The identification of a form of necrosis mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed-lineage kinase domain-like pseudokinase (MLKL) has led to a significant breakthrough that has fundamentally transformed our understanding of necrosis. Traditionally viewed as uncontrolled cell death, necrosis is now perceived differently in various human diseases due to this discovery.¹

Recent research suggests that necroptosis is a common mechanism of retinal cell death, alongside apoptosis. While the clinical manifestations and pathogenesis of retinal diseases differ, they share similar necroptotic signalling pathways. Inhibition of necroptosis offers promising neuroprotective effects for the treatment of various retinal degenerative disorders.¹

A study focussed on the role of necroptosis in retinal diseases and injuries. The review covered the main molecules involved in the necroptosis of retinal cells and their inhibitors that could help in the development of new therapeutic strategies for the management of retinal degenerative diseases. ¹

Figure 1. Molecular mechanisms of necroptosis¹

Adapted from: Zhang Q, et al. Int J Biol Sci. 2023.

A20: TNF-α-induced protein 3; ABIN1: A20-binding inhibitor of NF-κB; Casp-8: Caspase-8; cFLIP: Cellular FLICE-like inhibitory protein; cIAP1/2: Cellular inhibitor of apoptosis proteins 1 and 2; CYLD: Cylindromatosis; DAMP: Damage-associated molecular pattern; DNA: Deoxyribonucleic acid; DRP1: Dynamin-related protein 1; ESCRT-III: Endosomal sorting complexes III; FADD: Fas-associated protein with death domain; IKK: IκB kinase; LUBAC: Linear ubiquitin chain assembly complex; MLKL: Mixed-lineage kinase domain-like pseudokinase; NEMO: NF-κB essential modulator; NF-κB: Nuclear factor kappa B; OPTN: Optineurin; PARP: Poly-ADP ribose polymerase; PGAM5: Phosphoglycerate mutase family member 5; RIPK: Receptor-interacting protein kinase; ROS: Reactive oxygen species; SPATA2: Spermatogenesis associated protein 2; TAK1: Transforming growth factor beta-activated kinase 1; tAIF: Truncated apoptosis-inducing factor; TBK1: TANK-binding kinase 1; TBK2/3: TAK1- binding protein 2/3; TNFα: Tumour necrosis factor alpha; TNFR1: Tumour necrosis factor receptor 1; TRADD: TNFR1-associated death domain protein; TRAF2: TNF receptor associated factor 2.

Detecting necroptosis in retinal cells

Therapeutic options that target necroptosis in the retina
Newly identified chemical entities, including selective inhibitors, drugs, and chemical agents, have been found to modulate the necroptotic cascade pathway and may have potential therapeutic applications for various retinal disorders.¹

Figure 2. Domain organisation of necroptotic signalling proteins and their targeted chemical inhibitors¹

Adapted from: Zhang Q, et al. Int J Biol Sci. 2023.
KD: Kinase domain; ID: Intermediate domain; RHIM: RIP homotypic interaction motif domain; NED: N-terminal execution domain; psKD: C-terminal pseudokinase domain; RIPK1: Activated receptor-interacting protein 1; RIPK3: Activated receptor interacting protein 1; MLKL: Mixed-lineage kinase domain-like pseudokinase.

Care home residents commonly present with multiple co-morbidities and have complex care needs. Routine access to eye care has been widely acknowledged to facilitate early detection and timely treatment of age-related ocular pathologies, while also helping to maintain the independence and quality of life of residents in the care home setting, where they rely heavily on their care providers.¹

Studies assessing eye care provisions in care homes

The provision of eye care services in care home settings was assessed by two studies conducted in Canada and South India.¹

Evaluation of optometrist‑led eye care services

Two studies assessed the efficacy of optometrist-led eye care in the United States and Canada.¹

Home‑based diabetic screening programme evaluation

Impact of cataract surgery on outcomes

Refractive error correction and outcomes

• Evidence suggests inadequate eye care provision in care homes.1
• Proactive domiciliary optometrist-led services can improve eye care.¹
• Improved diagnosis and management of eye conditions observed.¹
• 53% of residents received direct ophthalmological interventions.¹
• 18.9% of residents were referred to other specialists for further benefit.¹

