Glaucoma: target intraocular pressures and current treatments James McAllister FRCS, FRCOphth

Transcription

1 Glaucoma: target intraocular pressures and current treatments James McAllister FRCS, FRCOphth Skyline Imaging Ltd Our Drug review of glaucoma management describes the use of target intraocular pressures in directing treatment, and the medical, laser and surgical management options. This is followed by an analysis of prescription data and sources of further information. The glaucomas are a group of conditions characterised by variably progressive loss of vision associated, typically, with visible loss of the normal appearance of the optic nerve. This form of optic atrophy shows not only pallor (as other forms of optic atrophy) but cavernous loss of nerve fibres described as cupping. Because of this nerve fibre loss there is reduced transmission of visual information to the brain with resultant deterioration of the visual field as well as reduced light/dark adaptation and poorer night vision. Fields can now be mapped with increasing accuracy to provide not only easier diagnosis but better monitoring of the disease process. Along with cupping and resultant visual field loss, elevation of intraocular pressure has been classically the objective measurement relied upon to detect glaucoma and judge the effectiveness of treatment. Again, this significantly enhances our management of the disease. 22 Prescriber 5 April

2 Figure 1. Early (top), moderate (centre) and advanced (above) stages of glaucoma Along with the improved computerised perimeters helping diagnosis of glaucoma and monitoring stability or change in the disease process, imaging systems are now increasingly being used in a similar way for assessing the optic nerve and the retinal nerve fibre layer. These systems help both at the diagnostic stage and in the assessment of change. Measuring intraocular pressure itself is normally done by applanation either using the technique generally carried out in hospitals with a Goldmann applanation tonometer that generates an image on the cornea that is touched with a small sterile prism and the end-point read off from the instrument, or using a noncontact form of applanation with a puff of air that reads in a similar fashion by changing the curvature of the corneal surface and reflecting the air back to a measuring device. Both methods provide accurate measurements. The normal measured intraocular pressure range is in the teens, with an average around 16mmHg and an upper limit of normal of 21, which used to be sufficient to decide whether treatment was commenced or not. The picture has changed, however. From our knowledge of the greater variation of intraocular pressure within the population after worldwide hospital and community studies, we are aware that this previously accepted range of pressure does not tell the true story and there are people with pressures above 21 but with no evidence of glaucomatous damage. This group known as ocular hypertensives may never develop glaucoma but require watching as some will convert, over a period of years, to true disease. Recent studies have suggested that this group should also be considered, in certain circumstances, for treatment to reduce this risk of conversion. 1 Large numbers of patients, perhaps as many as one-third, also present to our clinics with pressures less than 21 yet have evidence of visual field loss and/or optic nerve cupping that are identifiably glaucomatous. Some of this group, because of the diurnal variation in intraocular pressure over a 24-hour period, may have pressures at certain times of day or on certain days that are elevated and therefore may be ocular hypertensive or true glaucoma patients with high pressure but demonstrating raised intraocular pressure only at certain times. To make matters more complicated, within this group of patients are some who present with or develop progressive glaucomatous damage but never have pressures above 21, despite repeated measurements, and are described as having normal-tension glaucoma. 2 Each of these groups requires a somewhat different management approach, which will be discussed below. Recent work measuring corneal thickness by a technique known as pachymetry has shown that corneal thickness varies in different populations, which alters the measurement of intraocular pressure, in some cases by a significant amount. 3 Patients with thinner corneas are more likely to record lower intraocular pressures when measured by applanation tonometry. In practical terms, patients have thin, average or thick corneas and this, at times, could alter Prescriber 5 April

