Find out which myths are busted and which are plausible
Glaucoma is a leading cause of visual impairment and irreversible blindness worldwide.1-14 Primary open-angle glaucoma (POAG) accounts for 74% of all cases. There were approximately 57.5 million cases globally in 2015,2,4 and glaucoma is projected to affect 65.5 million individuals by 2021.2,4
The pathogenesis of glaucoma is complex.5,6 Intraocular pressure (IOP) is the sole modifiable risk factor.8 It has been well documented that a 20% to 30% decrease in IOP can consistently reduce the risk and trajectory of progression.1-33
Glaucoma is diagnosed when a correlation exists between structural and functional findings in the setting of relevant risk factors.1-14 Structural findings include optic disc cupping with evidence of nerve fiber layer infarction. Functional findings include relative perimetric losses (scotomata) directly attributable to areas of damaged axons (of ganglion cells) identified through structural mapping. Circumstantial risk factors include raised IOP (>24 mm Hg), increased age, family history of glaucoma, decreased central corneal thickness (<510 μm), female sex, and the presence of comorbidities such as migraine headache, sleep apnea, coagulopathy, hypertension, diabetes, and alpha-beta zone atrophy.1-14,16
Increased IOP results from poor aqueous humor egress (common) or aqueous humor over production (rare).8 Because altering genetic markers, blood flow, vascular pressure, and heart rate is not possible without profound risks, IOP is the only modifiable risk factor. Lowering the IOP via topical or oral medications or surgical procedures is the only means of arresting the disease’s progression.3-8
The word “myth” is derived from the Greek word muthos and the Latin word mythus.15 It means “a widely held but false belief; a misrepresentation of the truth and exaggerated conception; an unfounded notion.”15 Whether these “stories” occur because of misinterpreted data; loosely supported, perpetuated anecdotes (the whisper-down-the-lane effect); held traditions; or misguided beliefs, when encountered in medicine, they should be exposed, discussed, and debated. Sometimes the narrative, albeit not generally believed, is true with individuals forming erroneous conclusions.
The MythBusters television series attempted to test unusual claims for validity. When a myth was proved to be a misrepresentation of the truth, it was “busted.” In the case of the claim being possible, the myth was deemed plausible or supported.
Here, we provide evidence along with debates for 5 “myths” often discussed regarding glaucoma management.
A topical beta-blocker is a good choice for patients with normal tension glaucoma (NTG).
Three etiologies, sometimes 1 alone and sometimes multiple etiologies in combination, create the pathology of glaucoma. They are 1-11,14,16,17:
– Biomechanical mechanism (pressure dependent; raised IOP creates laminar bowing, crushing the axons that pass through it while also increasing resistance to nerve tissue perfusion)
– Vascular mechanism (non–pressure dependent; vascular dysregulation and poor oxygenation create nerve ischemia resulting in segmental destruction)
– Genetic mechanism (signaled apoptosis of axons of ganglion cells results in segmental loss)
The only modifiable risk factor for reducing glaucomatous progression is IOP lowering.1-11,14 Current guidelines for initial intervention suggest medical therapy with topical ocular hypotensives or selective laser trabeculoplasty (SLT).16,17
For cases in which the surgical option is undesirable, topical medications are required. In most instances, prostaglandin analogue (PGA) topical medications are selected first because of their efficacy and ease of use. Because topical beta-blocker medications can be absorbed by the conjunctiva, producing sympatholytic effects on the heart and lungs (decreased heart rate, bronchoconstriction), clinicians may be apprehensive to use them as a primary or adjunctive therapy. Some are reticent to use the agents in cases of NTG for fear of worsening the disease secondary to the possibility of reduced perfusion.
This is myth is busted.