Conjunctivochalasis (CCh) is a prevalent ocular condition associated with aging, which results in the accumulation of excessive conjunctival folds between the eyeball and the lower eyelid margin. CCh exacerbates dry eye disease by reducing the stability and storage capacity of the tear film.¹

1)Argon laser is widely used in ophthalmology due to its convenience, effectiveness, and safety for many types of intraocular and extraocular surgeries, such as conjunctival nevus removal, iridotomy, trabeculoplasty, and retinal photocoagulation.¹

2)As per another research article, the use of the argon laser procedure led to conjunctival shrinkage and, hence, proved effective for the treatment of CCh.¹

Aim:

Materials and Methods:

Results:

The table below lists the clinical outcomes of all eyes.¹

Table 1. CCh grade changes at 6 months after argon laser conjunctivoplasty¹

Adapted from Han J, et al, Medicine. 2023.

• CCh grades of 21 eyes (84%) decreased at 6 months after the modified argon laser conjunctivoplasty (p<0.001)¹
• Following laser conjunctivoplasty, there was a substantial reduction in total grade, calculated as 0.96 times 0.53 (mean ± standard deviation). The postoperative grade showed a significant decrease compared to the preoperative grade (p = 0.001).¹
• Of the 25 patients, 20 (80%) reported subjective satisfaction.¹
• 80% overall success rate was attainted with a single laser treatment.¹

Limitations of the study:

• The study had limitations such as small sample size and short follow-up period, which hindered drawing definitive conclusions about the long-term effects of argon laser therapy.¹
• As it was a retrospective chart review study without a control group, further studies with prospective design on larger patient groups with longer-term follow-ups are recommended, along with the inclusion of other factors such as tear breakup time, Schirmer's test results, and tear meniscus height.¹

• The modified argon laser conjunctivoplasty method is a safe, quick, and effective treatment option for symptomatic CCh, especially in mild-to–moderate cases.¹
• It is a non-invasive, cost-effective, and well-tolerated outpatient procedure that reduces damage to the surrounding tissue and can be used before considering other surgical options.¹

Key takeaway

Dry Eye Assessment and Management (DREAM) Study: Tear Osmolarity and Dry Eye Disease¹

Tear hyperosmolarity is termed one of the two main mechanisms of dry eye disease (DED) irrespective of cause. Hyperosmolarity has been identified as a cause of ocular surface inflammation and tear film instability. Tear osmolarity is influenced by tear production, evaporation, and drainage, and decreasing osmolarity could potentially improve dry eye disease, as hyperosmolarity is a key mechanism in its pathophysiology.¹

A multicentre study was conducted with the hypothesis that dietary supplementation would lead to an improvement in dry eye symptoms and signs.¹

Objective:

Methods:

Vital staining: The corneal and conjunctival epithelia of each eye were evaluated for staining using the standard fluorescein strip method, with a standardised post-instillation period for each of the vital stains. Grades for all staining were based on previously described methods and used a scale ranging from 0 to 3 in each of the five zones of the cornea and six zones of the conjunctiva, respectively.¹

Schirmer test: All subjects underwent a Type I Schirmer test, where standardised filter paper strips were placed on the distal portion of the tarsal conjunctiva of both eyes after the instillation of proparacaine ophthalmic solution. After five minutes, the portion of the strip wetted by tears was measured and recorded in millimeters.¹

Tearfilm breakup time (TBUT) by biomicroscopy: The TBUT was assessed using biomicroscopy, in which fluorescein was instilled and spread evenly over the cornea by blinking. The time between opening the eye and the appearance of the first dark spot or region over the cornea was recorded as the TBUT.¹

Non-invasive break-up time: Measurements of non-invasive break-up time, bulbar conjunctival redness, and tear film meniscus height were conducted in each eye.¹

Results:

• The DREAM study found that tear osmolarity was only weakly correlated with signs of DED, accounting for less than 5% of the variability in signs. Moreover, changes in tear osmolarity did not correlate with changes in DED signs and symptoms, suggesting a lack of causal relationship. This highlights the need for further research.¹