3 decision making, for example in the management of advanced glaucomas and of patients with borderline control of intraocular pressure or with borderline ocular hypertension. How common is glaucoma? The group of conditions known as glaucoma may now be considered to be the second leading cause of blindness (after cataract) in the developing and developed world, with greater prevalence partly associated with increasing longevity. There are many varieties of glaucoma grouped loosely into primary and secondary, but primary disease is by far the largest group. Although primary open-angle disease is the most common variety in the western world, in fact chronic angle closure is more common in particular ethnic groups, especially in the Chinese and Asiatic population, and may indeed affect at least as many people as open-angle disease, which affects western and Afro-Caribbean groups more frequently. 4 Glaucoma varies in its prevalence in different populations. A US survey found rates for primary openangle glaucoma of, for example, 2.2 per cent for white Americans aged 80 years and over compared with 11.3 per cent among blacks. 5 This review will focus on the management of primary open-angle glaucoma. Treatment Target pressure To help us to decide how aggressive treatment should be, the concept of target pressure is a very useful one. Patients with minimal disease (Group 1) with elevated intraocular pressure and with only modest optic nerve and visual field changes (see Figure 1) may only require pressures in the high teens for stability. Group 2, also with raised intraocular pressure but with more moderate visual field loss and cupping (see Figure 1), may need pressures around 15 or less. Group 3 with advanced visual field loss (see Figure 1) may need pressures as low as 10 or 12 to have the best chance of preventing further progression. 6 The group with normal-tension glaucoma starts with pressures below 21. Recent evidence-based medicine has now suggested that if intraocular pressure is lowered by a third, eg perhaps from 18 to 12, then there is a significant reduction (about 70 per cent) in the tendency for disease progression. 1 The final group to be considered are those with ocular hypertension, ie pressures in the higher 20s with no visual loss and no evidence of optic nerve or visual field changes. The decision to treat this group may be influenced by what are regarded as risk factors, eg a positive family history, a degree of myopia, diabetes, hypertension or other vascular disease. Again evidence-based medicine has suggested that, if intraocular pressure is reduced by approximately 20 per cent, then there will be an 80 per cent reduction in the risk of that person converting to true disease in their lifetime. 7 Treatment options In deciding on treatment, the relative risks of treatment, whether it be medical, laser or surgery, should be balanced with the need to obtain the treatment goal in each case to save sight. Figure 2 provides an algorithm to help us achieve best management. Bearing in mind the degree of existing optic nerve damage and presenting intraocular pressure in each case, it is usual to progress by a stepwise choice of monotherapy and then a combination of topical drugs. Medical treatments Research continues unabated towards developing drugs that either improve blood supply to the optic Forum If you have any issues you would like to air with your colleagues or comments on articles published in Prescriber, the Editor would be pleased to receive them and, if appropriate, publish them on our Forum page. Please send your comments to: The Editor, Prescriber, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ or to prescriber@wiley.com Prescriber 5 April

4 nerve or act as neuroprotective agents but, at present, pressure-lowering drugs are the only existing medications for effective treatment. 8 Until the early 60s the choice was limited to topical miotics (or cholinergic agents) that improved outflow, topical adrenergic drugs that reduced aqueous secretion (inflow), and systemic aqueous suppressants in the form of carbonic anhydrase inhibitors (reduced inflow). Beta-blockers In the late 70s the first topical beta-blocker timolol maleate was introduced and this increased our ability to control intraocular pressure, acting vigorously define ideal target pressure for each eye of each patient having decided on treatment goal introduce monotherapy, being conscious of patient s medical health and potential side-effects of each drug if target pressure achieved, monitor patient s optic discs/ visual field/quality of life and continue to reassess with appropriate frequency when monotherapy unsuccessful, either initially or later, then consider adding a second drug the process then continues, remembering compliance, tolerability and side-effects until maximum tolerated if stability of discs is not achieved and safe target pressure not obtained, consider argon laser trabeculoplasty to enhance aqueous outflow or surgery by chosen method (usually a form of sclerostomy or trabeculectomy); risks and advantages of proceeding to surgery will modify the decision in each case, and age and fragility of patient should be taken into account Figure 2. Recommended treatment plan for primary open-angle glaucoma as an aqueous suppressant (reducing inflow). The topical beta-blockers revolutionised medical treatment for the next 20 years. Alpha-agonists In the early 90s adrenergic agonists apraclonidine (Iopidine) and then brimonidine (Alphagan) were introduced to reduce inflow as well as having some additional effect on outflow channels. Carbonic anhydrase inhibitors Topical carbonic anhydrase inhibitors (CAIs), which reduce aqueous production, were also developed about the same time. Topical CAIs and alpha-agonists extended our range of available treatments and arrived at a period of time when doctors were becoming increasingly aware of the systemic side-effects of topical beta-blockers and oral CAIs. Prostaglandin analogues The most recent groups of drugs, known as prostaglandin analogues or hypotensive lipids, were developed at the end of the 90s. Instead of reducing inflow or increasing the conventional outflow pathways through the trabecular meshwork, they appear to open up an alternative route of aqueous egress through the suprachoroidal space. Though they are not suitable for all forms of glaucoma, they have contributed remarkably to obtaining very low intraocular pressures and, because of this alternative mechanism, appear to work well and may enhance the effects of other topical medications. They avoid the cardiovascular problems of the beta-blockers and reduce, though not completely eliminate, any respiratory depression and exacerbation of asthmatic conditions. They nonetheless have their own additional side-effect profile. Compliance Compliance is a real issue with glaucoma therapy. Patients are often elderly and may have other medications from their own doctor as well as eye drops, their eyesight itself may make it difficult to determine what they are using, their hands may have limited control from arthritis or tremor, and remembering to take regular medication is another factor. In order to help this problem, drug companies are producing combination therapies. Examples are combinations of prostaglandin and beta-blocker, alphaagonists (specifically brimonidine) and beta-blocker, and CAI and beta-blocker. Each has its own advantage and each reduces the number of drops that the patient 28 Prescriber 5 April

