A team of Mount Sinai investigators found that gene therapy in mouse models showed promise in preventing vision loss or blindness from serious retinal injury including optic nerve damage, and from retinal disease including diabetic retinopathy and glaucoma.

 could shift the paradigm in treatment for patients at risk of major vision loss from retinal degenerative diseases, which currently have no cure. 

The study is supported by the National Eye Institute (NEI), which is part of the National Institutes of Health, along with the Research to Prevent Blindness and The Harold W. McGraw Jr. Family Foundation.

According to the study, the team focused on retinal ganglion cells, which process visual information by sending images to the brain. These cells can degenerate as a result of retinal injury and retinal disease. 

The team of researchers demonstrated how reactivation of a key enzyme known as CaMKII and its downstream signaling in retinal ganglion cells through a gene therapy approach provided robust protection against further vision loss or impairment in multiple disease and injury models.

"Neuroprotective strategies to save vulnerable retinal ganglion cells are desperately needed for vision preservation," senior author Bo Chen, PhD, said in a statement. "We uncovered evidence for the first time that CaMKII is a key regulator of the survival of retinal ganglion cells in both normal and diseased retinas, and could be a desirable therapeutic target for vision preservation in conditions that damage the axons and somas of retinal ganglion cells."

Chen is an associate professor of ophthalmology and neuroscience, and director of the Ocular Stem Cell Program at the Icahn School of Medicine at Mount Sinai. 

He also is the McGraw Family Vision researcher at Icahn Mount Sinai, and a winner of the Pew Scholars in the Biomedical Sciences award given to young investigators showing outstanding promise.

Glaucoma is the leading cause of irreversible visual impairment worldwide, affecting 76 million people, some of whom will progress to blindness despite aggressive treatment to reduce the pressure in their eyes. 

Investigators noted that neuroprotective strategies to preserve the RGC’s axons and somas (and thereby prevent further vision loss are needed.

The investigators studied whether CaMKII could play such a therapeutic role. 

They tested the enzyme across a wide range of injury and disease animal models, including optic nerve damage, excitotoxicity (where nerve cells are destroyed by the overactivation of glutamate receptors that result in damage to the cell structure), and two glaucoma models that mimicked the pathophysiology of human disease with both high and normal intraocular pressure.

The team learned that CaMKII regulated the survival of retinal ganglion cells across many of these pathologies, and that in the small-animal excitotoxicity model, insults to the retinal ganglion cell’s somas or optic nerve injury to its axons led to inactivation of CaMKII and its downstream signaling target CREB (or cAMP response element binding protein).

“Intriguingly, we found that reactivation of CaMKII and CREB provided robust protection for retinal ganglion cells,” Chen noted in the statement, "and that CaMKII-mediated protection slowed down the disease progression in both glaucoma models."

That reactivation was made possible by a gene therapy approach deployed by the researchers to introduce a more active type of 

 into the original retinal ganglion cells to boost their activity. 

, with a mutated amino acid, was transferred to the targeted cells through an adeno-associated viral vector, a FDA-approved gene delivery system common to the growing field of gene therapy.

 could indeed be a valuable therapeutic target to save retinal ganglion cells and preserve vision in treating potentially blinding diseases like glaucoma," Chen said in the statement. "The fact that manipulation of CaMKII would involve a one-time transfer of a single-gene adds to its vast potential to treat serious retinal conditions in humans.”

Chen also pointed out that the next step is testing this in larger animal models, which may pave the way for starting clinical trials.

According to the news release, Mount Sinai has filed patent applications for this technology through Mount Sinai Innovation Partners (MSIP), the commercialization arm of the health system. 

MSIP is in active discussions with multiple companies to help advance this treatment to the clinic.

1 Bo Chen, PhD, et al. Preservation of vision after CaMKII-mediated protection of retinal ganglion cells. 

 July 22, 2021; httos://doi.org/10.1016/j.cell.2021.06.031

Articles

Investigators uncovered evidence that CaMKII could prove to be a desirable therapeutic target for vision preservation in conditions that damage the axons and somas of retinal ganglion cells.

