 (EYS) gene are the primary causes of retinitis pigmentosa (RP). RP25, a severe form of autosomal recessive RP, is seen in all ethnic groups with prevalence rates ranging from 5% to 33%, and patients who are affected early in life have no therapeutic recourse.

Francisco Diaz-Corrales, MD, PhD, Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain, and colleagues reviewed the knowledge about the effect of the 

Learning about autosomal recessive RP’s molecular mechanism has been hampered by the absence of a specific animal model for this human inherited retinal disease. Information about the protein’s cellular location and molecular features in different vertebrate animal models has provided some insight into the protein’s possible roles in the human retina.

Some things that are known is that the gene is the largest one in the human eye and extends for 2 Mb of genomic DNA in chromosome 6 (6q12.1-6q15). Studies disagree about the size of the 

 but both reported the gene is preferentially and abundantly expressed in human retina with minor expression in other tissues.

The size makes studying the gene difficult, Diaz-Corrales explained.

According to Diaz-Corrales, that difficulty arises from the complexity of the gene, which is divided into two distinct halves of the full-length EYS protein that likely have different roles and interactors.

“Shorter isoforms with just the epithelial growth factor (EGF)-rich or the Laminin G-rich sections will probably have particular localizations and functions, which will be relevant for analyzing and predicting the phenotypic impact of genetic variants,” Diaz-Corrales explained.

Affected patients generally begin to lose vision in the second and third decades of life; an early manifestation is night blindness and progressive constriction of visual fields. At a relatively young age, subcapsular cataracts can develop. The central vision generally is preserved until late in life.

Initially, fundus images show bone spicule pigmentation, pallor of the optic disc, retinal vessel attenuation, and a reduced or non-detectable electroretinogram response under scotopic and photopic conditions. With progression, thinning of the macula occurs. Fundus autofluorescence is helpful for determine the disease’s extent and diagnosis in cases with atypical presentation. In early-stage RP25, the peripheral ellipsoid zone is less visible, and the ellipsoid zone edge approximates the visual field along with disease progression.

Numerous mutations have been reported for EYS that include insertion, deletion, nonsense or missense substitution and splice site mutations, and these are manifested differently in different cohorts. However, truncating mutations lead to premature stop codons that remove laminin or epithelial growth factor domains, including frameshift and nonsense mutations.

Diaz-Corrales explained that because of the great variability in the severity of missense mutations and the lack of hotspots in EYS, identifying genotype–phenotype relationships is challenging. In addition, the full-length protein structure is divided into two distinct halves, as mentioned previously.

At 1 end is an N-terminal with a signal peptide followed by a stretch of EGF-like domains and a C-terminal rich in Laminin G domains interspaced with additional EGF-like domains at the other end. Different isoforms have been detected in the retina and other tissues. The diverse EYS isoforms, with particular domain composition and structure, perform specific roles depending on time, cellular compartment or tissue, complicating the analysis of the effect of mutations.

These can be gene/mutation-specific and those that exert a therapeutic effect apart from the genetic defect.

“Gene therapy can be applied in the early stages of degeneration when the retinal cells are impaired but the photoreceptor cells can be rescued by external genetic material,” he said.

The first gene therapy was approved to treat Leber congenital amaurosis caused by a defect in the 

. However, this approach may not work for EYS mutations because of the limited loading capacity of the viral vectors that hinders large gene delivery. A possible solution would be to use a reduced version of the gene to fit in the current vectors, i.e., a mini-

 with only essential information to prepare a protein to rescue the healthy phenotype.

Another gene therapy would be to use the gene(s) that substitute for 

 function in the murine retina and other species in which this gene is non-functional/absent once these factors are identified.

Additional methods for retinal delivery of transcripts exceeding 5 kb using the successful adeno-associated viral vectors (AAV) are theoretically feasible using dual AAV vectors. Transgenes approximating the size of the 

 transcript might be divided and co-infected in the same cell. To reconstitute the full-length transgene, possible mechanisms are trans-splicing through concatemerisation of AAV inverted terminal repeasts using donor and acceptor splicing sites or homologous recombination using sequence overlapping.

The limitations of these strategies depend on the efficiency of the specific splicing/DNA recombination events and frequency of generation of wrong concatemers.

A more recent technology proposed as a future treatment for many disorders caused by a genetic defect is the clustered regularly interspaced short palindromic repeats (CRISPR) system that edits the cell genome. Gene editing is a promising option for huge genes, because no exogenous gene has to be supplied to the diseased cells. Instead, their genome will be specifically modified to overcome the defect and produce a functional version of the protein. This technique has been successful in some blood cancers, but retinal evaluation remains preclinical.

