Clinical Review - Glaucoma

Section 1: Epidemiology and aetiology

Glaucoma is an optic neuropathy characterised by retinal nerve fibre loss causing irreversible visual field defect. Initially, peripheral field defects go unnoticed but in advanced glaucoma, where loss encroaches on central vision, blindness may occur.

It is important to identify glaucoma early because treated patients rarely become blind.

Glaucoma is common, more so in the elderly, with prevalence ranging from 0.1% at 40 years of age to 9.7% above 75.¹ Worldwide, glaucoma is the most common cause of preventable irreversible blindness and affects an estimated 6.6 million people.

In the UK, it accounts for 10-15% of certificate of visual impairment registrations, and 0.5 million people live with the disease.² It is thought that an equivalent number of cases is undiagnosed in the community. Whole-population screening for glaucoma is not recommended, because no single test confirms the diagnosis.

Risk factors
Age is the most important risk factor. The government has reintroduced funded eye tests for those over 60 years of age and from the age of 40 with first-degree relatives (threefold increased risk), because family history of the disease is important.

Population studies have found more glaucoma in people with diabetes, systemic hypertension and myopia. Glaucoma is more prevalent and occurs earlier in African and African-Caribbean populations, tending to be more severe and difficult to treat.³

The aetiology is incompletely understood. In most cases, pathological change at the optic disc is attributed to elevated intraocular pressure (IOP), although in up to one third, IOP is normal. In addition, disturbed autoregulation and glutamate excess may contribute to apoptotic neuronal cell death.

Molecular genetics has found more than 20 genetic loci and three genes with links to proteins at the drainage angle and optic disc. Better understanding of glaucoma genetics has the potential to revolutionise screening and therapy.

Classification
Classification of glaucoma is based on the appearance of the drainage angle. Primary open-angle glaucomas (POAG) are more common in the UK and are the focus of this article.

Glaucoma associated with potential angle closure is more common in people from eastern Asia and differs from open-angle glaucoma in initial treatment (laser iridotomy), late sequelae (obliteration of drainage angle) and post-surgical complications (uveal effusion and malignant glaucoma).

Global nerve fibre loss

Section 2: Making the diagnosis

Early glaucoma is asymptomatic. The diagnosis is usually suggested by a chance finding of one of three examination features: cupped disc, visual field defect or raised IOP. Disc changes or field defect (less commonly) may be sole manifestations of early disease.

Optic disc changes reflect the pattern of retinal ganglion cell death. Loss of neuroretinal rim ('cupping') and other features (see images) provide the most useful diagnostic keys.

Optic disc examination requires technical proficiency and is subjective, with change over time being difficult to monitor. Recently, the use of quantitative thickness imaging of retinal nerve fibres has supplemented stereoscopic disc photographs.

New applications allow change analysis - for example, Heidelberg retinal tomography (HRT), optical coherence tomography (OCT), scanning laser polarimetry (for example, Gdx) and retinal thickness analysis (RTA).

Diagnostic: Focal nerve fibre loss

Visual fields
Visual fields are the key to diagnosis, disease severity and progression. Glaucomatous field loss typically respects the horizontal midline, being the pattern characteristic of retinal nerve fibre damage.

An experienced patient takes about five minutes an eye to complete an automated field test. There is a learning curve and if initial defects are found, tests should be repeated.

Some patients find field tests arduous and perform unreliably, and test variability is common. Any discrepancy between pattern or extent of field loss and optic disc appearance is an indication for brain imaging (for example, pituitary adenoma), especially where IOP is normal.

Interpreting IOP
Raised IOP needs care in interpretation and measurement. High IOP (more than 22mmHg) is a statistical definition (outside two SD of the population mean) and may not apply to the individual.

Goldmann applanation tonometry (GAT) is the gold standard of IOP measurement, but needs interpretation. IOP readings vary with central corneal thickness and thin corneas pose an independent risk for glaucoma in ocular hypertension.

The physiological diurnal variation in IOP levels is exaggerated in eyes with glaucoma.

All newly diagnosed glaucoma should undergo central corneal thickness measurement and examination of the drainage angle (gonioscopy) and front of the eye, looking for features of secondary glaucoma (such as, associated with uveitis).

Where glaucoma is not confirmed (glaucoma suspect), disc imaging, field analysis and IOP may need to be re-evaluated serially for several years. NICE recommends using the same equipment to compare results at each subsequent review.⁴

Disc haemorrhage

Section 3: Managing the condition

The treatment strategy is to prevent further loss of visual field in the patient's lifetime. Although potentially promising avenues for glaucoma treatment include optimising ocular blood flow and using neuroprotective agents to prevent retinal cell death, at present our only available option is to lower IOP. Many studies show that lowering IOP prevents nerve fibre loss.⁵

Each patient is set a target pressure, the IOP below which optic nerve damage is not expected to occur. Thereafter, the patient is monitored to look for damage progression. If progression occurs despite this IOP being achieved, the target is lowered.

Tailoring treatment
Initially, lower IOP is achieved in most patients with daily eye drops - usually monotherapy with prostaglandin analogues/prostamides. These are effective, require once-daily dosing and have minimal systemic side-effects.

Therapy needs to be tailored to the patient. An infirm, elderly patient with minimal field loss may be better off with no treatment if problematic field loss is unlikely to develop in their lifetime.

Topical beta-blockers are today more often used as second-line therapy. A second, third and occasionally fourth drop is added to achieve target IOP. There are several classes of agents with different mechanisms of action that have a synergistic effect. Combination drops are frequently used (see table).

Punctal occlusion, used together with drop instillation, reduces systemic absorption, minimising general side-effects.

Laser therapy
Laser therapy has come back into favour because the newer lasers are less destructive than their predecessors. Selective laser trabeculoplasty (SLT) is thought to lower IOP by stimulating alterations in angle meshwork to increase outflow.

