Primary Glaucoma

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7 Primary Glaucoma

INTRAOCULAR PRESSURE

The concept of ‘normal’ IOP is based on a population survey in Europe where readings were assumed to be normally distributed and two standard deviations above the mean gave a normal upper limit of 21 mmHg, implying that only 2.5% of normal people would be expected to have ‘increased’ IOP. However, ‘normal’ IOP is not normally distributed but skewed to the right and as a result a greater proportion of the normal population has an IOP exceeding 21 mmHg than was predicted initially. This right skew increases with age and varies by race; for example, mean IOP in Japan is 11.6 mmHg but that in Barbados is 18.1 mmHg. IOP tends to be higher in older people. Measurement of IOP by methods that applanate the cornea (see Ch. 1) is affected by central corneal thickness which varies between people. The Goldmann applanation tonometer assumes a central corneal thickness of 520 μm; applanation underestimates IOP with thinner corneas and overestimates IOP with thicker corneas. As a rule increased corneal thickness of 10 μm artefactually increases the IOP by 1 mm and similarly underestimates IOP in thin corneas. This is of considerable importance after laser corneal refractive surgery. The factors that regulate IOP are those that alter the rate of aqueous production or outflow resistance.

AQUEOUS HUMOUR FORMATION AND OUTFLOW

Aqueous humour forms at a rate of 2–3μl/min during the day, the fluid volume of the anterior chamber being exchanged every 100 min. At night aqueous flow is approximately halved. Aqueous is formed by a combination of active and passive processes (diffusion and ultrafiltration). About 70 per cent of aqueous is actively secreted by the nonpigmented ciliary epithelium; sodium transport is crucial for this process. Although the ciliary epithelium itself does not have a neuronal supply blood vessels in the ciliary body are well endowed with sympathetic fibres through which drugs such as the sympathomimetics and β-blockers probably act. The mechanisms controlling aqueous secretion remain incompletely understood. There is no evidence, however, that the rate of aqueous production is increased in patients with POAG.

There are two routes of aqueous outflow: trabecular meshwork (conventional) and uveoscleral (nonconventional). Up to 90 per cent of aqueous outflow is through the trabecular meshwork and into Schlemm’s canal and the aqueous veins and is dependent on pressure. Increased resistance to outflow, because of age or disease, requires a higher ‘head’ of pressure to maintain the same throughput of fluid out of the eye resulting in a higher IOP. At least 50 per cent of resistance to outflow is located in the juxtacanalicular region of the trabecular meshwork and in POAG resistance to outflow in this region is thought to be abnormally high. Approximately 10 per cent of aqueous outflow is through the uveoscleral pathway although recent studies have suggested that outflow here may actually be much higher in the young. Aqueous flows through the interstitial spaces of the ciliary muscle into the supraciliary and suprachoroidal spaces and finally through the sclera or into the vortex veins. Uveoscleral flow is independent of pressure and decreases with age.

Table 7.2 lists the factors that potentially cause an increase in IOP; these include increased ciliary epithelial production of aqueous, an altered blood–retinal barrier and, more commonly, increased resistance of the conventional outflow channels. Table 7.3 shows factors that may cause a decrease in IOP: decreased aqueous production, structural alterations in the conventional outflow channels, and an increase in outflow by nonconventional routes.

PRIMARY OPEN ANGLE GLAUCOMA

PREVALENCE

POAG, or chronic simple glaucoma, is the most common form of glaucoma in the West. The median age-adjusted prevalence in people aged over 40 years taken from a number of population surveys is 1.6 per cent in Caucasians and 4.6 per cent in black people. Approximately 4 per cent of white people and 8 per cent of black people with glaucoma are bilaterally blind. Typically the onset is insidious and central visual acuity is not lost until the late stages of the disease. Most referrals follow opportunistic screening of the asymptomatic patient; alternatively patients present when both eyes become affected or coincidentally when the patient accidentally covers the ‘good’ eye and becomes aware of severe visual loss in the affected eye.

Considerable emphasis has been placed on screening the asymptomatic population as there is evidence that early treatment of the disease carries a better prognosis. The low overall prevalence of the disease means, however, that mass population screening is uneconomic and screening has to be restricted to higher risk groups. The major risk factors for glaucoma are raised IOP, older age and ethnic origin. Other risk factors include a positive family history, myopia, vascular disorders (systemic hypertension, nocturnal hypotension and vasospasm) and possibly diabetes. There is a continuous, exponential relationship between the level of IOP and risk of glaucoma. The prevalence of POAG also increases exponentially with age. Around 1 per cent of Caucasians aged 50 years have POAG, rising to 4 per cent in those aged 80 years. For black people, the respective values are 3 and 13 per cent.