Study: Gene therapy could preserve vision in patients with retinal disease, serious retinal injury

Retinal imaging should be an important part of the diagnostic process in potential cases of COVID-19 as 

findings offer further hints of potential infection, according to a new study.

Results of the study were reported by first authors Jose M. Ortiz-Egea, MD, and Jorge Ruiz-Medrano, MD, from the Department of Ophthalmology at Castilla La Mancha University in Albacete, Spain, and Puerta de Hierro-Majadahonda University Hospital in Madrid, Spain, respectively, and 

The following case report1 supports obtaining OCT images for patients with suspected 

A healthy 42-year-old caucasian male anesthetist reported acute development of a temporal relative scotoma in the left eye, the best-corrected visual acuity of which was 20/20. 

Investigators noted that he had treated patients with COVID-19 over the prior 5 weeks. Most ocular findings were normal, with no discromatopsia or afferent pupillary defect. 

Visual field testing showed no relevant findings associated with the focal loss of sensitivity, slit-lamp and fundus examinations appeared normal, and multimodal imaging showed or hypo- or hyper-autofluorescence in the area.

However, the investigators reported that a placoid, hyperreflective band at the level of the ganglion cell layer and the inner plexiform layer was seen in the swept-source OCT images. The outer retina was not affected at diagnosis and 1 month later.

The investigators noted that after the retinal examination, 7 days after symptom onset, the patient underwent an oropharyngeal swab test for SARS-CoV-2 RNA and an enzyme-linked immunosorbent assay (ELISA) to determine the immunoglobulin G and M levels. 

A real-time reverse-transcriptase polymerase chain reaction was negative. ELISA testing and a third rapid antibody detection test performed 7 days after symptom onset were positive.

“The ocular signs and symptoms in COVID-19 cases are rarely reported, but may be underestimated, especially those that affect the retina and occur in asymptomatic or paucisymptomatic cases,” the authors concluded. “The current case of COVID-19 was diagnosed based on a retinal ophthalmic examination.”


1. Ortiz-Egea JM, Ruiz-Medrano J, Ruiz-Moreno JM. Retinal imaging study diagnoses in COVID-19: a case report. J Med Case Rep 2021;15(15) https://doi.org/10.1186/s13256-020-02620-5

Investigators have found that optical coherence tomography findings could prove to be a diagnostic tool for COVID-19. 

Retinal imaging plays diagnostic role in COVID-19 cases

Pooled data from the phase 2 and 3 clinical trials of teprotumumab-trbw, (Tepezza; Horizon Therapeutics) showed that the drug significantly improved the clinical course of active thyroid eye disease (TED) over the long term in many patients and even in those with more severe baseline disease.

TED is characterized by inflammation and proptosis and diplopia refractory to treatment. 

Study: Therapy reduces proptosis, diplopia in TED



Teprotumumab, which seems to be an important therapeutic advancement for this patient population, is an insulinlike growth factor 1 receptor–inhibiting monoclonal antibody that received FDA approval in January 2020, based on 2 double-masked, placebo-controlled, multicenter, randomized trials carried out in the United States and Europe.

George J. Kahaly, MD, PhD, and colleagues took their investigation a step further in the current pooled analysis, focusing on proptosis and diplopia by evaluating the short- and long-term aggregate response to teprotumumab from the pair of phase 2 and phase 3 trials. 

He is a professor of medicine and endocrinology/metabolism, Department of Medicine I, Johannes Gutenberg University Medical Center, Mainz, Germany.

In those 24-week studies, the patients received either active treatment or placebo once every 3 weeks, for a total of 8 infusions. 

Patients were evaluated at 7, 24, and 51 weeks after the last infusion of teprotumumab. 

Advancement in TED treatment is a bright spot

The investigators calculated the composite outcome of the data from the 2 trials as the proportions of patients with improvement in 1 eye in at least 2 of these parameters: proptosis, diplopia, eyelid swelling, lid aperture, global motility, and the Clinical Activity Score (CAS) without decreases in at least 2 of these in either eye.

Eighty-four patients were randomly assigned to teprotumumab and 87 to placebo.