Two separate studies evaluated pulse rates and IOP lowering in patients placed on the topical beta-blocking preparation timolol.18,19 The reports demonstrated statistically significant reductions in the pulse rates of both groups.18,19 During sleep, an individual’s pulse reduces, naturally lowering perfusion to the optic nerve. Adding an agent capable of lowering the heart rate over a 24-hour period can further lower perfusion. In combination with the diurnal fluctuation of IOP (highest during sleep), anything that reduces perfusion has the potential to worsen glaucomatous disease.18,19
Timolol is considered the gold standard for topical IOP lowering. It is a first-line topical anti-glaucoma agent and an excellent supplemental agent when surgical or topical treatment has not provided the optimal target pressure. Because the agent has the capability to induce bronchoconstriction and pulse lowering, it should not be a first choice in cases with lung concerns, such as asthma or chronic obstructive pulmonary disease, or in cases of NTG.18,19 The most popular first-line topical agents are PGA medications.
Today, with the data provided by the LIGHT study, SLT is a legitimate first option. Topical beta-blockers are generally considered the very last line or not an option at all for NTG cases because of the central nervous system, cardiac, and respiratory adverse effects they may produce; safer topical and surgical alternatives exist.14,18,19
Brimonidine provides neuroprotection against glaucomatous damage.
Brimonidine tartrate is a sympathomimetic alpha agonist. It reduces IOP by enabling the trabecular meshwork and uveoscleral tissues to filter aqueous humor at a faster rate and by suppressing production of aqueous humor.20-23 Several studies have demonstrated that the pharmaceutical has a reparative/regenerative effect on optic nerve tissue.20-23
Investigators of another study concluded the compound was capable of reducing ganglion-cell death at a far greater rate than timolol.20 However, some unanswered questions of that study include the following:
– Did the brimonidine cohort perform better because of neuroprotection?
– Did it perform better because of its dual mechanism of action (IOP suppression and facilitation of uveoscleral/trabecular meshwork outflow)?
– Did it perform better because it provided better 24-hour IOP-lowering coverage?
– Did the timolol group suffer secondary to reduced perfusion at the nerve in the setting of reduced IOP suppression during sleep?
Investigators have demonstrated in the laboratory that crushed animal optic nerves regenerate when 2 nM of brimonidine was physically applied to the tissue.20-23 Whether these data can be applied to optic nerves sustaining glaucomatous damage in living persons remains in question.
This is myth is plausible.
Experimental data have demonstrated that brimonidine may be able to stimulate increased neural activity in the laboratory.20-24 Scientists were able to locate receptors in the retina and optic nerve capable of binding with the compound and making positive use of it. Results of laboratory experiments show that concentrations of as little as 2 nM can produce the beneficial effects. Recent work has revealed that when brimonidine is applied to the eye, up to 200 nM can be distributed into the vitreous humor, making it available for this sort of rehabilitation. Further research will determine whether this type of therapy should be considered for all patients with glaucoma, both controlled and in need of control.
With scientific evidence supporting the benefit of neuroprotection added to the known capability of IOP lowering, practitioners should consider brimonidine an excellent first choice in cases of NTG in which pressure reduction is required without lowering vascular perfusion. It would also be an excellent second-line choice for other cases of glaucoma requiring deeper IOP suppression.21-23
If research can prove brimonidine plays a direct role in nerve preservation or repair, IOP will no longer be the only modifiable risk factor. Further, if this is the case, ophthalmologic applications besides glaucoma may be on the horizon. Finally, although there is no detriment to using the medication and evidence has demonstrated a neuroprotective element to its use, clearly it does not provide healing that outpaces the rate of loss.
Myths 3 & 4
PGA preparations increase risk of macular edema after cataract surgery and in cases of uveitis.
PGA preparations are efficacious at lowering IOP. They work primarily by increasing uveoscleral outflow.25 Uveoscleral outflow accounts for approximately 10% to 20% of aqueous humor outflow under normal conditions. The traditional pathway of the trabecular meshwork accounts for 80% of aqueous humor drainage.7,29 A single drop of PGA places approximately 1.5 μg of active agent into ocular circulation. Investigators have successfully measured the levels of PGA in the posterior segment and found penetration into the vitreous to be minimal.26-28,30
These myths are busted.
PGAs rarely produce macular edema. They should not be discontinued unless macular edema is detected or is non-remitting.
