Ophthalmologists explore causes, consequences of pseudoexfoliation syndrome

Pseudoexfoliation glaucoma is an aggressive, asymmetrical, sneaky, sight-threatening disease.

Pseudoexfoliation, also called exfoliation syndrome (XFS), is the most common identifiable cause of open-angle glaucoma worldwide. XFS is characterized by the “production, deposition and progressive accumulation of a white, fibrillary, extracellular material in many ocular tissues, most prominent on the anterior lens surface and pupillary border,” Robert Ritch, MD, wrote in a 2016 review in the Asia-Pacific Journal of Ophthalmology.

The causes of XFS are not fully understood, although older age is a factor, as it is in most glaucomas, which according to one meta-analysis in Ophthalmology will be present in 76 million people worldwide in 2020.

Causes are thought to be both genetic and environmental, and not only eyes are affected. XFS is a systemic disorder of the extracellular matrix. The syndrome also has systemic associations: Microfibrillar material is found in the heart, blood vessels, lungs, liver and kidneys. XFS is a “unique disorder with extensive and often serious ocular and systemic manifestations and not, as it has long been termed, a ‘form’ or ‘type’ of glaucoma,” Ritch wrote. At the cellular level, a frequent finding in other age-related diseases involving aggregate accumulation is aberrations in cellular degradation, in particular in the mechanism of autophagy, the mechanism that digests misfolded polypeptides and aging macroscopic cellular components. XFS is characterized by abnormal lysosomes and mitochondria and disorganized microtubules. In addition to the LOXL1 gene abnormalities, five additional genes associated with XFS have been described.

Image: Shingleton BJ

In an interview with Ocular Surgery News, Ritch explained how XFS causes glaucoma: “The mechanism underlying exfoliation glaucoma is the iris rubbing over the lens during pupillary movement. The iris scrapes exfoliation material (XFM) from the lens surface, and at the same time, the XFM acts like sandpaper and scrapes the pigment off the back of the iris. This leads to a combination of XFM and pigment blocking the extracellular space of the trabecular meshwork. The trabecular meshwork itself also appears to produce XFM. But if you stop the pupillary movement, you stop the pigment from coming off the iris. We have found that one drop of 2% pilocarpine at bedtime in phakic eyes produces a 3-mm nonreactive pupil without visual side effects and prevents release of XFM and iris pigment, thus stopping further blockage of the trabecular meshwork and over time leading to decreased meshwork pigmentation.”

Characteristics of the sloughed material have been variably described as “fluffy,” as “flakes” and “fibrils,” or more specifically as “amyloid-like protein fibers” and “microfibrillar material.” Indeed, pseudoexfoliation is characterized by several biologic components, with the fibrin material likely being made of amyloid, laminin, some elastic fibers and other materials such as collagen basement membrane, according to OSN Glaucoma Board Member Bradford J. Shingleton, MD.

“It is an amorphous substance that looks amyloid-like on electromicroscopy but really isn’t,” Shingleton said.

Genetic, environmental factors

Investigators have been studying genetic risk factors for exfoliation syndrome for about a decade, according to Janey Wiggs, MD, PhD, and in 2007 an association between lysyl oxidase-like 1 (LOXL1) enzyme and pseudoexfoliation was found. LOXL1 is a cross-linking enzyme that is responsible for elastin formation and maintenance.

“LOXL1 genetic variants, the gene coding for the LOXL1 enzyme, are a major risk factor for exfoliation syndrome,” Wiggs said. “It’s a very robust association. Somewhere between 90% and 99% of people with the disease carry these risk factors.”

However, because up to 80% of normal people also carry these same genetic risk factors, LOXL1 is necessary, but not sufficient, for disease progression, Wiggs said.

“This means that there are either other risk factors that are present in people who have the disease, or there are protective factors present in the people who don’t have the disease,” she said.

Another genetic association was made by researchers in Singapore who identified the calcium channel protein gene CACNA1A.

“CACNA1A gene variants may result in fluctuations in calcium concentration that may stabilize or destabilize the fibrillar material that we characteristically find in patients with exfoliation syndrome,” Wiggs said.

