Enigma of a glaucoma

Indian researchers strive to crack the code of pseudoexfoliation as the elusive syndrome emerges as a leading cause of blindness

Enigma of a glaucoma

The prevalence of pseudoexfoliation (PXF) syndrome, a common cause of glaucoma-related blindness, is on the rise in India.

If the findings of a recent study by Indian researchers are anything to go by, not only is the rate of occurrence of PXF very high in certain parts of the country, it is also emerging as the number one cause of blindness related to glaucoma.

Different phenotypic variants of PXF found in the Indian population were associated with a 30% and 50% risk of ocular hypertension (OHT) and glaucoma respectively, concludes the study titled Clinical Spectrum of Pseudoexfoliation Syndrome—An Electronic Records Audit.

Unlike close or open angle glaucomas, PXF is a unique entity. It has ocular and systemic associations. The characteristic feature of the disease is the presence of dandruff-like pseudo exfoliative material over different parts of the eye, including the lens, pupil or the cornea.

“Pseudoexfoliation glaucoma doesn’t conform to the standard definition of glaucomas. It is the only form of glaucoma which is frequently associated with several conditions like cerebrovascular accidents, transient ischaemic attacks, stroke, cardiomyopathy, hypertension, bleeding disorders etc… Pseudoexfoliation is not a finding, it is a definitive diagnosis,” says Dr Aparna Rao, lead author of the study and the head of Glaucoma Service, LV Prasad Eye Institute, Bhubaneswar. 

Eyes with PXF are more prone to vaso-occlusive diseases. This age-related condition can also run a complicated clinical course, she explains.

Uncharted pathogenesis; No biomarker

PXF remains, largely, a mystery. No plausible theory is available to explain the pathogenesis of the disease. Different factors, including genetic, environmental and diet-related, are suspected to play a role in the formation of the diseases. The reasons why PXF lead to ocular hypertension and glaucoma in some people are yet to be figured out.

Mechanical blockage of the trabecular meshwork (TM) by exfoliation material (XFM) and ischaemic or molecular insults which cause irreversible tissue damage are among the reasons assumed for developing glaucoma. However, no direct evidence is available to correlate the risk of OHT or glaucoma and the extent of XFM.

In earlier stages, the disease will present itself with features such as radial pigments over the eye capsule.

“It is comparatively easy for a clinician to detect early signs of PXF when the disease is unmanifest by examining the eyes. But not all people with PXF are equally prone to developing OHT or glaucoma later. If we can identify those phenotypes that have a higher risk, chances of the disease developing into blindness can be brought down through effective intervention,” Dr Aparna says.

At the moment, a clinician can’t say whether the patient who is sitting in front of him with PXF could develop glaucoma. There is no biomarker to identify the risk in spite of the fact that the disease starts showing its signs very early.

When Dr Aparna and her team sifted through electronic medical records (EMR) of hospital database related to 110,313 PXF patients seen during the period of 2013–2015, they found that a total of 2,297 eyes of 1,150 PXF patients were identified, including 525 unilateral PXF. Of the unilateral PXF eyes, 105 had OHT and 131 had glaucoma, while bilateral cases had glaucoma in more than 50%. This translates into 30–50% risk of OHT or glaucoma among different phenotypic variants of PXF in this Indian cohort.

Despite their clinical importance, these phenotypic variants are unknown or hitherto unexplored.

The prevalence rate in India, nevertheless, differs from that of the rest of the world. It looks like the environment has an impact on the prevalence and progression of the disease. Factors such as temperature and altitude seem to influence the condition.

This heterogeneous condition showed a highly diversified presentation across the Indian population. It tends to be seen at a higher rate in hotter and coastal areas such as Bhubaneswar, West Bengal, Tuticorin, Kerala etc.. While the prevalence was highest in the eastern and southern regions of India, its occurrence was comparatively sparse in the west and the north. The nature of prevalence suggest that it may have clinical or local, eye-specific predisposing factors, apart from genetic and environmental conditions.

“We found a prevalence of 11.5% in a tertiary eye care centre in East India with a prevalence of 25% of exfoliation glaucoma and 13% with OHT in this hospital-based survey, which was higher in the combined forms of PXF than even the classical form of the disease,” comments Dr Aparna.

The numbers, however, can’t be directly extrapolated to population prevalence as this study was an EMR-based audit of a single centre, she cautions.

Early clues

The researchers found that different phenotypes of the disease seen in the Indian region had varied clinical features, which may signify the early onset of PXF without the evident, classical dandruff-like deposits and the described features that are associated with the presence of glaucoma. 

They also identified three stages of the disease, which needed further evaluation for assessing the differences in the risk of progression to ocular hypertension or glaucoma in each stage.

Long term studies are, nevertheless, warranted to confirm the differences in the baseline risk of OHT/glaucoma in different clinical forms of PXF and documenting the phenotypic variants is important for assessing future risks.

Other than reporting the overall prevalence of OHT and glaucoma in PXF in general, earlier studies have not elucidated the risk of developing glaucoma in different phenotypic patterns.

Probing the mysterious ways of the condition, Dr Aparna and her team have zoomed in on certain mechanisms and pathways strongly suspected to be involved in the development of the disease. Transforming growth factor (TGF), one molecule which is central to many cell processes and functions, has been identified to be playing a definitive role in the OHT/ PXG pathway.

Now, the researchers are in the process of tracing the molecular mechanism that outlines the pathway. “We have some preliminary data suggesting that the molecule (TGF) has a strong association with PXG. It is still a long way, though. As it needs to be put through a series of tests and clinically validated before we can say to the world that we’ve identified the culprit,” beams Dr Aparna. 

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