5 Figure 3. Sites of action of drugs used in glaucoma prostaglandin analogues, eg latanoprost, increase uveoscleral outflow cholinergic agonists, eg pilocarpine, constrict the iris leading to increased aqueous outflow carbonic anhydrase inhibitors, eg dorzolamide, reduce aqueous production alpha-agonists, eg apraclonidine and brimonidine, reduce aqueous production beta-blockers, eg timolol, reduce aqueous production and increase outflow uses as well as the amount of preservative that may cause irritation, but each combines the potential sideeffects of the individual drug contained within the combination. Side-effects and drug interactions Side-effects and awareness of potential side-effects are important for both the hospital clinician and the general practitioner in avoiding drugs that would be predicted to cause problems and being alert to side-effects for patients on treatment that may not be immediately obvious. Referring to the table of potential side-effects of drugs (see Table 1), contraindications for beta-blockers include asthma, respiratory disease and bradycardia as well as renal impairment, and side-effects can therefore include significant bradycardia, associated postural hypotension, arrhythmias, heart failure as well as fainting, bronchospasm and airways obstruction. Depression has been reported, as has peripheral oedema. It has been suggested that hypoglycaemia can be masked in patients with insulin-dependent diabetes. Typical ocular complaints can include reduction in corneal sensation and corneal and conjunctival irritation. The use of beta-blockers may interact with calciumchannel blockers and alter AV conduction, resulting in left ventricular heart failure. When prostaglandins are added to a betablocker the effectiveness of the medication is improved but the same side-effects of beta-blockers are added to those of prostaglandin analogues: conjunctival ocular symptoms include conjunctival redness (hyperaemia), burning and stinging with foreign body sensation, and changes in the eyelashes with increased length, thickness and pigmentation. Changes in iris pigmentation due to melanocytes may occur; patients with green or hazel eyes tend to have the most significant changes. Unusual episodes of uveitis (inflammation of the front of the eye) and oedema of the retina in patients who have had cataract operations have been reported. When drug reactions have occurred, then stopping the medication is appropriate and communication with the hospital clinic important. Measurement of baseline blood pressure and heart rate as well as regularity of pulse are therefore useful before starting patients on drugs and help in monitoring resolution of side-effects. Laser trabeculoplasty Laser trabeculoplasty is a technique for focussing argon light into the drainage channels at the angle of the eye between the iris and the cornea in an attempt to improve outflow. Discreet burns using carefully focussed light at low energies are believed to affect the mechanism, though the exact pathophysiology is still not fully understood. This provides an intermediary treatment for patients on maximally tolerated medical therapy before considering filtering glaucoma surgery. In recent years a new technique known as selective laser trabeculoplasty has been evolving. Very lowenergy pulses are delivered to the trabecular meshwork (the drainage channel area) and are believed to alter the behaviour of the meshwork to make it a more efficient outflow system. While research is still at a relatively early stage and longitudinal studies are still early, this technique shows great promise and may not only have the benefit of an interim staging of management between medical therapy and surgery, but may shift the timing of treatment to be at an earlier or even at a primary stage of glaucoma diagnosis. Surgery Glaucoma filtering surgery is employed, known as trabeculectomy, when other therapy, medical or laser or both, have been shown to be ineffective in obtaining a target pressure believed to be safe for the future health of the optic nerve. Along with intraocular pressure control, evidence of a deteriorating optic nerve 30 Prescriber 5 April