A third possible genetic risk factor contributing to the disease is clusterin, an extracellular matrix chaperone required for the prevention of extracellular protein aggregation, Wiggs said.

“An important feature of exfoliation syndrome is the white fibrin-like material that accumulates in the eye,” she said. “Clusterin is a protein that normally works to prevent aggregation of other denatured proteins. Clusterin helps remove proteins that are denatured before they form aggregates. Because of the role of the protein in preventing protein aggregation, clusterin is an excellent candidate gene for the disease is an interesting target for future research.”

Wiggs and colleagues at the Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, are also studying environmental risk factors.

“Our group has found several important environmental risk factors for the disease, including living in northern latitudes, caffeine consumption, [ultraviolet] light exposure in general. These are all published studies,” Wiggs said.

Pseudoexfoliation glaucoma

Exfoliation-related glaucoma requires thorough and frequent surveillance, according to OSN Glaucoma Section Editor Thomas W. Samuelson, MD.

“The bottom line is to treat it with respect,” he said. “It’s a more aggressive form of glaucoma. Some of the worst glaucomas that you would see on initial presentation are exfoliation related, often because it’s asymmetrical. It’s the most common form of asymmetrical glaucoma in my practice.”

Because pseudoexfoliation syndrome is frequently associated with cataract and glaucoma, surgeons should suspect glaucoma in eyes with pseudoexfoliation undergoing cataract surgery.

“The first consideration is to have a high index of suspicion for glaucoma, either manifest at the time or impending, because it’s a very strong risk factor for glaucoma,” Samuelson said, with some studies suggesting up to a 40% chance of glaucoma development in eyes with pseudoexfoliation.

Pseudoexfoliation-related glaucoma presents earlier than primary open-angle glaucoma and tends to present with higher IOP. It is also associated with a greater incidence of narrower angles and chronic angle-closure glaucoma, according to Shingleton.

“There’s a higher frequency of more advanced disc damage at the time of diagnosis and visual field loss at the time of diagnosis. It tends to progress more rapidly than primary open-angle glaucoma, and there tends to be a greater IOP fluctuation — diurnal fluctuation — than with primary open-angle glaucoma. Those are important caveats,” Shingleton said.

As soon as exfoliation is identified, patients should be seen at least yearly and more frequently if they have other risk factors such as ocular hypertension, thin cornea, a strong family history or a narrow angle, Samuelson said.

“It’s not rare at all for patients to be asymptomatic with a pressure of 40 mm Hg or 50 mm Hg and only discover their glaucoma when they notice that they have poor vision. By then, of course, it’s often far advanced. The reason you see that sort of presentation is because it’s often so asymmetrical and the other eye is often carrying the day and functioning normally, and the patient is unaware of the vision loss in the affected eye,” Samuelson said.

For younger patients with normal IOP, OSN Glaucoma Board Member Alan S. Crandall, MD, is satisfied with scheduling yearly visits. For other patients, he may insist on more frequent visits.

“I make sure they understand the potential risk for glaucoma, explain the diagnosis of glaucoma and also explain that there are no symptoms. Therefore, it is mandatory that they keep their visits,” Crandall said. “The problem with pseudoexfoliation is that you can have rapid increases in IOP.”

Diagnosis and treatment

Gonioscopy is an important tool in the diagnosis and clinical management of patients with pseudoexfoliation, particularly because these patients can have a phacomorphic component and a narrow angle due to the tendency for lax zonules, according to Samuelson.

For Crandall, “[It’s] important to do gonioscopy because there is also significant deposition of pigment and pseudoexfoliation material in the angle of the eye, which may be at least part of the cause of the high pressure.”

The “three-ring sign” seen at the slit lamp on the anterior lens capsule is a clear diagnostic indication of XFS, showing deposits in the pupillary area, a clear intermediate zone and granular material in the peripheral zone.

“The iris rubs the XFM off the lens and gives you that three-ring sign,” Ritch said. “You get a central disc, a clear zone and a peripheral granular zone. The clear zone is caused by the iris rubbing over the lens.”

