Glaucoma is a major cause of blindness throughout the world. Between 67 million and 105 million people are estimated to have glaucoma worldwide. 1 The concepts and definition of glaucoma have evolved in the past 100 years, but they still remain imprecise. The word glaucoma originally meant ‘ Clouded' in Greek: it was originally used to mean increased IOP associated corneal edema. Today, it does not refer to a single disease entity but to a group of diseases that differ in their clinical presentation, pathophysiology and treatment. 2

Currently, glaucoma can be defined as a multifactorial optic neuropathy with a characteristic loss of optic nerve fibers presenting as classical optic nerve head features and visual field changes which may or may not be associated with elevated IOP and angle anomalies in the presence or absence of any cause for the disease. Contrary to the earlier belief when IOP was considered to be the sole factor in the causation of glaucoma, the role of intraocular pressure in the current definition is only one of the multiple factors responsible for the disease.

The current and evolving hypothesis states that in glaucoma, the impact of nerve damaging factors is amplified by the level of IOP.

The ultimate goal of glaucoma therapy is to delay, stop and sometimes reverse the damage to the optic nerve and ganglion cell loss caused by the glaucomatous process. 2 The only way to do this at present is to control the IOP.

An English oculist, W. Mackenzie first suggested the role of increased IOP in glaucoma in 1835. 1 For 150 years physicians have prescribed ocular hypotensive agents for their glaucoma patients, even before they understood why the drugs worked. 1

The goal of glaucoma treatment is to preserve the visual field of patients and prevent the loss of visual field that is associated with the disease. In a study by neurophysiologist Lars Furen, it was estimated that humans lose approximately 5000 axons per year in the normal ageing process even if glaucoma is not present. 3

Appropriate therapy of glaucoma should achieve 3 targets 4 :

1. Decrease of IOP

2. Enhancement of outflow facility

3. Neuroprotection

arget pressure is the IOP below which the rate of the retinal ganglion cell loss is no greater than the spontaneous rate caused by ageing.

The correlation between intraocular pressure and visual field defect has been recognized for over 20 years 1 . Considering the intraocular pressure as a primary variable glaucoma can be classified as:

1. High-tension glaucoma (IOP> 21mm of Hg)

2. Normal Tension Glaucoma (IOP<21 mm of Hg)

This group encompasses various glaucomas with an intraocular pressure > 21 mm of Hg, classical visual field changes and disc changes. From various epidemiological studies, the prevalence of glaucoma is known to increase with higher intraocular pressure.

In a population based prevalence survey of more than 5000 individuals aged 40 and over in Baltimore, participants who had a screening intraocular pressure greater than 30 mm of Hg were over 38 times more likely to have glaucoma (as defined in the study) than individuals with an intraocular pressure below 15 mm of Hg. 1,5 The Australian Blue Mountain Eye Study found the odds ratio of developing glaucoma was 4 to 7 times higher in patients with a screening intraocular pressure greater than 21 mm of Hg than in patients with lower intraocular pressures, and the odds of developing glaucoma were 2 to 8 times higher in patients with intraocular pressure asymmetry between left and right eyes greater than 3 mm of Hg than in patients with smaller intraocular pressure asymmetry. 1 So the level of intraocular pressure is directly related to the likelihood of glaucoma. High-tension glaucoma can be categorized as: -

- Early manifest glaucoma,

- Moderate glaucoma and

- Advanced glaucoma

Early Manifest Glaucoma

This may be defined as an intraocular pressure >22 mm of Hg but less than 30 mm of Hg, a visual field with an MD of less than -4dB and disc changes.

The Early Manifest Glaucoma Trial was designed to evaluate the effectiveness of reducing intraocular pressure in early, previously untreated Open Angle Glaucoma. 1 ' 6 ' 7 Participants were randomized in two groups— 129 eyes received treatment in the form of Argon Laser Trabeculoplasty + Betaxolol and 129 eyes received no treatment. Investigators reported a significantly lower rate of progression of perimetric damage in patients in whom intraocular pressure was reduced by a mean of 25% (5.1 mm of Hg) with Betaxolol drops and Argon Laser Trabeculoplasty (45%) compared to those untreated (62%). Time to onset of such progress, was also delayed -- median 66 months in the untreated group vs. median 48 months in the observed cohort.

For every 1 mm drop in intraocular pressure, a 10% reduction of the risk of glaucomatous progress was observed. This study strengthened the current standard clinical management of glaucoma as progress was found to be significantly and substantially lower in the initially treated patient.

Moderate Glaucoma

In patients with moderate glaucoma the objective is to lower the intraocular pressure to an appropriate level as determined by the treating clinician. It is essential to follow up and document the disc and visual field to ensure stability over time. If the disease is found to be progressing the target intraocular pressure is to be reset further lower down.

Advanced Primary Open Angle Glaucoma

The Advanced Glaucoma Intervention Study 1,8,9,10 is one of the most widely cited long-term studies of glaucoma progression and in its relationship to intraocular pressure. Participants included patients with definite glaucomatous visual field abnormalities and an inadequate response to maximally tolerated medical therapy.

