
This article was reviewed by Francis S. Mah, MD

Managing bacterial keratitis often is not a straightforward process. Several controversies surround its diagnosis and treatment, according to Francis S. Mah, MD.

Mah is the director of cornea and external disease and co-director of refractive surgery at the Scripps Clinic in La Jolla, California.


The current preferred practice recommendation for most cases of keratitis is empiric therapy without performing smears or cultures. 

Confocal microscopy key to diagnosing infectious keratitis 

The cases that fall under this recommendation have a peripheral corneal ulcer smaller than 2 mm and no stromal melting, however, physicians can opt to culture with the use of vital stains for cultures and corneal scrapings.

Cultures and smears are needed in cases with a corneal infiltrate that is central; large; in the middle to deep stroma; chronic or unresponsive with atypical clinical features that suggest fungal, amoebic, or mycobacterial keratitis; and in patients with a vegetable trauma or who wore contacts while in a hot tub.

As Mah pointed out, culturing is important to identify the organism, determine antibiotic sensitivity, guide therapeutic modifications in unresponsive patients, decrease potential toxicity caused by unnecessary medications, and categorize microbial pathogens by examining stained smears of corneal scrapings.

Scanning laser confocal microscopy is useful in the diagnostic process to view the various corneal layers. 

Confocal microscopy: Seeing what does not meet the eyes

Recent advances in this technology facilitate enhanced resolution and microscopic power making it useful to diagnose infectious keratitis including bacterial, fungal, and especially parasitic organisms.


A therapeutic keratoplasty is indicated in patients with progressive ulceration, extensive corneal involvement, the presence of a descemetocele, and perforation. 

A keratoplasty is performed in 3% to 6% of all bacterial ulcers, with the most common pathogens being 

The microbial cure rates range from 90% to 100% and 69% to 100% have a clear graft at 1 year, Mah explained.

However, the timing of the surgery can be critical.

“A slight delay in the surgery improves the surgical outcome,” Mah pointed out.

How surgeons can improve when using their nondominant hand

Antibiotic administration carries the hope of sterilization and corneal transplantation before further melting, perforation, or complications develop.



“There was always a question regarding use of commercial fluoroquinolones or fortified antibiotics from a compounding pharmacy,” Mah said.

Empiric therapy to treat bacterial keratitis with topical fluoroquinolones and/or fortified antibiotics, such as cefazolin, vancomycin, and tobramycin, can be considered, he said. 

This approach includes a loading dose every 5 to 15 minutes for the first hour and then applications every 15 minutes to 1 hour around the clock.

“[Adherence to] this regimen is key,” he emphasized.

Mah said the preferred treatment in most cases is topical antibiotic eye drops, which can achieve high tissue levels. Application of ointments can be useful at bedtime for cases that are less severe, as well as an adjunctive therapy.

Topical broad-spectrum antibiotics are used initially in the empiric treatment of bacterial keratitis.

Combination drops may help patients challenges by multiple glaucoma meds

For patients who have central or severe keratitis such as that extending into the deep stroma or when an infiltrate exceeds 2 mm with extensive suppuration, a loading dose as mentioned previously is needed and is followed by frequent instillations. With less severe keratitis, less frequent dosing is appropriate.

“I prefer dosing every 1 to 2 hours because of uncertainty about complete patient [adherence] and I want to have an edge in treatment during the first 24 to 48 hours,” he said.

Monotherapy with a fluoroquinolone is as effective as a fortified combination therapy with ciprofloxacin 0.3%, ofloxacin 0.3%, or levofloxacin 1.5%, all of which are approved to treat bacterial keratitis.

Mah pointed out that in in vitro studies, besifloxacin, gatifloxacin, and moxifloxacin have been shown to cover gram-positive pathogens better compared with the earlier-generation fluoroquinolones. 

However, these drugs are not FDA-approved to treat bacterial keratitis, despite the results of randomized controlled trials that reported that moxifloxacin and gatifloxacin were equivalent to the combination of fortified cefazolin/tobramycin and possibly better than ciprofloxacin.

Topical moxifloxacin: Best choice before cataract surgery?

Fluoroquinolone monotherapy to treat corneal perforation needs to be confirmed in future studies. 