Familial and genetic factors have been implicated in susceptibility to glaucoma but the mechanisms that lead to the development of glaucoma are not yet known. In some families the pattern of inheritance is autosomal dominant with reduced penetrance. The role of genes is complex; susceptibility is probably under multigenic influence and disease may not manifest without the presence of other risk factors. At present identified glaucoma genes account for fewer than 5 per cent of cases of primary glaucoma. The first glaucoma gene to be identified was the MYOC/TIGR gene which codes for the protein myocillin found in the trabecular meshwork and also in the ciliary body, retina and optic nerve head. Steroids induce the expression of myocilin in the trabecular meshwork. Other gene mutations and polymorphisms have been reported. For example, OPTN, which codes for a protein thought to be involved in the tumour necrosis factor (TNF) signalling pathway and OPA1, which codes for a dynamin guanosine triphosphatase involved in forming and maintaining the mitochondrial network have been implicated in normal-pressure glaucoma; GSTM1, which codes for glutathione S-transferase, may be associated with POAG.

PATHOGENESIS OF GLAUCOMA

Optic nerve damage

Loss of visual function in glaucoma results from retinal ganglion cell damage and death. There is some evidence that larger ganglion cell axons may be more susceptible to injury than small axons, although this is controversial. Ganglion cells with larger fibres subserve the functions of movement detection and contrast sensitivity (magnocellular pathway) and blue–yellow colour vision (koniocellular pathway). Those with small diameter fibres are responsible for acuity and red–green colour sense (parvocellular pathway). Tests that detect loss of contrast sensitivity, movement thresholds and blue–yellow colour vision are promising tools for earlier diagnosis.

The mechanisms underlying neuronal damage are still not fully elucidated and include mechanical deformation, vascular insufficiency and neurotoxic injury. These processes are not mutually exclusive and the final common pathway is thought to be ganglion cell apoptosis (cell death without inflammation).

Mechanical damage from raised IOP may be mediated in a number of ways. High pressure will distort the plates of the lamina cribrosa, compressing ganglion cell axons and blocking retrograde flow of neurotrophic factors to the ganglion cell body. Distortion of lamina plates may also disrupt capillaries that lie within the plates. Astrocytes, which provide physiological and structural support to ganglion cell axons and maintain the trabecular beams of the lamina cribrosa, may become dysfunctional resulting in disrupted axoplasmic transport, direct neurotoxicity (e.g. from nitric oxide or TNFα), and disruption of the extracellular matrix and cribosal plate architecture. The trabeculae of the lamina cribrosa are at the site of maximum mechanical stress in the eye. This is greater when the sclera is thinner, when the optic disc is larger (e.g. in highly myopic eyes), and at the vertical poles of the disc. Theoretically collagen or elastin may be structurally abnormal in some eyes making them more susceptible to IOP damage than others.

A vascular mechanism may have several components relating to systemic blood pressure (BP), local vascular damage and autoregulation. The concept of ‘perfusion pressure’ (mean BP minus IOP) is important in describing the potential effect of either raised IOP or low BP, particularly in the nocturnal hypotension that affects some patients. A primary vessel defect or poor autoregulation involving the short posterior ciliary arteries and the circle of Zinn–Haller that supply the laminar region (see Ch. 17) could cause local vascular insufficiency. Vascular insufficiency may directly damage neurones through ischaemia, hypoxia, or indirectly by activation of astrocytes.

ASSESSMENT OF THE EYE WITH PRIMARY OPEN ANGLE GLAUCOMA

Key components for assessment of the glaucomatous eye are: IOP measurement, gonioscopy, examination of the optic disc and retinal nerve fibre layer and visual field examination. The techniques of IOP measurement and gonioscopy are covered in Ch. 1.

Gonioscopy

In addition to the ‘openness’ of the angle, the profile of the iris approach to the angle should be noted, the amount and distribution of pigment in the angle and, if present, the extent of peripheral anterior synechiae. Spaeth’s grading describes the iris profile as steep, regular or concave, or as having a plateau configuration (anterior chamber deep centrally but shallow peripherally with a prominent peripheral roll of iris seen on indentation gonioscopy). In heavily pigmented eyes the peripheral iris may be particularly bulky and a cause of angle crowding and closure.

Table 7.4 describes angle grading, derived from Scheie and Shaffer.

Table 7.4 Angle grading (derived from Scheie and Shaffer)

Angle grade Angle width Description
4 35–45° Wide open
3 20–35° Open
2 20° Apex of angle not visible, scleral spur visible
1 10° Posterior half of meshwork not visible, spur not visible, Schwalbe’s line visible
0 No angle structures seen