6 Mechanism of action Side-effects Topical Systemic Beta-blockers reduce aqueous secretion local irritation, corneal anaesthesia, as all beta-blockers, exacerbated (reduce inflow) punctate keratitis, conjunctival asthma, bradycardia, increased dryness heart block, systemic hypotension, reduced exercise tolerance, CNS depression, lethargy, depression Prostaglandin analogues increase aqueous outflow, local irritation, conjunctival headache, dyspnoea, exacerbation increase uveoscleral pathway hyperaemia (redness), growth of of asthma eyelashes (hypertrichosis), hyperpigmentation of light irises and skin, macular oedema, iritis, keratitis, blurred vision Alpha-agonists reduce aqueous production follicular conjunctivitis, contact dry mouth, lethargy/headache (reduce inflow) as well as blepharodermatitis reduce episcleral venous pressure and some improvement in outflow Carbonic anhydrase inhibitors decrease aqueous production Topical formulations (reduce inflow), direct effect blurred vision, ocular irritation, alteration of taste (bitter taste), on ciliary body conjunctival hyperaemia headache, dizziness, systemic CAI side-effects Systemic formulations metabolic acidosis, headache, dizziness, thirst, paraesthesia, polyuria, blood dyscrasia, caution in diabetes, renal problems, sulphonamides sensitivity Cholinergics/miotics improve outflow, specific in blurred vision, miosis, lacrimation, sweating, rhinitis, frequency of angle-closure glaucoma local irritation, poorly tolerated micturition, dizziness, flushing, by young abdominal pain, hypertension (cholinergic effects) Sympathomimetics decrease aqueous production irritation, hyperaemia sympathomimetic side-effects, and increase aqueous outflow palpitations, tachycardia, GI upset, anxiety/sweats, cardiac arrhythmias, dizziness Table 1. Mechanism of action and topical and systemic side-effects of drugs used to treat glaucoma Prescriber 5 April

