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Progressing glaucoma despite optimal medical therapy


Dr Jose Estevez
BMedSci (VisionSci) MOptom
South Australian Health & Medical Research Institute, Adelaide SA; Flinders University


Open angle glaucoma is classified as ‘primary’ if the cause of elevated IOP is unknown and the anterior chamber angles (ACA) are open.

The diagnosis of primary open angle glaucoma (POAG) revolves around structural (optic nerve head) and functional (visual field) parameters. These two tests are the most important for detection, follow-up and management over time. Having the ability to detect subtle changes or signs of progression of the disease is key to confirming the diagnosis.

It is clear from many studies that IOP is a major risk factor for POAG.1,2 The cut-off for ‘normal’ IOP is 21 mmHg; this arbitrary number originated from a study that showed it represented the 95 per cent confidence limit for normal people. However, this assumes the distribution of IOP in populations is normal but in fact, it is skewed to the right.3 This right skew increases with age and varies with race. Therefore, there is a proportion of people with IOP exceeding 21 mmHg who do not have glaucoma and many will be diagnosed with ocular hypertension (OH).

The Ocular Hypertension Treatment Study (OHTS) indicated that the risk of POAG conversion for an OH patient was 9.5 per cent over five years, with the risk increasing if IOP is greater than 24 mmHg.4 Other significant risk factors identified in landmark studies include genetic predisposition (such as first-degree relative with POAG or mutated myocilin gene), race, disc haemorrhages and thinner central corneal thickness (CCT).4-6 Myopia, diabetes, systemic hypertension and vascular insufficiencies have also been suggested as relevant risk factors but not consistently shown.7

This case highlights glaucoma diagnosis, management and progression despite pressure-lowering therapy.




An 82-year-old male presented for a glaucoma review. His medical therapy for glaucoma had been changed to Ganfort (bimataprost 0.03%/timolol 0.5%).

Ocular history

Diagnosed with POAG in 2012 due to:

• Elevated IOP (R 27 L 28 mmHg by Goldmann)

• Open angle on gonioscopy (ciliary body band visible 360 degrees)

• Thinning of the NRR (R 0.6 with inferior rim thinning L 0.8 with concentric thinning (Figures 1 and 2)

• Thinner than average corneas (R 506 L 521 microns)

• Corresponding VF defects

• RNFL thickness as significantly low on OCT (Figure 3).

Began medical therapy with Xalatan 0.005% nocte. Target pressure set at 18 mmHg in both eyes.


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Figure 1. Colour fundus photograph of the RE captured in 2012


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Figure 2. Colour fundus photograph of the LE captured in 2012


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Figure 3. Visual field and OCT combined report in 2012


Progression noted in 2013

• IOP R 19 L 20 mmHg, target not met

• Visual field progression, particularly in the RE where the MD has dropped from -4.23 to -8.25 and the PSD from 5.20 to 9.70

• Switched to Xalacom 0.005%/0.5% nocte; aim for 20 per cent reduction

• OCT also shows progression with a drop in average thickness in the LE from 70 microns down to 63 microns (Figure 4)

• IOL implant LE

• Review in eight weeks


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Figure 4. Visual field and OCT combined report in 2013


Further progression in 2015

• IOP of 12 mmHg in both eyes

• C/D RE 0.7 with inferior rim thinning and associated infero-temporal disc haemorrhage LE 0.8 with concentric rim thinning

• Rapidly progressing glaucoma in RE (Figure 5) and relatively stable glaucoma in the LE (Figure 6)

• Acceptable IOP currently but clearly not low enough, therefore begin Ganfort 0.03%/0.5% nocte

• Set target pressure of < 12 mmHg in both eyes at all occasions

• Review 3/12

• May need surgical intervention in the near future


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Figure 5. Guided progression analysis of the RE from 2012 to 2015


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Figure 6. Guided progression analysis of the LE from 2012 to 2015



The clinical diagnosis of POAG for this 82-year-old Caucasian male was made in 2012, after having had elevated IOP of ~27 mmHg since at least 2009. The raised IOP together with thinning of the NRR led to the diagnosis of POAG. Importantly, the patient had characteristic and corresponding VF defects. The ACAs were open on gonioscopy, and the patient had significant risk factors such as older age and thinner than average CCT. No signs of secondary glaucomas were present such as pigment dispersion, pseudo-exfoliation, uveitis and rubeosis irides or other optic neuropathies such as anterior ischaemic optic neuropathy.


