The patient is on a prostaglandin, but he continues to progress. Should you add a second drop or refer?

Recently, an optometric colleague sent a 74-year-old white female to the Glaucoma Institute of State College. He diagnosed her with glaucoma a few years previously and was concerned about her optic nerve progression, as seen with OCT.

The patient reported both parents had glaucoma, and that she had uneventful cataract extraction performed three years previously. Entering acuities were 20/25 OU, IOPs were 18 mmHg OU, and she reported good compliance with one drop of a prostaglandin in both eyes at night before bed. Her TMax (highest reported IOP reading) was 24 mmHg OD and 25 mmHg OS. Angles were open. Pachymetry was 563 OD and 571 OS. The patient’s OCT images showed progression OU in both the ganglion cell complex and nerve fiber layer. Her VF revealed a dense superior arcuate scotoma approaching fixation OD and superior and inferior arcuates OS. (See image below.)

How would you manage this patient? In fact, how should we manage any glaucoma patient using one drop, but still showing disease progression? Here, I discuss when, specifically, we should add another glaucoma medication, the second medication options, the related follow-up, when we should refer and how I managed the patient described.

WHEN TO ADD

Consider adding a second drop if you notice progression of the VF or progression in the optic nerve, as detected by comparing optic nerve photos or by OCT.

The main goal in the management of glaucoma is to preserve visual function. The primary method of measuring visual function is by performing a VF test. Most VF units have the capability of using software to aid optometrists in detecting both event-based and trend-based progression. Event-based analysis shows whether the VF changed from last visit, while trend-based analysis shows whether the VF is changing over a longer time period.

Serial optic disc and nerve fiber layer photography may be used to determine glaucomatous structural progression. Optic nerve progression can include neuroretinal rim thinning, excavation, notching and nerve fiber layer defects.¹ This method can also help detect subtle optic nerve hemorrhages and beta-zone peripapillary atrophy changes, which are known risk factors for progression.²

Progression seen via OCT can be found in the nerve fiber layer and the macula. Nerve fiber and macular thinning can occur focally, globally or both. The three most common progression patterns are a new defect, deepening of an existing defect or widening of an existing defect.³

Sometimes field, photo and OCT progression can be subtle. Optometrists should be especially vigilant if a patient has thin corneas, low hysteresis or a high TMax.

SECOND DRUG OPTIONS

A prostaglandin alone may not be enough to get the IOP low enough. In the Ocular Hypertensive Treatment Study, 40% of patients needed two or more medications to achieve a 20% reduction.⁴ When a prostaglandin alone — often the first line of treatment — is not enough to stave off disease progression, the following medication options are at our disposal:

• Beta-blockers. In addition to primary open-angle glaucoma, patients who benefit from this drug category include those who have a postoperative IOP spike or an acute angle closure, as beta-blockers rapidly reduce aqueous production. An additional benefit is the possibility of once a day dosing, as patient compliance is always an issue when adding more than two drops per day. In fact, one study shows that compliance decreases as more drops are used per day, and it also decreases as more types of drops are used.⁵
• Rho-kinase (ROCK) inhibitor. A rock inhibitor decreases IOP in ocular hypertension and open-angle glaucoma patients, as it increases aqueous humor outflow through the trabecular meshwork. This medication is dosed once daily, again, helping practitioners in their patient non-compliance battle.

That said, not every patient who has disease progression will benefit from these once-a-day drop options, so it is important to be mindful of the benefits of carbonic anhydrase inhibitors (CAIs), alpha-adrenergic agonists and fixed combination drops: (See: “Medication Compliance Tips,” p.26.)

• CAIs. This oral and topical drug category is valuable for patients who have an acute angle-closure and open-angle glaucoma, as it decreases aqueous production. The dosing regimen is twice a day (off label) or three times a day, when added to a prostaglandin.
• Alpha-adrenergic agonists. This drug category, dosed twice (off label) or three times a day, reduces aqueous production and increases uveoscleral outflow, benefitting open-angle glaucoma patients.
• Fixed combination drops. These drops can improve compliance by increasing the number of medications, reducing the number of drops needed by the patient. The only drawback is possibly adding a nighttime dosage of a beta-blocker that may have a limited result on aqueous production and a possible deleterious nocturnal hypoperfusion.

Something else to keep in mind when prescribing adjunctive therapy is patient sensitivity to benzalkonium chloride, a preservative contained in many glaucoma medications that can disrupt ocular surface homeostasis by stripping oil from the outer lipid layer and inducing dry eye and ocular surface disease.⁶

WHEN TO REFER

Consider referring for an assessment of glaucoma surgical interventions if the patient is:

1. On two medications and still progressing
2. Appears to be noncompliant and may need laser or surgical intervention
3. Rapidly progressing

If the patient has exfoliation glaucoma, pigmentary glaucoma, narrow angles or normal tension glaucoma, vigilance is needed, as these cases may progress more rapidly:

