MIGRAINE AND GLAUCOMA

 

Migraine is a primary debilitating headache disorder affecting 10% to 15% of people worldwide. The cumulative lifetime incidence of migraine was reportedly 43% in women and 18% in men in the US. The prevalence is believed to be lower in Asians than in Caucasians.

Migraine is linked to endothelial dysfunction and is considered a systemic vasculopathy. Interestingly, systemic vascular diseases also occur in glaucoma patients and are considered to be risk factors for the development of glaucoma.

Whether migraine is simply a concomitant condition in glaucoma patients or a risk factor per se for glaucoma remains unknown.

Charles defined migraine as a disorder with both vascular and neural involvement as part of its pathophysiology.

Various reports have found migraine to be a significant risk factor for primary open-angle glaucoma (POAG).

However, the association between migraine and glaucoma is still controversial.

Xu et al. performed a systemic review and meta-analysis to study this association. 

8 case–control and 3 nested case–control/cohort studies revealed a statistically significant relationship between migraine and POAG.

Subjects who suffered from migraine had a 24% higher risk of developing POAG when compared to those who had never suffered from migraine.

Lin et al. have also found that subjects with migraine were 1.2 times more likely to have POAG compared with those without migraine.

The Glaucoma Inheritance Study found that migraine history was significantly associated with familial POAG compared to those with sporadic POAG, implying that migraine is an important heritable risk factor for glaucoma.

The mechanism for the association between the two conditions is attributed to vascular dysregulation, which occurs in some glaucoma patients.

REFERENCES:

Xu C, Li J, Li Z, Mao X. Migraine as a risk factor for primary open-angle glaucoma: A systematic review and meta-analysis. Medicine (Baltimore). 2018;97:e11377.

Chen HY, Lin CL, Kao CH. Does Migraine Increase the Risk of Glaucoma?: A Population-Based Cohort Study. Medicine (Baltimore). 2016 May;95(19):e3670.

Huang JY, Su CC, Wang TH, Tsai IJ. Migraine and increased risk of developing open-angle glaucoma: a population-based cohort study. BMC Ophthalmol. 2019;19:50.

Lin HC, Chien CW, Hu CC, et al. Comparison of comorbid conditions between open-angle glaucoma patients and a control cohort: a case-control study. Ophthalmology 2010;117:2088–95.

Ahmad SS. Controversies in the vascular theory of glaucomatous optic nerve degeneration. Taiwan J Ophthalmol. 2016;6:182-186.

AI-POWERED DISCOVERY OF RIPK-INHIBITOR

 

Artificial intelligence (AI) technologies have found multiple roles and advantages in drug discovery.

Those technologies have significantly advanced the discovery of newer drugs through target identification and high-throughput screening.

AI can utilize experimentally validated conformational and physicochemical features of protein-ligand compounds to create statistical models. These models enable predictions in three directions—binding site, binding affinity, and binding pose—to provide predictions that are more applicable to real-world scenarios.

AI technologies are also useful for handling computationally intensive tasks and making rational decisions based on complex multimodal knowledge.

Tu et al from China have reported the Artificial Intelligence-enabled discovery of a RIPK3 inhibitor with neuroprotective effects in an acute glaucoma mouse model.

An acute ocular hypertension model was used to simulate pathological ocular hypertension in vivo.

The study involved a series of AI methods, including large language models (LLM) and graph neural network models, to identify the target compounds of RIPK3. Subsequently, these target candidates were validated using molecular simulations (molecular docking, absorption, distribution, metabolism, excretion, and toxicity [ADMET] prediction, and molecular dynamics simulations) and biological experiments (Western blotting and fluorescence staining) in vitro and in vivo.

In this study, the authors used LLM as an AI-driven drug screening tool and ChatGPT to conduct targeted drug queries for RIPK3.

The authors sorted the candidate drugs based on the prediction of their binding affinity to RIPK3 using graph neural network (GNN) models and the predicted results were validated using biological experiments.

The study involved AI models (GraphDTA, MGraphDTA, and WGN-NDTA), and reconstructed DynamicBind, another model architecture that uses deep equivariant geometric diffusion networks to predict affinity.

The authors also performed molecular docking and molecular dynamic simulations to validate the predictions of the GNN models.

In conclusion, these studies identified a compound called HG9-91-01 using AI methods. The compound exerts neuroprotective effects in acute glaucoma.

Retinal ganglion cells (RGCs) had a high survival rate and reduced loss of retinal layers on exposure to HG9-91-01.

