Researchers, clinicians continue to determine driving force behind glaucoma

“Glaucoma is a disease where people still go blind despite our best efforts and technology. We don’t understand the underlying pathophysiology well enough to help all patients,” John P. Berdahl, MD, from the Vance Thompson Vision Institute, said in an interview with Primary Care Optometry News.

“As we deepen our understanding of the basic pathophysiology, doctors and scientists will be able to identify new targets to help people from going blind from this common malady,” he added.

The potential concerns surrounding the identification of glaucoma are diverse and broad in their individual application, according to J. James Thimons, OD, private practitioner at Ophthalmic Consultants of Connecticut and PCON Editorial Board member. Other factors such as vascular issues, autoimmune problems, inflammatory elements, trauma and genetic history are of importance but have predictive elements aside from intraocular pressure.

“Intraocular pressure is the only consistently present component of the diagnostic and therapeutic process that we can actually move. I think the focus has been directed toward IOP because it’s something we can modify,” Thimons said.

“Now there are tools that we can use to measure the eye pressure around the clock, and we may find new information,” Murray Fingeret, OD, FAAO, who practices in Hewlett, N.Y., and is a PCON Editorial Board member, said in an interview. “In many of these patients who we thought did not have elevated IOP, when we allow them to measure it on their own, we may find something different.”

Image: Berdahl JP

However, IOP is not the whole story.

In the U.S. about 33% of primary open angle glaucoma (POAG) is normal tension glaucoma (NTG), and in Japan that statistic climbs to 90% (Mizoue et al.).

“Clearly IOP is not the only factor in glaucoma ... in fact it’s not even in the definition of glaucoma,” Berdahl said.

Furthermore, many people with high eye pressure never get glaucoma, he said. “So, there’s got to be a big picture that we are missing here.”

“Glaucoma has large variation in its presentation. Each glaucoma patient brings with them a unique set of genetic, environmental and medical risk factors that make it difficult to pinpoint what is driving the disease,” Scott A. Anthony, OD, FAAO, who practices at the Louis Stokes VA Medical Center in Cleveland, said in an interview.

Anthony said that one would assume that many glaucoma patients would have similar disease characteristics. “In practice, it often feels as if no two glaucoma patients are alike. I think this bears out in glaucoma research as well.”

Abstract concepts such as low blood pressure and toxicity to the back of the eye are in need of consideration as well, according to Fingeret.

“They are concepts that we can see in research settings but clinically we don’t see them or understand them. They are harder to gain traction,” he said. “We like when things are simple to figure out, like high pressure and high damage; it’s easy to understand.”

Cerebrospinal fluid

One hypothesis that Berdahl and others are investigating is the relationship between cerebrospinal fluid (CSF) pressure and glaucoma.

To measure CSF pressure, the only viable option thus far is through a lumbar puncture. It is difficult to determine how well the pressure measured in the CSF correlates to behind-the-eye pressures, he said.

“That said, the preponderances of the data suggest that CSF pressures matter in glaucoma, and low CSF pressures put people at risk, and high CSF pressures may be protective,” Berdahl said.

He and fellow researchers discovered that CSF pressures were 33% lower in subjects with POAG compared with nonglaucomatous controls. Their data support the hypothesis that CSF pressure may play an important contributory role in the pathogenesis of POAG, they said.

Image: Omodaka K. Copyright: ©2015 Omodaka et al. doi.org/10.1371/journal pone.0122347.

“This finding supports the concept that higher translaminar pressure differences, whether the result of elevated IOP, reduced CSF pressure or both, play an important role in glaucomatous optic nerve damage,” according to their study.

Optic nerve perfusion

Great progress has been made in evaluating optic nerve perfusion and its role in glaucoma pathogenesis, according to Anthony. Ocular coherence tomography angiography is making headway in defining more precisely how optic nerve perfusion relates to glaucoma in its many forms.

Glaucoma may be occurring, in part, from irregularities in microvascular circulation in the optic nerve, and studies have shown compromised perfusion in some glaucoma patients, Anthony said.

The degree to which reduced ocular nerve perfusion pressure is contributing to glaucoma pathogenesis is still unknown.

“Is it the cause of the disease or a consequence of it?” Anthony proposed.

Axoplasmic flow has been shown to be critical for the overall health of the nerve, Thimons added.

