Focus on Glaucoma

The art and science of glaucoma management

Continuing research changes our understanding of glaucoma, right down to IOP’s reliability in treatment.

By Nathan M Radcliffe, MD

While the mainstay of glaucoma therapy is to lower intraocular pressure (IOP), our knowledge of glaucoma diagnosis and treatment continues to evolve. Here I review some recent advances in our understanding of the disease; revisit some topics that are in constant evolution; and discuss a few topics that ophthalmologists consider of timeless interest in their management of patients with glaucoma.

THE TRUTH ABOUT IOP

The moving target

Because IOP is the main target of glaucoma therapy, considering the nuances of lowering IOP can enhance our ability to care for glaucoma patients. And while IOP might be the main target of glaucoma therapy, it is not a particularly easy target. IOP fluctuations occur frequently. In the observation arm (n=810) of the Ocular Hypertension Treatment study (OHTS), 13% of eyes had a 20% difference in IOP between consecutive visits; another 66% of eyes had a change in IOP of 3 mm Hg or less. One tenth of eyes had a change in IOP of up to 5 mm Hg between visits.¹

While it is a good idea to check the IOP at the same time of day after initiating therapy, IOP may fluctuate with a different diurnal pattern from day to day. And though monocular trials are an intuitive way to assess efficacy (and a good way to investigate for eyedrop side effects), IOP will fluctuate differently between fellow eyes – and fellow eyes may respond differently to the same therapy.²

Is it really lower?

In IOP-lowering medical trials, around 15% to 30% of patients do not seem to experience significant IOP reduction from topical therapy, and this may be more likely in patients with lower baseline IOP.³ Additionally, consider that IOP fluctuation can mask or mimic the effects of IOP lowering therapy. This and other emerging data suggest that IOP measurements should probably be taken with a grain of salt.

In a large study examining which IOP factors were closely related to the progression of the visual field, Dr. De Moraes and colleagues demonstrated that several pressure variables were related to progression.⁴ The mean IOP value, the amount of IOP fluctuation and the peak IOP value were all related to progression, but the peak IOP value was most closely related to progression. In other words, one can get the best sense of which patients are going to progress by just looking at the highest IOP number in the chart.

CORNEAL BIOMECHANICS AND GLAUCOMA

The role of corneal thickness

To measure the IOP, we must go through the cornea. Currently, we have no clinically useful methods of assessing the pressure that also do not rely on a portion of corneal assessment (e.g., pushing on the cornea to estimate the IOP). While initially it was felt that corneal thickness was important only because it impacted the accuracy of IOP measurements, we now realize that the story is more complex. In OHTS, patients with a cornea that was 40 μm thinner had a 70% higher risk of developing glaucoma.⁵

By plugging in some values using a glaucoma risk estimator derived in part from OHTS (available online by Googling “glaucoma risk estimator,” or at ohts.wustl.edu/risk/calculator.html), it may surprise you to learn that having a pressure 10 mm Hg higher only adds half of the risk as if the patient had a cornea that was 100 μm thinner.

If corneal thickness tells you about the shape of the cornea, then corneal hysteresis tells you how the cornea behaves while it is being deformed. Investigations into corneal biomechanical properties have provided additional information regarding glaucoma risk.

The corneal hysteresis factor

Corneal hysteresis is defined as the difference between the air-jet pressure at inward and outward corneal applanation, and is a reflection of corneal viscous damping or “biomechanical properties.” Patients that might have a lower corneal hysteresis include those with glaucomatous damage and/or high IOP, those with keratoconus, and those who are older. Blacks and Hispanics, who have a higher risk of glaucoma, also have been shown to have lower corneal hysteresis.⁶ It is measured using the Ocular Response Analyzer (ORA; Reichert Corp.).