Mah recounted that some retrospective studies reported concerns about increased risk associated with monotherapy in patients with severe bacterial keratitis compared with use of fortified topical antibiotics, ie, cefazolin and tobramycin.

Combination therapy should be used to treat severe unresponsive infections, for nontuberculous mycobacteria, and for methicillin-resistant 

Systemic antibiotics, although rarely needed, can be used in severe cases of keratitis in which the infection has entered adjacent tissues, for impending or frank perforation, and for gonococcal keratitis.


These treatments include cycloplegic agents and a collagen shield or bandage contact lens to increase the antibiotic concentration. 

A bandage contact lens also can be considered for stromal melting as well as vitamin C, topical medroxydrogesterone, topical N-acetylcysteine, and oral tetracycline.

Crosslinking for infectious keratitis may be beneficial for treating moderate bacterial keratitis. “The procedure accelerates epithelialization, shortens the treatment course, and minimizes or negates the need for surgery and other serious complications such as perforation,” Mah explained.

The use of steroids in keratitis is controversial and remains inconclusive, in that no increased risk of adverse events has been found, and steroids may improve outcomes with large central ulcers and severely decreased visual acuity. No benefit has been seen in 

According to Mah, the take-home message regarding keratitis therapy is to culture if the lesion is large, serious, or unusual; administer sufficient medication in a timely manner; carefully monitor therapeutic and adverse effects; and consider referral of Descemet’s anterior lamellar keratoplasty or penetrating keratoplasty early, but not too early. 

Mah is a consultant to Alcon, Allergan, Bausch + Lomb, Novartis, Kala, EyeVance, and Glaukos.

Articles

Ophthalmologists can opt to use vital stains for cultures and corneal scrapings.

Preferred practice patterns for bacterial keratitis address existing controversies

This article was reviewed by Jennifer E. Thorne, MD, PhD



For ophthalmologists, increasing the knowledge base about uveitis is important for several reasons.

“Epidemiologic studies of uveitis frame the medical need for uveitis specialists and training programs by defining the disease scope and disease burden and helping to justify research support,” said Jennifer E. Thorne, MD, PhD, director of the Division of Ocular Immunology and Uveitis, and Cross Family Professor of Ophthalmology and Epidemiology, Wilmer Eye Institute, Johns Hopkins University of Medicine and Public Health in Baltimore, Maryland.

Published population-based studies, according to Thorne, detail the burden of visual morbidity, including blindness, societal cost, and loss of quality of life.

It takes a village to beat visual system diseases in children


During the past 6 decades, 4 major epidemiologic studies have been undertaken by Rochester, Minnesota (1962), the Northwest Veterans Affairs (VA) Centers in Oregon and Washington (2008), and 2 by Kaiser Permanente in California (2004) and Hawaii (2013) that reported the incidence and prevalence of uveitis in the United States.

Moreover, Thorne said she believes that the growth of large insurance databases and the IRIS database will result in additional studies.

In the 4 studies, the incidence rates of uveitis increased with age in each of the studies per 100,000 person-years and ranged from 17.4 in Minnesota, 24.9 in Hawaii, 25.6 in the Northwest VA study, and 52.4 in California.

The active prevalence of uveitis in the United States per 100,000 persons also increased with age, except in the Northwest VA study. The prevalence rates were 57.5 and 58.0 in Hawaiian studies (2006 and 2007), 69.0 in the Northwest VA study, and 114.5 in California.

Exploring possibilities of myopia prevention and control in the US

Uveitis rates vary considerable outside the United States; the highest rates were seen in India (730 per 100,000 person years) and the lowest in Italy (11.4 per 100,00 person years).


Thorne said uveitis is a leading cause of visual impairment.

“In the US, the disease is estimated to be the fifth- or sixth-leading cause of blindness, accounting for 10% to 15% of cases of blindness,” she said.

Studies of uveitis in the Netherlands and India report visual impairment in at least 1 eye in about one-third of cases; in the Aravind group in India, about 1 in 5 affected eyes was blinded by uveitis, but none was affected bilaterally.

The actual rates of blindness and visual impairment may be underestimated because the World Health Organization does not use uveitis as a cause of visual loss, Thorne pointed out. 

 Evaluating 3-year recurrence rate in non-infectious posterior segment uveits post-FAi

Analysis of the anatomic location of uveitis showed that worsening visual outcomes were seen when the posterior segment was involved.