Cell replacement is another option that may work for advanced retinal dystrophy to regenerate damaged cells. The cell sources can be either ocular-derived retinal progenitor cells or cells differentiated in vitro from embryonic stem cells or induced pluripotent stem cells.

For very advanced RP cases, prosthetics are another option. An electronic retinal implant, i.e., the Argus II epiretinal implant (Second Sight Medical Products), can provide artificial vision. This artificial vision can help some blind people to gain navigation autonomy after rehabilitation and training.

A more sophisticated approach is optogenetics, in which surviving retinal cells that are non-photosensitive are transformed to be light-sensitive via genetic modification.

Promising experimental results have been observed but clinical trials are needed. In Europe, the ongoing PIONEER phase I/IIa clinical trial (NCT03326336) combines optogenetics directed to remaining retinal ganglion cells using a light-amplification device.

Finally, intervening in the neurodegenerative process induced by RP is another possibility. Neuroprotection can extend photoreceptor life, delay the disease course, and increase the possible success of gene/cell therapy.

According to Diaz-Corrales, intrinsic difficulties associated with the study of EYS-retinopathy include the size of the gene and the absence of a mouse or rat animal model of the disease.

Diaz-Corrales has no financial disclosures related to this content.

1. Garcia-Delgado AB, Valdes-Sanchez L, Morillo-Sanchez MJ, et al. Dissecting the role of EYS in retinal degeneration: clinical and molecular aspects and its implications for future therapy. 

2021;16; https://doi.org/10.1186/s13023-021-01843-z

2. Abd El-Aziz MM, Barragan I, O’Driscoll CA, et al. EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa. 

3. Collin RWJ, Littink KW, Klevering BJ, et al. Identification of a 2 Mb human ortholog of drosophila eyes shut/spacemaker that is mutated in patients with retinitis pigmentosa. 

Articles

Investigators believe the therapy could prove to be an option for the treatment of other retinopathies. 

EYS gene complexity key to treatment of retinitis pigmentosa 

Cheryl Guttman is a medical writer based in Deerfield, Ill.

Bausch + Lomb and Clearside Biomedical recently announced the FDA granted approval of triamcinolone acetonide injectable suspension (Xipere) for suprachoroidal use for the treatment of macular edema associated with uveitis.

Formerly known as CLS-TA, the novel product represents the first treatment approved by the FDA for injection into the suprachoroidal space. 

The product is a proprietary preservative-free formulation of triamcinolone acetonide (TA), and the injection is performed as an in-office procedure using a proprietary syringe and needle platform (SCS Microinjector).

Study targets use of swept-source OCT to measure macular hole volume

The FDA approval was based on results of PEACHTREE (NCT02595398), a randomized, controlled, masked phase 3 clinical trial comparing treatment with 2 injections of suprachoroidal TA (weeks 0 and 12) or a sham procedure. 

PEACHTREE met its primary end point by showing statistical superiority of suprachoroidal TA vs sham for the percentage of eyes achieving a best-corrected visual acuity (BCVA) gain greater than or equal to 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline to week 24 (47% vs 16%, 

The study also met all secondary end points, including reduction in macular edema and improvement in anterior chamber and vitreous inflammation, and found the investigational corticosteroid was safe and well tolerated. 

Data from MAGNOLIA (NCT02952001), an extension study, showed the treatment benefit of suprachoroidal TA could persist for at least 9 months in many patients.

Steven Yeh, MD, is the first author of the published article reporting the PEACHTREE study and is a professor of ophthalmology at the Truhlsen Eye Institute, University of Nebraska Medical Center in Omaha.

“The approval of Xipere is an exciting advance in the care for patients with intraocular inflammation and macular edema associated with noninfectious uveitis,” he said. “Corticosteroids are a mainstay of treatment for this condition, and Xipere represents a new method of drug delivery that was well tolerated, showed good safety, and had striking benefit for improving visual acuity and other efficacy measures.”

Yeh pointed out that PEACHTREE assessed visual acuity is the primary end point. “This is an important point because of all the measurable clinical features of uveitic macular edema, vision is the one that most affects quality of life for our patients,” he said.

Yeh said the efficacy and safety of suprachoroidal TA may be understood by its pharmacokinetics, which show suprachoroidal delivery results in very compartmentalized distribution of the corticosteroid, targeting the pathology while limiting exposure to tissues that are adversely affected by corticosteroids. 