Regarding treatment, there are three options, according to Crandall: medication, laser surgery and incisional surgery.

“In general, if a patient has pseudoexfoliation and an increase in pressure from the last visit and the person feels they should likely lower the pressure, they don’t have a surgical cataract, and they don’t have any other issues that would preclude the use of drops, most commonly the physician will start with a medication,” Crandall said. “That most commonly turns out to be one of the prostaglandin analogues. If that lowers the pressure by 20% or 30% and is well tolerated by the patient, then you would just follow them at a 4- to 6-month interval to make sure that they continue on that path and the pressure doesn’t go up.”

If IOP starts to rise, a second medication — a beta-blocker alone or in combination with Alphagan P (brimonidine tartrate ophthalmic solution 0.1% or 0.15%, Allergan), Azopt (brinzolamide ophthalmic suspension 1%, Alcon) or Cosopt (dorzolamide hydrochloride and timolol maleate, Akorn) — may be warranted.

“This is the way most physicians treat their average glaucoma patients. You have to vary that a little bit with each person, but that would be a general rule,” Crandall said.

For a patient whose IOP increases from 21 mm Hg to 30 mm Hg, the ophthalmologist can add a third medication or opt to perform selective laser trabeculoplasty or argon laser trabeculoplasty. However, laser treatment rarely reduces IOP in the long term, Crandall said.

“The average is 2 to 3 years, and the pressure starts to go back up. And you can rarely stop the drops. You do the SLT, and then you still need to follow them closely,” he said.

A second SLT is an option, but close monitoring is still needed, Crandall said.

In patients being treated for mild to moderate pseudoexfoliation glaucoma who develop cataracts, cataract surgery alone may be sufficient to lower IOP by 7 mm Hg or more. However, cataract extraction with microincision glaucoma surgery with the iStent (Glaukos) may be an option for some patients, Crandall said.

“The iStent usually gives you two to three more points of lowering compared to an eye that just had cataract extraction, so that could be significant and very helpful. You usually don’t get to stop all the drops, although frequently you can stop one or two of the drops, at least temporarily,” he said.

For moderate to severe glaucoma, trabeculectomy or endophotocoagulation may be required to keep IOP under 14 mm Hg, Crandall said.

“If everything works out, you’re going to be able to get the patient off most of their medicines. There, you’re looking at getting the pressure below episcleral venous pressure, which you can’t do with most of the MIGS devices,” he said.

Pharmacologic treatment of exfoliation-related glaucoma is fairly straightforward, Samuelson said.

“I think that the pharmacologic management is pretty similar to other forms of open-angle glaucoma, so I don’t necessarily change my strategy in terms of pharmacologic pressure reduction,” he said.

Samuelson said he performs SLT for exfoliation-related glaucoma as frequently or slightly more frequently than he uses it to treat typical cases of open-angle glaucoma.

Ritch said that a single dose of 2% pilocarpine can stop pupillary movement and that nasolacrimal occlusion can double the duration of action of pilocarpine.

“Giving 2% pilocarpine at bedtime is sufficient to give you a 3-mm nonreactive pupil for 24 hours,” Ritch said. “Therefore, you don’t have to use it four times a day. Patients don’t get blurred vision from it, and that stops the pigment from rubbing off the iris and the iris from rubbing the exfoliation material off the lens. You stop clogging the meshwork.”

By preventing the trabecular meshwork from being clogged, pilocarpine increases trabecular outflow, Ritch said.

“[Pilocarpine does not just] lower pressure, although when you’re sleeping and at night, the other drugs don’t really work, except for the prostaglandins,” he said. “Pilocarpine is the only drug we have right now to increase trabecular outflow. You’re stopping the material from coming off the iris and the lens, and therefore, it’s acting to inhibit the underlying mechanism of glaucoma, not for intraocular pressure per se but to block the mechanism of pigment and exfoliation material release so that you don’t get more material in the trabecular meshwork.”

Pseudoexfoliation cataract

It is more common for cataracts to develop in eyes with pseudoexfoliation than in eyes without pseudoexfoliation, and in these patients, small pupils and zonular weakness are the two greatest challenges associated with cataract surgery, according to Shingleton.