Two longitudinal studies, one of which was prospective, have now shown that having a lower corneal hysteresis is associated with glaucoma progression, and that hysteresis is more closely associated with field and optic nerve worsening than corneal thickness.^7,8 Furthermore, patients with a lower hysteresis appear to have a greater degree of IOP reduction from medical and laser glaucoma treatments (a finding that is somewhat counter-intuitive given that lower hysteresis is also associated with more glaucoma progression).^9,10 Unlike corneal thickness, hysteresis will increase as the IOP is decreased, and likely fluctuates more than corneal thickness. Corneal hysteresis is therefore best described as a dynamic behavior of the cornea, and one that is related to glaucoma risk.

Our understanding of corneal biomechanical properties and how they influence glaucoma risk is still evolving, but the available data suggest the corneal hysteresis may be more important than corneal thickness for glaucoma risk.

ANGLE CLOSURE DIAGNOSIS, TREATMENT

Gonioscopy is essential

Angle closure is an important and often undetected cause of blindness from glaucoma. In China, as of 2001, there were an estimated 28 million people with occludable angles, with 91% of the glaucoma-related blindnesses caused by angle closure.¹¹ (See chart, page 10.) One could argue there is no less expensive but more powerful tool, providing such a high payoff for patient care, than gonioscopy, although OCT produces fantastic images (Figure 1). Perform gonioscopy at baseline in any patient with glaucoma or suspected glaucoma or with the appearance of anterior chamber shallowing or peripheral iridocorneal narrowing. We should repeat gonioscopy more frequently in patients who are older and hyperopic.

Figure 1. While gonioscopy remains the gold standard, optical coherence tomography can provide objective and illustrative characterizations of the angle. The top image demonstrates a normal, open angle while the bottom image demonstrates a closed angle with iris in contact with the peripheral cornea.
COURTESY: NATHAN M. RADCLIFFE, MD

Repeat gonioscopy in a patient with a change in IOP profile, and in any patient after a procedure that affects the angle has been performed. In general, we should perform gonioscopy with good regularity, as the angle appearance may vary, and our patient’s angle status may change or evolve as the disease progresses.

More so than ever, the skill set acquired by performing routine gonioscopy has an increasing utility. Consider that the emerging field of minimally invasive or micro-incisional glaucoma surgery (MIGS) depends upon intraoperative gonioscopy to place a number of glaucoma implants into Schlemm’s canal, the subconjunctival space or the supraciliary space from an ab interno approach. (See related story, page 40.)

A look at laser treatments

For patients with occludable angles, the preferred treatment is the laser peripheral iridotomy to equalize the pressure between the anterior and posterior chambers. In addition to inflammation or bleeding, dysphotopsia is perhaps the most concerning potential side effect. It can be challenging if not impossible to eliminate, although it will often resolve on its own, likely as a result of neuroadaptation.

According to Spaeth and colleagues, up to 4% of patients undergoing the iridotomy procedure may experience dysphotopsia.¹² The authors concluded that the likelihood of dysphotopsia was higher in patients who have partially or completely exposed iridotomies compared with complete eyelid coverage.

Recently, Dr. Ike Ahmed and colleagues performed a randomized, prospective, masked, fellow eye comparative study that sought to determine whether the location of the peripheral iridotomy, superior versus temporal, was associated with the rate of dysphotopsia.¹³ The study included more than 200 patients undergoing bilateral iridotomy, and randomly assigned them to have a superior laser in one eye and a temporal laser in the other. The authors determined that 10.7% of those with the superior iridotomy experienced new onset linear dysphotopsia while only 2.4% of those with a temporal iridotomy experienced this side effect. Bleeding was similar in the two groups and occurred in about 10% of patients. A temporal iridotomy was more painful, and the amount of eyelid coverage did not seem to relate to dysphotopsia.

In summary, please take the time to discuss dysphotopsia with patients prior to iridotomy, and consider also preferentially placing the iridotomy in the temporal location.