Oxidative stress

While oxidative stress is not a clinical consideration in current glaucoma management, a large body of research strongly suggests it may be a causative factor in glaucoma and a target for future glaucoma therapies, according to Anthony.

There is likely a direct correlation between oxidative stress and optic nerve perfusion, whereby incremental disruptions in optic nerve perfusion can lead to formation of reactive oxygen species that damage the localized microenvironment, Anthony said, citing research from Mozaffarieh.

“This negative cycle could lead to retinal ganglion cell (RGC) apoptosis and morphological changes to the optic nerve,” he said.

Fingeret questions whether oxidative stress is a byproduct of glaucoma or a cause.

“We know that oxidative stress occurs when tissues become damaged or changed,” he said.

It is unclear whether the oxidative stress is primary or secondary to glaucoma, he said.

“While there are a series of molecules being studied, there is nothing yet in the glaucoma treatment world that is available for oxidative stress,” Fingeret continued. “We are using a lot of the tools that are coming out of Parkinson’s, traumatic brain injury and neurogenerative research.”

The connection between optic nerve perfusion and oxidative stress is that perfusion decreases the availability of essential nutrients to the cellular matrix, Thimons explained. At this stage, oxidative stress begins. Oxidative stress is intertwined with IOP, as IOP decreases perfusion of vascular supply of axoplasmic support to the tissue, he said. IOP, axoplasmic flow reduction and vascular reduction all combine to create oxidative stress.

Potential treatment for oxidative stress

“Certain drugs have been looked at and researchers have found some interesting potential pathways,” Thimons said. “Anything that will produce a reduction in the inflammatory process – inflammation-blocking antioxidants – is a key potential element in cellular integrity.”

Efficacy of treatment with antioxidants may depend on the patient’s age, according to research in the British Journal of Ophthalmology. The relationship between oxidative stress and visual field loss may be strongest in relatively young patients with open-angle glaucoma, according to the study.

Researchers assessed systemic oxidative stress with skin autofluorescence (SAF). The younger subjects with open-angle glaucoma with high SAF had significantly lower better-eye mean deviation than the younger subjects with normal SAF, but the older subjects had similar better-eye mean deviation regardless of SAF, according to researchers.

SAF was negatively correlated with mean deviation in the youngest subjects but not in the older ones.

Ginkgo biloba may assist in increasing blood flow, but nothing as of yet is able to conquer that space, Thimons said. Simple drugs such as doxycycline are being explored to see if they can provide low level blockage of the matrix metalloproteinase-9 cycle, which causes cellular death.

Omega-3s have also been explored, he said, but the theory is hypothetical and only in the clinical trial phase.

“I anticipate as we move forward there will be a focus on this because that is the piece of the puzzle that is important in conjunction with IOP,” Thimons said. “If we could lower the pressure and add a protective coating – if you will – that would be a major step forward.”

He believes that two new potential drugs from Aerie Pharmaceuticals, Rhopressa (netarsudil ophthalmic solution 0.02%) and Roclatan (netarsudil 0.02%/latanoprost ophthalmic solution 0.005%) may offer promise.

In the Rocket 4 study, which included approximately 700 patients, Rhopressa demonstrated noninferiority compared to twice-daily timolol in patients with baselines above 20 mm Hg to below 25 mm Hg, as reported by Ocular Surgery News.

Roclatan, a fixed-dose prostaglandin combination eye drop, reduced IOP more than each of its individual components at all time points measured, thus meeting its 90-day primary efficacy endpoint in the Mercury 1 trial, according to Aerie Pharmaceuticals.

Both drugs have a novel pathway for IOP-lowering but they may also have the capacity to demonstrate oxidative interface, Thimons said.

They represent two new categories of drugs and are “incredibly unique,” he added.

Lamina cribrosa

Research is also uncovering the importance of lamina cribrosa evaluation in diagnosing and managing glaucoma.

“I’m inclined to believe that glaucoma is a disease of slowed axonal transport across the lamina cribrosa,” Berdahl said.

Recent advances in imaging have significantly improved the ability to evaluate the lamina cribrosa in patients with glaucoma, allowing a means to study the putative site of neural damage, according to Abe and fellow researchers.