Key concepts in management of POAG

Early diagnosis is always preferred, even if some disease progression may have already occurred, as in this case. A major long-term issue is compliance with medication and adherence to treatment. Therefore, it is important to educate patients and simplify drop regimens.8

A treatment plan is necessary and includes a target pressure. In the current case report, the initial target pressure was set at 18 mmHg (down 33 per cent), which is an appropriate reduction for early-to-moderate POAG.9 This is the IOP that is judged to have the best probability of limiting disease progression. However, before a target pressure can be decided, the clinician must have a clear idea of the baseline pressure.

Phasing IOP measurements may be useful to factor in IOP fluctuations throughout the day.10 If disease progression is noted, as occurred 2013, controlled-trials recommend a further 20 per cent reduction in IOP.11 Finally, the target IOP also depends on the level of damage already present, with advanced glaucomatous loss requiring more aggressive pressure lowering.12

Two or more VF tests should be performed in the first year of diagnosis. The aim of these repeated visual fields is to set high-quality baselines to allow comparison over time and detect early signs of progression. The clinician should identify a moment when progression has occurred either by event analysis or trend analysis.

Trend analysis quantifies the rate of loss on a VF index (VFI) in individual sectors or points. Linear regression is used to visualise and predict visual loss. In the current case, the VFI showed a downward trend (-5.6 dB/year) in the RE, indicating progression and vision loss (Figure 5). In the LE of this patient, the VF showed a relatively stable line but with variability.

Medical therapy

The NHMRC Glaucoma guidelines recommend the initial treatment of patients with early-moderate POAG to be with topical IOP-lowering agents because that is the simplest and safest choice. Exceptions include pregnant/lactating women, known medication intolerances or suspected poor compliance.9 Medications with the least amount of side-effects, administration, lowest effective concentration and most convenient delivery system should be chosen.

Best first line therapy for POAG

It is recommended to start with monotherapy to reach target therapy. Latanaprost 0.005% is commonly chosen because it has once-daily dosage, average IOP lowering of ~25-35 per cent, minimal systemic contraindications and few local side-effects. It increases uveoscleral outflow.

Importantly, relative contraindications to Latanaprost include macular oedema and history of herpetic keratitis.13 Side-effects to monitor include conjunctival hyperaemia, reactivation of herpetic disease, uveitis (controversial), macular oedema, peri-orbital fat atrophy (long-term use) and peri-ocular skin hyperpigmentation (reversible) and iris hyperpigmentation.9,11 Systemic side-effects are rare. Our patient was reviewed in March 2012 after the diagnosis to assess whether the target IOP was met, which was plenty of time as prostaglandins can take three to five weeks for maximal effect.9

Other prostaglandins are also a reasonable choice. Bimataprost 0.03% has been found to give the largest IOP reduction (33 per cent), followed by latanaprost (31 per cent) and then travaprost (27 per cent) in a meta-analysis of controlled trials.14 This added benefit of 1-3 mmHg must be weighted against the higher incidence of conjunctival hyperaemia, although no patients withdrew from treatment because of this in a 12-week trial.15 Therefore, it is reasonable to switch between prostaglandin analogues, if the first one does not meet the target pressure.

It is also reasonable to start with the beta-blocker timolol 0.5% bid, if there are no systemic contraindications. However, given its potential systemic side-effects, twice-daily dosing and potentially lower IOP lowering, it is often reserved as a combination agent or second line therapy.

What happens if progression is identified or target pressure not met?

Once progression is noted, a lower target pressure is needed. The patient was switched to the combination drop Xalacom (xalatan 0.005%/timolol 0.5%). At this point it is important to consider the safety profile of both drugs. Xalatan has been discussed above. Timolol, a non-selective beta-blocker, suppresses the production of aqueous at the ciliary body.

Importantly, all patients beginning therapy with a beta-blocker must be questioned about their systemic health, with particular emphasis on cardiorespiratory health. Once treatment is deemed safe and initiated, the clinician should enquire with the patient about symptoms such as coughing, dizziness, difficulty breathing and mood disturbances.

A beta-blocker reduces IOP by 20-25 per cent with a quicker onset of action (30 minutes), effects last 12 hours and maximal effect is at two to four weeks. However, 20 per cent of the population are non-responders to beta-blockers, and tachyphylaxis occurs in up to 50 per cent of the population after two years.9 Finally, beta-blockers are found to lower the IOP poorly during sleep as aqueous production is lowest during sleep.

At the point where the patient is rapidly progressing in the RE, additional IOP lowering is needed. Ganfort (bimataprost 0.03%/timolol 0.5%) has been shown in clinical studies to be one of the strongest combination drops available with the lowest diurnal variation.16 Given the rapid progressive nature, it would have been reasonable to refer the patient for laser and/or incisional surgery.17 Fortunately, Ganfort managed to meet the target pressure (12 mmHg) and provide stabilisation of the disease.