FDA approves XIPERE for treatment of macular edema associated with uveitis

“Findings from preclinical studies show there is rapid dispersion of TA into the choroid and retina after suprachoroidal injection and persistence of high levels of the corticosteroid for more than 3 months. However, exposure of the anterior segment to the corticosteroid is limited,” he said. “Therefore, suprachoroidal TA offers the potential for rapid and effective control of uveitic macular edema with the potential to limit corticosteroid-related complications of cataract, IOP elevation, and glaucoma exacerbation.”


PEACHTREE randomized 160 patients 3:2 to treatment with triamcinolone 4 mg/0.1 mL or sham procedure. All anatomic subtypes of uveitis were represented in the study population.

Approximately 50% of patients in the suprachoroidal TA arm and two-thirds of controls were phakic. Mean time since uveitis diagnosis was 177 weeks in the suprachoroidal TA arm and 107 weeks in the control arm.

 Mean BCVA at baseline was approximately 55 letters in the suprachoroidal TA arm and 54 letters in the controls. Mean central subfield thickness (CST) in the 2 groups was 481 and 525 μm, respectively.

The secondary end point in PEACHTREE was mean change from baseline in CST measured by spectral domain optical coherence tomography at 24 weeks. 

Additional end points included mean change in BCVA in ETDRS letters by visit, mean change in CST by visit, and changes in signs of inflammation as evaluated by the Standardization of Uveitis Nomenclature scales. 

Mean reduction in CST from baseline to week 24 was significantly greater in the suprachoroidal TA arm than the sham group (153 vs 18 μm, 

Patients treated with suprachoroidal TA gained a mean of 9.6 ETDRS letters from baseline at week 4 and showed further improvement thereafter, reaching a mean gain of 13.8 ETDRS letters at week 24 compared with just 3.0 ETDRS letters in the control group (

Rescue therapy was allowed beginning at week 4 if patients met prespecified criteria or were not improving. It was received by 13.5% of patients in the suprachoroidal TA arm and 72% of control patients.

Tracking macrophages in the macular circulation with commercial OCT


Patients from PEACHTREE were eligible for participation in MAGNOLIA if they completed PEACHTREE without needing any rescue therapy. 

Of 46 patients originally randomized to suprachoroidal TA and 7 originally randomized to sham, 28 in the suprachoroidal TA group and 5 patients in the control group entered the extension study.

During the 24-week follow-up period in MAGNOLIA (48 weeks post randomization and 36 weeks after the second injection), 11 of the 28 patients originally treated with TA received rescue therapy, and 3 were withdrawn because of an adverse event. 

Thus, 14 of the 28 patients (50%) required no rescue therapy. Three of the 7 patients who had been in the PEACHTREE control arm received rescue therapy, and 2 others withdrew.

MAGNOLIA investigated median time to rescue treatment during the extension period as its primary end point and showed it was significantly longer in the triamcinolone group than in the control arm (257 days vs 55.5 days). 

At the end of the study, patients originally treated with suprachoroidal TA had a mean BCVA gain from baseline (PEACHTREE entry) of 12.1 ETDRS letters and a mean CST reduction of 174.5 μm.


No serious adverse events considered by the investigators to be related to treatment with suprachoroidal TA were recorded during PEACHTREE or MAGNOLIA. 

In PEACHTREE, the rate of elevated IOP pertaining to the corticosteroid (this analysis excludes events on the day of the procedure) was higher in the control group than in the triamcinolone arm (15.6% vs 11.5%), and the rate of cataract formation was only slightly higher in the triamcinolone group than among eyes receiving sham injection (7.3% vs 6.3%).

“It is important to note that in PEACHTREE, the suprachoroidal TA injection was well tolerated and associated with a lower rate of elevated IOP than the sham control procedure where rescue therapies could be administered during the trial,” Yeh said.


Yeh said all investigators participating in the premarketing clinical trials received special training for administering the injection. 

“The procedure used for suprachoroidal TA injection is a nuanced technique. However, it is very reproducible, can be learned by any ophthalmologist who is comfortable administering intraocular injections, and is well tolerated by patients,” he said.


Yeh is a consultant to Clearside Biomedical, Bausch + Lomb, Allergan, Regenxbio, Adverum Biotechnologies, and Buoy Health.

1. Khurana RN, Merrill P, Yeh S, et al. Extension study of the safety and efficacy of CLS-TA for treatment of macular oedema associated with non-infectious uveitis (MAGNOLIA). 