SLT works in about 70% of cases and can be repeated when the effect wears off, usually after several years.

Laser destruction of the ciliary body reduces IOP by lowering aqueous production (laser cyclophotocoagulation) and is usually reserved for end-stage, often secondary glaucomas. Endoscopic laser cyclophotocoagulation, available in a few centres, can be used to treat glaucoma at an earlier stage.

Drainage surgery
Surgery is usually reserved for when medical treatment fails. In trabeculectomy, a channel under the conjunctiva is created for drainage and often supplemented with topical antimetabolites to prevent blockage of outflow by fibrous scarring.

When trabeculectomy fails or is likely to fail, a glaucoma drainage tube is inserted to create an alternative outflow pathway.

All glaucoma drainage surgery requires intensive outpatient postoperative care over several months, with secondary minor procedures often being necessary.

Section 4: Prognosis

Today most treated glaucoma patients will not go blind. The main risk factors for blindness are advanced disease at presentation and sub-optimal IOP control.

 Treatment and follow-up of glaucoma is life-long. The major challenge is to identify progression. Significant nerve fibre loss may occur with minimal apparent deterioration in visual field or disc. Subtle change requires sophisticated analysis that can detect deterioration against a background of normal ageing changes and other patient factors.

Frequency of follow-up depends on disease severity and stability. Stable patients with early glaucoma can be managed in well-equipped community clinics with specialist support. Advanced and unstable glaucoma is better managed in secondary care, where intensive monitoring and intervention can be done.

Fewer than half of all patients take their drops correctly.⁶ Multiple drops worsen compliance. Co-operation with regimens significantly improves outcomes and cost-efficiency.

Section 5: Case study

A 64-year-old Caribbean woman was found to have left disc haemorrhage on diabetic eye-screening photographs, and was referred for tests to exclude glaucoma. There was no family history of glaucoma.

Eye clinic examination confirmed that IOPs were at the upper limit of normal (21mmHg) in both eyes.

Her corneal thicknesses were slightly reduced, gonioscopy revealed open narrow angles with early cataracts and 6/9 (0.2LogMAR) vision in each eye. Visual fields show missed spots on the right but both fields were unreliable, with multiple fixation errors.

Left: HRT left eye. Right: HRT right eye showed a cupped disc

Raised IOP
No definite glaucoma damage was found and she was brought back to look at the range of IOP levels over one day (phasing) and repeat fields a few months later.

This confirmed that she tended towards raised IOP in both eyes. Her levels ranged from 22-26mmHg right and 20-25mmHg left.

The right visual field was slightly improved from the previous visit but HRT showed a right cupped disc. She had documented disc haemorrhages in both eyes, so she was started on drops bilaterally to lower her IOPs to the mid-teens.

She now has a diagnosis of right glaucoma and left glaucoma suspect. She is using topical prostaglandin analogue at night with IOPs at 14mmHg in both eyes. Both fields and HRT are poor because of a developing cataract. She is under six-monthly review.

This case illustrates the importance of taking strategic decisions based on quantitative data where possible, and the difficulty of preventing visual field loss based on uncertainty.

Section 6: Evidence base

Clinical trials

• Normal tension glaucoma study (NTGS 1998).

This study found significant reduction in glaucoma damage in 'normal IOP' patients with progressing glaucoma if treated, compared with control over four years.

• Advanced glaucoma intervention study (AGIS 2000).

This study found reduced mean field loss with lower IOPs in patients randomised to laser or surgery where medication had failed to prevent glaucoma progression.

• Ocular hypertension treatment study (OHTS 2002).

This study found less development of glaucoma loss in patients with IOP >21mmHg randomised to treatment, compared with control over five years.

Guidelines

• Glaucoma: diagnosis and management of chronic open-angle glaucoma and ocular hypertension. CG85. London, NICE, 2009.

Diagnosis and care of glaucoma and ocular hypertension in adults.

Key text

• European Glaucoma Society guidelines, third edition.

This is a comprehensive account of the diagnosis and treatment of glaucoma, with clear definitions.

The guidelines are freely available to download from the European Glaucoma Society website.

However, be aware that the flowcharts in the introductory chapter are not entirely in agreement with the NICE guidelines.

Available from: www.eugs.org/eng/EGS_guidelines.asp

Online

•  www.nhs.uk/Conditions/Glaucoma/Pages/Introduction.aspx

Reasonably good one-page summaries of basic facts with review of treatments to remind users about key aspects.

Recommended app

• GONE Project

iPad app for training in identification of glaucomatous changes in optic discs.

• Contributed by Ms Gilli Vafidis, consultant ophthalmic surgeon, Central Middlesex Hospital and the London Clinic, and Ms Samantha Levin, consultant ophthalmic surgeon, Central Middlesex, Garden and Wellington hospitals

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References

1. Mitchell P, Smith W, Attebo K et al. Prevalence of open-angle glaucoma in Australia. The Blue Mountains Eye Study. Ophthalmology 1996; 103(10): 1661-9.

2. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006; 90: 262-7.

3. Racette L, Wilson MR, Zangwill LM et al. Primary open-angle glaucoma in blacks: a review. Surv Ophthalmol 2003; 48(3): 295-313.

4. Glaucoma: diagnosis and management of chronic open angle glaucoma and ocular hypertension.

5. Nouri-Mahdavi K, Hoffman D, Coleman AL et al. Predictive factors for glaucomatous visual field progression in the Advanced Glaucoma Intervention Study. Ophthalmology 2004; 111(9): 1627-35.

6. Patel SC, Spaeth GL. Compliance in patients prescribed eye drops for glaucoma. Ophthalmic Surg 1995; 26(3): 234-6.