At the 24-week evaluation, the authors reported that more patients randomly assigned to teprotumumab achieved a minimal 2-mm decrease in proptosis compared with placebo—77% vs 15%, respectively, a difference that achieved significance (P < .0001). 

The number of diplopia responders was also significantly higher with teprotumumab than placebo at week 24—70% vs 18%, respectively, except among tobacco users and those with a low thyrotropin binding inhibiting immunoglobulin serum concentration.

 Large improvements in quality of life also were seen. The beneficial results also withstood the test of time. 

Thyroid eye disease: Not limited to visual impairment

Seven weeks after the last dose of teprotumumab, the following responses were seen: proptosis (87%), diplopia (66%), and the composite ophthalmic response (92%). 

There was no evidence of acute TED rebound 7 weeks after the last drug infusion. 

No new safety concerns were found during follow-up or in the pooled analysis compared with the safety evaluation in the 24-week studies. 


This study was funded by Horizon Therapeutics.

1. Kahaly GJ, Douglas RS, Holt RJ, Sile S, Smith TJ. Teprotumumab for patients with active thyroid eye disease: a pooled data analysis, subgroup analyses, and off-treatment follow-up results from two randomised, double-masked, placebo-controlled, multicentre trials. 

. 2021;9(6):360-372. doi:10.1016/S2213-8587(21)00056-5

Sustained findings over long term indicate no rebound of disease.

Phase 2/3 results show teprotumumab effective treatment option for TED

"may actually be detectable in the eyes of patients, in the form of nerve damage that can be seen in the cornea.

"Long COVID" is the term used to identify a wide range of symptoms experienced by up to 30 percent of patients long after they have recovered from acute SARS-CoV-2 infection. 

These symptoms include brain fog, headaches, fatigue, loss of taste and/or smell, and more.

long COVID may be detected in the form of nerve damage that can be seen in the cornea.

Investigators pointed out that the nerve damage in the cornea can be detected by corneal confocal microscopy (CCM). 

According to the study, the investigators used the technology to identify corneal nerve damage and increased dendritic cells in cases of long COVID. 

They compared the results of 40 patients with previous COVID-19 infections against CCM observations of 30 healthy individuals who never had the disease.

The team, led by lead author Gulfidan Bitirgen, MD, from the Department of Ophthalmology at Necmettin Erbakan University in Konya, Turkey, noted that CCM could be used to detect long COVID through corneal scans of a subset of the COVID-19 group showing greater corneal nerve fiber damage and loss, along with higher counts of dendritic cells, than healthy participants.

"To the best of our knowledge, this is the first study reporting corneal nerve loss and an increase in DC density in patients who have recovered from COVID-19, especially in subjects with persisting symptoms consistent with long COVID," Bitirgen wrote in the study.

The investigators acknowledged that the work was a small observational study that could not confirm that COVID-19 actually caused the corneal abnormalities in the patients, the possible links show potential evidence of how SARS-CoV-2 infection may contribute to neurological and neuropathic problems.

Moreover, the investigators explained that this could be the result of potential disruptions to healthy nerve fiber development, leading to an increase in dendritic cells summoned as part of our immune response.

"These findings are consistent with an innate immune and inflammatory process characterized by the migration and accumulation of DCs in the central cornea in a number of immune mediated and inflammatory conditions," the investigators explained. "Further study of the relative change in mature and immature DC density and corneal nerves in COVID-19 patients over time may provide insights into the contribution of immune and inflammatory pathways to nerve degeneration."

The team found that the mean time after the diagnosis of COVID-19 was 3.7±1.5 months. 

Patients with neurological symptoms 4 weeks after acute COVID-19 had a lower CNFD (p = 0.032), CNBD (p = 0.020), and CNFL (p = 0.012), and increased DC density (p = 0.046) compared with patients in the control group.

Moreover, the patients without neurological symptoms had comparable corneal nerve parameters, but increased DC density (p = 0.003). 

There were significant correlations between the total score on the NICE long COVID questionnaire at 4 and 12 weeks with CNFD (ρ = −0.436; p = 0.005, ρ = −0.387; p = 0.038, respectively) and CNFL (ρ = −0.404; p = 0.010, ρ = −0.412; p = 0.026, respectively).

