Miniscule fixation eye movements play a major role in amblyopia, according to Dr Fatema Ghasia, associate professor of ophthalmology and director of the Vision Neuroscience and Ocular Motility Laboratory at the Cole Eye Institute, Cleveland Clinic, Ohio, United States.

Dr Ghasia explained that the visual system contains a built-in paradox. Gaze fixation is necessary to inspect the minute details of an object; however, when an individual is attempting to fixate on an image, and when the highest visual acuity is achieved, the eyes are not completely motionless, but instead tiny, involuntary fixation eye movements counteract the fading of the peripheral details during fixation by overriding the neural adaptation.

Physiological fixation eye movements produce motion that causes variability in a position only within the fovea; this is stable fixation. “In normal subjects, fixational saccades—the fast-time movements—alternate with intersaccadic drifts,” Dr Ghasia said. “The microsaccades are binocular, with small amplitudes of less than one degree, and they are conjugate: that is, the amplitude and direction are the same between the two eyes, and they occur at [approximately] one-to-two per second.” In patients with amblyopia, the picture differs in that fixation is more unstable compared with that in the fellow eye.

Amblyopia is a neurodevelopmental disorder occurring secondary to an abnormal visual experience during early childhood. Dr Ghasia said that it affects 2–4% of the population and can arise from anisometropia, strabismus, deprivation or mixed mechanisms. She demonstrated that, when evaluating scatterplots of eye positions obtained from patients with anisometropic and strabismic amblyopia, the eye with amblyopia has more fixation instability compared with the fellow eye.

Characterising amblyopic fixation instability

Dr Ghasia and her colleagues measured fixation eye movements using a remote desktop camera to record binocular, fellow eye and amblyopic viewing conditions in 115 subjects with anisometropic amblyopia, strabismic amblyopia or mixed amblyopia of different severities and controls.

A representative case was that of a patient who had severe amblyopia without nystagmus. The fixation was unstable in the amblyopic and fellow eyes, especially during the amblyopic eye viewing conditions. Increases in the drift and amplitude of the amblyopic eye were seen.

Another patient had fusion maldevelopment nystagmus, or latent nystagmus, which develops with disrupted binocularity during early infancy. This patient had seesaw oscillations seen during binocular viewing. The oscillations were more pronounced during fellow and amblyopia eye viewing, particularly during the amblyopic eye viewing condition.

Another feature of fusion maldevelopment nystagmus is the slow phase of the nystagmus. It is always directed toward the nose, Dr Ghasia explained. “When the fellow eye is compared [with] the amblyopia eye viewing, there is a reversal in the nystagmus direction, which is the hallmark of fusion maldevelopment nystagmus,” she said.

Patients with amblyopia can also have nystagmus that does not meet the criteria of fusion maldevelopment nystagmus. Dr Ghasia described a patient in whom the nystagmus was most evident during the amblyopia viewing condition, as indicated by seesaw traces. “The key feature is that there is no direction reversal of the nystagmus between the fellow and amblyopia eye viewing conditions,” she said.

When Dr Ghasia evaluated the distribution of these fixation eye movement characteristics based on the amblyopia type, she found that patients with anisometropic amblyopia were less likely to have nystagmus, strabismus patients were more likely to have nystagmus with and without fusion maldevelopment nystagmus, and those with mixed amblyopia had an equal distribution of different fixation eye movement waveforms.

Patching therapy, in which the good eye is patched and the amblyopia eye is viewing, is the most common treatment for amblyopia. “However, despite good [adherence], 40% of patients have recurrent/residual amblyopia—the predictors of which are the amblyopia severity and older age at diagnosis,” Dr Ghasia said.

Moreover, her study and those of other investigators have shown that fusion maldevelopment nystagmus worsens during monocular viewing. This raises the question of whether the outcomes vary with patching in the presence of fusion maldevelopment nystagmus.

“We hypothesised that patients without nystagmus would respond quicker and have more improvement over a short period compared [with] those without fusion maldevelopment nystagmus,” Dr Ghasia said. In light of this, they recruited 53 amblyopic patients who had eye movement recordings during at least 12 months of follow-up after the start of patching therapy, and evaluated patching duration, extent of visual acuity improvement and stereopsis improvement.

Dr Ghasia reported that she did not observe a substantial difference in patching duration but there was perhaps less vision improvement in patients with mixed amblyopia. She also saw better stereopsis in patients with anisometropic amblyopia.

However, in the same cohort, when the fixation eye movement waveform characteristics were categorised, patients with fusion maldevelopment nystagmus required much longer treatment durations than those without nystagmus. In addition, the visual acuity improvement was less over the treatment course and there was worse stereopsis, with little improvement at the end of treatment.

Interest has turned to development of newer treatments for amblyopia, one of which is dichoptic treatment. Dr Ghasia explained the use of this therapy. Different stimuli are presented to each eye. Lower-contrast stimuli are presented to the fellow eye and 100% contrast is presented to the amblyopic eye, to counteract suppression and allow for binocular combination.

Large-scale paediatric studies have shown mixed results regarding treatment effectiveness. This raised the question of whether fixation eye movement abnormalities explain the varying responses during dichoptic treatment. To find an answer, Dr Ghasia and her colleagues measured fixation eye movement during four trials in which the amblyopic eye contrast was the same at 100% and the fellow eye contrast was lowered.