“Pupils tend to be a little smaller in eyes with pseudoexfoliation, but surgeons now are much more comfortable taking care of small pupils because of our experience with Flomax (tamsulosin, Boehringer Ingelheim),” he said, referring to the drug’s tendency to interfere with pupil dilation and cause intraoperative floppy iris syndrome.

“Generally, that’s not too much of an issue, but there’s no question that miotic pupils have to be dealt with more commonly in pseudoexfoliation,” he said.

Samuelson described ways to handle small pupils in cataract surgery.

“As far as the intraoperative considerations, the most common issue is the fact that the pupil doesn’t dilate as well, so you have to deal with a smaller pupil,” he said. “In general, the iris behaves fairly well. It’s a stiffer iris as opposed to a floppy iris, so most of the time you can simply put up with a slightly smaller pupil or use one of the many very effective pupil extenders, if needed, to improve visualization.”

For healthy patients with cataract and no comorbidities, Samuelson lays odds of an uneventful surgery at more than 99%. For patients with exfoliation, “I reduce that percentage to 98%,” he said, explaining that, unless the patient has obvious phacodonesis or extremely dense cataracts, pseudoexfoliation itself is little reason to expect a more complicated surgery.

However, patients with pseudoexfoliation are more prone to zonular laxity than other patients.

“I don’t hesitate to use capsular support rings or something like the MacKool capsular hooks if the lens is very lax or loose,” Samuelson said.

The cause of zonular weakness is hard to identify, according to Shingleton.

“There’s no question on electron microscopy there’s infiltration of pseudoexfoliation material at the origin and the insertion of the zonules. This probably leads to disinsertions of the zonules,” he said. “There’s certainly lysis and stromal enzyme degradation of the zonules, and there’s fragmentation of the zonules. This is all documented on electron microscopy.”

Shingleton said there is a risk of potential intraoperative complications resulting from weak zonules.

“If there are no signs of weak zonules presenting preoperatively or intraoperatively, there’s probably about a 2% incidence of encountering weak zonules and having potentially complicated cataract surgery,” Shingleton said. “If there are signs of weak zonules preoperatively or intraoperatively, that goes to a whole new level. That can approach a 10% or 12% risk of having complicated surgery.”

Lens subluxation or previous complicated cataract surgery in the fellow eye because of weak zonules may predict weak zonules in the second eye, Shingleton said.

“If there’s subluxation of the lens, where there’s true, obvious zonular dehiscence, or if the fellow eye had surgery and had complicated surgery because of weak zonules, the percentage incidence of encountering weak zonules in that eye approaches 50%. You can’t just generalize in terms of your approach to pseudoexfoliation eyes. You need to be aware of the potential risk in all of the eyes. Then you have to identify the high-risk eyes.”

Shingleton said that surgeons should also look for anterior chamber depth asymmetry between the two eyes or within one eye.

“The shallower eye tends to be the one with weaker zonules. If there’s anterior chamber depth asymmetry within a given eye, especially shallower inferiorly related to superiorly, that’s a very important sign. If there’s iridodonesis, that’s important. Phacodonesis, that’s a definite sign you’ve got weak zonules. Those things are critical for people to understand,” Shingleton said.

Shingleton and colleagues reported in the Journal of Cataract and Refractive Surgery in 2008 that in eyes with pseudoexfoliation undergoing cataract surgery, IOP reduction was greater in eyes with higher preoperative IOP.