The investigators also found that the patients with more severe cases of COVID-19 often exhibited greater corneal nerve damage. 

They maintained that it could be possible that the eye abnormalities found in the study stem from the way the disease presents in patients.

According to the team, additional research with a greater number of patients will be needed to follow up on initial findings, but the results offer additional evidence of how closely eye health is connected to overall health.

“Corneal confocal microscopy identifies corneal small nerve fiber loss and increased DCs in patients with long COVID, especially those with neurological symptoms. CCM could be used to objectively identify patients with long COVID,” the investigators concluded. “Corneal confocal microscopy may have clinical utility as a rapid objective ophthalmic test to evaluate patients with long COVID.”



1 Gulfidan Bitergen, MD, et al; Corneal confocal microscopy identifies corneal nerve fibre loss and increased dendritic cells in patients with long COVID, 

A team of investigators used corneal confocal microscopy to identify corneal nerve damage in cases of long COVID. 


‘Long COVID’ may be linked to nerve damage in the cornea

What are the consequences of untreated flares? Flares are worsening of inflammation, which is the root cause of dry eye disease. Flares impact the quality of life of every suffering patient. Flares impact their reading speed. Flares impact their ability to work effectively. Even if they show up to work and sit in that office chair, or maybe in front of the monitor, maybe their work productivity is not as strong as it would be otherwise. That’s called presentism, meaning they are present but are not so productive. There’s also higher absenteeism among patients who suffer from dry eye flares.

Another important point is when their eyes hurt, they’re not able to wear their contact lenses. This can attribute to all kinds of issues. Some patients feel differently about their image with spectacles versus contact lenses. Maybe they can’t play sports because it’s difficult to participate with spectacles on. Flares also impact the mood of the patient. They’re grumpier. They snap back at family members, at colleagues. And lastly, if we don’t treat and stabilize that tear film, we’re going to have refractive surprises when it comes to nailing that outcome, especially if the patient has paid their hard-earned dollars for presbyopia-correcting IOLs [intraocular lenses] or toric IOLs. We may not be able to nail that refractive target based on measurements on an unreliable and dysregulated tear film. It’s critical to tune up the surface prior to corneal procedures like Lasik and all cataract surgeries, whether monofocal or advanced technology IOLs.

When a patient is suffering from ocular discomfort, their eyes are tearing, they say it feels like they have gravel or pieces of glass in their eye. “I can hardly keep my eyes open.” They are describing a dry eye flare. What are they looking for? They are looking for you to help them come up with quick relief.

Steroids do a great job because they are anti-inflammatory. They calm that inflammation and suppress that vicious cycle. We are fortunate that we now have an FDA-approved steroid, loteprednol etabonate 0.25%, specifically with the indication to treat dry eye flares on an intermittent basis for up to 14 days. That is a great way to start giving that patient the comfort they need.

Perhaps you’re going to co-introduce a long-term therapy with an immunomodulator. This short-term steroid will jump-start things, making the patient feel better. Some of the immunomodulators take weeks to months to work. This way, while they’re working the patient is getting the benefit of the steroid. So it’s a one-two punch. One is the immediate relief for the patient who’s desperate, and the other is the long-term chronic therapy.

The other thing is the steroid is safe. We want something that’s quick acting. We want something that’s safe. The ester steroid has an extremely safe profile, and clinical studies have demonstrated that.

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Cynthia Matossian, MD, FACS, discusses the short- and long-term treatment options for dry eye flares.

Treatment Options for Dry Eye Flares

Reviewed by Raymond Buncic, MD, CM, FRCSC

It is vital for ophthalmologists to differentiate ocular nystagmus, saccadic disorders, and central nervous system nystagmus to reach the correct diagnosis and decide on the management, according to Raymond Buncic, MD, CM, FRCSC, a senior clinical neuro-ophthalmologist in the Department of Ophthalmology and Vision Sciences at the Hospital for Sick Children in Toronto, Canada.

Buncic recommended that ophthalmologists pay studied attention to the direction of eye movements, the speed of movement, and the presence or absence of patterns in the movement.