7 or evidence of deteriorating visual field will influence the decision to proceed to surgery. The potential advantages of surgery may include the patient no longer requiring to use medication and a reduction in diurnal pressures spikes (fluctuations of intraocular pressure throughout the 24-hour period that may themselves cause damage), but have their own added risks of any surgical procedure such as infection and the possibility of secondary complications such as overdrainage at an early stage and failure either at an early or late stage, necessitating return to medical treatment. If compliance is an issue and studies have shown that compliance is not as good in any medical treatment as we would like to believe then interventive surgery at a relatively early stage may indeed be a sightsaving procedure. Summary The increasing choice of individual drugs as well as combination therapy make choosing the appropriate treatment for a patient with glaucoma, normally in the hospital clinic, more bewildering. Guidelines have been developed under the umbrella of the European Glaucoma Society, American Glaucoma Society and our own Royal College of Ophthalmology. Treatment decisions are made on an individual basis depending on the various risk factors, height of intraocular pressure, state of the optic nerve, myopia, associated morbidity and age of the patient. Treatment of ocular hypertension is becoming more of an issue. It is estimated that approximately 10 per cent of individuals labelled as having ocular hypertension will convert to open-angle glaucoma over a 10-year period. With primary open-angle glaucoma the concept of target pressure is important, though an absolute level is not realistic, rather a guideline when commencing or changing treatment. The Royal College guidelines do not specify which individual treatment to commence a patient on, but it is generally felt that prostaglandin analogues rather than beta-blockers are sensible for starting monotherapy at the current time, choosing individual drugs rather more than combinations until stability is established. Frequent monitoring of the intraocular pressure, optic nerve and visual field is important. The use of imaging systems for the optic nerve and computerised visual fields allow some of the monitoring to be done by technicians, optometrists or other personnel, and this sharing of management can potentially give more time for the consultant ophthalmologist and his or her clinical team for making decisions about future patient care in an increasingly busy health service. References/suggested further reading 1. Kass MA, et al. Arch Ophthalmol 2002;120: Collaborative Normal Tension Glaucoma Study Group. Ophthalmology 2001;108: La Rosa FA, et al. Arch Ophthalmol 2001;119(1): Foster PJ, et al. Br J Ophthalmol 2001;85: Tielsch JM, et al. JAMA 1991;266: Spaeth GL, et al. Pathogenesis and risk factors in glaucoma. Berlin: Springer, 1999; American Academy of Ophthalmology. Clinical update from multi-center randomized clinical trials, subspecialty in glaucoma. American Academy of Ophthalmology, November Kitazawa Y, et al. Graefe s Arch Clin Exp Ophthalmol 1989;227: Acknowledgements Digital photographs kindly provided by Dr Irina Gout, Prince Charles Eye Unit, King Edward VII Hospital, Windsor, Berkshire. Mr McAllister is consultant ophthalmic surgeon at the Prince Charles Eye Unit, Windsor, Berkshire Forum If you have any issues you would like to air with your colleagues or comments on articles published in Prescriber, the Editor would be pleased to receive them and, if appropriate, publish them on our Forum page. Please send your comments to: The Editor, Prescriber, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ or to prescriber@wiley.com 36 Prescriber 5 April

8 Prescription review In 2007, 6.7 million scrips were dispensed for treatments for glaucoma at a total cost of 97.6 million a 4 per cent volume growth and 7 per cent cost growth over Prostaglandin analogues remained the largest category, representing 48 per cent of scrips and 62 per cent of spending. Latanoprost (Xalatan) alone accounted for over one-third of prescribing and almost half of total costs for glaucoma treatments. Although beta-blockers (still dominated by timolol) accounted for the next most widely prescribed category (19 per cent of scrips, 7 per cent of costs), combined formulations were becoming more popular and accounted for higher spending (16 per cent of scrips, 19 per cent of costs). Special preparations of pilocarpine (0.1 per cent, 6 per cent) remained the most expensive scrips at 57 and 98 respectively. Table 2. Number and cost of prescriptions for drugs used in glaucoma in England, 2007 No. scrips (000s) Cost ( 000s) Beta-blockers timolol levobunolol betaxolol carteolol Carbonic anhydrase inhibitors dorzolamide dorzolamide plus timolol brinzolamide Prostaglandin analogues latanoprost latanoprost plus timolol travoprost bimatoprost Miotics and sympathomimetics pilocarpine dipivefrine brimonidine Resources Groups and organisations The International Glaucoma Association (IGA), 15 Highpoint Business Village, Henwood, Ashford, Kent TN24 8DH; tel: ; website: www. iga.org.uk; SightLine: Offers advice and support to glaucoma sufferers, campaigns for improved glaucoma services and aims to increase public awareness of glaucoma. Also funds clinical research into the nature and treatment of the condition. The Partially Sighted Society, Queen s Road, Doncaster, South Yorkshire DN1 2NX; tel: ; website: LHON/uk-pss.htm. Offers information and advice, publications, aids to vision, enlargement services and local support to help patients make the most of their vision. The Royal National Institute of the Blind (RNIB), 105 Judd Street, London WC1H 9NE; tel: ; website: Helpline: Provides talking books, value-for-money holidays and special products such as easy-to-see watches. It also offers information, advice and a wide range of publications. Royal College of Ophthalmologists, 17 Cornwall Terrace, London NW1 4QW; tel: ; website: Useful website Moorfields Eye Hospital: Eyehealth/Commoneyeconditions/Glaucoma. Further reading BMJ Collected Resources. All articles published in the BMJ regarding ophthalmology since January Guidelines for the management of open angle glaucoma and ocular hypertension. Royal College of Ophthalmologists, Prescriber 5 April