The 2 faces of glaucoma

Reviewed by Yvonne Ou, MD

Glaucoma is not only a pressure-dependent optic nerve disease but also a pressure-independent retinal disease, according to Yvonne Ou, MD, associate professor in residence and academic director of the Glaucoma Division, Department of Ophthalmology, University of California San Francisco.

The case for intraocular pressure (IOP) independence
Results from a large number of important studies seem to support Ou’s contention.

A study on the prevalence of open-angle glaucoma reported that nearly 40% of patients with primary open-angle glaucoma do not have elevated IOP,¹ which suggests, she noted, that IOP-independent risk factors are at work here.

Related: Drainage device offers IOP lowering capabilities at 1 year

Low ocular perfusion pressure, defined as systolic pressure below 125 mm Hg, was associated with a higher risk of progression of glaucoma in the Early Manifest Glaucoma Trial.²

In addition, results from the Low-pressure Glaucoma Treatment Study showed that the use of the neuroprotective agent brimonidine equals less progression of visual field damage compared with timolol, a β-blocker, despite equal reductions in IOP with the 2 agents.³

Neurodegenerative disease
Glaucoma is also a retinal neurodegenerative disease, aspects of which are compartmentalized neurodegeneration and retinal ganglion cell (RGC)–type susceptibility.

Ou pointed out that this information can lead to identification of new biomarkers, including novel imaging and functional assessments.

RGCs differ in their functional capabilities (ie, the ON and OFF cells react to light increases and decreases, respectively), and their dendrites are positioned at different locations in the inner plexiform layer (IPL).

Related: IPL offers glaucoma biomarker for early-stage disease

Two types of RGCs are the ON-sustained α RGCs and OFF-transient α RGCs.

Regarding the former, when investigating a murine model of elevated IOP, Ou and colleagues noted that following 7 days of transient IOP elevation and the subsequent return to baseline IOP, RGCs maintained dendritic area and increased the radius of the receptive field.

In contrast, those 2 parameters shrank in association with the α OFF-transient cells.

Another observation regarding the ON-sustained cells was that the synaptic density decreased following the IOP elevation.⁴

A newer generation of optical coherence tomography (OCT) known as visible-light OCT (vis-OCT) has a better axial resolution than conventional OCT and can visualize the sublaminae in the IPL.

Related: Seeking a new frontier with intraoperative OCT

The ON-sustained ganglion cells were shown to be more resilient after IOP elevation in contrast to loss of the OFF-transient ganglion cells.⁴ The loss of these cells may be indicative of their selective vulnerability.

This resilience of the ON-sustained ganglion cells raises the question about the reversibility of their impaired function that includes early synapse loss and dysfunction, dendrite shrinkage, loss of electroretinography (ERG) amplitude and size of the receptive field, axonal transport deficits, and microglial activation.⁵ 

Ou’s team evaluated ERG measurements of the changes in the ON and OFF pathways and reported that a sinusoidal flicker stimulus at varying frequencies can separate the pathways, and the OFF pathway is associated with higher temporal frequencies.

Ou and her team used a handheld ERG with sinusoidal high- and low-frequency stimuli to evaluate glaucoma patients and controls.

This study found that eyes with glaucoma have decreased ERG responses at higher frequencies compared with controls.

Related: Exploring the evolution of interventional glaucoma

At lower frequencies, there was no difference in the responses, suggesting that the OFF pathway may be more vulnerable in glaucoma.

“Our current paradigm is that glaucoma exhibits optic nerve damage as evidenced by optic disc and retinal nerve fiber layer structural abnormalities or visual field abnormality,” Ou concluded.

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Yvonne Ou, MD
e:Yvonne.Ou@ucsf.edu
This article is adapted from Ou’s presentation at the American Glaucoma Society’s 2021 annual meeting. She has no financial interest in this subject matter.

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References
1. Dielemans I, Vingerling JR, Wolfs RC, Hofman A, Grobbee DE, de Jong PT. The prevalence of open-angle glaucoma in a population-based study in the Netherlands. The Rotterdam Study. Ophthalmology. 1994;101(11):1851-1855. doi:10.1016/s0161-6420(94)31090-6

2. Leske MC, Heijl A, Hyman L, Bengtsson B, Dong L, Yang Z; EMGT Group. Predictors of long-term progression in the early manifest glaucoma trial. Ophthalmology. 2007;114(11):1965-1972. doi:10.1016/j.ophtha.2007.03.016

3. Krupin T, Liebmann JM, Greenfield DS, Ritch R, Gardiner S; Low-Pressure Glaucoma Study Group. A randomized trial of brimonidine versus timolol in preserving visual function. Results from the Low-pressure Glaucoma Treatment Study. Am J Ophthalmol. 2011;151(4):671-681. doi:10.1016/j.ajo.2010.09.026

4. Ou Y, Jo RE, Ullian EM, Wong ROL, Santina LD. Selective vulnerability of specific retinal ganglion cell types and synapses after transient ocular hypertension. J Neurosci. 2016;36(35):9240-9252. doi:10.1523/JNEUROSCI.0940-16.2016

5. Fry LE, Fahy E, Chrysostomou V, et al. The coma in glaucoma: retinal ganglion cell dysfunction and recovery. Prog Retina Eye Res. 2018;65:77-92. doi:10.1016/j.preteyeres.2018.04.001