In 2022, a review article titled ‘A deep dive into the latest European and Glaucoma Society (EGS) and Asia-Pacific Glaucoma Society (APGS) guidelines’ provided recommendations for the diagnosis of primary angle-closure glaucoma (PAC). However, a slight update was done in 2023 to the figure. After the modifications, the definition of primary angle- closure glaucoma was in sync with the APGS guidelines depicted in the below figure.¹

Figure 1. Diagnostic algorithm for PAC glaucoma by the APGS1

Adapted from Murthy GJ, et al. Indian Journal of Ophthalmology. 2023

APGS: Asia-Pacific Glaucoma Society; IOP: intraocular pressure; PAC: Primary angle closure.

Inclusion of acetazolamide/mannitol depends on the level of intraocular pressure (IOP) and its safety. The mechanism of action of anti-glaucoma drugs works with elevated IOP as they act at the receptor level. The lack of an effect of pilocarpine on the sphincter pupillae is due to the elevated IOP resulting from a pupillary block, leading to sphincter ischemia.¹

The EGS and APGS guidelines recommend:¹

• The ideal intraocular pressure (IOP) should be tailored to each individual.
• Continuously reassessed based on the current stage of disease.

• Age-related macular degeneration (AMD) accounts for 8.7% of blindness worldwide, making it a leading cause of blindness in western countries. In the next 20 years, the prevalence of AMD is expected to rise by 47%.
• It is crucial to identify causal, modifiable risk factors for advanced AMD before applying preventative measures.
• A two-sample mendelian randomisation (MR) was conducted; summary-level data of genetic variants were obtained from study samples that did not overlap with those for advanced AMD and its subtypes associated with certain genetic variants (Figure 1).

• The largest genome-wide association studies (GWAS) for these exposures yielded summary-level statistics for smoking features, alcohol intake, body mass index (BMI), blood pressure, and glycaemic traits.
• The study outcomes are explained in Figure 2.

AMD: Age-related macular degeneration; CI: Confidence interval; GA: Geographic atrophy; OR: Odds ratio; SD: Standard deviation.

• There was insufficient data to demonstrate that genetically predicted blood pressure, BMI, or glycaemic traits were related to advanced AMD.

Conclusion

In conclusion, according to genetic data:
• Increased alcohol consumption has a potential causal association with the risk of geographic atrophy (GA).
• Smoking initiation and lifetime smoking behaviour may be causally associated with the risk of advanced AMD.
• Smoking cessation reduces the risk of advanced AMD compared to continuing to smoke.
• These associations were stronger in the case of neovascular AMD than in the case of GA.

To lower the prevalence of advanced AMD in the elderly, public health campaigns and programmes promoting smoking cessation and reduced alcohol consumption should include information that these behaviours can lead to blindness.

Source:
Kuan V, Warwick A, Hingorani A, et al. Association of Smoking, Alcohol Consumption, Blood Pressure, Body Mass Index, and Glycemic Risk Factors With Age-Related Macular Degeneration: A Mendelian Randomization Study. JAMA Ophthalmol. 2021;139(12):1299–1306. doi:10.1001/jamaophthalmol.2021.4601

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A variety of ocular diseases can cause serous subretinal fluid (SRF) in the macula, which might mimic central serous chorioretinopathy clinically (CSC). A wide variety of diseases and conditions can also present with SRF in the macula and can therefore clinically mimic CSC.

Since distinguishing between these diseases and CSC might be difficult, the author provides an extensive differential diagnosis of CSC. The study highlights the pathogenic mechanisms specific to each disease, which aid in the differential diagnosis. These diseases can be broadly categorised into 12 main pathogenic subgroups (Figure 1).

The study also includes:

• The diseases, clinical characteristics, differential diagnostic aspects, and treatment options pertaining to the diseases.
• Two new clinical pictures associated with macular subretinal fluid accumulation, namely serous maculopathy with the absence of retinal pigment epithelium and serous maculopathy due to aspecific choroidopathy.