Dr Ghasia showed data from two patients with moderate amblyopia with small-angle strabismus. In the first example, as the fellow eye contrast was lowered, the amblyopic eye picked up fixation. In the second patient, as the fellow eye contrast was lowered, the strabismus angle increased and the amblyopic eye did not pick up fixation. Thus, the first patient was more likely to respond to the treatment than the second patient.

She also showed data from a patient with anisometropic amblyopia who exhibited increased fixation instability of the fellow and amblyopic eyes at lower fellow eye contrasts. The increased instability could potentially affect the ability of the amblyopic eye to attend to the presented targets and could have treatment implications.

Dr Ghasia noted the key takeaways from this research (see 

) before stating that future studies quantifying fixation eye movements before and during treatment are critical. These may serve as a missing link to understanding the mechanisms responsible for varying therapeutic efficacy seen with current treatment regimens.

This article is adapted from Dr Ghasia’s presentation at the Cleveland Eye Bank Foundation Virtual Vision Symposium. She has no financial interest in this subject matter.

Articles

Minute movements are related to patching treatment outcomes in patients.

Unravelling the mysteries of amblyopia and fixation eye movements

Genetic eye disorders are an important cause of visual impairment in children and adults, affecting approximately 1 in 1,000 people worldwide.

 They can affect any part of the eye and may present in isolation (non-syndromic) or as a syndrome in association with systemic involvement.

The United States Food and Drug Administration approval in 2017 of Spark Therapeutics’ Luxturna gene therapy for patients with biallelic 

-related retinal dystrophy opened the door for multiple new therapeutic strategies. Significant advancements in the field of inherited retinal diseases (IRDs) are making genetic testing essential for every patient, as emerging therapies may become an option for them in the near future.

IRDs are some of the most prevalent genetic eye disorders, affecting over 2 million people globally. They encompass a broad spectrum of progressive and stationary conditions and are the most frequent cause of sight loss in working age populations, causing a significant socioeconomic impact.

Mutations in over 300 genes responsible for IRDs have been identified. All Mendelian inheritance patterns are seen with IRDs.

Retinitis pigmentosa (RP) is the most prevalent type of IRD and affects 1 in 3,000 people worldwide.

 It is characterised by progressive rod photoreceptor degeneration, resulting in nyctalopia and progressive constriction of the visual field in a concentric pattern and, at later stages, loss of central vision due to the involvement of cones. It may be an isolated non-syndromic condition or part of a syndrome.

Usher syndrome is an autosomal recessive condition characterised by RP, auditory impairment and a variable level of vestibular dysfunction. It is the most common cause of deaf–blindness worldwide, with a prevalence of 4–17 per 100,000, accounting for about 18% of RP cases.

The triad of signs seen on retinal examination in Usher syndrome is mid-peripheral bone spicules, a waxy pale optic disc and arteriole attenuation.

Clinically, Usher syndrome is divided into three subtypes, mainly based on the severity of the congenital sensorineural hearing loss and the presence of vestibular dysfunction. Usher syndrome type 2 (USH2) is the most frequent form and is characterised by adolescent-onset RP, moderate-to-severe hearing loss from birth and intact vestibular function.

Ten causative genes have been identified to date. Usher genes encode proteins expressed in the inner ear and retina involved in actin-based intracellular trafficking, scaffolding, cell adhesion and signalling.

Six genes have been identified for Usher syndrome type 1 (USH1), with 

 accounting for over half of USH1 cases. Three gene loci have been described for USH2, with the 

 gene being responsible for over 80% of USH2 cases. So far, one gene, 

 is the most prevalent causative gene in Usher patients worldwide. It is also responsible for 23% of non-syndromic RP.

 is a large, 72-exon gene located on the long arm of chromosome 1q41; it codes the usherin transmembrane protein, present in the retina and cochlea where it plays roles in the intracellular transport of proteins within photoreceptors and in supporting the correct development of the stereocilia of inner ear hair cells, respectively.

 include a heterogeneous spectrum of missense, nonsense, indels frameshift, splice-site, deletion and duplication. Common pathogenic variants are found in exon 13; the most frequent is a single nucleotide deletion in exon 13, c.2299delG, p.(Glu767Serfs*21), which is associated with exon splicing producing a truncated usherin, and which causes USH2. A second common variant in exon 13 is a missense mutation, c.2276G>T, p.(Cys759Phe), which can cause a non-syndromic RP.

-associated retinopathy is challenging because of its broad spectrum of mutations and the large gene size. Although no treatment has been approved yet, numerous therapeutic approaches are under development for Usher-related RP. The retina is an excellent candidate for therapeutic application because of its accessibility and immune privilege status, while the progressive sight loss of RP makes it an important therapeutic target.

Approaches for treating RP in Usher syndrome

Current therapeutic approaches include gene replacement; gene editing; nonsense suppression; antisense oligonucleotides; small-molecule therapies; and non-gene-specific therapies. Gene replacement using adeno-associated viral vectors (AAVs) has proven safe and effective in patients; however, its limited capacity of 4.7 kb means it is not suitable for carrying the 15.7 kb 

 cDNA. Dual hybrid AAV has a cargo capacity of 14 kb, which is still not sufficient, and its efficacy is limited.

 cDNA mediated by lentiviral-based equine infectious anaemia virus—UshStat—was the subject of a trial (NCT01505062) that was terminated early by its sponsor Sanofi following a review of clinical priorities. A second study evaluating the long-term safety of Ushstat is ongoing.