 2021;bjophthalmol-2020-317560. doi:10.1136/bjophthalmol-2020-317560

Triamcinolone acetonide injection approved for treatment of macular edema.

Therapy shows efficacy, durable benefit, favorable safety profile

Robotically aligned optical coherence tomography (RA-OCT) can provide high-quality volumetric retinal and optic nerve images of patients in the emergency department (ED), the findings of which correlated well with the clinical examinations, according to pilot study results presented at the Women in Ophthalmology 2021 Summer Symposium.

This technology has the potential to be useful in telemedicine, according to Eun Young (Alice) Choi, MD, and Anthony Kuo, MD, senior author and associate professor of ophthalmology at Duke University School of Medicine in Durham, North Carolina.

Patients who present to the ED with ocular injuries may need to undergo a fundus examination, but there are scenarios in which that need may not be met for various reasons. For example, using RA-OCT may meet that need in remote areas.

In a pilot study, Choi and her colleagues tested the ability of RA-OCT to obtain remote fundus imaging of patients who presented to the Duke University ED with ocular complaints.

Six patients (3 men, 3 women; age range, 24-84 years) were recruited for the study over the course of 6 nonconsecutive days. Patients who presented with penetrating ocular trauma or loss of blood were excluded.

The swept-source OCT machine provided a 32° field of view of the retina, including the fovea and optic nerve head. Rectangular volumes and full-width B-scans were acquired in triplicate. Thickness maps were generated with semiautomatic segmentation of selected volumes.

The ophthalmology resident on call evaluated the patients and documented the imaging findings and diagnosis.

The clinician who operated the RA-OCT during imaging of 2 patients was positioned behind a Plexiglas barrier 6 feet away from the patients. Another 4 patients underwent imaging while the operator was in a separate room that was connected remotely to the RA-OCT via a local network.

A trained reader who was masked to the examination reviewed the OCT images, according to Choi.

The investigators reported that the images they obtained were of high quality and agreed with the clinical examinations. The documented pathologies included drusen and retinal thinning. In cases in which the retinal appeared normal, soft drusen were seen on OCT images.

Although the pathologies imaged in the pilot study were limited to findings in only a few patients, Choi envisions a future for RA-OCT in telemedicine.

RA-OCT is an investigational device being used under a research protocol. The device was developed by Joseph Izatt, PhD, of Duke Biomedical Engineering; Mark Draelos, MD, PhD, of Duke Biomedical Engineering and Surgery; and Ryan McNabb, PhD, of Duke Ophthalmology.

This article was adapted from Dr Choi’s presentation at the Women in Ophthalmology 2021 Summer Symposium, August 26-29, 2021, Amelia Island, Florida. Choi has no financial interest in this subject matter.

Kuo has no financial interest in this subject matter.

A pilot study tests the technology to obtain remote fundus imaging of patients. 

Robotically aligned OCT an option for use in telemedicine

Piñero is a senior researcher and lecturer from the same group and is responsible for the advanced optometry unit of the Department of Ophthalmology of Vithas Medimar International Hospital, Alicante, Spain. 

Neurodevelopmental disorders (NDDs) are characterized by early-onset deficits of variable severity in personal, social, academic, or occupational functioning, as defined in the 

Diagnostic and Statistical Manual of Mental Disorders

 Developmental deficits may vary from very specific limitations of learning or control of executive functions to global impairments of social skills or intelligence.

Alterations in ocular movements and a large variety of visual problems have been associated with certain types of NDDs in children, which has lent support to the idea that the NDDs represent an etiological factor.

 Specifically, different types of accommodative, binocular, and oculomotor alterations have been reported in dyslexia, attention deficit/hyperactivity disorder (ADHD), and developmental coordination disorder (DCD).

Investigations carried out to date only suggest the potential for visual problems to be a comorbidity in these conditions, so it cannot be concluded that these alterations are causal factors. Indeed, one hypothesis proposes that the concept of dorsal stream vulnerability can be used to explain a cluster of problems that are common to many NDDs, including poor motion sensitivity, visuomotor spatial integration for planning actions, attention, and number skills.

To attempt to shed more light on the link between visual problems and NDDs, we recently conducted a clinical study to analyze the distribution of oculomotor and visual alterations, defined according to standard clinical tests in children with dyslexia, ADHD, and DCD (3 of the more common NDDs that can be examined easily in clinical practice). We compared the distribution with that obtained in healthy children without ocular pathology but with and without oculomotor anomalies.