ADVANCES IN OPTIC NERVE IMAGING

OCT innovations

Optical coherence tomography (OCT) is a fantastic diagnostic tool in the detection of glaucoma and its progression (Figure 2). The current standard in OCT is spectral domain OCT, and swept-source OCT is arriving. The evolution from time domain to spectral domain OCT (SDOCT) brought us from 100 A-scans collected per second with an axial resolution of 20 microns (time domain) up to 30,000 A-scans per second with an axial resolution of 5 microns (spectral domain).

Figure 2. Spectral domain optical coherence tomography image demonstrates two superior retinal nerve fiber layer defects that correspond well to two distinct inferior arcuate scotomas on the visual field test.
COURTESY: NATHAN M. RADCLIFFE, MD

The SDOCT tool came about when the moving reference mirror of time-domain OCT was replaced with Fourier domain analysis of wave signals. As a result, significantly larger data sets could be acquired in a short period of time. This leap forward allowed the rapid acquisition of data cubes in the macula or encompassing the optic nerve complex, both which now assist in glaucoma analysis. Over the past seven years, advances in OCT have mainly occurred through significant software upgrades, as the hardware platform has recently been stable (at least until swept-source OCT becomes commonplace). But this evolving ophthalmic imaging is a double-edged sword, as new technology increases costs and renders baseline data obsolete, while providing new diagnostic capabilities and efficiencies.

So – keep these points in mind

As the software gets more elaborate, the opportunity for artifacts and misinterpretation grows. When interpreting an OCT, consider the signal strength and, separately, the overall data quality. The signal strength, which simply describes the quality of the light signal coming in and out of the eye, is a separate issue from the scan quality. Signal strength is decreased by media opacities including dry eye, posterior capsular opacification and cataract. It is also lower in eyes with a long axial length.

Furthermore, long axial lengths are associated with both lower OCT signal quality and lower retinal thickness values. But, the normative databases typically exclude myopic eyes, limiting the conclusions we can draw from OCT studies in these patients. In an eye with decreased visual acuity, a normal appearing macula on the OCT along with low signal strength, cataract, dry eye, corneal scarring or capsular opacity are possible causes of the decreased acuity.

Also consider that a significant change in signal strength from one day to the next can have large effects on output variables such as average retinal nerve fiber layer thickness. These fluctuations can mask or mimic progression.

Detecting glaucoma in the macula

Macular OCT in glaucoma patients deserves additional consideration. Most OCT platforms provide opportunities to evaluate for glaucoma within the macula, either by segmenting out the ganglion cell layer, the ganglion cell layer plus the retinal nerve fiber layer (RNFL), or the entire macular thickness (Figure 3). All three approaches have been shown to successfully identify glaucoma. Even in patients with a primary diagnosis of glaucoma, macular health is very important. In glaucoma care, standard testing may miss macular disease.

Figure 3. A macular OCT scan with ganglion cell analysis demonstrates an inferior nerve fiber layer and ganglion cell defect in the right and a normal result on the left.
COURTESY: NATHAN M. RADCLIFFE, MD

For example, the standard 24-2 visual field test samples the macular area quite sparsely (every six degrees) and can easily miss central visual defects. Thus, a patient with 20/400 visual acuity and a full-thickness macular hole will have a normal field of vision if the foveal sensitivity monitor is not turned “on.” Given that the macula occupies less than 5% of the retinal surface area but contains nearly 33% – almost a third of the retinal ganglion cells – the potential importance of monitoring this tissue for glaucoma is obvious.

Evaluation for glaucoma in the region responsible for central vision makes sense for myriad reasons. Glaucomatous damage within the macula will impact its function; glaucoma does affect central vision, even early in the disease.¹⁴ In moderate glaucoma, up to one half of eyes could have glaucoma within the central three degrees of fixation.¹⁵ Also, artifacts caused by macular pathology can elevate RNFL values. Two that occur frequently, for example, are epiretinal membranes and vitreous traction. Diffuse diabetic macular edema and normal RNFL values might mask glaucomatous optic atrophy because the edema can mask RNFL loss.