Work on non-viral DNA plasmid vectors is ongoing at the University College London Institute of Ophthalmology with the generation of robust plasmids that have successfully incorporated the entire 15.7 kb 

 cDNA and shown proof of-principle for production of usherin in zebrafish and human cell models. These vectors have a lower transfection efficacy compared with AAV, hence work is underway to couple the DNA plasmids with nanoparticles to improve penetration into photoreceptors.

Gene editing, which uses nuclease enzymes to cut around point mutations, small indels and splice site mutations, and recombination with template DNA containing a wild-type sequence to correct mutations in DNA, is suitable for any gene size. This approach is promising for large genes such as 

Clustered regularly interspaced short palindromic repeats (CRISPR/Cas), a gene-editing system, has been used for successful 

 editing of c.2299delG and c.2276G>T mutations in 

patient-derived fibroblasts and pluripotent stem cells. Eliminating off-target mutations and improving efficacy in post-mitotic photoreceptor cells remains a challenge for this approach.

 pathogenic variants are nonsense, and therefore could be an ideal target for translational readthrough-inducing drugs (TRIDs). These are small molecules such as ataluren or designer aminoglycosides (NB124) that bind to the translational machinery and insert amino acids at the site of premature stop codons, instead of release factors, thus restoring up to 25% of functional protein. The use of ataluren for 

 nonsense mutations in human embryonic kidney and patient-derived fibroblasts showed an increase in expression of usherin compared with control.

An important and promising modality for IRD therapy is antisense oligonucleotides (ASOs). Synthetic ASOs are single-stranded nucleotides approximately 15–30 bases long. They can be designed to bind to target pre-mRNA or mRNA of disease-related genes by base pairing and modulate target gene expression by the restoration of correct splicing. Gene size is not an obstacle in this approach but it is relatively mutation-dependent, and the half-life of these molecules means they require re-administration.

ASOs have been under investigation in several clinical trials. In February 2022, a Phase 2/3 trial (Illuminate) investigating the use of intravitreal sepofarsen (QR-110) for the treatment of Leber congenital amaurosis caused by a splicing defect in the 

 gene showed no benefit compared with a sham procedure.

In November 2021, Phase 1 of the Aurora trial, which assessed the safety and tolerability of QR-1123 for patients with autosomal dominant RP due to a P23H mutation in the 

 gene, was completed and met its key objectives.

The use of ASOs is also being investigated in 

-related RP. An ASO called QRX-411 targets the deep intronic mutation c.7595_2144A>G in intron 40 of 

 gene, causing the introduction of pseudoexon 40 due to incorrect splicing. Administration of QRX 411 was shown to partially restore correct splicing in patient-derived fibroblasts and in an optic cup model in preclinical work.

Most recently, a double-masked, randomised, controlled, multiple-dose Phase 2/3 clinical trial (Sirius; NCT05158296) of QR-421a (ultevursen) has been initiated at Moorfields Eye Hospital in London and several other centres worldwide. The aim is to target RP associated with 

 mutations in exon 13. Considering that the two most common 

mutations are located in exon 13, the success of this therapeutic approach would help a large number of syndromic and non-syndromic 

QR-421a is designed to facilitate in-frame skipping of exon 13 in the 

 gene during pre-mRNA splicing to restore a shorter but functional protein. The production of a shortened version of usherin without exon 13 has been demonstrated in patient-derived retinal organoids, with partial restoration of protein expression also observed in treated zebrafish larvae.

The Phase 1/2 Stellar study, which evaluated safety, tolerability and efficacy of a single injection of QR-421a in adult subjects, demonstrated benefit in treated versus control eyes in multiple visual parameters. The injection was well tolerated and no serious adverse events were reported.

Sirius aims to establish the safety and efficacy of multiple doses of QR-421a over 24 months in patients aged 12 and over with advanced vision loss. The trial aims to recruit 81 patients with vision worse then 20/40 and its primary endpoint is a change in best corrected visual acuity at 18 months compared with control.

There is a huge range of new therapeutic approaches and clinical trials for genetic eye diseases. Genetic testing of patients is now paramount because of the range of gene- and mutation-specific treatments that are emerging. These therapies hold much promise and are giving hope to a community of patients that previously had no therapeutic options available to them.

Dr Ocieczek completed her ophthalmology training in Warsaw, Poland, and is now a clinical research fellow at Moorfields Eye Hospital, London, UK. She has no conflicts of interest to declare.

Mariya Moosajee, MBBS, BSc, PhD, FRCOphth

Prof. Moosajee is a consultant ophthalmologist in genetic eye disease at Moorfields Eye Hospital and Great Ormond Street Hospital for Children, professor of molecular ophthalmology at UCL Institute of Ophthalmology and group leader of Ocular Genomics and Therapeutics at the Francis Crick Institute in London. She was named as one of the top 100 most influential people in ophthalmology in The Ophthalmologist Power List 2022. She is the site principal investigator for the ProQR Sirius Study at Moorfields Eye Hospital and has received honoraria from ProQR.

1. Méjécase C, Malka S, Guan Z, et al. Practical guide to genetic screening for inherited eye diseases. 

2. Toms M, Pagarkar W, Moosajee M. Usher syndrome: clinical features, molecular genetics and advancing therapeutics. 

3. ProQR Announces top-line results from phase 2/3 Illuminate trial of sepofarsen in CEP290-mediated LCA10. 

www.globenewswire.com/news-release/2022/02/11/2383604/33039/en/ProQR-Announces-Top-Line-Results-from-Phase-2-3-Illuminate-Trial-of-Sepofarsen-in-CEP290-mediated-LCA10.html

4. Positive results of QR-421a phase 1/2 clinical trial for Usher syndrome and non-syndromic retinitis pigmentosa. 

www.proqr.com/files/2021-03/Community%20Statement%20QR-421a%20program%20results%20March2021_0.pdf

5. Sirius - phase 2/3 clinical trial for USH2A mediated retinitis pigmentosa. 

www.proqr.com/sirius-and-celeste-studies-for-ush2a-retinitis-pigmentosa

Increasing understanding of the genetics behind Usher syndrome suggests that treatment may become possible in the very near future.