We evaluated a total of 69 children (6 to 13 years old) in a prospective, nonrandomized comparative study, conducted at the Child Development Unit of the Alto Aragón Polyclinic in Huesca, Spain. All children were evaluated by an optometrist, an ophthalmologist, a speech therapist, a psychologist, and a neuropediatrician.

Among the children recruited for the study, 3 groups were clearly differentiated. These included a control group; healthy children with oculomotor abnormalities; and children with an NDD diagnosis. No comorbidity of NDD was present in any case.

A complete visual examination was conducted, including the measurement of uncorrected and corrected distance visual acuity; manifest and cycloplegic refraction; a cover test; a Maddox rod test; the measurement of near point of convergence (NPC); distance and near stereopsis; a Worth Four Dot Test; fusional vergence measurement; monocular and binocular accommodative facility; amplitude of accommodation; accommodative response at 40 cm (monocular estimation method); and a subjective evaluation of oculomotricity with the Northeastern State University College of Optometry (NSUCO) oculomotor test and the developmental eye movement (DEM) test.

An objective evaluation of oculomotricity was carried out with the eye tracker Tobii EyeX (Tobii) and Clinical Eye Tracker software (Thomson Software Solutions) in a subsample of 15 healthy children and 17 children with NDDs.

We found significantly worse near stereopsis in children with NDDs compared with healthy children (60.1 ± 71.2 vs 30.7 ± 23.9 in; 

 < .001) and in those with oculomotor abnormalities but without NDDs (60.1 ± 71.2 vs 30.8 ± 18.9 in; 

 = .001). Likewise, a significantly lower amplitude of accommodation was found in children with NDDs compared with healthy children in both the right eye (11.4 ± 2.8 vs 9.0 ± 2.0 D; 

 = .001) and the left eye (10.1 ± 2.8 vs 9.2 ± 1.9 D; 

No statistically significant differences between the groups were found in the measurement of near and distance phoria (

 ≥ .059). According to standard criteria, no statistically significant differences were present among the groups in the number of cases with binocular or accommodative disorders (

The comparison between the 3 types of NDDs included revealed the presence of a significantly lower amplitude of accommodation in children with DCD compared with those with dyslexia. Furthermore, less exophoria at near was present in children with dyslexia compared with children with ADHD
(

Concerning oculomotricity, significantly impaired scores were found with the subjective test (NSUCO and DEM tests) in children with NDDs compared with healthy children (

 < .001), with no significant differences between children with oculomotor abnormalities but without NDDs and children with NDDs (

 ≥ .063). Regarding eye tracking analyses, we found a significantly higher number of hypometric saccades in children with NDDs compared with healthy children (

A complete visual examination was conducted, including measurement of uncorrected and corrected distance visual acuity; manifest and cycloplegic refraction; cover test; Maddox rod test; measurement of near point of convergence (NPC); distance and near stereopsis; four-dot Worth test; fusional vergence measurement; monocular and binocular accommodative facility; amplitude of accommodation; accommodative response at 40 cm (monocular estimation method); and subjective evaluation of oculomotricity with Northeastern State University College of Optometry’s Oculomotor (NSUCO) and developmental eye movement (DEM) test.

An evaluation of oculomotricity was carried out with the Eye Tracker Tobii Eye X (Tobii) and the Clinical Eye Tracker software (Thomson Software Solutions) in a subsample of 15 healthy children and 17 children with NDDs.

Likewise, we found a significantly higher percentage of regressions in the group of children with NDDs when a time interval of presentation between stimuli of 1 second was used (

 = .012). Significant correlations were found between different NSUCO scores and percentage of regressions, number of saccades completed, and number of hypometric saccades.

Children with dyslexia, ADHD, and DCD show an altered oculomotor pattern and a more reduced amplitude of accommodation; however, this is not always compatible with the diagnostic criteria of an accommodative insufficiency. Accommodative and binocular vision problems are not always present in these children and so cannot be considered an etiological factor.

Hypometric saccades and regressions are commonly present in children with NDDs. However, oculomotor anomalies can be present in children with and without NDDs, and therefore they do not seem to be a good diagnostic criterion of these complex types of disorders.

Future research should be focused on the analysis of the impact of oculomotor alterations associated with NDDs and how complementary binocular and accommodative anomalies affect the child’s development. This is critical because it will help define a standardized scientific-based approach for the treatment of visual and oculomotor problems in children with NDDs. This, in turn, will help prevent exposure to pseudotherapies and treatments based on visual approaches that are not useful.

Bilbao is based at the Department of Optometry, Policlínica Alto Aragón in Huesca, Spain. She has no financial disclosures related to this content.