“Since patients with noninfectious intermediate, posterior, and panuveitis can require chronic regional and systemic treatment compared with only topical drops, much of the morbidity and cost of the uveitis may be attributed to these patients,” she said.

When it comes to cost and care, a 2011 study reported that uveitis has a high socioeconomic impact that is comparable to 

Patients with uveitis, on average, are younger than those with 

, and the lifetime direct and indirect costs would be expected to be higher among patients with uveitis.

 in which they retrospectively analyzed the insurance claims of employees in the United States. 

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They considered the uveitis-associated direct costs, defined as inpatient stays, emergency department visits, outpatient visits, and prescriptions, in patients with noninfectious intermediate, posterior, and panuveitis and reported that those patients had twice the number of visits compared with controls, which translated to direct costs of $12,940 compared with $3730.

Analysis of the indirect costs, defined as absenteeism from work and disability, indicated that patients with uveitis had 10.3 days of disability compared with 4.6 days for controls and 18.7 days lost from work compared with 8.4 days for controls, which translated to a cost of $3144 compared with $1378.

The caveat regarding the results is that cases of anterior uveitis were not included in the analyses, nor were patients with uveitis who were unemployed or who had insurance through Medicaid or Medicare, for example.

Tackling the challenge of noninfectious uveitis 

Thorne concluded that population-based studies show varied estimates of the incidence and prevalence rates of uveitis in the United States and internationally.

“Uveitis appears to increase with increasing age in most studies,” she said. “Visual morbidity is significant in patients with uveitis but may be underreported because uveitis is often not listed as a cause of visual loss in global assessments of blindness.” 

Thorne has no financial interest in this subject matter


1. De Smet MD, Taylor SRJ, Bodaghi B, et al. Understanding uveitis: the impact of research on visual outcomes. 

. 2011;30(6):452-470. doi:10.1016/j.preteyeres.2011.06.005

Direct and indirect resource use, healthcare costs and work force absence in patients with non-infectious intermediate, posterior or panuveitis

. 2016;94(5):e331-e339. doi:10.1111/aos.12987

Studies highlight need for specialists and training programs focusing on the disease

Uveitis: A leading, underestimated cause of visual morbidity in patients


Excitement took wing in the scientific community in the early 1990s, when the first-ever gene therapy trial showed significant success, only to crash at the end of the decade with a patient’s tragic death.

Twenty years later, the excitement is back and greater than before. Although safety remains a concern, investigators are breaking ground in cell and 

, and many believe that ultimately, a string of cured cancers will follow.

Novel gene therapy/medical device combo sheds light on retina in RP

“We can absolutely cut the number of cancer deaths down so that one day in our lifetimes it can be a rare thing for people to die of cancer,” said Patrick Hwu, MD, president and CEO of Moffitt Cancer Center in Florida and among gene therapy’s pioneers. “It still may happen here and there, but it’ll be kind of like people dying of pneumonia. It is like, ‘He died of pneumonia? That is kind of weird.’ I think cancer can be the same way.”

The excitement returned in spades in 2017 when the FDA signed off on a gene-therapy drug for the first time, approving the chimeric antigen receptor (CAR) T-cell treatment tisagenlecleucel (Kymriah; Novartis) for the treatment of Bcell precursor acute lymphoblastic leukemia. At last, scientists had devised a way to reprogram a person’s own T cells to attack tumor cells.


“We’re entering a new frontier,” said Scott Gottlieb, MD, then the FDA Commissioner, in announcing the groundbreaking approval.

Gottlieb wasn’t exaggerating. The growth in CAR T-cell treatments is exploding. Although only a handful of cell and gene therapies are on the market, the FDA predicted in 2019 that it will receive more than 200 investigational new drug applications per year for cell and gene therapies, and that by 2025, it expects to have accelerated to 10 to 20 cell and gene therapy approvals per year.

“Essentially, you can kill any cancer cell that has an antigen that is recognized by the immune cell,” Hwu said. “The key to curing every single cancer, which is our goal, is to have receptors that can recognize the tumor but don’t recognize the normal cells.” 

Receptors recognizing and then attacking normal cells is what can cause toxicity.Cell therapy involves cultivating or modifying immune cells outside the body before injecting them into the patient. 