What happens if the patient continues to progress and/or wants to delay surgery?

In the event of the patient still progressing and surgery is wanted to be delayed, a third-line treatment can be initiated, with a CAI (brinzolamide 1%) or an alpha2-agonist (brimonidine 0.2%). However, polypharmacy severely reduces the risks of non-compliance, reduces efficacy through wash-out of earlier medications with later medications, and increases exposure of preservatives.11 Both of these agents require dosing two to three times daily. Thus, surgical intervention must be seriously considered once a third drop is being taken into account. A link to neuroprotection with alpha-agonists has been identified in one trial but is not certain due to a high-drop-out rate in the brimonidine arm.18

Prognosis for our patient with POAG

It is certain from treatment/no treatment trials that long-term IOP reduction can slow glaucoma progression.5,6 The decision to treat must take into account the risk of visual disability, binocular function, age, severity of disease in both eyes and any comorbidity (ocular or systemic). The baseline IOP is important, as is the presence of other risk factors.19 It seems that this patient may be on his way to surgical intervention, as he appears to have aggressive disease. Close monitoring is needed.


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Table 1. Other important contraindications and side-effects of beta-blockers10-12


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Table 2. Important contraindications and side-effects of CAIs10-12


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Table 3. List of important systemic side-effects of alpha-agonists, which occur in five to 10 per cent of users10-12


1. Quigley H. Neuronal death in glaucoma. Prog Ret Eye Research 1999; 18: 1: 39-57.

2. Wilson RM, Martone JF. Epidemiology of Chronic Open-Angle Glaucoma. In: The Glaucomas. St Louis: Mosby, 1996. p. 753-769.

3. Duker JS, Yanoff M. Ophthalmology, 3rd ed. St Louis, MO: Mosby Elsevier, 2009. p. 1538.

4. Gordon MO, Beiser JA, Brandt JD et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol 2002; 120: 6: 714-720.

5.  Heijl A. Reduction of intraocular pressure and glaucoma progression. Arch Ophthalmol 2002; 120: 10: 1268.

6. Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am J Ophthalmol 1998; 126: 498-505.

7. Burr JM, Mowatt G, Hernández R, Siddiqui M et al. The clinical effectiveness and cost-effectiveness of screening for open angle glaucoma: a systematic review and economic evaluation. Health Tech Assess 2007; 11: 100-206.

8. Maier PC, Funk J, Schwarzer G, Antes G, Falck-Ytter YT. Treatment of ocular hypertension and open angle glaucoma: meta-analysis of randomised controlled trials. BMJ 2005; 331: 134.

9.  Tsai JC. Medication adherence in glaucoma: approaches for optimizing patient compliance. Curr Opin Ophthalmol 2006; 17: 190-195.

10. NHMRC Guidelines for the screening, prognosis, diagnosis, management and prevention of glaucoma 2010. Australian Government, National Health and Medical Research Council. Commonwealth of Australia 2010.

11. American Optometric Association. Optometric Clinical Practice Guideline: Care of the Patient with Open Angle Glaucoma, 2nd ed. St Louis, MO: American Optometric Association, 2002.

12. European Glaucoma Society. Terminology and Guidelines for Glaucoma, 2nd ed. Savona, Italy: European Glaucoma Society, 2003.

13. Shrivastava A, Singh K. The impact of cataract surgery on glaucoma care. Curr Opin Ophthalmol 2014; 25: 19-25.

14. 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: 916-921.

15. Van der Valk R, Webers CA, Schouten JS. Intraocular pressure-lowering effects of all commonly used glaucoma drugs: a meta-analysis of randomized clinical trials. Ophthalmology 2005; 112: 1177-1185.

16. Casson RJ, Liu L, Graham SL, William J, Morgan H et al. Efficacy and safety of bimatoprost as replacement for latanoprost in patients with glaucoma or ocular hypertension a uniocular switch study. J Glaucoma 2009; 18: 582-588.

17. Cheng J, Cheng S, Gao L, Lu G, Wei R. Intraocular pressure-lowering effects of commonly used fixed-combination drugs with timolol: a systematic review and meta-analysis. PLoS ONE 2012; 7: 9: e45079.

18. SLT/Med Study Group. Selective laser trabeculoplasty versus medical therapy as initial treatment of glaucoma: a prospective, randomized trial. J Glaucoma 2012; 21: 460-468.

19. Low Pressure Glaucoma Treatment Study Group. Risk factors for visual field progression in the Low Pressure Glaucoma Treatment Study. Am J Ophthalmol 2012; 154: 702-711.


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