By scanning the nerve and macula in our glaucoma patients, many of whom are older, we can confirm that central visual field defects are not caused by other age-related macular pathologies. Therefore, including macular OCT analysis at the time of optic-nerve head imaging for glaucoma patients might be an important way to provide a comprehensive analysis of visual function.

SURGICAL TREATMENT

MIGS

Fortunately for most glaucoma patients, their physician can manage the disease with pharmacotherapy. Glaucoma is chronic, often slowly progressive and usually does not require glaucoma surgery. However, someone who is 70 years old today can, on average, expect to live until age 87, and this level of longevity indicates that at the very least cataract surgery is likely. MIGS are used during cataract surgery for this reason.

The iStent trabecular micro-bypass stent (iStent, Glaukos Corp.), receiving FDA approval in 2012, is the first commercially available MIGS device. Implanted into Schlemm’s canal from an ab interno approach, this 1-mm-long heparin-coated nonferromagnetic titanium device, in concept, bypasses the site of greatest outflow resistance (the juxtacanalicular trabecular meshwork). Ab interno stent placement is typically performed before (or after) cataract extraction and intraocular lens placement and before viscoelastic removal. Excellent gonioscopic visualization is required, a skill that will be relied upon for most MIGS procedures.

Samuelson et al.¹⁶ reported a prospective, randomized, multicenter study involving 240 patients each taking one to three ocular hypotensive medications. Besides requiring cataract surgery, these patients’ eyes had mild to moderate glaucoma and IOPs of 24 mm Hg or less. These patients had a mean, unmedicated IOP of 25.4 ± 3.6 mm Hg. After randomization to undergo either iStent with cataract surgery or cataract surgery only, one year after surgery, 72% of eyes receiving iStent plus cataract extraction had an IOP less than or equal to 21 mm Hg compared to 50% of eyes receiving cataract surgery alone (P<0.001). A 20% or greater IOP reduction was achieved in 66% of study eyes compared to 48% of control eyes (P=0.003). Medication drop use was reduced to 0.2 ± 0.6 in the iStent group versus 0.4 ± 0.7 in the cataract surgery group (P=0.016).

One reason MIGS has become popular is that established glaucoma surgeries, while effective, can result in significant complications. MIGS surgeries, on the other hand, are designed to be as safe as cataract surgery. We see from the iStent trial and from high quality long-term data from the OHTS that after cataract surgery alone, up to 40% to 50% of patients with ocular hypertension may experience a >20% IOP reduction.¹⁷

About those significant complications

Consider data from the tube versus trabeculectomy (TVT) study, in which more than 200 eyes (having either undergone prior cataract extraction or trabeculectomy) with high IOP on medications were randomized to either a 350-mm Baerveldt implant (Advanced Medical Optics) or to trabeculectomy with 0.4mg/mL concentration mitomycin C, for four minutes.¹⁸ After five years, IOPs were similar between groups and ranged from 12.6 to 14.4 mm Hg on average, which represents about a 50% reduction from baseline. The number of drops was significantly lowered as well, from a baseline of about 3.0 down to 1.4 in the tube group and 1.2 in the trabeculectomy group (P>0.05). However, after five years, 29.8% of the tube surgeries had stopped controlling the IOP and 46.9% of the trabeculectomies (P= 0.025).

Complication data from this randomized prospective trial highlight the need for safer surgeries. Early postoperative complications occurred in 21% of tube surgeries and 37% of trabeculectomy surgeries (P=0.012).¹⁹ At five years, complications occurred in 34% of Baerveldt implants and 36% of trabeculectomies.

Roughly 20% of either group of eyes required reoperation for these complications. Persistent corneal edema turned out to be the most common complication, occurring in 17 patients in the tube group and nine patients in the trabeculectomy group.

One lesson learned from this study was that for glaucoma patients who required eye surgery, the risk of reduced visual function from corneal decompensation was significant (Figure 4).