Piñero is part of the Optics and Visual Perception Group, Department of Optics, Pharmacology and Anatomy at the University of Alicante in Spain, and is based at the Department of Ophthalmology, Vithas Medimar International Hospital in Alicante. He has no disclosures related to this content.

Diagnostic and Statistical Manual of Mental Disorders (DSM-5)

. 5th ed. American Psychiatric Publishing; 2013.

2. Posar A, Visconti P. Neurodevelopmental disorders between past and future. 

. 2017;12(3):301-302. doi:10.4103/jpn.JPN_95_17

3. Bilbao C, Piñero DP. Diagnosis of oculomotor anomalies in children with learning disorders.

. 2020;103(5):597-609. doi:10.1111/cxo.13024

4. Bilbao C, Piñero DP. Clinical characterization of oculomotricity in children with and without specific learning disorders. 

 2020;10(11):836. doi:10.3390/brainsci10110836

5. Molina R, Redondo B, Vera J, García JA, Muñoz-Hoyos A, Jiménez R. Children with attention-deficit/hyperactivity disorder show an altered eye movement pattern during reading. 

. 2020;97(4):265-274. doi:10.1097/OPX.0000000000001498

6. Hussaindeen JR, Shah P, Ramani KK, Ramanujan L. Efficacy of vision therapy in children with learning disability and associated binocular vision anomalies.

. 2018;11(1):40-48. doi:10.1016/j.optom.2017.02.002

7. Falkenberg HK, Langaas T, Svarverud E. Vision status of children aged 7-15 years referred from school vision screening in Norway during 2003-2013: a retrospective study. 

. 2019;19(1):180. doi:10.1186/s12886-019-1178-y

8. Mahone EM, Mostofsky SH, Lasker AG, Zee D, Denckla MB. Oculomotor anomalies in attention-deficit/hyperactivity disorder: evidence for deficits in response preparation and inhibition. 

. 2009;48(7):749-756. doi:10.1097/CHI.0b013e3181a565f1

9. Loe IM, Feldman HM, Yasui E, Luna B. Oculomotor performance identifies underlying cognitive deficits in attention-deficit/hyperactivity disorder.

. 2009;48(4):431-440. doi:10.1097/CHI.0b013e31819996da

10. Bucci MP, Brémond-Gignac D, Kapoula Z. Poor binocular coordination of saccades in dyslexic children. 

.2008;246(3):417-428. doi:10.1007/s00417-007-0723-1

11. Grisham D, Powers M, Riles P. Visual skills of poor readers in high school. 

. 2007;78(10):542-549. doi:10.1016/j.optm.2007.02.017

12. Kapoula Z, Bucci MP, Jurion F, Ayoun J, Afkhami F, Brémond-Gignac D. Evidence for frequent divergence impairment in French dyslexic children: deficit of convergence relaxation or of divergence per se? 

. 2007;245(7):931-936. doi:10.1007/s00417-006-0490-4

13. Atkinson J. The Davida Teller Award Lecture, 2016: visual brain development: a review of “dorsal stream vulnerability” – motion, mathematics, amblyopia, actions, and attention.

14. Braddick O, Atkinson J, Akshoomoff N, et al. Individual differences in children’s global motion sensitivity correlate with TBSS-based measures of the superior longitudinal fasciculus. 

. 2017;141:145-156. doi:10.1016/j.visres.2016.09.013

15. Bilbao C, Piñero DP. Objective and subjective evaluation of saccadic eye movements in healthy children and children with neurodevelopmental disorders: a pilot study. 

 2021;5(2):28. doi:10.3390/vision502002816.

16. Bilbao C, Piñero DP. Distribution of visual and oculomotor alterations in a clinical population of children with and without neurodevelopmental disorders. 

. 2021; 11(3):351. doi:10.3390/brainsci11030351

Investigators find that youth show altered ocular movements, reduced amplitude of accommodation. 

Link between neurodevelopmental disorders, visual problems studied

Various formulations of anti-inflammatory prophylaxis in conjunction with cataract surgery performed similarly to control central subfield thickness.

Danish researchers reported that a comparison of a combination eye drop comprised of a corticosteroid and a nonsteroidal anti-inflammatory drug (NSAID) was not superior to either NSAID eye drop monotherapy or a sub-Tenon dexamethasone depot for controlling the postoperative central subfield thickness (CST) after uncomplicated cataract surgery. However, about half of the patients in the depot group needed additional therapy to control inflammation.