Landscape of genetic therapies for USH2A-related retinitis pigmentosa

With all due respect to how quickly healthcare evolves, it was not all that long ago that regenerative medicine—an industry that is expected to grow to approximately $152 million annually by 2026 in the United States

—was viewed as more science fiction than actual medical science. This was the prevailing sentiment as recently as the early 1990s.

Despite the significant medical breakthroughs we had already begun to achieve at that time, such as the Human Genome Project, cloning, radiosurgery and the SmartPill, the first known usage of the term ‘regenerative medicine’ in 1992

 was simply applied to technologies that would be relevant to hospitals in the future. Today, that future has clearly become reality, as the science of regenerative medicine and its related products—stem cells, edited genes and other biomaterials—can be utilised to help the body heal itself in a variety of ways when administered appropriately.

As we have progressively learned more about the hundreds of different biological pathways in the human body, we have also gained a better understanding of how the body heals naturally through those pathways. From chronic skin wounds and traumatic brain injuries to diabetes and certain cancers, the use of regenerative medicine has grown exponentially.

From an ophthalmological standpoint, biologics have proven effective in treating one of the most chronic and debilitating conditions, affecting some 350 million people worldwide: dry eye disease (DED). DED is a condition that produces a myriad of symptoms due to a loss of homeostasis in the eye’s tear film. It can be managed with the introduction of biological eye drops, administered individually or in tandem with other modalities based on disease severity, to return tear film back to a state of homeostasis while preventing further disease progression and improving the corneal surface.

Biologics include a range of products such as vaccines; blood and blood components; allergenics; somatic cells; gene therapy; tissues; and recombinant therapeutic proteins.

 They may be isolated from a variety of natural sources, typically proteins from humans, animals or microorganisms, and can also consist of sugars, nucleic acids or a combination of such substances.

Biologics are acellular and complex, however, since they are not a pharmaceutical product, they are less likely to produce adverse effects in patients. Their ability to promote healing without scarring is a significant benefit in the treatment of DED and other corneal disorders, such as meibomian gland dysfunction, which is the most common cause of DED.

Meibomian glands that do not function properly produce an incorrect amount of lipids to cover the tear film surface so there is evaporative loss of the aqueous layer and dryness/inflammation; evidence shows that the use of a biologic on the cornea can significantly help to keep the tear film healthy.

Ophthalmologists and optometrists are also becoming more aware that if we can keep the corneal surface in good overall health, we can also decrease complications and affect outcomes with cataracts (both before and after surgery), photorefractive keratectomy refractive surgery and LASIK surgery, all of which can also result in inflammation.

Although the human body is designed to heal, a lack of healing can occur on the corneal surface if inflammation persists. Some investigators have described DED as “a vicious cycle of corneal epithelial damage and inflammation”.

And when chronic inflammation is present, patients are at higher risk for cancer because their cells continually try to regenerate but cannot quite do so because of the nature of the inflammatory environment. However, when we can control the inflammation, the patient has more of a microenvironment in which regeneration can be better controlled.

So, what are the biologics options that are currently available for the treatment of DED? They include the following (see 

Autologous serum, a blood-derived eye drop that mimics the biochemical properties of natural basal tears to heal the ocular surface epithelium;

Autologous platelet-rich plasma, a preparation that concentrates platelets in a small volume of plasma to treat the ocular surface; and

Preservative-free allogeneic drops that can be used to stimulate stem cell communication without cell contact.

In particular, allogeneic drops are becoming more commonly prescribed as a maintenance therapy for mild-to-moderate or severe DED, especially when there are corneal findings such as punctate epithelial keratitis. Other conditions that respond to this treatment include neurotrophic keratitis and exposure keratitis. These drops can also be used in patients with DED who have not responded to traditional therapies and patients who have had post-surgical ocular surface issues.

The use of biologics can decrease the inflammatory response associated with graft-versus-host issues that can arise after a corneal transplant or other currently common surgical procedures on the cornea. Other autoimmune diseases that result in chronic inflammation, such as Sjögren’s syndrome, Stevens-Johnson syndrome, diabetes and essentially any condition in which the immune system is turning on itself are also candidates for biological therapies.

It is the ability to regenerate that is the novel element of biologics, which provides an opportunity that is not available with drugs, surgery or radiation. And as the science behind regenerative medicine continues to evolve and the field diversifies, we will see more iterations of treatments that will help us to care for patients across the healthcare spectrum. We will also see more regulation and safer care planning.

However, it is important to note that there are not yet many products on the market that fit the true biologic category, especially for the eye. Despite this, there continues to be broad marketing of unapproved products

 described as regenerative medicine therapies, such as natural growth hormones. The United States Food and Drug Administration (FDA) has received reports of blindness, tumour formation, infections and more because of the use of unapproved products, and has urged all physicians act ethically and legally when deciding to prescribe a biologic to any patient. 

There also exists misinformation on the general use of stem cellsto improve various corneal surface problems. The problem with stem cells in this regard is that they require a delivery system that will typically involve injection; there are reports of stem cell injections into the eye causing many complications for patients.