“There is growing evidence of association between lamina cribrosa structure and other structural and functional measures of glaucoma, which suggests that evaluation of the lamina cribrosa may prove a useful addition to clinical imaging options for detecting glaucoma and glaucoma progression,” the researchers wrote.

Lamina cribrosa imaging may improve the understanding of mechanisms of glaucomatous RGC injury and may be a useful biomarker of increased risk of neural losses, they added.

“It may be that vascular perfusion (decreased blood flow) plays an important role in glaucoma, or it could be that it’s a biomarker for other conditions that may be a more fundamental, underlying cause like a pressure differential across the lamina cribrosa that impedes axonal transport,” Berdahl said.

“Ortho-grade axonal transport has a hard time traveling from the brain side of the optic nerve into the eye because of the pressure gradient that occurs – from a high eye pressure or a low intracranial pressure,” he continued. “This may lead to the metabolic needs of the intraocular portion of the optic nerve and the ganglion cells to become unmet while also limiting the ability to remove the metabolic waste, leading to a nerve that can have RGC loss.”

Blood pressure, sleep apnea, type A

Fingeret suggests that some individuals are overtreated for their high blood pressure by their family physician or cardiologist.

“There’s no such thing as a blood pressure being too low for many,” he said.

However, glaucoma is a case where low blood pressure can be deleterious, Fingeret noted.

Other research suggests links between glaucoma and those with obstructive sleep apnea as well as those with type A behavior.

The basic science in the area of glaucoma has begun to focus on the issue of axoplasmic flow and oxidative stress as part of the larger complement, Thimons said.

“My hope is that as we continue to go down this path, one or more of the new therapeutic options will have some compacity to implement treatment above and beyond IOP control,” he said. “Yes, IOP is important and plays a role, but there are other factors present that we need to account for and, if we can help mediate those, we are looking at a much more successful algorithm in managing glaucoma for the long-term.”

“Glaucoma management requires some acceptance by the provider that we don’t fully understand what is causing the disease,” Anthony said. “IOP does not define this condition and, despite our recognition of factors such as optic nerve perfusion and oxidative stress, there is no consensus about the pathogenesis of glaucoma.” – by Abigail Sutton

• References:
• Abe RY, et al. Curr Ophthalmol Rep. 2015;doi:10.1007/s40135-015.0067-7.
• Berdahl JP, et al. Ophthalmology. 2008;doi:10.1016/j.ophtha.2008.01.013.
• Bubella RM, et al. J Glaucoma. 2014;doi:10.1097/ITG.0b013e3182707421.
• Mizoue S, et al. Clin Ophthalmol. 2014; doi:10.2147/OPTH.S57640.
• Mozaffarieh M, Flammer J. Curr Opin Pharmacol. 2013;doi:10.1016/j.coph.2012.10.001.
• Omodaka K, et al. PLOS One. April 15, 2015. doi.org/10.1371/journal.pone.0122347
• Rhopressa shows positive topline efficacy results in Rocket 4 phase 3 trial. Ocular Surgery News/Healio.com. Oct. 27, 2016.
• Zhao X J, et al. J Glaucoma. 2016;doi:10.1097/ITG.0000000000000349.

• For more information:
• Scott A. Anthony, OD, FAAO, is in practice at the Louis Stokes VA Medical Center in Cleveland and is a member of the Optometric Glaucoma Society. He can be reached at: Scott.Anthony@va.gov.
• John P. Berdahl, MD, specializes in advanced cataract, corneal and glaucoma surgery at the Vance Thompson Vision Institute in Fargo, N.D. He can be reached at: john.berdahl@vancethompsonvision.com.
• Murray Fingeret, OD, FAAO, is in practice in Hewlett, NY. He can be reached at: murrayf@optonline.net.
• J. James Thimons, OD, is a private practitioner at Ophthalmic Consultant of Connecticut in Fairfield. He can be reached at: JThimons@gmail.com.

Disclosures: Berdahl is a consultant for Alcon, Allergan, Glaukos, Equinox, Invisia and New World Medical. Fingeret is on the speakers bureau for Heidelberg Engineering; is a consultant for Aerie, Alcon, Allergan, Carl Zeiss Meditec, CenterVue, Inotek and Topcon; and serves on advisory boards for Alcon, Allergan and Bausch + Lomb. Anthony and Thimons reported no relevant financial disclosures.