Figure 4. Corneal disease may occur in eyes that have undergone tube shunt placement. This image demonstrates an aphakic eye with a clear corneal transplant and a tube shunt placed inside of the eye.
COURTESY: NATHAN M. RADCLIFFE, MD

Case in point: Another tube study, the prospective Ahmed Baerveldt Comparison Study found the Ahmed valve (New World Medical) to represent a safer option (at least during the first year) than the Baerveldt, with a serious complication rate in the Ahmed group of 20% while the Baerveldt group had a 34% complication rate (P = 0.014).²⁰ Failure rates were similar between the two groups at one year (14% to 16.4%).

Weighing complications

The data from the traditional glaucoma surgical trials above demonstrate high efficacy but higher complication rates, and prompt one to consider how MIGS surgeries compare to the standard glaucoma incisional surgeries. A multi-center retrospective study compared ab interno trabeculotomy (Trabectome, NeoMedix) to traditional trabeculectomy.²¹ In this study, 115 patients with uncontrolled glaucoma not undergoing cataract extraction underwent ab interno trabeculotomy and were compared to 102 patients who underwent a trabeculectomy with mitomycin C.

After two years, 22.4% of the ab interno trabeculotomy patients experienced a surgical success while 76.1% of trabeculectomy patients were successful. However, only 4.3% of ab interno trabeculotomy patients had complications (though most had an early transient hyphema) whereas 35.3% of trabeculectomy patients had a complication (similar to the TVT study above). For some patients who achieved success in the safer surgery, the avoidance of complications must have been worth it, but many ab interno trabeculotomy patients did not achieve success. A series from the Mayo clinic presented similar, modest, long-term efficacy data after Trabectome, indicating that after a few years, only 62% of patients undergoing ab interno trabeculotomy had an IOP < 21 mm Hg while 22% had an IOP < 18 mm Hg.²²

The complication data from the tube versus trabeculectomy study and modest efficacy results from safer surgeries has reframed the glaucoma treatment conversation. To begin with, pharmacotherapy remains the primary treatment for glaucoma. However, a gap between medical therapy and traditional surgical therapy still exists, and MIGS procedures may provide a nice compromise between safety and efficacy for cataract patients whose pressures are not adequately controlled with medications, but whose disease is not severe enough to justify a ~30% risk of complications.

Finally, while the majority of surgical options increase the outflow of aqueous humor, an ab interno endoscopic cyclophotocoagulation (ECP) utilizes endoscopy with an 810-nm diode laser to reduce the amount of aqueous humor produced. ECP can be repeated and titrated without leaving any conjunctival scars, and it does not alter the outflow pathway anatomy (and does not preclude any future glaucoma surgical options).

Kahook and colleagues followed 25 patients with a baseline IOP of 24.5 mm Hg after ECP. At 6 months of follow-up, the IOP was 16.0 mm Hg (a 35% reduction), with reduced medication usage from 2.5 to 1.9 medications.²³ While hypotony is possible following any glaucoma surgery, it is rare after endoscopic cyclophotocoagulation, and the safety profile is similar to cataract surgery alone.

CONCLUSIONS

In summary, the art of glaucoma management remains just that. IOP reduction remains the primary target, but we are learning new insights about corneal biomechanics and IOP fluctuation, particularly with respect to glaucoma progression. Angle closure remains important; gonioscopy, in the office and the operating room, is more essential than ever.

New data suggest that performing an iridotomy temporally (rather than superiorly) may reduce the likelihood of linear dysphotopsia. Optic nerve imaging continues to evolve, and OCT provides an excellent approach for evaluating glaucoma in the optic nerve and the macula, where functionally important vision loss may occur. MIGS surgeries have evolved to provide safe options for patients with mild to moderate glaucoma. And while we appreciate the efficacy of incisional glaucoma surgeries, they carry significant risks that must be weighed. With these developments in mind, we have many excellent tools and options available to care for our patients with glaucoma into 2015 and beyond. OM

REFERENCES