RRD: Rhegmatogenous retinal detachment; TRD Tractional retinal detachment.

Serous maculopathy with the absence of retinal pigment epithelium and serous maculopathy due to aspecific choroidopathy (Figure 2, A and B).

In conclusion, serous SRF in the macula can mimic CSC and manifest with a wide range of diseases and conditions. Inflammatory diseases and malignancies are on one end of the spectrum, while genetic diseases and ocular developmental anomalies are on the other. However, each of these conditions can be distinguished diagnostically from CSC using the appropriate clinical tools and ophthalmological examinations.

Source:
van Dijk EHC, Boon CJF. Serous business: Delineating the broad spectrum of diseases with subretinal fluid in the macula. Prog Retin Eye Res. 2021 Sep;84:100955. doi: 10.1016/j.preteyeres.2021.100955.

NON-2022-15053 - Date of creation January 2023

• Glaucoma is a progressive optic neuropathy with the potential to cause blindness. The most important and most modifiable risk factor for the development of glaucoma is raised intraocular pressure (IOP).
• Phacoemulsification-endocyclophotocoagulation (phaco-ECP) provided IOP lowering or reduction of topical therapy use in heterogenous glaucoma populations.

Objective

To assess the safety and efficacy of endocyclophotocoagulation with phacoemulsification (phaco-ECP) in surgically naive, primary open-angle glaucoma (POAG).

IOP: Intraocular pressure; SD: Standard deviation.

Figure 1 shows the changes in intraocular pressure over the time of study

Intraocular pressure outcomes showing (a) mean IOP (±95% CI) per year and (b) mean number of ocular hypotensive agents (±95% CI) per year.
Significant change from baseline in both outcomes was seen at all timepoints, corrected for multiple comparisons (****p<0.0001).

Table 1 shows the annual summary measures of all study eyes (final visit per year).

Last pre-operative observation was carried in the case of subsequent filtration surgery (n=1).
IOP: Intraocular pressure; MD: Mean deviation; PSD: Pattern standard deviation; SD: Standard deviation.

The study concludes that ECP combined with phaco-ECP lowers IOP and reduces the need for topical medication. It also provides an excellent safety profile in a unique, surgically naive POAG population, and so it should be explored as an alternative to minimally or micro-invasive glaucoma surgery devices.

Source:
Yap, T.E., Zollet, P., Husein, S. et al. Endocyclophotocoagulation combined with phacoemulsification in surgically naive primary openangle glaucoma: three-year results. Eye (2021). https://doi.org/10.1038/s41433-021-01734–4

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• The aim of the European Glaucoma Society Guidelines (EGS) is to support the ophthalmologists in managing people with, or at risk of, glaucoma and to provide useful information to trainees.
• Guidelines emphasises on patients’ care, well-being, and optimal personalised care.
• Decision-making ultimately should be individualised to the patient's needs and circumstances, ideally guided by the best available evidence.

ONH: Optic nerve head; RNFL: Retinal nerve fibre layer.

GRADE: Grading of recommendations, assessment, development, and evaluations; IOP: Intraocular pressure; OCT: Optic coherence tomography; PACG: Primary angle closure glaucoma;
RNFL: Retinal nerve fibre layer; VF: Visual field.

Guidelines recommend an effective communication with patients to understand their history, which can be vital for prognosis. Direct questions at follow-up are highly essential to treat and manage patients. It is recommended to educate the patient about the disease condition and treatment and provide support and care.

Figure 1 shows that recommended evaluation of functional loss over time guides individualised treatment.

IOP: Intraocular pressure (IOP) level causing damage; L: Difference of visual function between the age-matched normal and the function at the time of diagnosis;
RoP: Angle representing physiological loss and disease progression; T: Time interval between birth and the time of diagnosis.

Source:
Azuara-Blanco A, Bagnasco L, Bagnis A, et al. European Glaucoma Society Terminology and Guidelines for Glaucoma, 5th Edition. Br J Ophthalmol. 2021;105(Suppl 1):1–169. doi: 10.1136/bjophthalmol-2021-egsguidelines.

NON-2022-15053 - Date of creation January 2023