VA, visual function are going the way of ocular inflammation

“We need to first differentiate between the type of eye movement and categorize it as an ocular nystagmus or not,” he explained. “We need to know if it is truly nystagmus at all and differentiate it from a saccadic disorder like opsoclonus, which may require a more general medical assessment and management.”

One of the key characteristics of nystagmus is that it most often has a slow phase during its repetitive eye movement, Buncic said. 

In contrast, saccadic disorders feature no slow phase, are irregular and fixation dependent, have variable movement, and lack recognizable patterns and a repetitive nature, he said.

“It can be hard to tell if there is slow movement because the movements are so fast,” Buncic explained. “We also look for patterns of movement to see if it is the same nystagmus over and over. We look at eyes for symmetry of movement.”

Multicolor and autofluorescence imaging: What’s in a name?

Once an ophthalmologist has decided that the presentation is nystagmus, then it must be determined if it is an ocular type of nystagmus or a neurological type of nystagmus, according to Buncic.

To differentiate between ocular and neurological nystagmus, clinicians need to consider features that might provide clues as to the nature of the nystagmus, he explained. 

In ocular nystagmus, vision is often affected, intensity is variable, and movement is usually constantly monoplanar (ie, not changing direction from horizontal to vertical). 

In contrast, in neurological nystagmus, there is often oscillopsia, movement is multidirectional, and there is a repetitive pattern of movement (ie, downbeat nystagmus or see-saw nystagmus).

In cases of ocular nystagmus with movements in the horizontal plane, conversion to a vertical nystagmus in up or down gaze indicates more of a neurological problem, Buncic noted.

Some forms of nystagmus can be more easily detected than others because of the small amplitude of movements.

Do you 'need' or just 'want' that new diagnostic imaging device?

“Typically, the movements are either slow in both directions (pendular) or slow in one and quick or jerky in the other (jerk nystagmus) in primary gaze,” he said.

In cases of incomplete albinism, when iris transillumination may be difficult to see with the microscope in the moving eyes, multichannel visual evoked potentials (VEP) are useful to demonstrate the abnormal chiasmal visual fiber crossing that exists in albinism, explained Buncic.

Assessing for infantile nystagmus involves obtaining developmental and family history and performing a clinical assessment of vision. 

Buncic stressed that it is critical to consider the presence of any abnormality that may be impeding vision in the front or back of the eye.

, maculopathy, foveal hypoplasia, optic nerve hypoplasia, or atrophy, are usually obvious on examination, according to Buncic.

“Some of these will require a neurological investigation,” he noted. “The ocular exam is very important and involves documentation with photography and OCT [optical coherence tomography]. This gives us a chance to look back and contemplate when we have a few quiet moments for further analysis.”

Visualization with en face OCT offers value for ophthalmologists

When a less obvious retinal problem such as a retinal dystrophy is suspected or the fundus looks normal, an electroretinogram will usually prove helpful in establishing the diagnosis, Buncic pointed out.

If spasmus nutans, usually characterized by exceptionally large amplitude head bobbing and abnormal head posture, is suspected, imaging should be conducted to rule out the rare, reported cause of an optic nerve tumor (optic glioma), he said.

In a series of infants with nystagmus presenting with optic pathway gliomas at the Hospital for Sick Children, Buncic noted that the main diagnostic trait was later onset.

“The overriding diagnostic characteristic was slightly later onset, 3 months or later after birth,” he said. “The other main criterion was initial uniocularity.”

Buncic and co-investigators did not find any cases of spasmus nutans in their series of optic pathway gliomas, but spasmus nutans is reported in these gliomas in the literature.

Monocular nystagmus is a clue toward either amblyopia or an optic pathway glioma, Buncic explained.

“There should be supporting evidence for amblyopia if you are going to make that diagnosis,” he said.

It takes a village to beat visual system diseases in children

As a rule, if a neurological nystagmus is suspected, a child should be referred for magnetic resonance imaging and for management by a neurologist, he said.

The 2 most important saccadic disorders to keep in mind are opsoclonus-myoclonus syndrome, which can be caused by a neuroblastoma in children or be parainfectious, and the intermittent, voluntary “nystagmus” in children, which is benign but can be very alarming and distressing to parents when children continue to engage in this activity, Buncic concluded. 