In addition, the utilisation of stem cells is not ideal because they are difficult to grow, and if they are not treated correctly within the appropriate microenvironment and do not receive needed nutrients, they will die. Stem cells also act differently throughout different parts of the body because of the microenvironments they are in, and if they are not working properly, they never quite heal.

We can accomplish more without stem cells when working with products that are acellular, which tend to offer better delivery systems, such as drops, and for which adverse effects are not of particular concern. Medicine in the future will probably not need cells at all.

We also expect to see more progress in the aspect of preventative care through biologics. Depending on when we initiate treatments, outcomes can be significantly improved. For instance, if we incorporate a biologic at the point of mild or moderate DED, we could potentially prevent severe cases by allowing the body enough assistance to get to a healing phase and not to a phase of chronic inflammation and scarring.

It is clear that regenerative medicine holds a prominent place in our present healthcare space and provides future hope for the treatment of many different conditions.

Dr Harrell is the founder, chairman and CEO of Regenerative Processing Plant.

1. Regenerative medicine market size to hit USD 151,949.5 million by 2026. News release. Globe Newswire. 7 Mar 2022. Accessed online 20 Apr 2022. https://www.globenewswire.com/news-release/2022/03/07/2397751/0/en/Regenerative-Medicine-Market-Size-to-Hit-USD-151-949-5-Million-by-2026-Exhibit-a-CAGR-of-26-1.html

2. A very brief history of regenerative medicine. Genesis Biologics. 18 May 2018. Accessed online 20 Apr 2022. https://genesisbiologics.com/brief-history-regenerative-medicine/

3. What are “biologics” questions and answers. FDA. 6 Feb 2018. Accessed online 20 Apr 2022. https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/what-are-biologics-questions-and-answers

4. Promising novel treatment for dry eye disease revealed by new research. News release. University of Manchester. 13 Jan 2022. Accessed online 20 Apr 2022. https://www.manchester.ac.uk/discover/news/promising-novel-treatment-for-dry-eye-disease-revealed-by-new-research/

5. Important patient and consumer information about regenerative medicine therapies. US Food and Drug Administration (FDA). 9 Jul 2021. Accessed online 20 Apr 2022. https://www.fda.gov/vaccines-blood-biologics/consumers-biologics/important-patient-and-consumer-information-about-regenerative-medicine-therapies

Biologic treatments can be utilised to help the eye heal itself in inflammatory conditions such as dry eye disorder.

Bringing biologics to eye health: Regenerative medicine for inflammatory disorders

Today’s presbyopia-correcting IOLs, such as the PanOptix Trifocal (Alcon) and Tecnis Synergy (Johnson & Johnson Vision), incorporate very sophisticated optical technologies that can provide patients with an unsurpassed range of vision. These implants, combined with excellent biometry and the greater predictability of modern IOL formulas, have led to very high levels of patient satisfaction in my practice. I believe we are truly in a golden age of presbyopic vision correction.

However, we must expect there to be a period during which the eyes and brain adapt to these sophisticated optics postoperatively. In most cases, neuroadaptation takes the form of gradually decreasing night-time dysphotopsias or gradually improving clarity of vision. In my experience, neuroadaptation to presbyopia-correcting IOLs is nothing like the challenges that patients experience in adapting to monovision, or even to multifocal contact lenses.

Patients can typically drive and use their phones from Day 1. I find that good patient selection—considering both ocular anatomy and patient personality—and clear communication with patients about what to expect postoperatively are essential for success.

Preoperative testing to determine candidacy for lens options is very important. Patients with unusual topography, greater amounts of higher-order aberrations or unusually large pupils may experience more night-time dysphotopsias and should be counselled carefully if a premium lens is offered.

It is also important to understand how preoperative phakic lens status affects postoperative impressions. Younger patients seeking refractive lens exchange or those with very mild cataracts may never have been challenged with quality-of-vision problems and will tend to have high expectations of matching their preoperative clarity. On the other hand, someone with significant cataract has already adapted to glare and contrast loss that is likely to be much worse than anything they will experience with an IOL.

For me, it is fundamentally important that a patient has a strong desire to be free of spectacles. This will motivate them to persist and tolerate any inconveniences during the immediate postoperative process. If the surgeon has to talk someone into having a presbyopia-correcting IOL, it is a recipe for potential disappointment.

I ask patients directly about their personality traits: “Are you meticulous or picky? Do you flow through holidays calmly or tend to tense up when you are out of your element? Do you transition well or tend to get stressed by change?” In my experience, patients are not offended by this type of questioning. Rather, they appreciate the chance to express their persona to someone who is trying to make the best recommendation for them.

The younger the patient, the healthier the crystalline lens and the more demanding the personality, then the more preoperative counselling will be required. I do not necessarily avoid these patients, but I am direct and specific with them. I tell them they will see more glare and halos and that these will lessen over time but may not go away entirely.

After showing them images of dysphotopsias, I ask whether they think such symptoms would bother them. If so, we may look at another solution that may not provide the same range of vision but has a lower chance of dysphotopsias.

In our experience, patients sometimes find that it takes time to appreciate crisp quality of vision across their full range with the Synergy lens. At no point have I had a patient tell me they cannot function at any one distance, but they may notice that vision improves from near to intermediate to far. I do not see this as a problem because, in the end, we are seeing spectacular results that are better than ever before (

A golfer I recently treated is a perfect example. After bilateral Tecnis Synergy implantation, he told me he could drive his golf cart around and see his scorecard with no problem. When he teed off, he could see the ball initially but had a little trouble tracking it in motion after 100 yards or so. Sunglasses in bright sunlight helped him in the short term. Within a few months of surgery, he had no complaints and was ecstatic about the visual performance of the lens.

