Australia's Leading Ophthalmic Magazine Since 1975

     Free Sign Up     

Australia's Leading Ophthalmic Magazine Since 1975

     Free Sign Up     
Report

Primary open angle glaucoma: An eye disease of something more general?

05/03/2019By Lewis Williams PhD
Share:
With experts from every corner of the globe meeting in Melbourne for the 8th World Glaucoma Congress, LEWIS WILLIAMS explores some of the recent research that has advanced our understanding of the disease.

Of all the common ocular diseases, primary open-angle glaucoma (POAG) has perhaps been the subject of more research and shifts in perception than any other. Despite many advances, the disease has resisted all attempts to establish a full understanding of what it is, as well as the development of an umbrella theory that encompasses normal-tension glaucoma (NTG), ocular hypertension, and hypertensive glaucoma.

Furthermore, glaucoma remains the leading cause of irreversible blindness worldwide. That is partly due to the insidious onset of the disease. The gradual loss of peripheral vision, especially in the absence of routine eye examinations, usually means that by the time its presence is detected, the disease is already well advanced. By that stage, a patient’s central vision is also usually affected to some extent.

The irreversible nature of the disease means that there is nothing that can be done for accumulated vision losses, but suitable treatment can slow its progression. In an estimated 90% of those cases, blindness can be prevented. Those considerations make regular screenings for glaucoma particularly important, especially among members of at-risk groups.

However, POAG is not only a posterior pole issue. Increased outflow resistance at or near the trabecular meshwork can also result in elevated intraocular pressure (IOP) and ‘glaucoma’. However, the possibility exists that such a form of ‘glaucoma’ is different from those affecting, resulting from, or resulting in posterior pole pathology. Angle-closure and secondary glaucomas are not considered here.

The optic neuropathy in glaucoma involves the alteration and remodelling of the tissues located in the optic disc. This includes the lamina cribrosa, which is displaced posteriorly and thinned, leading to the characteristic disc cupping, and an apparent thinning or narrowing of the disc’s rim.

Current thinking is that the distorted lamina cribrosa initiates, or at least contributes to, a blockade of axonal transport of neurotrophic factors within retinal ganglion cell (RGC) axons. That is followed by apoptotic degeneration of the RGCs themselves.

The physical loads placed on that region are also theorised to cause molecular and functional changes in the cell population of the optic nerve. That includes, for example, the astrocytes and microglia, remodelling of the extracellular matrix, alterations to the local microcirculation, and subsequently, the shrinkage and atrophy of the relevant relay neurons in the magnocellular and parvocellular layers of the lateral geniculate nucleus (LGN).

There is increasing evidence that more than just the eye is involved in POAG. This raises the possibility that POAG is not specifically an ocular condition, but rather a condition in which the ocular manifestations are the most obvious, and possibly the easiest, to monitor. Glaucoma’s current established description as an ocular neuropathy might even be an oversimplification.

Additional complications include the predilection of some races to be more prone to glaucoma, the 50% rate of undiagnosed cases in the developed world, and the apparent increase in the incidence of the disease. These factors have contributed to a 20% increase in glaucoma blindness worldwide between 1990 and 2015, despite treatment being readily available in the developed world.

The 8th World Glaucoma Congress happening at the Melbourne Convention and Exhibition Centre at the end of March is likely to see the release of a wealth of new knowledge from the world’s leading glaucoma researchers and clinicians. The selection of presenters shows the breadth and depth of the faculty invited by the organisers.

It is difficult to think of an Australian ophthalmological or optometrical academic with an interest in glaucoma research that is not scheduled to appear. Add to that the huge number of US-based, European, and Asia-Pacific academics and clinicians joining the faculty, and it is reasonable to assume that few aspects of glaucoma will be left unaired.

Apart from advancing our knowledge, it is possible that our perceptions of glaucoma might, once again, undergo further revision.

POAG risk factors:

In descending order of importance:

  • Myopia ≥6 D (possibly from the resulting weaker scleral support)

  • A family history of the disease,

  • Some racial groups, especially black and Latino peoples,

  • The elderly (>80 years).

POAG is also more likely when the following clinical signs are present, in descending order of importance:

  • Increased cup:disc ratio (CDR),

  • Elevated IOP: ≥22 mm Hg (still the only modifiable risk factor for optic nerve damage and blindness.

Diurnal IOP variation [2 – 6 mm Hg] complicates the matter further and somewhat surprisingly, is the same in NTG glaucoma),

  • The presence of a Drance haemorrhage,

  • An increased CDR asymmetry between eyes (≥0.3),

  • Thinner corneas (<555 microns).

Changing perceptions

In late 2015, the American Academy of Ophthalmology defined POAG as: “A chronic, progressive optic neuropathy in adults in which there is a characteristic acquired atrophy of the optic nerve and loss of retinal ganglion cells and their axons. This condition is associated with an open anterior chamber angle by gonioscopy.”

It is noteworthy that IOP or increased pressure is not mentioned in the definition. POAG is also regarded by most as being a multifactorial disease. Interestingly, tonometers have not been consigned to the museum just yet.