Controlling the inflammatory response and reducing the risk of pseudophakic cystoid macular edema after cataract surgery is important to patient safety and successful surgical outcomes, but cataract surgeons have no clear path to the appropriate choice, according to Jesper Hølberg Erichsen, MD, PhD, from the Department of Ophthalmology, Rigshospitalet Glostrup, Glostrup, Denmark.

To clarify the options, the investigators conducted a randomized, single-center clinical trial from February 1, 2018, to August 15, 2019, that included patients undergoing uncomplicated phacoemulsification for age-related cataract. One experienced surgeon performed all surgeries in 1 eye of each patient.

The investigators recounted that the patients were randomized to 1 of the following anti-inflammatory prophylactic interventions: a combination eye drop comprised of prednisolone, 1%, and ketorolac tromethamine, 0.5%, with/without preoperative initiation (preoperative prednisolone plus NSAID [control] and postoperative prednisolone plus NSAID groups); ketorolac monotherapy with/without preoperative initiation (preoperative and postoperative NSAID groups); or sub-Tenon depot of dexamethasone phosphate (sub-Tenon group). The eye drops were instilled 3 times daily for 3 weeks postoperatively. The CST 3 months postoperatively was the main outcome measure.

The investigators reported that the mean CSTs in all groups were very similar at the study endpoint in the 470 study patients (mean age, 72.2 years). Ninety-four patients were included in each of the study groups. Specifically, the mean CST was 250.7 μm in both the preoperative prednisolone plus NSAID group and the postoperative prednisolone plus NSAID group, 251.3 μm in the preoperative NSAID group, 249.2 μm in the postoperative NSAID group, and 255.2 μm in the sub-Tenon group.

No significant differences in CST or visual acuity were seen compared with the control or between the preoperative and postoperative groups. However, in the sub-Tenon depot group, 56.6% of 83 participants for whom data were available needed additional anti-inflammatory treatment.

Erichsen and colleagues concluded, “No differences in CST or visual acuity were detected between the combination of prednisolone and NSAID eye drops vs. NSAID monotherapy or sub-Tenon dexamethasone depot, although more than one-half of patients in the sub-Tenon arm received additional anti-inflammatory treatment. Initiating prophylaxis 3 days preoperatively was not superior to initiation on the day of surgery. Monotherapy with NSAIDs may be preferred in uncomplicated cataract surgery.”

Erichsen JH, Holm LM, Jacobsen MF, et al. 

Prednisolone and ketorolac vs ketorolac monotherapy or sub-Tenon prophylaxis for macular thickening in cataract surgery: a randomized clinical trial

2021;139:1062-1070. doi: 10.1001/jamaophthalmol.2021.2976

Investigators set out to better define therapeutic options for controlling the inflammatory response and reducing the risk of pseudophakic cystoid macular edema after cataract surgery.

Combination, monotherapy or sub-Tenon prophylaxis: similar results?

An specializes in glaucoma treatment at the Mason Eye Clinic at the University of Missouri in Columbia.

Micro-invasive glaucoma surgery (MIGS) has become a popular option for facilitating a reduction in intraocular pressure (IOP) when medical therapy has not adequately done so or is not a viable option.

These procedures involve various approaches including improving aqueous humor outflow through the trabecular meshwork (TM) or other components of the conventional pathway such as Schlemm’s canal. MIGS is less invasive and therefore poses a lower risk for complications than traditional glaucoma surgeries such as trabeculectomy and glaucoma drainage devices (tube shunts). 

However, MIGS does not always achieve target IOP. This presents a significant glaucoma treatment challenge, as every millimeter of mercury above target pressure represents an increased risk for disease progression and ultimately, vision loss.

Many surgeons believe that prescribing topical eye drops following MIGS will not deliver additional IOP reduction, particularly when the procedure has already targeted the diseased TM. My colleagues and I set out to test this hypothesis in one specific treatment scenario by comparing the IOP lowering effects of netarsudil ophthalmic solution 0.02% (Rhopressa, Aerie Pharmaceuticals) on eyes with previous Kahook Dual Blade (KDB) goniotomy versus goniotomy-naïve eyes.

KDB goniotomy (KDB, New World Medical), a common MIGS surgery, involves the removal of a small section of TM to create an opening into Schlemm’s canal to increase aqueous humor outflow. MIGS procedures that target the TM, including KDB goniotomy, experience a “floor effect” of IOP lowering due to their inability to further bypass episcleral venous pressure (EVP) and distal resistance in the conventional outflow pathway.

Netarsudil is a Rho kinase inhibitor that is thought to lower IOP through two primary mechanisms: 

1) increasing aqueous outflow through the TM cells, 2) reducing EVP.