This article is based on a presentation at the virtual Jack Crawford Day Conference, a pediatric ophthalmology update. Buncic has no financial disclosures related to this content.

First step is ruling out ocular nystagmus, saccadic disorder.

A patient’s eye movements can unlock diagnosis


Mitch Shultz, MD, Chang Shultz Vision (Northridge, CA), speaks on the capabilities of eyeTELLIGENCE™ (Bausch + Lomb), a cloud-based database system, combined with Stellaris Elite (Bausch + Lomb) vision enhancement systems, to look at energy-fluid metrics,  provide surgeons with the capacity to refine procedures, and give patients better outcomes. 

Mitch Shultz, MD, speaks on the capabilities of a cloud-based database system to look at energy-fluid metrics, provide surgeons with the capacity to refine procedures and give patients better outcomes. 

Refining surgical procedures with cloud-based analytical software

Reviewed by Friederike C. Kortuem, MD, MSc

Treatment with voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics) resulted in a short-term change in the foveal morphology in a 15-year-old girl with visual impairment, according to Friederike C. Kortuem, MD, MSc, from the Eye Clinic Tübingen, Eberhard Karls University of Tübingen in Baden-Württemberg, Germany. 

The impairment included nyctalopia and decreased visual acuity (VA) in early childhood.

Visual deterioration generally occurs early in Leber congenital amaurosis type 2 (LCA2) and early-onset severe retinal dystrophy (EOSRD), from as soon as birth to 5 years of age. 



First patient dosed in optogenetic gene therapy trial



Characteristically, rapid degeneration of the rods and cones, visual field reduction, sluggish or near-absent pupillary responses, photophobia, nystagmus, and nyctalopia can occur. By the 4th decade of life, patients usually are legally blind.

Subretinal administration of voretigene neparvovec-rzyl in an adeno-associated viral vector was approved in the US by the FDA in 2017 and in Germany in 2019 to treat retinal dystrophies caused by bi-allelic RPE65 mutations; RPE65 is involved in the vitamin A restoration cycle in the eye.


The current patient had an RPE65 homozygous mutation. The VA in the right eye at examination was 20/63, and the anterior segment was unremarkable. 

The retinal examination in that eye showed central macular atrophy, narrowed vessels, and diffuse peripheral atrophy.

 Kortuem demonstrated the overall decreased retinal thickness in the right eye.

The clinical examinations included measurement of the best-corrected VA (BCVA), spectral-domain 

 (OCT), and adaptive optics retinal imaging.

Investigators start pivotal subretinal gene therapy trial

At baseline, the patient was injected with the gene therapy vector, which was successfully positioned between the neural retina and the retinal pigment epithelium. 

She was evaluated at baseline and then at 2 and 5 weeks and 3 months following treatment.

At baseline, compared with healthy individuals of the same age, this patient’s retina was thinner. 

Kortuem showed that the central fovea had alterations in its layers and the retinal structures were not well demarcated, in contrast to the parafoveal layer with a preserved outer retina and photoreceptors.

As soon as 2 weeks after treatment, the foveal layer started to change. The external limiting membrane was visualized in the fovea.

“The overall disrupted appearance improved,” Kortuem commented.

After 5 weeks, the layering of the central fovea further improved out to 3 months.

Expansion study examines safety, efficacy of subretinal gene therapy for X-linked RP

The adaptive optics images obtained at baseline showed a mosaic of disrupted photoreceptor cells that, according to Kortuem, is characteristic of inherited retinal diseases. 

Following treatment, the superior nasal area appeared partly clear, and the cones were identifiable. 

In the first 5 weeks following treatment, the initially patchy areas seemed to be decreasing over time. 

These morphologic rescue parameters changed gradually over time and were correlated partly with the improvement in the foveal-mediated vision after the treatment.

Regarding the safety of the treatment, no signs of inflammation were observed.

Cone functionality improved slightly and the patient reported “brighter” vision, which she also reported 5 weeks after surgery. At 3 months after surgery, the objective changes persisted.