The neuroprotective effects of HG9-91-01 were attributed to the inhibition of PANoptosis (apoptosis, pyroptosis, and necroptosis).

Also, HG9-91-01 can regulate key proteins related to PANoptosis, indicating that this compound exerts neuroprotective effects in the retina by inhibiting the expression of proteins related to apoptosis, pyroptosis, and necroptosis.

ROLE OF RIPK3 IN NECROPTOSIS:

The loss of RGCs during glaucoma progression involves various types of cell death, and necroptosis, a process similar to apoptosis, may play a significant role in RGC death. Necroptosis is initiated by receptor-interacting protein kinase (RIPK) 1, RIPK3, and mixed-lineage kinase domain-like (MLKL). RIPK3 is an important signaling molecule located downstream of RIPK1, and phosphorylation of RIPK3 or RIPK1 activates MLKL, thus initiating necroptosis. However, the relationship between RIPK1 and RIPK3 is non-linear. As RIPK3, but not RIPK1, is essential for necroptosis, “necroptosis” is more accurately described as “RIPK3-dependent cell death”.

RIPK3 is highly expressed in the ganglion cell layer (GCL) of injured retinas in vivo. Compounds that target RIPK3 and regulate the necroptotic cascade can be used to treat various retinal diseases. Therefore, RIPK3 inhibitors are promising candidates for the treatment of neurodegenerative ocular diseases.

REFERENCE:

Tu X, Zou Z, Li J, Zeng S, Luo Z, Li G, Gao Y, Zhang K. Artificial intelligence-enabled discovery of a RIPK3 inhibitor with neuroprotective effects in an acute glaucoma mouse model. Chin Med J (Engl). 2025 Jan 20;138(2):172-184.

 

GLAUCOMA FIELD DEFECT CLASSIFIER (GFDC)

 

Glaucoma Field Defect Classifier (GFDC) is a web application that automates glaucoma grading based on Hodapp-Parish-Anderson (HPA) criteria without requiring patient-identifiable data.

In a study presented by Cambridge University, UK, researchers, the GFDC web-application output matched the ground truth defined by human researchers applying HPA criteria for every perimetry result.

Perimetry appraisal using GFDC was significantly faster than a manual application of HPA criteria. However, the duration of manual appraisal exhibited greater variation, with some manual assessments being faster than any GFDC-facilitated assessment.

Simple thresholds for mean deviation and central global plot decibel values are explicitly coded into the algorithm.

To interpret pattern deviation plots, a computer vision algorithm is designed to identify plot boundaries and result points. A matrix is generated based on the pattern deviation identified at each result point, which is then used to apply encoded HPA criteria.

This web-application has the potential to facilitate the incorporation of HPA-based visual field assessment at scale.

100% sensitivity for the detection of any glaucomatous field defect and a severe field defect suggests that no patients would be dismissed as a false negative by GFDC, maximizing safety with deployment.

100% specificity for detecting severe field defects indicates that the algorithm can identify patients at high risk or with significant deficits without compromising efficiency by including other patients as false positives.

Adopting standard criteria for visual field appraisal in glaucoma clinics would ameliorate one of the most severe sources of arbitrary discrepancy in diagnosis, assessment of progression, prognosis, and identification of vision impairment.

Using an explicitly coded computer vision algorithm reduces the time required for clinicians to leverage validated criteria, overcomes black box limitations associated with machine learning approaches, and minimizes the possibility of erroneous decisions made for uninterpretable reasons.

SOFTWARE AVAILABLE THROUGH:

https://github.com/RohanSanghera/gfdc

REFERENCE:

Thirunavukarasu AJ, Jain N, Sanghera R, Lattuada F, Mahmood S, Economou A, Yu HCY, Bourne R. A validated web-application (GFDC) for automatic classification of glaucomatous visual field defects using Hodapp-Parrish-Anderson criteria. NPJ Digit Med. 2024 May 18;7(1):131. doi: 10.1038/s41746-024-01122-8. PMID: 38762669; PMCID: PMC11102533.

EXTREME WEATHER EVENTS AND GLAUCOMA

 

Extreme weather events (EWEs) (e.g., heatwaves and cold spells) are reportedly associated with high morbidity through various physiological mechanisms. Similarly, extreme heat and cold temperatures also affect the structure and function of the eye and vision. EWEs are significantly associated with increased glaucoma prevalence, and the risk of glaucoma increases with the intensity of heat waves and cold spells.