Investigators uncover improved vectors for ocular gene therapy

Cells may be autologous (self-provided) or allogeneic (donor-provided); they include hematopoietic stem cells and adult and embryonic stem cells. Gene therapy modifies or manipulates cell expression. There is considerable overlap between the 2 disciplines.

Juliette Hordeaux, PhD, senior director of translational research for the University of Pennsylvania’s gene therapy program, is cautious about the FDA’s predictions, saying she would be “thrilled” with 5 cell and/or gene therapy approvals annually.

“For monogenic diseases, there are only a certain number of mutations, and then we’ll plateau until we reach a stage where we can go after more common diseases,” Hordeaux said.

“Safety has been the main brake around adeno-associated virus vector (AAV) gene therapy,” added Hordeaux, whose hospital’s program has the institutional memory of both Jesse Gelsinger’s tragic death during a 1999 gene therapy trial as well as breakthroughs by Carl June, MD, and others in CAR T-cell therapy. “Sometimes there are unexpected toxicity [events] in trials.…I think figuring out ways to make gene therapy safer is going to be the next goal before we can even envision many more drugs approved.”

In total, 3 CAR T-cell therapies are now on the market, all targeting the CD19 antigen. Tisagenlecleucel was the first. Gilead Sciences received approval in October 2017 for axicabtagene ciloleucel (axi-cel; Yescarta), a CAR T-cell therapy for adults with large B-cell non-Hodgkin lymphoma. 

Kite Pharma, a subsidiary of Gilead, received an accelerated approval in July 2020 for brexucabtagene autoleucel (Tecartus) for adults with relapsed or refractory mantle cell lymphoma.

Gene therapy surgical pearls for successful outcomes


Another CD19-directed therapy under FDA review, for relapsed/refractory large B-cell lymphoma, is lisocabtagene maraleucel (liso-cel; JCAR017; Bristol Myers Squibb). Idecabtagene vicleucel (ide-cel; bb2121; Bristol Myers Squibb) is under priority FDA review, with a decision expected by March 31, 2021. 

The biologics license application seeks approval for ide-cel, a Bcell maturation antigen–directed CAR therapy, to treat adult patients with multiple myeloma who have received at least 3 prior therapies.

The number of clinical trials evaluating CAR T-cell therapies has risen sharply since 2015, when investigators counted a total of 78 studies registered on the ClinicalTrials.gov website. In June 2020, the site listed 671 trials, including 357 registered in China, 256 in the United States, and 58 in other countries.

Natural killer (NK) cells are the research focus of Dean Lee, MD, PhD, a physician in the Division of Hematology and Oncology at Nationwide Children’s Hospital. He developed a method for consistent, robust expansion of highly active clinical-grade NK cells that enables repeated delivery of large cell doses for improved efficacy. 

This finding led to several first-in-human clinical trials evaluating adoptive immunotherapy with expanded NK cells under an FDA Investigational New Drug application. 

He is developing both genetic and nongenetic methods to improve tumor targeting and tissue homing of NK cells. His efforts are geared toward pediatric sarcomas.

“The biggest emphasis over the past 20 to 25 years has been cell therapy for cancer, talking about trying to transfer a specific part of the immune system for cells,” said Lee, who is also the director of the Cellular Therapy and Cancer Immunology Program at Nationwide Children’s Hospital at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

Gene panel offers expanded diagnostic capability of inherited retinal diseases


The pivot toward treating COVID-19 and other diseases


However, Lee said, NKs have wider potential. “This is kind of a natural swing back. Now that we know we can grow them, we can reengineer them against infectious disease targets and use them in that [space],” he said.

Lee is part of a coronavirus disease 2019 (COVID-19) clinical trial, partnering with Kiadis, for off-the-shelf K-NK cells using Kiadis’ proprietary platforms. Such treatment would be a postexposure preemptive therapy for treating COVID-19. 

Lee said the pivot toward treating COVID-19 with cell therapy was because “some of the very early reports on immune responses to coronavirus, both original [SARS-CoV-2] and the new [mutation], seem to implicate that those who did poorly [overall] had poorly functioning NK cells.”

The revolutionary gene editing tool CRISPR is making its initial impact in clinical trials outside the cancer area. Its developers, Jennifer Doudna, PhD, and Emmanuelle Charpentier, PhD, won the Nobel Prize in Chemistry 2020.