Years of apoptotic RGC death precede any detectable retinal damage. It is only after the retinal nerve fibre layer (RNFL) deteriorates that glaucoma becomes detectable by visual field testing. Therefore, RNFL thickness assessment by optical coherence technology (OCT) is advantageous, as earlier detection of ocular changes is now possible. Patients with elevated IOP, thin (central) corneas, and enlarged cup:disc ratios (CDR) might benefit from the preventative treatments currently being researched, such as experimental neuroprotective measures.

AFT Pharmaceuticals
advertisement

Recently, the work of Yücel (2013) and Wang J et al. (2016) reported that glaucoma is not only an eye disease, but is also associated with the injury or degeneration of brain structures along the retino-geniculo-cortical (visual) pathway, starting with the loss of RGCs. They reviewed the pattern of visual and non-visual brain structural changes in 25 POAG patients and 25 age-gender-matched normal controls, using MRI and both volume based analysis (VBA) and surface based analysis (SBA) of the whole brain. The LGN, visual cortex (V1 and V2), amygdala, and hippocampus were also analysed.

While the VBAs showed no significant differences in the grey matter volumes of patients, the SBAs revealed significantly reduced cortical thickness in the right frontal pole and volume shrinkage in the LGN bilaterally, right cortex V1, and left amygdala. Structural abnormalities were correlated with clinical findings in a subset of the patients, revealing that the left LGN volume was correlated negatively with bilateral CDRs. Additionally, the right LGN volume was correlated positively with the mean deviation of the right visual hemi-field, and the right V1 cortical thickness was correlated negatively with the right CDR in glaucoma.

These results demonstrate that POAG affects both vision-related structures and non-visual cortical regions. Moreover, alterations of the brain’s visual structures reflect the clinical severity of glaucoma. Many glaucoma patients continue to lose vision despite treatment to lower IOP, so there is strong interest in novel strategies to prevent vision loss.

Greenfield et al. (2017) highlighted emerging risk factors for POAG as low cerebrospinal fluid pressure (CSF-P) and low ocular perfusion pressure (OPP), both of which correlate with optic nerve damage. They noted that the optic nerve head can be affected by the two local pressurised zones: the pressure of the intraocular space, and the pressure from the subarachnoid space due to the CSF.

Importantly, the lamina cribrosa is the interface between both those opposing regions and the pressure differential between them (the so-called translaminar pressure difference) can cause structural alterations to the optic disc. They also raised the possibility that the optic nerve cupping observed in patients with elevated IOP can also occur in patients with low CSF-P. They reported both prospective and retrospective studies showed that the CSF-P in glaucoma patients was significantly lower. In the prospective study, loss of vision was correlated positively with translaminar pressure differences and negatively with CSF-P.

However, because a lumbar puncture pressure assessment does not necessarily represent the actual CSF-P, current research is targeting the development of a non-invasive CSF-P measuring technique. Importantly, either low blood pressure or high IOP can lead to low OPP and an increased risk of developing POAG. They also noted the possibility that lowering blood pressure by systemic medication might also alter the risk of POAG.

Recent advances

Continuing the research into CSF’s involvement in glaucoma, University of Toronto researchers have shown that, in the mouse model at least, CSF flushes out the optic nerve in the normal eye but does not flow normally in mice with glaucoma. Professors Neeru Gupta and Yeni Yücel, with graduate student Emily Mathieu, showed that CSF from the brain penetrates the optic nerve, rather than simply surrounding it.

They demonstrated that in the glaucomatous mouse, far less CSF enters the optic nerve than is normal. They believe that the exchange involving CSF, most probably nutrition in and metabolic by-products out, is essential to normal optic nerve function and any disruption can result in optic nerve damage, such as that seen in glaucoma. They have yet to uncover the causes or reasons for CSF flow disruption and just what the impacts on the optic nerve are.

From an Australian perspective, it is interesting that the team claimed to have discovered a decade ago that the eye has a lymphatic system. That would be ‘news’ to Emeritus Professor H Barry Collin, who published papers in 1966 about the eye’s lymphatic system, based on his PhD research at the University of Melbourne in the early 1960s.

The Toronto team postulated that the inability to remove fluid from the eye causes a build-up of pressure, and that pressure is a major risk factor for glaucoma. If NTG is the same disease, or a closely related one, it may be that it is not pressure per se, but damage via some other mechanism. Team member Yücel also raised the possibility that their discovery might explain space flight-associated neuro-ocular syndrome, referring to optic nerve fluid shifts and vision impairment suffered by astronauts on extended space missions.

With the large volume of ongoing glaucoma research around the world, and some of the results of that research being aired in Melbourne in March, it is hoped that our knowledge and understanding of the disease will advance treatments for the disease. Unfortunately, it is probable that a cure is still some way off. In the interim, vigilant patient screenings are required to facilitate early intervention, so that irreversible losses are minimised and progression reduced or eliminated.

 


References:

Greenfield DS et al., 2017. Current and Emerging Therapies for Managing Glaucoma. MedEdicus CME Monograph 1 Dec 2017

Wang J et al., 2016. Structural brain alterations in primary open angle glaucoma: a 3T MRI study. Scientific Reports Vol: 6, Article #: 18969

Yücel Y, 2013. Central nervous system changes in glaucoma. J Glaucoma 22: S24 – S25)

large leaderboard
advertisement





rectangle
advertisement
Editor's Suggestion
Hot Stories

Display 1
advertisement


OR
 

Subscribe for Insight in your Inbox

Get Insight with the latest in industry news, trends, new products, services and equipment!