Another risk factor for the development of glaucoma and diabetic retinopathy based on the Rural Epidemiology for Glaucoma (REG-China) study is long-term exposure to air pollution.[1,2]

A study by Zhang et al has reported on the impact of heatwaves and cold spells on glaucoma in rural China, through a national cross‑sectional study. The REG-China study was conducted in ten provinces of China, and 36,081 adults aged 40 years or more were included.[3]

The study found that glaucoma was more strongly affected by heat waves than by cold spells. The effects of both heat waves and cold spells were higher in males than females and in smokers than nonsmokers.

Overall, the risk of glaucoma in general, PACG, and POAG increased with the intensity of heat waves and cold spells.

Those with a family history of glaucoma were more sensitive to cold spells.

Higher heatwaves were significantly correlated with a higher odds ratio (OR) of glaucoma, with the OR (95% CI) ranging from 1.014 (1.009, 1.018) to 1.090 (1.065, 1.115) by different definitions. This study found that in heatwaves, mean daily temperatures above the 95th percentile (HW15) for more than four consecutive days had the highest risk for glaucoma.

Higher ambient temperature is a risk factor for the development of glaucoma. However, some studies have shown that IOP tends to be higher on cold days than on hot days.

Similar results have been reported from other countries like the US, Australia, the UK, Finland, and Singapore.

REFERENCES:

1. Shan A, Chen X, Yang X, Yao B, Liang F, Yang Z, Liu F, Chen S, Yan X, Huang J, Bo S, Tang NJ, Gu D, Yan H (2021) Association between long-term exposure to fine particulate matter and diabetic retinopathy among diabetic patients: a national cross-sectional study in China. Environ Int 154:106568.

2. Yang X, Yang Z, Liu Y, Chen X, Yao B, Liang F, Shan A, Liu F, Chen S, Yan X, Huang J, Bo S, Liu Y, Tang N, Gu D, Yan H (2021) The association between long-term exposure to ambient fine particulate matter and glaucoma: a nation-wide epidemiological study among Chinese adults. Int J Hyg Environ Health 238:113858.

3. Zhang A, Wang Q, Yang X, Liu Y, He J, Shan A, Sun N, Liu Q, Yao B, Liang F, Yang Z, Yan X, Bo S, Liu Y, Mao H, Chen X, Tang NJ, Yan H. Impacts of heatwaves and cold spells on glaucoma in rural China: a national cross-sectional study. Environ Sci Pollut Res Int. 2023;30:47248-47261.

 

GLAUCOMA AWARENESS MONTH

 

January is “GLAUCOMA AWARENESS MONTH”. This is the month that reaffirms our commitment to increase patient awareness and knowledge of this potentially blinding condition. 

The Glog is primarily for ophthalmologists, optometrists, and other healthcare workers (HCW) to share information regarding glaucoma. However, we would also like to have the general public use this platform to improve their understanding of this disease.

As glaucomatologists, we aim to improve our detection capabilities so that the disease can be diagnosed at molecular levels. Technologies like smart contact lenses, DARC method, and newer structural-functional tests are focused on early detection. The management of this disease has seen rapid strides with several new drugs discovered in the last few years and some in the pipeline. Surgical methods have also seen a boost with valves and MIGS procedures. Laser procedures are also being utilized more commonly as we develop a better understanding of them. 

For the patient, it is important to come for regular checkups, the priority being high for relatives of glaucoma patients and to follow the instructions of the HCW managing the individual.

With the increased use of social media platforms, it has become easier to share information with the general public.

We hope that The Glog will continue to be a medium to improve awareness of Glaucoma among both caregivers, as well as patients, and the public.

Thank you for patronizing The Glog and your firm support.

With best regards

Shoeb

Dr. Syed Shoeb Ahmad

METABOLIC SYNDROME AND GLAUCOMA

 

Metabolic Syndrome (MetS) is a cluster of metabolic abnormalities being regarded as a significant risk factor for chronic diseases. The association of MetS with glaucoma was studied in a meta-analysis by Li et al.

MetS is defined by the presence of three or more of the following:

• Waist circumference≥102  cm in men or ≥88  cm in women,
• Triglycerides≥150 mg/ dL,
• HDL cholesterol (HDL-C) < 40  mg/dL in men or < 50 mg/dL in women,
• Blood pressure≥130/85 mmHg,
• Fasting glucose≥100 mg/dL.

 

The exact mechanisms linking MetS to glaucoma are still undefined, but several plausible pathways have been proposed.