• Exfoliation glaucoma (XFG). This causes an extremely aggressive form of glaucoma, requiring aggressive treatment. XFG weakens the lens capsule, resulting in the classic bull’s eye pattern on the lens, which is caused by the mechanical rubbing against the pupillary frill, best visualized upon dilation.⁷ A careful inspection of the pupillary frill will reveal whitish fibers that can be visualized even if the patient is pseudophakic. This mechanical friction will release iris pigment with resultant iris transillumination defects that occur closer to the pupillary margin, in contrast to pigmentary glaucoma in which transillumination defects occur in the mid-periphery. Exfoliation may respond well to SLT, but may wear off sooner.
• Pigmentary glaucoma. Pigmentary glaucoma may also cause a more aggressive disease. The hallmark signs include K spindles, pigment in the trabecular meshwork and transillumination defects in the mid-peripheral iris. There may also be pigment near the lens equator. Pigment dispersion syndrome patients experience a posterior bowing of the mid-peripheral iris, which creates iridozonular touch. Pigment dispersion glaucoma (PDG) patients may have reverse pupillary block. As the eye blinks, aqueous humour moves into the anterior chamber, causing a reverse pupillary block that presses the iris onto the lens’ surface and zonules. A total of 25% to 50% of patients with pigment dispersion syndrome (PDS) develop PDG.⁸ When these patients experience IOP spikes or show VF or optic nerve progression, they should be referred for assessment of a peripheral iridotomy.
• Narrow angles. Glaucoma progression despite two drugs can be a sign of narrow angles. As a result, consider re-evaluating the angle as a potential cause. While angle assessment is typically achieved by gonioscopy, angle imaging, such as angle OCT or B-scan, is becoming more common. If O.D.s suspect a narrowing angle, consider performing (if permitted) or referring for a laser peripheral iridotomy.
• Normal Tension Glaucoma (NTG). If the patient has never had an untreated IOP above 21 mmHg and he progresses despite having seemingly controlled IOP on a prostaglandin and a second medication, other factors may be at play, such as a low nocturnal blood pressure, low intracranial pressure or a low ocular perfusion pressure.^9,10 Research shows 20% of NTG patients will continue to progress despite seemingly controlled IOPs.¹¹

OUR PATIENT

We prescribed a CAI for twice a day use at 8am and 5pm, while continuing the prostaglandin at bedtime. The referring optometrist reported an additional 3 mmHg to 4 mmHg IOP reduction vs. the prostaglandin alone. The OCT taken six months later showed stability. The patient is currently doing well on the same therapy.

A prostaglandin alone may not be enough to ensure stability, but an additional drug, which we can prescribe, may be the answer. Knowing when to refer the patient is crucial, but referring does not necessarily need to be the default. Hopefully, this article will help optometrists better navigate the options when this occurs. OM

REFERENCES

1. Lloyd M, Mansberger S, Fortune B, et al. Features of optic disc progression in patients with ocular hypertension and early glaucoma. J Glaucoma. 2013; 22: 343–8.
2. Lee E, Kim TW, Weinreb RN, Park KH, Kim SH, Kim DM. ß-zone Parapapillary atrophy and the rate of retinal nerve fiber layer thinning in glaucoma. Invest Ophthalmol Vis Sci. 2011; 52: 4422–7.
3. Leung CK, Yu M, Weinreb RN, Lai G, Xu G, Lam DS. Retinal nerve fiber layer imaging with spectral-domain optical coherence tomography: Patterns of retinal nerve fiber layer progression. Ophthalmology. 2012; 9: 1858-66.
4. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Archives of Ophthalmology. 2002; 6: 701-13.
5. Patel SC, Spaeth GL. Compliance in patients prescribed eyedrops for glaucoma. Ophthalmic Surg. 1995; 3: 233-6.
6. Lee SY, Wong TT, Chua J, Boo C, Soh YF, Tong L. Effect of chronic anti-glaucoma medications and trabeculectomy on tear osmolarity. Eye. 2013; 10: 1142-50.
7. Plateroti P, Plateroti AM, Abdolrahimzadeh S, Scuderi G. Pseudoexfoliation syndrome and pseudoexfoliation glaucoma: a review of the literature with updates on surgical management. J Ophthalmol. 2015;2015.
8. Farrar SM, Shields MB, Miller KN, Stoup CM. Risk factors for the development and severity of glaucoma in the pigment dispersion syndrome. Am J Ophthalmol. 1989 3: 223–29.
9. Normal Tension Glaucoma Study Group: Comparison of glaucomatous progression between untreated patients with normal−tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol. 1998; 4: 487-97.
10. Choi J, Jeong J, Cho HS, Kook MS. Effect of nocturnal blood pressure reduction on circadian fluctuation of mean ocular perfusion pressure: a risk factor for normal tension glaucoma. Invest Ophthalmol Vis Sci. 2006; 3: 831-6.
11. Midena Grieshaber MC, Flammer J. Blood flow in glaucoma. Curr Opinion in Ophthalmol. 2005; 2: 79-83.

DR. CYMBOR is the co-director of the Glaucoma Institiute of State College and is a member of the Optometric Glaucoma Society. He is a partner at Nittany Eye Associates. Disclosures: Optovue Speaker’s Bureau. He can be reached at mcymbor@nittanyeye.com.