Although I aim for plano with the lens, I almost always err toward the first plus in the dominant eye and the first minus in the non-dominant eye if I have the choice. In most cases, this strategy provides a nice full range of focus, but it may not be appropriate in every eye. For example, if the cornea is flatter centrally, that eye may need more power, so I will err towards the first minus, regardless of ocular dominance.

Although preoperative evaluation is certainly a team effort in our practice, I believe it is important for the implant recommendation to come directly from the physician rather than from a counsellor. My goal is that after a deliberate and intentional process to select the best technology for them, patients feel understood and can relax and embrace the surgeon’s recommendation.

I try to communicate in a way that is sincere and reality-based, projecting confidence and competence. I tell patients that their vision will continue to get sharper—and they will become more and more enthusiastic about their vision—as the brain gets used to the new optics. Sunglasses or tinted lenses, brimonidine at night or dry eye therapies may help during the neuroadaptation period, or at least help the patient feel that they are participating in the healing process.

Being honest about potential night vision symptoms or delays because of neuroadaptation does not scare patients away or dissuade them from making premium choices. It simply makes their journey with today’s wonderful presbyopia-correcting implants a better one.

Dr Brooks is in private practice at Brooks Eye Associates in Plano, Texas, United States. He has no financial relationships to disclose related to this article.

It is important to select good candidates for presbyopia-correcting IOL implantation and frankly discuss postoperative adjustment issues for a successful outcome.

Surgical options for normalising neuroadaptation

Ophthalmologists have seen a progression in cyclophotocoagulation (CPC), with each generation becoming more doctor- and patient-friendly. Dr Shan C. Lin, a glaucoma specialist at the Glaucoma Center of San Francisco, California, United States, recently described some of the recent advancements in the technology.

The first attempt at CPC was trans-scleral cyclophotocoagulation (TCPC), which has its limitations. In some cases, the treatment did not reach the targeted tissue because the tissue was not visualised, and the pars plana was often treated instead.

In addition, there was the potential for the surrounding structures to be damaged. Excessive treatment using TCPC can occur and cause an audible popping and explosion of the ciliary processes and pars plana, which can result in inflammatory conditions such as cystoid macular oedema (CMO).

Introduction of the G-Probe Illuminate Delivery Device (Iridex Corporation) helped to address these problems. This technology uses a diode laser to treat the ciliary processes through the sclera and reduces the intraocular pressure (IOP) by decreasing aqueous production. “This latest generation of the technology allows identification of the ciliary process locations either before or at the time of treatment,” Dr Lin said.

He explained that the locations of the ciliary processes can vary among the different ocular quadrants and among different patients with glaucoma, and cited a study

 reporting that the ciliary processes can range from 2 to 5 mm behind the limbus.

Endoscopic CPC is a newer technology that facilitates direct visualisation of the ciliary processes as they are being treated. Probes with different gauge sizes (18-, 19-, 20- and 23-gauge) are available for this intraoperative procedure. In addition, the availability of curved probes allows a greater area to be treated within the same incision, according to Dr Lin.

A typical procedure, as he described, is one performed in a patient with pseudophakia through a limbal approach. “The goal is to cause shrinkage and whitening of the ciliary processes,” he said.

 of endoscopic CPC, involving 68 patients with a range of glaucoma types, found that the IOP decreased from approximately 27 mm Hg preoperatively to approximately 17 mm Hg postoperatively. In addition, the numbers of medications decreased from approximately three to two.

The complications associated with endoscopic CPC included fibrin exudate (24%), hyphaema (12%), CMO (10%), vision loss (6%; because of CMO in most cases) and choroidal detachment (4%).

Micropulse is the newest of the technologies. The Cyclo G6 Glaucoma Laser with the MicroPulse P3 probe (Iridex) is a trans-scleral procedure designed to deliver laser energy in a pulse pattern to avoid excessive damage to the tissues. This procedure also differs from the G-Probe in that the treatment is aimed at the pars plana rather than the ciliary processes, and it involves a slow sweeping motion along the superior and inferior limbuses rather than the discrete spot placement of the G-Probe.

An advantage of this new technology is that it can be performed either in a clinic or in the operating theatre, but Dr Lin prefers performing the procedure in the operating theatre for increased control and patient comfort. In addition, there are no pops involved with the treatment.

Dr Lin cautioned that the sweeping motion should avoid the 3 and 9 o’clock positions. “Having slower sweeps with the MicroPulse facilitates better uptake of the laser and efficacy,” he said.

 with follow-up of almost 7 years detailed the long-term efficacy and durability of this treatment. The authors reported a 43% reduction of IOP at 78 months in 14 patients and a concomitant reduction in medications from 1.8 to 1.1. However, numerous treatments were needed, with an average of approximately 4.5, to achieve IOP lowering.

Dr Lin also reported results of MicroPulse technology in a retrospective analysis of 54 patients with a baseline IOP of 24 mm Hg, three-quarters of whom had primary open-angle glaucoma. Postoperatively, the average IOP was 17 mm Hg (

 = 0.0002). Success in this study was defined as IOP lowering of 20% or more with or without medications, which was met in 68% of patients. Seven of the eyes required re-treatment.