Although the mechanism is well understood and the literature is clear in describing this phenomenon, clinical data demonstrate that macular edema is generally not attributable to the use of PGAs.26-28,30 In cases in which macular edema was found after cataract surgery in the setting of concurrent PGA use, the most common contributing factor was the untimely withdrawal of the topical steroid (fast taper), according to one study.28 Further, multiple clinical trials have demonstrated that these agents neither have a high propensity to reactivate old ocular inflammations nor produce macular edema when used in cases with active ocular inflammation.26-28
PGAs lower IOP effectively and are easy to use. These agents create great stability for patients who require them. The literature does not encourage blind cessation following cataract surgery or discontinuation in the event of uveitis acquisition.26-28 The literature recommends that it is not unreasonable to continue use with successfully treated patients who have not realized any complications.
PGA preparations take too long to work to be considered for acute IOP lowering.
As mentioned, the prostaglandin class of medications works to increase the efficiency of the secondary aqueous outflow pathway (uveoscleral outflow pathway).7,25,29 To a lesser degree, PGAs also increase the traditional outflow pathway. The agents have 2 distinguishable ocular interactions26-28,31-33:
– Long-term, improved extracellular matrix spacing over time with episcleral venous effects
– Short-term, oculohypotensive effects
In a head-to-head study, PGAs were compared with timolol for lowering IOP in cases of chronic angle closure glaucoma and found to be at least as effective as timolol as a monotherapy solution.33
This myth is busted.
Eye care practitioners absolutely can use these agents as part of their armamentarium for lowering acutely raised IOP.
Although practitioners should not judge the long-term maximum effect of PGAs for weeks, the agents have been documented in the literature and anecdotally (the authors’ experience) as having the ability to play a significant role in acute IOP reduction. Application may be considered for cases of poorly adherent open-angle glaucoma and cases of pupil block angle-closure glaucoma. PGAs have a role in lowering acutely elevated IOP from any cause. If measured head-to-head against topical apraclonidine and timolol, a topical PGA would not outperform them. However, because PGAs clearly can have a positive impact on IOP lowering with virtually no adverse effects, they should be considered as an excellent addition if required.26-28,31-33
The incidence of glaucoma will continue to rise. The more ammunition provided to the armamentarium of risk reduction, the better. All practitioners should seek to base clinical management algorithms on scientific platforms created by data supported by evidence-based documentation. Medical myths should be discussed, debated, and dispelled when detected so a clear and uncontroversial path of disease management can be advertised and maintained.
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8. Brubaker, RF. Targeting outflow facility in glaucoma management. Surv Ophthalmol. 2003;48(suppl 1):S17-S20. doi: 10.1016/s0039-6257(03)00003-1
9. Stamer WD, Braakman ST, Zhou EH, et al. Biomechanics of Schlemm’s canal endothelium and intraocular pressure reduction. Prog Retin Eye Res. 2015;44:86-98. doi: 10.1016/j. preteyeres.2014.08.002
10. Goel M, Picciani RG, Lee RK, Bhattacharya SK. Aqueous humor dynamics: a review. Open Ophthalmol J. 2010;4(9):52- 59. doi: 10.2174/1874364101004010052
11. Kanski J. Clinical Ophthalmology: A Systematic Approach, 6th ed. Elsevier Butterworth- Heinemann; 2007:1-100.
12. Gupta D, Chen PP. Glaucoma. Am Fam Physician. 2016;93(8):668-674.
13. Bucolo C, Platania CBM, Drago F, et al. Novel therapeutics in glaucoma management. Curr Neuropharmacol. 2018;16(7):978-992. doi: 10.2174/1570159X15666170915 142727
14. Gazzard G, Konstantakopoulou E, Garway-Heath D, et. al. Selective laser trabeculoplasty versus drops for newly diagnosed ocular hypertension and glaucoma: the LiGHT RCT. Health Technol Assess. 2019;23(31):1-102. doi: 10.3310/ hta23310
15. Myth. Merriam-Webster. Accessed March 10, 2021. https://www.merriam-webster.com/dictionary/myth
16. Keller KE, Acott TS. The juxtacanalicular region of ocular trabecular meshwork: a tissue with a unique extracellular matrix and specialized function. J Ocul Biol. 2013;1(1):3.
