7 Primary Glaucoma

David Garway-Heath, Paul Foster, Roger Hitchings

Aqueous Humour Formation and Outflow

Congenital and Developmental Glaucoma

CLASSIFICATION OF GLAUCOMA

Glaucoma is a term used to describe a group of conditions that share a chronic progressive optic neuropathy. Glaucomatous optic neuropathy is characterized by structural changes in the optic nerve head in which the neural rim is thinned and the cup enlarged; there is usually corresponding visual field loss and raised intraocular pressure (IOP).

Glaucoma may be classified as primary when the cause of the disease is unknown, or secondary when an increase in IOP occurs secondary to another ocular disease. Primary glaucomas may be further subdivided, as shown in Table 7.1.

Table 7.1 Primary glaucomas

Primary open angle glaucomas

Primary open angle glaucoma

Normal pressure glaucoma

Primary juvenile glaucoma

Primary angle closure glaucomas

Acute angle closure glaucoma

Intermittent angle closure glaucoma

Chronic angle closure glaucoma

Primary congenital glaucomas

Primary congenital glaucoma

Primary infantile glaucoma

Glaucoma associated with congenital anomalies

The term ‘ocular hypertension’ describes an eye that has an IOP above the normal range with a normal visual field, optic disc and retinal nerve fibre layer; normal pressure (or low tension) glaucoma describes an eye with primary glaucoma and open angles but with an IOP in the normal range. Primary open angle glaucoma (POAG) is considered in most detail as it is the most prevalent form of glaucoma. Much of the information, however, is relevant to all three groups.

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.

Fig. 7.1 In a population survey of 2000 Caucasian males aged over 40 years, the normal mean IOP was found to be 16.0 mmHg with a standard deviation of 2.5 mmHg. Two standard deviations from the mean is 21 mmHg, which is usually regarded as the (statistical) upper limit for normal IOP; however, the distribution is skewed with a longer tail to the right, and most of these people have ocular hypertension. Glaucoma patients with an IOP lower than 21 mmHg are regarded as having normal pressure glaucoma; above this level they have either ocular hypertension or glaucoma.

Fig. 7.2 Diurnal pressure curves show that IOP is dependent on posture and time of day. IOP is always higher when supine in comparison to an erect posture. This graph shows that during the day IOP is always lower when erect than when supine. (Night time measurements of IOP were only taken in the supine position). IOP tends to be higher in the mornings than later in the day. IOP also varies seasonally, being slightly higher in winter. Whatever the mechanisms regulating IOP the end result is that the two eyes of an individual usually have a similar IOP.

Fig. 7.3 Variation in IOP during the day is often exaggerated in patients with POAG, clearly illustrated by the 2-hourly pressure readings of the right eye of this patient. Note the ‘normal’ levels from 17.00 to 19.00 hours and the rapid pressure rise between 19.00 and 21.00 hours. It is obviously necessary to have frequent IOP measurements to manage patients with disease progression despite ‘controlled’ IOP. Glaucoma surgery significantly dampens diurnal curves.

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.

Fig. 7.4 Aqueous is secreted by the ciliary epithelium and flows past the equator of the lens through the posterior chamber and the pupil to reach the anterior chamber. Aqueous leaves the anterior chamber and enters the canal of Schlemm by the trabecular meshwork. It then passes into collector channels and aqueous veins to reach the episcleral veins. Resistance to flow is greatest at the trabecular meshwork. A proportion of aqueous also leaves the eye by draining into the suprachoroidal space and is known as the uveoscleral or nonconventional outflow pathway.

Fig. 7.5 Aqueous humour passes through the canal of Schlemm to drain into collector channels (in the sclera) which empty into the conjunctival veins. This anastomosis can be seen as ‘aqueous’ veins in the conjunctiva.

Fig. 7.6 The trabecular meshwork has an inner lamellated and an outer nonlamellated cribriform (juxtacanalicular) region. The lamellated meshwork is further divided into a uveal portion (between scleral spur and iris root) and a corneoscleral portion (between cornea and scleral spur). The lamellated region is made up of connective tissue plates with a core of elastic and collagen fibres covered by trabecular cells. The juxtacanalicular region has no collagen beams and consists of an elastic network and layers of cells (cribriform cells) within an extracellular matrix. The ciliary muscle tendon inserts into the inner meshwork and scleral spur.

Fig. 7.7 The corresponding angle anatomy can be seen in this histological section.

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.

Table 7.2 Factors that may cause an increase in IOP

Table 7.3 Factors that may cause a decrease in IOP

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

Trabecular meshwork

In POAG with elevated IOP there is increased outflow resistance and reduced outflow facility. Factors that may contribute to this include an abnormal amount or composition of extracellular matrix, plaque-like deposits in the juxtacanalicular meshwork, changes in trabecular meshwork endothelial cells and in the cytoskeleton of trabecular cells, accelerated trabecular cell death and collapse of trabecular beams.

Fig. 7.8 (Left) Scanning electron micrograph showing an en face view of the normal meshwork from the anterior chamber. (Right) Transmission electron micrograph showing details of the meshwork bordering Schlemm’s canal (SC)in a normal eye. Aqueous enters the canal as a result of the formation of giant vacuoles (GV) that rupture into the canal.

Rights were not granted to include this figure in electronic media. Please refer to the printed book.

Reproduced with permission from Johnson J. Glaucoma 2001, pp 55–67.

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.

Fig. 7.9 Histological sections of normal disc (left) and cupped disc (right).

Fig. 7.10 A coronal digest preparation demonstrates the pores in the lamina cribrosa through which the retinal axons pass. The pores have a larger diameter with less supporting collagenous tissue superiorly and inferiorly; this is the area in which glaucomatous visual field damage initially occurs.

Rights were not granted to include this figure in electronic media. Please refer to the printed book.

Reproduced from Arch Ophthalmol 1990; 108: 51–143.

Fig. 7.11 Laminar digests illustrating posterior displacement of the lamina cribrosa with glaucomatous damage: (top left) normal adult; (bottom left) moderately severe glaucoma; (bottom right) end stage glaucoma.

Reproduced with permission of the Editor, Arch Ophthalmol.

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	0°	No angle structures seen