For patients with sickle cell disease (SCD), CRISPR was used to reengineer bone marrow cells to produce fetal hemoglobin, with the hope that the protein would turn deformed red blood cells into healthy ones.

 National Public Radio did a story on one patient who, so far, thanks to CRISPR, has been liberated from the attacks of SCD that typically have sent her to the hospital, as well from the need for blood transfusions.

nternet hawkers of stem cell therapies raising red flags

“It is a miracle, you know?” the patient, Victoria Gray of Forest, Mississippi, told NPR. Shewas among 10 patients with SCD or transfusion-dependent beta-thalassemia treated with promising results, as reported by the 

Stephen Gottschalk, MD, chair of the department of bone marrow transplantation and cellular therapy at St Jude Children’s Research Hospital, said, “There’s a lot of activity to really explore these therapies with diseases that are much more common than cancer.”

Animal models use T cells to reverse cardiac fibrosis, for instance, Gottschalk said. Using T cells to reverse pathologies associated with senescence is also being studied. 

Hordeaux said she foresees AAV being used more widely to transmit neurons to attack neurodegenerative diseases because he neurons are easily transduced by AAV naturally.


Speed is of the essence, as delays can be the difference between life and death, but the approval process takes time. The process of working out all kinks in manufacturing also remains a challenge. 



Exploring novel gene therapy approaches to treat ocular disease



Rapid production is difficult, too, because of the necessary customization of doses and the need to ensure a safe and effective transfer of cells from the patient to the manufacturing center and back into the patient.

Other factors that can slow down launches include insurance coverage, site certification, staff training, reimbursement, and patient identification.

“CAR T, I think, will become part of the standard of care,” Gottschalk said. “The question is how to best get that accomplished. To address the tribulations of some autologous products, a lot of groups are working with off-the-shelf products to get around some of the manufacturing bottlenecks.” 

1. Bristol Myers Squibb provides regulatory update on lisocabtagene maraleucel (liso-cel). News release. Bristol Myers Squibb; November 16, 2020. Accessed January 11, 2021. [Au: please add] 

https://news.bms.com/news/details/2020/Bristol-Myers-Squibb-Provides-Regulatory-Update-on-Lisocabtagene-Maraleucel-liso-cel/default.aspx

2. Wei J, Guo Y, Wang Y. et al. Clinical development of CAR T cell therapy in China: 2020 update. 

. Published online September 30, 2020. doi:10.1038/s41423-020-00555-x

3. Stein R. CRISPR for sickle cell diseases shows promise in early test. Public Radio East. November 19, 2019. Accessed January 11, 2021. [Au: please add] 

https://www.publicradioeast.org/post/crispr-sickle-cell-disease-shows-promise-early-test

4. Esrick EB, Lehmann LE, Biffi A, et al. Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease. 

. Published online December 5, 2020. doi:10.1056/NEJMoa2029392

5. Yednak C. The gene therapy race. PwC. February 5, 2020. Accessed January 11, 2021. 

https://www.pwc.com/us/en/industries/health-industries/library/gene-therapy-race.html

Investigators continue to break new ground, giving hope to patients, physicians.

The untapped potential of cell and gene therapy as treatment option


This article was reviewed by Robert S. Feder, MD

The adage of out with the old, in with the new may apply to dictums about dystrophies. Robert S. Feder, MD, offers contemporary perspectives on corneal dystrophies and pearls to guide ophthalmologists.

Feder is a professor of ophthalmology and the chairman of Cornea and External Disease Service at Feinberg School of Medicine at Northwestern University in Chicago, Illinois.

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Physicians have been taught to think of corneal dystrophies as being inherited, bilateral, affecting only 1 layer, and sparing the perilimbal cornea. In addition, they may consider them as progressive and unassociated with systemic disease.

Feder urged physicians to rethink their beliefs about corneal dystrophies in light of the number of exceptions to these rules. He pointed out that they should also consider information garnered from genetic analysis. 

This will lead to a new understanding of the relationships between dystrophies and genotypic and phenotypic heterogeneity.

In addition, Feder noted, some of the dystrophies may actually be degenerations, such as epithelial basement membrane dystrophy (EBMD), which is not inherited in most cases. 