 This MOA is unique compared to other available IOP lowering pharmacologic therapies. Dosed as one drop QD and prescribed typically as an adjunctive therapy, netarsudil has been shown to produce consistent IOP reductions across a range of baseline pressures.

Our retrospective chart review2 analyzed data on 50 eyes of 37 adult glaucoma patients treated with netarsudil at Mason Eye Institute at the University of Missouri in Columbia, Missouri between February 2017 and October 2020. The KDB group (n = 25) included adult glaucoma patients who had undergone KDB goniotomy with cataract surgery, then started on netarsudil with no additional eye surgeries.

Control eyes (n = 25) included those with history of cataract surgery but no goniotomy or any other angle surgeries, and were started on netarsudil for at least one month with no additional ocular procedures. 

The two groups had comparable baseline characteristics, including age, gender, ethnicity as well as type and severity of glaucoma, baseline IOP, and number of medications (all P≥0.05).

We defined the primary outcome as ≥ 20% decrease in IOP at the 1 month follow-up visit compared to the IOP measured at the time of netarsudil prescription. Secondary outcomes included adverse reaction to medication, and rate of medication discontinuation for any reason.

Upon completion of the analysis, we found that netarsudil had a significantly greater IOP lowering effect in eyes treated with prior KDB goniotomy compared to eyes without history of goniotomy.

This effect was independent of surgical outcomes of KDB goniotomy. Eighty percent of KDB-treated eyes achieved netarsudil treatment success (defined as minimum 20% IOP reduction) compared to 52.0% (13 out of 25) of control eyes (P = 0.037). Percent IOP reduction was 29.5±16.1% in KDB-treated eyes and 19.4±14.0% in control eyes (P=0.022).

Based on these results, which we presented at the American Glaucoma Society annual meeting, we hypothesize that netarsudil may facilitate additional IOP-lowering effects through its unique MOA, which targets EVP in addition to the trabecular meshwork. 

In KDB-treated eyes, the excision of TM at the nasal angle may allow for a greater concentration of netarsudil to travel downstream to the distal outflow system and act on episcleral veins to reduce EVP, producing a synergistic affect.

The overall rate of adverse reactions was 48.0%, most commonly reported as redness, allergy, and blurred vision. Consistent with previous studies, no adverse reactions were serious or vision-threatening, and all resolved upon discontinuation of the medication. The overall discontinuation rate was 58.0% with average treatment duration of 5.8 months prior to discontinuation.

Though adverse events led to some discontinuations, insurance-related challenges were the most common reason, as the timeframe in which these cases were treated includes a period prior to widespread coverage adoption of Rhopressa, which was the FDA approved in December 2017. Currently, 8 out of 10 insured patients have coverage for Rhopressa.


Contrary to a widely held perception, these data clearly indicate that patients who do not achieve a target IOP after an angle surgery such as KDB goniotomy may benefit from the use of netarsudil post-surgery. 

Though adverse reactions such as hyperemia are common, netarsudil is not known to cause any systemic side effects and is generally well tolerated. Continued improvement in insurance coverage makes this medication a viable option for many patients. Once-a-day dosing also helps to promote adherence.

Taking all of these factors into consideration and recognizing the critical importance of getting glaucoma patients to their target IOP, surgeons may want to consider prescribing this medication to patients with previous angle surgery to facilitate greater IOP reduction.

Of course, further research is needed to evaluate this and other combination approaches. As such, we are in the process of planning a randomized controlled trial to determine if this result is unique to the combination of KDB goniotomy and netarsudil therapy, or if additional IOP-lowering might be achieved through the use of other topical eye drops following various MIGS procedures.

An is an ophthalmologist in Bethesda, Maryland and is affiliated with multiple hospitals in the area, including University of Missouri Health Care-Columbia and Harry S. Truman Memorial Veterans Hospital. She received her medical degree from McGill University Faculty of Medicine.  Haochen (Emily) Xu, BA, contributed to this article. 


1. Tanna et al. Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension. 

2. Xu et al. Comparison of Response to Netarsudil in Kahook Dual Blade Goniotomy Treated Eyes and Goniotomy-Naïve Eyes. Poster presented at: The American Glaucoma Society Virtual Annual Meeting; March 4, 2021.

The unique MOA may deliver a synergistic effect when prescribed post-surgically.

Netarsudil provides IOP lowering in goniotomy treated eyes 

He is director of The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, and chief medical editor of Ophthalmology Times.

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