“Basically, the take-home message is if you take all comers with pseudoexfoliation, there’s a small statistical drop in pressure with cataract surgery alone. If you take eyes with higher pressures with pseudoexfoliation, the pressure reduction is even greater,” Shingleton said. “If the preop pressure is less than 20 mm Hg, the pressure reduction is about 1 mm Hg or 2 mm Hg. If the preop pressure is 21 mm Hg to 25 mm Hg, the pressure reduction approaches 6 mm Hg. And if the preop pressure is greater than 25 mm Hg, the pressure reduction approaches 10 mm Hg. So, it’s directly related to the preoperative pressure level, which has also been demonstrated in eyes without pseudoexfoliation.” – by Matt Hasson

• References:
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• Pasquale LR, et al. Invest Ophthalmol Vis Sci. 2012;doi:10.1167/iovs.12-10085.
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• Ritch R. Asia Pac J Ophthalmol (Phila). 2016;doi:10.1097/APO.0000000000000187.
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• The laser in pseudoexfoliation (LIP) study. https://clinicaltrials.gov/ct2/show/NCT01704989. Updated 2012.
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• For more information:
• Alan S. Crandall, MD, can be reached at John A. Moran Eye Center, 65 N. Mario Capecchi, Salt Lake City, UT 84132; email: alan.crandall@hsc.utah.edu.
• Robert Ritch, MD, can be reached at New York Eye and Ear Infirmary, 310 E. 14th St., New York, NY 10003; email: ritchmd@earthlink.net.
• Thomas W. Samuelson, MD, can be reached at Minnesota Eye Consultants, 710 E. 24th St., Suite 100, Minneapolis, MN 55404; email: twsamuelson@mneye.com.
• Bradford J. Shingleton, MD, can be reached at Ophthalmic Consultants of Boston, 50 Staniford St., Suite 600, Boston, MA 02114; email: bjshingleton@eyeboston.com.
• Janey Wiggs, MD, PhD, can be reached at Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, 234 Charles St., Boston, MA 02114; email: janey_wiggs@meei.harvard.edu.

Disclosures: Crandall reports he is a consultant for Abbott Medical Optics and Alcon. Ritch, Samuelson, Shingleton and Wiggs report no relevant financial disclosures.

Do you place capsular tension rings in all pseudoexfoliation patients undergoing cataract surgery?

Rings reduce risk of dislocation

In every patient with pseudoexfoliation, surgeons should consider both placement of a capsular tension ring and performing anterior optic capture through a centered capsulotomy, as described by Devranolu and others. While late lens/bag dislocations only occur in 1% to 3% of cataract cases, they are associated with pseudoexfoliation more than half the time, according to a Mamalis 2009 study. Most dislocations are bilateral, and the mean time to dislocation in various studies is 8 years to 13 years, so this complication befalls patients in their very late years, when they are the poorest candidates for complex surgery.

Using a CTR is like buying a cheap insurance policy. While it will not eliminate the risk of a late dislocation, it is likely to reduce that risk. When combined with optic capture, it just may be enough to prevent anterior capsular phimosis, which leads to most cases of dislocation and is, by itself, a complication worth preventing.

Whether zonular laxity is evident or not, placing a CTR routinely in every pseudoexfoliation patient is strongly supported by a growing body of evidence. Our patients deserve this extra measure of effort and cost to boost their chances of a lifetime of high-quality vision.

John A. Hovanesian, MD, FACS, is OSN Cataract Surgery Section Editor. Disclosure: Hovanesian reports no relevant financial disclosures.

• Reference:
• Davis D, et al. Ophthalmology. 2009;doi:10.1016/j.ophtha.2008.11.018.

Rings not needed for all patients

I find that in my surgical practice that only a minority of pseudoexfoliation patients have signs of loose zonules during cataract surgery. Thus, I do not feel that it is necessary to place them in every patient with a clinical history of pseudoexfoliation. Sometimes, the less done intraocularly, the better, as I have seen a CTR go through a capsule, rip out more zonules and require sewing in a lens (or placement of an anterior chamber IOL).

However, if I note any laxity/dehiscence of the zonules during surgery or even an odd laxity of the capsule itself, I have no hesitation in putting in the CTR to both stabilize the bag for in-the-bag IOL implantation and hopefully cause peripheral adhesions that may further stabilize the bag over time. There is also the added expense of the CTR, which is not insignificant. All in all, I believe an attitude of a doctor “to do no harm” is warranted. If there is no visible reason to put the CTR in, leave it alone.

Jeffrey Whitman, MD, is an OSN Cataract Surgery Board Member. Disclosure: Whitman reports no relevant financial disclosures.