Returning to baseline post-corneal collagen crosslinking for keratoconus



New technologies, including confocal microscopy, anterior-segment optical coherence tomography (AS-OCT), and corneal tomography, are helpful in differentiating various dystrophies.

Feder offered some examples from the International Classification of Corneal Dystrophies (IC3D) that suggest the merits of a change in our thinking about corneal dystrophies.

“Is keratoconus a dystrophy given that it is inherited in some families? Should cornea plana be considered a dystrophy due to its [being] genetically similar to posterior amorphous stromal dystrophy? Is a ‘new’ dystrophy really new considering its genetic similarity to an existing dystrophy?” he asked.

He also called attention to the misnomer of Schnyder crystalline corneal dystrophy, also known as Schnyder corneal dystrophy, in which crystals are present in only half of cases.

In addition, the presentation of some corneal dystrophies in the pediatric population of patients can differ dramatically from that in seen adults.

Harnessing 1-2 punch of KAMPs for corneal infection, inflammation

 is an evidence-based reclassification of corneal diseases created through a collaborative effort of world experts in the field.

“The traditional classification of epithelial, Bowman layer, stromal, and endothelial dystrophies has been adjusted to reflect a contemporary understanding of the dystrophies,” Feder said.

Changes to the second edition of the IC3D combined the epithelial and subepithelial dystrophies, such as the Meesmann Stocker-Holt variant, EBMD, gelatinous drop-like corneal dystrophy, and subepithelial mucinous corneal dystrophy, which now fall under the same umbrella. 

The epithelial-stromal transforming growth factor beta-induced (TGFBI) dystrophies now include Reis-Bücklers and Thiel-Behnke; lattice type I, III, and IV; and granular types 1 and 2 dystrophies because they share a similar genetic abnormality.

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Painful corneal erosions are common in the diseases of this group because the abnormal keratoepithelin protein interferes with normal adherence at the epithelial basement membrane complex. 

Lattice II was removed from the classification as it is familial amyloidosis rather than a corneal dystrophy.

The stromal dystrophy classification more accurately includes macular, congenital hereditary stromal, Schnyder corneal, fleck, posterior amorphous stromal, and pre-Descemet dystrophies.

The endothelial dystrophy classification still includes Fuchs and posterior polymorphous corneal dystrophies; however, the dominant form of congenital hereditary endothelial dystrophies was eliminated from the classification.

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Genetic analysis can help identify a specific dystrophy and aid in patient counseling (increasingly available, although insurance may not pay). Further, new technologies can help clinicians better characterize dystrophies.


EBMD is present in 50% of patients with recurrent erosions, but only 10% of patients have symptomatic erosions. Feder advised examining the fellow eye to identify the characteristic fingerprints, maps, and dots of EBMD. 

Blurred vision resulting from irregular astigmatism associated with this dystrophy often goes unrecognized; keratometry or corneal topography can identify the irregular astigmatism. 

Contact lens overrefraction provides dramatic visual improvement in these patients and may lead surgeons to consider epithelial debridement. 

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Reis-Bücklers and Thiel-Behnke corneal dystrophies are very similar, as they both have the 

 genetic abnormality. Modern technology has made the conditions easier to differentiate. Thiel-Behnke, Feder explained, has a honeycomb appearance and Reis-Bücklers, a coarser, fishnet appearance.

AS-OCT shows a sawtooth appearance at Bowman layer in Thiel-Behnke but not in Reis-Bücklers. 

Confocal microscopy shows characteristic hyperreflectivity in Reis-Bücklers that is greater than that in Thiel-Behnke, whereas Thiel-Behnke has shadows that are not seen in Reis-Bücklers. 

Finally, transmission electron microscopy can be used to demonstrate curly filaments in Thiel-Behnke and rod-shaped bodies in Reis-Bücklers.

Granular corneal dystrophy exhibits 2 forms. The classic type has central opacities in the superficial and mid stroma with intervening clear cornea and peripheral sparing, whereas the Avellino variant is superficial and exhibits both granular and lattice findings. 

 abnormality should avoid laser refractive surgery because opacities become more prominent. If there is doubt, genetic testing can help.

The classic crystalline lattice lines seen in patients with lattice dystrophy are not seen in children with the disease. 

Children typically show stromal haze, dots, and short fine lines. These findings are also seen in keratoplasty patients with recurrent lattice dystrophy.