The potential complications of the technology include rare unexplained visual loss, hypotony, ocular inflammation and CMO. In anatomical assessments using ultrasound biomicroscopy, there were no observable changes comparing before and after treatment.

MicroPulse controls the thermal effect by chopping a continuous wave of the energy beam into repetitive short pulses interrupted by relaxation times, which makes for less thermal damage to the targeted area. Dr Lin said the technology is also thought to stimulate biological factors, such as cytokines and growth factors, at the treatment area.

Iridex recently introduced a revised MicroPulse P3 (REV-2) probe with a footplate that helps with limbal alignment, improves tissue coupling for better laser delivery, makes the technique easier to perform and potentially has fewer complications. “Diode TCPC with the G-Probe is typically reserved for blind, painful eyes, and now is available with transillumination,” Dr Lin said.

“Endoscopic CPC can be useful in some cases. However, there are risks associated with penetrating surgery,” he said. “Micropulse TCPC is useful for patients with refractory glaucoma, with less inflammation and, possibly, less risk than with [the] diode laser.”

This article is adapted from Dr Lin’s presentation at the Glaucoma Research Foundation 25th Annual Glaucoma Symposium that took place in 2021. Dr Lin is a consultant to Iridex Corporation.

1. Agrawal P, Martin KR. Ciliary body position variability in glaucoma patients assessed by scleral transillumination. 

2. Chen J, Cohn RA, Lin SC, et al. Endoscopic photocoagulation of the ciliary body for treatment of refractory glaucomas. 

3. Chew P, Aquino MC. Long-term efficacy of micropulse diode transscleral cyclophotocoagulation in the treatment of refractory glaucoma. Abstract presented at: 12th European Glaucoma Society Congress; 19–22 June 2016; Prague, Czech Republic.

Each new generation of cyclophotocoagulation options results in more accurate visualisation of the ciliary processes, greater ease of use and fewer complications.

Advancements in cyclophotocoagulation: The good, the better and the best

This four-part series of articles summarises an afternoon of presentations, plus a debate, on the topic of corneal ectasia that was held as part of the 29th Cologne Adventsymposium, an annual meeting organised by Laserforum e.V., in Cologne, Germany, on 4 December 2021. Chaired by Drs Omid Kermani and Georg Gerten, the presentations each considered the condition from a different perspective and are available 

In Part 1, we look at the role of eye rubbing in keratoconus. This is based upon a presentation that ophthalmologist Prof. Damien Gatinel gave during the one-day event.

The contribution of exogenous traumatic factors to keratoconus was first pointed out by the late John Nottingham in 1854;

 since then, all studies published on the risk factors for keratoconus have mentioned high friction. The thesis that Prof. Gatinel supports is that eye rubbing is not a trivial risk factor but rather a causal factor without which the disease would not occur.

According to Prof. Gatinel, the stake of this debate is not only academic: if this conjecture, which is summarised as “no rub, no cone,” is true then there is tremendous hope that we can not only halt the progression of this disease but prevent it as well. “It remains a mystery to me how the ophthalmological community remains largely reluctant to accept this theory that obeys the laws of physics and is corroborated by clinical evidence,” Prof. Gatinel said.

Keratoconus occurs when the energy delivered by friction exceeds the natural resistance capacities of the cornea, which vary from subject to subject, resulting in permanent deformation. There must, of course, be a favourable genetic environment; however, Prof. Gatinel believes that keratoconus is not primarily a genetic disease but also a behavioural one. Excessive rubbing is 

 but its action may be triggered and/or potentiated by certain genetic cofactors.

A recent article concluded that mechanical causes were necessary for keratoconus to develop in genetically susceptible individuals.

 Another recent study found that eye rubbing with the knuckles was the most important predictive factor for keratoconus, whereas the presence of a family history was not significant.

Many elements plead against an entirely genetic origin for keratoconus, Prof. Gatinel pointed out. Firstly, if keratoconus were purely genetic, it should always be bilateral; truly unilateral forms are debated but Prof. Gatinel is convinced that they do exist 

. And secondly, there is a large predominance of sporadic cases (85% vs 15% with a family history). Despite intensive research, a specific gene for keratoconus has not yet been found.

“In my opinion, the genetic dimension to keratoconus is indirect and concerns the degree of corneal resistance (for example corneal thickness or the quality of the stromal collagen) and the susceptibility to allergies and other factors that encourage patients to rub their eyes. The discordance between monozygotic twins suffices to discard the genetic root cause hypothesis,” Prof. Gatinel said 

Contrary to what is sometimes suggested, Prof. Gatinel was very clear that the cause of keratoconus is not inflammation. The inflammatory dimension of keratoconus arises from the causes of eye rubbing (allergy or dryness) and the consequences of the rubbing (e.g., excretion in tears of inflammatory mediators), he believes. Chronic inflammatory pathologies of the cornea result in focal thinning associated with focal flattening and not steepening (as evidenced by the sequelae of interstitial, microbial or interface keratitis after LASIK, which commonly causes a hyperopic shift).

In addition, Prof. Gatinel pointed out that it is wrong to consider that keratoconus corresponds to an ectasia with a stretching of the corneal tissue. Indeed, his group recently showed that the corneal surface area does not differ significantly between healthy eyes and keratoconic eyes.

Prof. Gatinel believes that the term “corneal ectasia” should be reserved to describe the morphological changes that the cornea undergoes in Marfan syndrome, in which the corneas are typically softer and thinner but flatter. The cornea in keratoconus is thin but steep and this thinning and steepening are focal.