Both MetS and glaucoma share common risk factors, such as aging, hypertension, and obesity.

Vascular dysregulation, oxidative stress, and inflammatory processes seen in MetS could contribute to optic nerve damage, further supporting the hypothesis of a link between the two conditions.

The meta-analysis by Li involved 9 studies involving 2,258,797 participants.

The pooled results showed that MetS was significantly associated with an increased risk of glaucoma (OR: 1.34, 95% CI 1.15–1.55, p<0.001). Individuals with MetS had a 34% higher likelihood of developing glaucoma compared to those without MetS.

The results of subgroup analysis indicated hypertension and hyperglycemia were both associated with an increased risk of glaucoma. Still, the association with glaucoma was not significant for obesity, hypertriglycemia, or a low HDL-C. However, the difference among the subgroups was not statistically significant (p=0.05).

There is still controversy about the association of MetS and glaucoma due to conflicting results from previous studies, prompting further research on the subject.

 REFERENCE:

Li F, Luo Y, Li X, Dai Y, Xiang Q. Association between metabolic syndrome and the risk of glaucoma: a meta-analysis of observational studies. Diabetol Metab Syndr. 2024 Dec 18;16(1):300. doi: 10.1186/s13098-024-01532-4. PMID: 39696489; PMCID: PMC11657432.

GLAUCOMA-RELATED OCULAR SURFACE DISEASE PART-3

 

Almost all antiglaucoma medications, especially those containing preservatives, affect the ocular surface. Beta-blockers, particularly preserved timolol maleate, disrupt tear film stability, reduce basal and relative tear secretions, and cause xerotic alterations in conjunctival epithelium potentially leading to conjunctival cicatrization.

PUNCTATE EPITHELIAL EROSIONS FROM ANTI-GLAUCOMA MEDICATIONS

Patients with severe conjunctivochalasis have worse TFBUT, lissamine green staining, Schirmer testing, and a higher OSDI score.

Prostaglandin analogs apparently have the least effect on conjunctival fibrosis, but they induce obstructive Meibomian gland dysfunction.

Pilocarpine and timolol also directly affect Meibomian epithelial cells and may influence their morphology, survival, and proliferative capacity.

The Meibomian gland changes after monotherapy prostaglandin analog use are related to worse OSD and poor compliance.

These findings support using preservative-free regimens to improve compliance and minimize the adverse effects of antiglaucoma eye drops on conjunctival, corneal, and Meibomian gland structures.

The most commonly used preservative in anti-glaucoma medications is benzalkonium chloride (BAK). It can severely disrupt the ocular surface and alter corneal sensitivity.

There is also conflicting evidence regarding the role of surgically induced conjunctival modifications as a risk factor in the pathogenesis of G-OSD.

Reports have found an increase in tear osmolarity and a four-fold increase in the use of ocular lubricants in patients who underwent MMC-augmented trabeculectomy.

A study found ocular surface complications in approximately 15% of patients after trabeculectomy. The most common were corneal epitheliopathy (11%), filamentary keratitis (3%), and Dellen formation (1.7%).

Lee has pointed out that dry eye symptoms and increased osmolarity may occur in post-trabeculectomy patients in the absence of TBUT and Schirmer test abnormality.

However, a recent 3-year study by Ambaw et al demonstrated that after undergoing successful trabeculectomy, patients had reduced tear levels in 37 of 40 pro-inflammatory lipid mediators.

Laser scanning confocal microscopy and impression cytology found an increase in goblet cell density, and a decrease in limbal dendritic cell density, sub-basal corneal nerve inhomogeneity, Meibomian gland density, and HLA-DR positivity, corresponding to an overall objective improvement of the ocular surface after successful trabeculectomy surgery.

HAPPY NEW YEAR

 

A new year has dawned on our continuing journey to explore and find the best possible management of glaucoma.

In the almost 9 years since the start of this blog, we have published more than 350 posts and received a good response from the visitors. There have been more than 160000 visits to The Glog, inspiring us to do more. The feedback from everyone has helped us correct our mistakes and improve our work.

In this blog, we focus on all aspects of glaucoma, from the basics, like anatomy, physiology, and pharmacology, to the clinical and investigative aspects of this disease. I hope this blog will continue to guide and help all those who need information about glaucoma.

We are always open to guest authors and contributors. So, feel free to contact us any time.

Wishing everyone a happy new year.

Best regards

Dr. Syed Shoeb Ahmad