mites inside the lash follicles cause the condition, patients also can have follicular distention, hyperplasia, eyelash loss, and eyelid keratinization.

 blepharitis and bacterial blepharitis are also strongly correlated.


Despite its prevalence, there have been few treatments for 

 infestation, and there are no treatments approved for that specific indication. 

Although many patients with 

 infestation come to me having already been prescribed an immunomodulator such as cyclosporine (Cequa; Sun Pharma; Restasis; Allergan) or lifitegrast (Xiidra; Novartis), these medications treat the ocular surface sequelae of 

 infestation rather than the infestation itself. 



Making dry eye manageable for patients working from home


We could hypothesize that these medications might increase the ability to fight 

 by reducing inflammation and improving skin health, but we do not have evidence to support that idea.

Certain comorbidities, such as diabetes, place patients at higher risk for 

 blepharitis, so a primary care physician should help manage any systemic condition that has not been adequately controlled. 

To prepare a patient with 

 infestation for surgery, I usually use a combination of mechanical and chemical methods to remove collarettes, kill mites, and enhance skin barrier function in the patient.



For patients, home maintenance is important to help keep the 

 population under control. It is key to communicate this to patients.

In the office, we can perform microblepharoexfoliation using mechanical tools (AB Max; Myco Industries; BlephEx) or kits that combine tools and agents to treat Demodex (Cliradex; Bio-Tissue; ZEST; Zocular).



Where to start with treating OSD patients

and rosacea, intense pulsed light (IPL) therapy (Optima IPL; Lumenis) can be used to decrease the 

 burden in patients also afflicted with rosacea.

, ivermectin can be prescribed orally or topically (Soolantra; Galderma) to control the facial Demodex burden.


At home, good hygiene is essential to keep 

 under control after in-office treatment, but traditional shampoos are not very effective. 

Cleansing towelettes with 4-terpineol isolate (Cliradex; Bio-Tissue), the miticidal component of tea tree oil, have the highest antidemodectic activity of all the commercial cleansers.


Patients use the towelettes to clean the eyelids, lashes, and face. Hypochlorous acid cleanser (Avenova; NovaBay Pharmaceuticals), which I use for many dry eye patients, has minimal effect on 

but it can be used as a complementary therapy to 4-terpineol isolate.

Patients can also use a device at home that cleans the eyelid margins and stimulates the meibomian glands (NuLids; NuSight Medical), as well as gel cleaner for the eyelids and lashes (ZocuShield; Zocular).


 blepharitis are very new, and more treatments are in development. They are the consequence of our growing understanding of the disease and the pressing need to address it effectively. 

We have gone from strictly mechancal approaches to removing the mites, to chemical options, to the possibility of pharmaceutical options for the treatment of patients with this issue.



Amid pandemic, friendly bugs can help protect the eye from infection

 burden that is driving blepharitis and inflammation is growing rapidly, making it easier than ever to resolve the problem before elective surgery and keep patients on track long term. 




Periman is an ocular surface disease expert and director, dry eye services and clinical research, Periman Eye Institute, Seattle, Washington.

1. Gao YY, Di Pascuale MA, Li W, et al. High prevalence of Demodex in eyelashes with cylindrical dandruff. 

. 2005;46(9):3089-3094. doi:10.1167/iovs.05-0275

2. Liu J, Sheha H, Tseng SCG. Pathogenic role of Demodex mites in blepharitis. 

2010;10(5):505-510. doi:10.1097/ACI.0b013e32833df9f4

3. Liang L, Liu Y, Ding X, Ke H, Chen C, Tseng SCG. Significant correlation between meibomian gland dysfunction and keratitis in young patients with Demodex brevis infestation. 

. 2018;102(8):1098-1102. doi:10.1136/bjophthalmol-2017-310302

4. Fishman HA, Periman LM, Shah AA. Real-time video microscopy of In vitro Demodex death by intense pulsed light. 

2020;38(8):472-476. doi:10.1089/photob.2019.4737

5. Cheung IMY, Xue AL, Kim A, Ammundsen K, Wang MTM, Craig JP. In vitro anti–demodectic effects and terpinen-4-ol content of commercial eyelid cleansers. 

 2018;41(6):513-517. doi:10.1016/j.clae.2018.08.003

6. Kabat AG. In vitro demodicidal activity of commercial lid hygiene products. 

 2019;13:1493-1497. doi:10.2147/OPTH.S209067

New options open possibilities for treatment, resulting in better outcomes for patients.


Treating Demodex blepharitis efficiently before surgery

® reader, Sergio, recently sent me a report on a survey of almost 1300 physicians with the headline “Nearly half of doctors are ‘seriously’ rethinking their careers, finds COVID-19 survey.” 

The article begins with data from the CDC to the effect that 1 in 16 Americans (5.9%) infected to date with 

This rethinking is most common amongst primary care doctors, with 50% of internists and 55% of family physicians described as such.

“Just what the heck is ‘rethinking’” you ask? According to the surveyors, it can mean anything from tweaking your practice to throwing in the towel. The results show:

> 9% of doctors say they are going to retire.

> 6% will “quit medicine and start a new career.”

I find the survey results a tad confusing. The categories strike me as overlapping or poorly defined. 

For example, what is the difference between retiring and closing your practice for good? What is the difference between leaving patient care and quitting medicine and starting a new career? Are some of these people going to become hospital administrators or work in the pharmaceutical industry? 


Planning is important — even when “nobody knows nothing”

If so, they would not be retired, rather they would still be in medicine but no longer caring for patients. Will they be one of those characters who spend their days writing editorials in medical publications instead of doing something that contributes to society?