He added that molecular mechanisms and signalling pathways that would select a specific part of the cornea to deform spontaneously under the sole influence of the forces of intraocular pressure have not been described; rather, the influence of an external mechanical force better accounts for the characteristics seen.

Repeated rubbing eventually causes a focal thinning and a subsequent biomechanical weakening of corneal integrity. In the early stages, this causes a vertical sag and this explains the frequent early induction of against-the-rule or oblique astigmatism.

In 1965, the English statistician Sir Austin Bradford Hill proposed a set of nine criteria to provide epidemiological evidence of a causal relationship between a presumed cause and an observed effect 

 Prof. Gatinel demonstrated that the hypothesis “no rub no cone” satisfies these criteria, as follows.

Regarding the first three criteria (strength, consistency, specificity), the literature abounds with articles showing that eye rubbing is always associated with keratoconus. It has been discovered that in unilateral or very asymmetric forms, the most affected eye is always the most rubbed and highly correlates with a side or stomach sleeping position with prolonged compression of the orbit 

The fourth criterion (temporality) is particularly important. In all cases, rubbing precedes the appearance of keratoconus by months or years. These actions are sometimes unnoticed—a small proportion of patients say they do not rub but, in Prof. Gatinel’s experience, once awareness of rubbing has been raised it is acknowledged by nearly 100% of patients during the second visit.

Speaking about the fifth criterion (dose-response relationship), Prof. Gatinel explained that when difficulty arises in separating corneas affected by keratoconus from those with forme fruste, it is because there is a continuum between healthy corneas and very deformed corneas. In early forms of keratoconus, rubbing is typically recent or much less vigorous and frequent.

Prof. Gatinel recently published a study that shows that rubbing with the knuckles is worse than rubbing with the softer pulp of the fingers;

 this correlation between severity of rubbing and severity of deformation vehemently pleads for an external cause. The extreme variability of the topographic presentation modes of corneal deformation is matched only by the extreme variability of rubbing in duration intensity and frequency.

He went on to describe how the next three criteria relate to plausibility and coherence, occasionally confirmed by experimental evidence. Corneal resistance can be reduced by eye rubbing itself and this is a mechanical route to keratoconus,however, in addition to the mechanical stress induced by the action of shear and compression forces, the action of rubbing the eyes triggers the local secretion of cytokines, proteases and metalloproteinases.

 These molecules weaken the stromal tissue and make it more vulnerable to the action of friction.

Prof. Gatinel is not surprised that cases of eye subluxation, hyphaema, glaucoma and retinal detachment have been attributed to excessive eye rubbing. A ptosis is sometimes observed on the most-rubbed side of the eye; this is also not surprising, because the eyelid also suffers repeated trauma.

Regarding the ninth criteria (analogy), the IntraCor technique for presbyopia correction (intrastromal femtosecond laser surgical compensation of presbyopia with six concentric intrastromal ring cut) is an analogous model which shows that the selective severe incisional biomechanical weakening of the central stroma induces its immediate deformation.

Another analogy that is useful to distinguish direct causal responsibility from optional risk factor, according to Prof. Gatinel, is that of sunburn, which is more common in patients with a clear phototype—pale skin—but which absolutely requires exposure to ultraviolet light. As some phototypes are more UV-sensitive, some keratotypes may be more sensitive to eye rubbing.

Prof. Gatinel summarised by explaining that the “no rub no cone” conjecture meets the Bradford-Hill criteria. There is ample evidence that keratoconus requires interaction with environmental factors for a genetically determined predisposition to manifest as a phenotypically apparent disease, he stated: among these factors, excessive eye rubbing is a must 

“Beyond the academic debate, refusing to admit the causal and essential role of excessive rubbing deprives us of the possibility of halting the progression of the disease or even eradicating it by educating patients at risk,” Prof. Gatinel concluded.

The content of Prof. Gatinel’s presentation was debated with the other presenters—Prof. Renato Ambrósio Jr. (Brazil), Prof. Dan Reinstein (UK), Dr Tim Archer (UK) and Prof. Farhad Hafezi (Switzerland)—and with members of the online audience.

 It is widely believed that there is no unilateral keratoconus. How does this fit with the predominant cause of keratoconus being chronic trauma from eye rubbing?

 There are published cases of strictly unilateral keratoconus. There is no consistent model for keratoconus that explains the focal stiffening and weakening without an external force working on the cornea. Therefore, if you rub only one eye then you will have unilateral keratoconus; if you rub both eyes you will have bilateral keratoconus; and if you rub one eye more than the other you will have more pronounced keratoconus on that eye. This seems elementary to me.

In keratoconus, the cornea is not initially soft. When you have a soft cornea for other reasons, such as Marfan syndrome, the evolution is completely different from keratoconus. This simple observation should make us step back from what we believe and consider keratoconus as a cornea that has been made softer, or in which softness has increased focally, because of rubbing trauma, which creates focal mechanical stress whose action is amplified by the biomolecular consequences of rubbing.

 We have found easy consensus that keratoconus is a bilateral disease that can be very asymmetric in many cases. The point is that even though keratoconus is bilateral we can have a traumatic, biomechanically-induced ectasia, in only one eye or sometimes in both eyes, which is really hard to distinguish from keratoconus.

Eye rubbing is an essential factor in the development of keratoconus. “No rub, no cone” is the rule: a genetic predisposition for the disease will come to nothing without excessive eye rubbing.

Ophthalmology Times Europe June 2022

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The pathophysiology and pathomorphology of corneal ectasia: Keratoconus will not develop without eye rubbing