17. Brubaker RF. Introduction: three targets for glaucoma management. Surv Ophthalmol. 2003;48(suppl 1):S1-S2. doi: 10.1016/s0039-6257(03)00002-x
18. Tattersall C, Vernon S, Singh R. Resting pulse rates in a glaucoma clinic: the effect of topical and systemic beta-blocker usage. Eye (Lond). 2006;20(2):221-225. doi: 10.1038/ sj.eye.6701859
19. Mizoue S, Nitta K, Shirakashi M, et al. Multicenter, randomized, investigator-masked study comparing brimonidine tartrate 0.1% and timolol maleate 0.5% as adjunctive therapies to prostaglandin analogues in normal-tension glaucoma. Adv Ther. 2017;34(6):1438-1448. doi: 10.1007/s12325-017-0552- 5
20. Donella JE, Padilla EU, Webster ML, Wheeler LA, Gil DW. Alpha(2)-adrenoceptor agonists inhibit vitreal glutamate and aspartate accumulation and preserve retinal function after transient ischemia. J Pharmacol Exp Ther. 2001;296(1):216- 23.
21. Saylor M, McLoon LK, Harrison AR, Lee MS. Experimental and clinical evidence for brimonidine as an optic nerve and retinal neuroprotective agent: an evidence-based review. Arch Ophthalmol. 2009;127(4):402-406. doi: 10.1001/ archophthalmol.2009.9
22. Kent AR, Nussdorf JD, David R, Tyson F, Small D, Fellows D. Vitreous concentration of topically applied brimonidine tartrate 0.2%. Ophthalmology. 2001;108(4):784-787. doi: 10.1016/s0161-6420(00)00654-0
23. Wheeler LA, Lai R, Woldemussie E. From the lab to the clinic: activation of an alpha-2 agonist pathway is neuroprotective in models of retinal and optic nerve injury. Eur J Ophthalmol. 1999;9(suppl 1):S17-S21.
24. 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
25. Parrish RK, Palmberg P, Sheu WP, XLT Study Group. A comparison of latanoprost, bimatoprost, and travoprost in patients with elevated intraocular pressure: a 12-week, randomized, masked-evaluator multicenter study. Am J Ophthalmol. 2003;135(5):688-703. doi: 10.1016/s0002- 9394(03)00098-9
26. Horsley MB, Chen TC. The use of prostaglandin analogs in the uveitic patient, seminars in ophthalmology. Semin Ophthalmol. 2011;26(4-5):285-289. doi: 10.3109/08820538.2011.588650
27. Peyman GA, Bennett TO, Vlchek J. Effects of intravitreal prostaglandins on retinal vasculature. Ann Ophthalmol. 1975;7(2):279-288.
28. Chang JH, McCluskey P, Missotten T, et al. Use of ocular hypotensive prostaglandin analogues in patients with uveitis: does their use increase anterior uveitis and cystoid macular oedema? Br J Ophthalmol. 2008;(92);7:916-921. doi: 10.1136/ bjo.2007.131037
29. Tamm ER. The trabecular meshwork outflow pathways: structural and functional aspects. Exp Eye Res. 2009;88(4):648-655. doi: 10.1016/j.exer.2009.02.007
30. Wand M, Shields BM. Cystoid macular edema in the era of ocular hypotensive lipids. Am J Ophthalmol. 2002;133(3):393- 397. doi: 10.1016/s0002-9394(01)01412-x
31. Toris CB, Gabelt BT, Kaufman PL. Update on the mechanism of action of topical prostaglandins for intraocular pressure reduction. Surv Ophthalmol. 2008;53(suppl 1):S107-S120. doi: 10.1016/j.survophthal.2008.08.010
32. Winkler NS, Fautsch MP. Effects of prostaglandin analogues on aqueous humor outflow pathways. J Ocul Pharmacol Ther. 2014;30(2-3):102-119. doi: 10.1089/ jop.2013.0179
33. Cheng JW, Cai JP, Li Y, Wei RL. A meta-analysis of topical prostaglandin analogs in the treatment of chronic angle-closure glaucoma. J Glaucoma. 2009;18(9):652-657. doi: 10.1097/IJG.0b013e31819c49d4