Whatever the details, the authors concludes that if all these doctors quit clinical practice, the loss of such a large chunk of the medical workforce (9% + 8% + 6% + 3% = 26%) would leave the rest of us doctors overwhelmed.

But with these surveys, as with the polls before Presidential elections these days, you never know.

On a positive note, 49% of responding physicians say they plan to make no significant changes and others plan to “change the practice setting.”

One hospitalist from Iowa, rather than bemoaning his job during the pandemic, said this in the survey: “It has actually galvanized me. I think I am privileged to provide inpatient medicine at just the moment in history when the need is so great.”

Certainly we have known from the earliest days of the pandemic—

when Dr. Li Wenliang died in Wuhan, China after first reporting the outbreak

—that ophthalmologists are at risk from the disease. Will that translate into a fear that leads many of us to quit medicine?

The word “ophthalmologist” doesn’t appear anywhere in the article and there is no breakdown by subspecialty, but I am not seeing or hearing of a mad rush for the exits by my ophthalmologist colleagues. 

® is going to perform a hopefully more valid survey of a large group of the smarter and best-looking ophthalmologists.

Are you, dear reader, planning to respond to 



Read more by editorials by Peter McDonnell

Pandemic forces some to reconsider careers.

Thinking and rethinking ophthalmology: Are you?

This article was reviewed by Edward Holland, MD

The first prescription ocular corticosteroid indicated specifically for short-term treatment of 

 disease (DED)—loteprednol etabonate ophthalmic suspension 0.25% (Eysuvis; Kala Pharmaceuticals)—has received FDA approval, which comes with expectations for providing rapid relief of signs and symptoms of DED.

Being the first drug approved in this class for the short-term treatment of DED also implies that it differs from the plethora of DED treatments available. 



Boosting short-term dry eye management in patients



Although cyclosporine ophthalmic emulsion 0.05% (Restasis; Allergan) and lifitegrast ophthalmic solution 5% (Xiidra; Novartis) are good chronic anti-inflammatory medications, the difference is that reaching peak benefit often takes weeks to months.

“With Eysuvis, patients will get immediate relief from the signs and symptoms of 

because of the rapid action of corticosteroids against inflammation,” said Edward Holland, MD, director of Cornea Services at Cincinnati Eye Institute and a professor of ophthalmology at the Univeristy of Cincinnati. “The clinical trials of the drug showed that symptomatic improvement began within 1 or 2 days of instillation of the drop. Having an approved corticosteroid is going to change how we manage dry eye.”

Recently, a realization that has emerged from the study of DED is that most of the patient population experiences flares, on average, 4 to 6 times a year, according to Holland. Moreover, the majority of the 17 million patients with DED say they experience flares vs continuous symptoms. 

For patients who treat flares when they occur, a short-term treatment is probably enough. There are patients who have more severe symptoms and are on chronic medications who will have flares as well and need additional treatment.



As cyclosporine options grow, focus remains on the vehicle



Currently available formulations do not provide relief from these painful episodes. Some patients can be totally asymptomatic in between flares and do not require maintenance therapy, but want to address the flares as they occur. 

Other patients need maintenance therapy, but can experience breakthrough episodes of DED flares despite ongoing treatment.

“Previously, we did not have a therapy that could target the episodes of flares,” Holland said.

AMPPLIFY mucus-penetrating particle (MPP) drug delivery technology developed by Kala Pharmaceuticals seems key to the rapid onset of symptomatic relief experienced by patients. MPP enhances penetration of loteprednol etabonate through the ocular mucous layer, improving drug delivery to ocular surface tissues to target the immune responses that drive acute DED flares.

“Loteprednol etabonate is a very good corticosteroid with good safety profile and high potency,” Holland said. “I think it is going to be very effective and perhaps a first-line prescription therapy for all 


FDA approval was based on the results of 4 clinical trials—1 phase 2 and 3 phase 3 trials—that reported significant improvements in the signs and symptoms of dry eye.

In STRIDE 3 (NCT03616899), the last phase 3 multicenter, randomly selected, double-masked, placebo-controlled, parallel-arm trial, the effects of Eysuvis were compared in 901 patients with DED (447 who received active drug and 454 control patients) who instilled drops 4 times daily for 2 weeks. 

Conjunctival hyperemia improved significantly after 2 weeks of dosing in the phase 3 trials, and in 2 of the 3 phase 3 trials ocular discomfort also improved significantly.

The treatment is approved for a course of up to 2 weeks. Because 

 is characterized by inflammation, the hope is that the inflammation will be knocked down, and the tendency to progress—creating the potential need for chronic therapy—dampened, Holland said.



Myths and misconceptions about autologous serum for dry eye

In all trials, the most common adverse effect was pain associated with drop instillation.

Holland is anticipating a “new era in the treatment of dry eye disease” and says that Eysuvis offers promise to the millions of patients with disease flares.

“For the first time, we will be able to offer 

 patients a therapeutic option that provides rapid relief for both the signs and symptoms of the disease and that is safe and well tolerated,” he said.

Kala Pharmaceuticals plans to launch Eysuvis in the United States by the end of 2020.


Ophthalmology Times: December 2020

Leber hereditary optic neuropathy: Outlining disease’s natural course

Investigators focus on preventing postcataract surgery endophthalmitis

Treating Demodex blepharitis efficiently before surgery

Thinking and rethinking ophthalmology: Are you?

Short-term dry eye treatment option receives FDA approval