Fuchs dystrophy has many faces. Early-onset disease can occur in the first decade of life, mostly in females. Transmission microscopy shows a thickened anterior banded layer in Descemet membrane and degenerated endothelial cells. 

Late-onset disease (defined as occurring in the fourth decade or later) has numerous genotypes.

Although specular microscopy may be helpful in early disease, Feder commented that it is not useful when the guttata are confluent. 

In these cases, pachymetry performed in the morning can identify patients with early endothelial decompensation. These patients may complain of blurred vision in the morning that takes an hour or more to clear.

Changing patient conversations around cataract surgery

In the presence of edema, endothelial keratoplasty is therapeutic and can be combined with cataract surgery. Descemet stripping only is a novel approach for the patient with little lens change and only central corneal involvement. Administrating topical rho-kinase inhibitor may help speed postoperative healing.

 alone can be considered in eyes with guttata but without edema because of the good visual acuity that can be achieved. 

 is inadequate due to corneal edema or scarring, open-sky cataract surgery combined with penetrating keratoplasty is still an option.

Feder emphasized that IC3D is the new gold standard for classifying the dystrophies. 

Genetic analysis, which is increasingly available, can identify a specific dystrophy and help with patient counseling; however, insurance coverage is not guaranteed. 

New technologies can better characterize the dystrophies, which is particularly helpful as presentations in children differ from those in adults. 

Hardware, software offer surgeons a window to cornea diagnosis

Phenotypic and genotypic heterogeneity is important to recognize, some dystrophies may actually be degenerations.

“It’s time to rethink the old dictums about dystrophies in terms of classification, diagnosis, and management,” Feder concluded. 

Feder has no financial interest in this subject matter.


1. Weiss JS, Moller HU, Aldave AJ, et al. IC3D classification of corneal dystrophies—edition 2. 

2015;34:117-159; doi: 10.1097/ICO.0000000000000307

Physician provides contemporary perspective and pearls to guide ophthalmologists.


More than meets the eye with corneal dystrophies

This article was reviewed by Arshad M. Khanani, MD, MA

neovascular age-related macular degeneration (AMD)

 can be a stumbling block in treatment adherence because of the need for very frequent dosing to maintain vision.

Adeno-associated virus gene therapy vector (ADVM-022, Adverum Biotechnologies) has demonstrated the potential to reduce that burden substantially based on the phase 1 OPTIC [NCT03298867] trial results.



“ADVM-022 is a gene therapy vector designed for continuous delivery of aflibercept [Eylea, Regeneron Pharmaceuticals] by a single in-office intravitreal injection,” said Arshad M. Khanani, MD, MA, managing partner and director of clinical research at Sierra Eye Associates in Reno, Nevada. “The AAV.7m8 capsid allows for efficient retinal transduction after the intravitreal injection.”

The preclinical data from 2 studies of nonhuman primates showed that ADVM-022 facilitated stable long-term protein expression up to both 21 and 30 months after 1 intravitreal injection.

“The continuous expression of aflibercept after 1 injection of ADVM-022 results in levels seen 3 to 5 weeks after a bolus intravitreal injection of aflibercept,” said Khanani.



The OPTIC Trial is a phase 1, 2-year multicenter dose-ranging trial of ADVM-022 to treat 

 with a primary objective of assessing the safety and tolerability of 1 injection of therapy. 

The secondary outcomes were the best-corrected visual acuity (BCVA), the status of the anatomy based on spectral-domain optical coherence tomography, and the need for supplemental anti-VEGF therapy, according to Khanani.

Four patient cohorts have been enrolled in the study. Cohorts 1 and 4 (6 and 9 patients, respectively) received high doses (6x1011 vg/eye). 

Cohorts 2 and 3 (6 and 9 patients, respectively) received lower doses (2x1011 vg/eye). 

Investigators observe dramatic decrease in treatment burden seen in OPTIC study.

Ophthalmology Times: February 15, 2021

Preferred practice patterns for bacterial keratitis address existing controversies

Uveitis: A leading, underestimated cause of visual morbidity in patients

The untapped potential of cell and gene therapy as treatment option

More than meets the eye with corneal dystrophies

ADVM-022 offers sustained anatomic improvements in wet AMD

Study targets strategies for CI-DME

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