The VA remained stable from baseline to week 5 and then improved by 1 line to 20/50. The contrast sensitivity also remained stable over time.

Retinal therapeutic clinical trials address disease at cor

Chromatic pupil campimetry showed a dramatic increase in the central 10 degrees of the pupil from week 2 to week 5 and this improvement persisted to month 3.

“Rapid changes in the photoreceptor morphology seen on OCT and adaptive optics imaging after successful gene therapy in patients with LCA and EORD can be quantifiable at the individual level,” Kortuem concluded. 


e:friederike.kortuem@med.uni-tuebingen.de


This article is adapted from Kortuem’s presentation at the Association for Research in Vision and Ophthalmology 2021 virtual annual meeting. She has no financial interest in this subject matter.

As soon as 2 weeks after treatment, changes occur to foveal layer.

Gene therapy sparks foveal morphologic changes in LCA

Once-daily instillation of oxymetazoline hydrochloride ophthalmic solution 0.1% resulted in rapid, sustained elevation of the upper eyelids in patients with acquired blepharoptosis, according to Jason Bacharach, MD, director of research, North Bay Eye Associates, Petaluma, California, who reported the results of a phase 3 trial

Blepharoptosis occurs frequently, with incidence rates ranging from 4.7% to 13.5% of adults that increase with age. The major effect of this disorder, regardless of how minor the degree of ptosis, is the interference with the superior visual field and consequent declines in the health-related quality of life as patients find themselves limiting their daily activities, he explained.

Patients with blepharoptosis previously had to undergo surgery to achieve the appropriate position of the upper eyelid. Use of a drug to correct the eyelid position could eliminate the complications associated with surgery.

In this study, the data were pooled from 2 prospective, randomized, placebo-controlled safety and efficacy phase 3 trials of oxymetazoline.

 The investigators furthered their evaluation of oxymetazoline by evaluating the time at which the drug affected the eyelid elevation beginning at 5 minutes after instillation and the durability of that change in elevation. The studies reported were funded by RVL Pharmaceuticals, Inc., an affiliate of Osmotica Pharmaceuticals.

The investigators measured the changes in the marginal reflex distance-1 (MRD-1) at additional time points over multiple days with the focus on the onset of action on days 1, 14, and 42. The MRD-1 was defined as the distance between the center of the pupillary light reflex and the upper eyelid margin with the eye in primary gaze.

A total of 203 patients were randomly assigned to active treatment and 101 to placebo.

The onset of action of oxymetazoline 0.1% was fast, beginning 5 minutes after instillation.

On day 1, the mean changes in the MRD-1 compared with baseline at 5 and 15 minutes after instillation were 0.59 ± 0.72 mm and 0.93 ± 0.81 mm, respectively; the respective changes with placebo at the 2 time points were 0.20 ± 0.57 mm and 0.32 ± 0.64 mm. The differences at both times reached significance (p<0.001).

On day 14, with active treatment the respective mean changes from baseline at the 2 time points were 0.77 ± 0.85 mm and 1.11 ± 0.92 mm; the respective mean changes with placebo were 0.42 ± 0.78 mm and 0.41 ± 0.83 mm. The difference both reached significance (p<0.05).

On day 42, the same drug effect was seen at the 2 time points, with mean changes of 0.86 ± 0.85 mm and 1.04 ± 0.91 mm, respectively. The respective changes with placebo were 0.42 ± 0.80 mm and 0.47 ± 0.93 mm. The differences also reached significance (p<0.005).

At 2 to 6 hours after instillation on days 1 and 14, significant (p<0.001) improvements also were seen compared with placebo. “At all time points, the proportion of subjects with a positive treatment response to treatment (>0% MRD- 1 increase) exceeded 15% greater in the oxymetazoline 0.1% group (range ,16.6–36.1% more responders vs. vehicle), with the largest differences observed 2 and 6 hours post-instillation,” they commented.

Based on these results, investigators concluded that oxymetazoline 0.1% provided rapid and sustained upper eyelid elevation. “Together with data that showed superior visual field improvement and a favorable safety profile, this analysis supports oxymetazoline 0.1% as an effective non-surgical treatment for acquired ptosis,” they said.

Bacharach receives consulting fees from Osmotica Pharmaceuticals.

Bacharach J, Wirta DL, Smyth-Medina R, et al. Rapid and sustained eyelid elevation in acquired blepharoptosis with oxymetazoline 0.1%; randomized phase 3 trial results. 

Slonim CB, Foster S, Jaros M, et al. Association of oxymetazoline hydrochloride, 0.1%, solution administration with visual field in acquired ptosis: a pooled analysis of 2 randomized clinical trials. 

. 2020;138:1168–1175. doi:10.1001/jamaophthalmol.2020. 3812

Use of a drug to correct the eyelid position could eliminate the complications associated with surgery. 

Novel therapeutic approach offers nonsurgical option for acquired blepharoptosis

Al Saati is chief of the Anterior Segment Division at Prince Sultan Military Medical City, Riyadh, Saudi Arabia. 



 have a very high-tech, sophisticated optical system that works excellently when the cornea is in perfect condition. Therefore, they are contraindicated in patients who have corneal haze, scar, or oedema.

A patient who has a posterior corneal elevation is susceptible to higher-order aberrations (HOAs) or early keratoconus. 

Early clinical experience with next-generation lens

Consequently, many surgeons will refrain from using premium IOLs in such cases. As one of the first surgeons in Saudi Arabia to use a trifocal lens, I meticulously select my patients.



In Saudi Arabia, keratoconus is prevalent because of the dry atmosphere, seasonal allergies, and consanguinity. 

However, not all patients have the same severity of disease. Some live their entire lives without knowing they have keratoconus or without signs of the condition. Others present early with signs and symptoms.

Many patients who present to me with the desire to be spectacle-free have questionable corneal tomography images. 

The first patient with keratoconus I treated with a trifocal lens (AT LISA tri toric 939 M/MP; Carl Zeiss Meditec) was one of my colleagues, a 52-year-old physician with a mild but stable form of keratoconus.

Her central cornea seemed to be normal and the steepening was at the inferior part of the cornea, sparing the central 5-mm zone. The HOA at the 6-mm zone was 1.2 μm, outside the normally accepted range of up to 0.5 μm.



Curvature-changing IOL: New frontier in cataract and presbyopia surgeries

The patient was keen to try trifocal lenses, so after long discussion and counselling the procedure was undertaken. 

Postoperatively, she was incredibly happy, with uncorrected visual acuity 6/6 at near, distance, and intermediate. She had no visually disturbing aberrations.

I then performed the same procedure on her sister, who suffers from subclinical keratoconus and who also responded very well. 

That is when I began to consider premium 

 for certain cases of patients with keratoconus. I developed my own criteria for selection and, so far, patients have been very satisfied.

I have performed this procedure on 4 patients (8 eyes) with different categories of keratoconus but who all have 1 thing in common—the central 5-mm zone with an accepted range of HOA. It is not extremely high, but it is apparent that they do not have a normal posterior cornea.



Estimating the total cornea power in keratoconus patients


During diagnosis, all patients undergo a routine, complete ophthalmic examination, which includes dry and wet refraction. 

Patients also undergo a meticulous clinical assessment and detailed history taking, including family history, previous trauma, allergies, any spectacles changes and the frequency of these changes, and contact lens use.

Next, we perform corneal tomography, which is key for diagnosing keratoconus and precisely shows the anterior corneal curvature and the posterior corneal curvature.

Using 4-maps analysis, I perform the Belin/Ambrosio Enhanced Ectasia analysis and I study them carefully. Then I check the elevation maps, both in the forms of best-fit sphere and the best-fit toric ellipsoid.

I compare the maps and see whether the patient has good spectacle correction. If the patient does not have high central aberration, I then consider implanting a trifocal lens.

I speak with the patients about HOA photic phenomena and explain that they should anticipate some glare and halos over time. 

Presbyopia-correcting IOL with nondiffractive design offers gains

I show them a picture of what glare and halos will look like so they know what to expect in the coming weeks. I also discuss mental adaptation and how their vision might be adapted to some aberration.

Trifocal IOLs can, if implanted with caution, be suitable for patients with keratoconus.

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