789 eyes of 591 patients were randomized to sequentially undergo either Trabeculectomy -- ALT -- Trabeculectomy or ALT – Trabeculectomy -- Trabeculectomy and additional medication as necessary. They measured intraocular pressures every 6 months for up to 8 years following surgery to reduce intraocular pressure. The study concluded that eyes with an intraocular pressure less than 18 mm of Hg on 100% visits experienced a low visual field progression close to 0% (fig 1).

Figure 1. Relationship between different levels of IOP and subsequent visual loss in a long-term study. This graph from the AGIS shows that only patients with a mean IOP under 18 mmHg at 100% follow-up visits showed mean changes in visual field defect score close to zero. The AGIS 7. Relationship between the control of IOP and visual field deterioration. Am J Ophthalmol 130: 429-440, Oct 2000

Figure 2: Relationship between different levels of IOP and subsequent visual loss in a long-term study in the AGIS, patients with a mean IOP under 14 mmHg over the first 18 months of follow-up exhibited the least change in visual field over up to 8 years of follow-up. The AGIS 7. Relationship between the control of IOP and visual field deterioration. Am J Ophthalmol 130: 429-440, Oct 2000

Eyes with less than 18 mm Hg intraocular pressure on 50% visits estimated a worsening of visual field by 0.63 units of visual field score. Although, the average change in the visual field was close to zero in the former group, a proportion of the eyes did experience worsening despite having intraocular pressure thought to be safe. In the predictive analysis, the mean visual field loss from baseline measured in eyes with a mean intraocular pressure between 14 and 17.5 mm of Hg over the first 3 visits was 3 times that of mean intraocular pressure less than 14 mm of Hg on these visits (fig 2).

The clinical implication of the study are profound - intraocular pressure levels that are often considered adequate goals of treatment (near 17 mm of Hg) were associated with more progressive visual field loss than were lower intraocular pressure levels.

The term refers to typical glaucomatous optic disc changes and visual field loss in eyes that have a so-called normal intraocular pressure, open angles, and the absence of any contributing ocular or specific systemic disorders. 2 Involving 230 patients at 24 centres in the Collaborative Normal Tension Glaucoma Study, participants were randomized to intraocular pressure lowering treatment or no treatment. 1,11,12 The follow-up examinations were scheduled every 3 months during year 1 and every 6 months thereafter for up to 8 years. Intraocular pressure reduction by 30% reduced the risk of progressive visual field loss.

Even for glaucoma patients with normal intraocular pressure a progression rate of 12 % in the treated group and 26.5% in the untreated group was noted.

So in conclusion, treatment is beneficial, the goal showed to reduce intraocular pressure by approximately 30%.

Ocular hypertension may be defined as an intraocular pressure 21 mm of Hg or greater, normal visual fields, normal optic discs, open angles, and absence of any ocular or systemic disorders contributing to the elevated intraocular pressures. 2

A lower intraocular pressure prevents or delays the onset of visual field loss and optic disc damage in individuals with ocular hypertension as shown in the Ocular Hypertension Treatment Study. 1,13,14 A total of 1636 participants with no evidence of glaucomatous damage and aged 40-80 years and with an intraocular pressure between 24 and 32 mm of Hg in one eye and 21 mm and 32 mm of Hg in the other eye were randomized to either observation or treatment with commercially available ocular hypotensive medications. The goal in the medication group was to reduce the intraocular pressure by 20% or more and to reach an intraocular pressure of 24 mm of Hg or less. After 60 months, the treated group achieved a 22.5% mean reduction of intraocular pressure, compared with a 4.0% reduction in the untreated group. The cumulative probability of developing primary open angle glaucoma was 4.9% in the treated group as compared to 9.5% in the observation group. The massive Ocular Hypertension Treatment Study database also afforded the opportunity to determine some demographic and clinical factors associated with conversion to glaucoma from simple Ocular Hypertension.

The companion paper to the primary Ocular Hypertension Treatment Study publication revealed that older age, larger cup disc (ClD ratio), greater pattern standard deviation (PSD higher intraocular pressure and thinner central corneal thickness (CCT) appear to be good predictors for the development of glaucoma in patients with ocular hypertension. 14 as shown the figure 3 below.

The strength of CCT as a predictor for the conversion to glaucoma over the range of IOP values and cup disc ratios suggests that measurement of CCT should be an essential element to the standard work-up of patients with ocular hypertension. 1,14

Figure 3: Relationship between central corneal thickness and IOP. Update on Glaucoma trials: Focal Points Vol. 21, No. 9, Sep 2003

The question of when to treat ocular hypertensives is still a matter of debate. Tilting the balance towards treatment is the presence of risk factors like black race, high myopia, and age more than 65 years, a family history of primary open angle glaucoma, thinner corneas and the presence of systemic risk factors like diabetes mellitus and systemic hypertension associated with ocular hypertension. Although the guidelines of when to treat in a case of ocular hypertension are controversial, most clinicians would treat in case of:

1. IOP> 30 mm of Hg - Every case should be treated

2.  IOP >25 mm of Hg with a risk factor

3. IOP> 21 mm of Hg with vein occlusion in the other eye.

Besides other patients needing liberal approach include:

- One-eyed patients

- Young patients

- Patients opting for treatment

The importance of diurnal variation

Intraocular pressure in an individual fluctuates throughout the day and night. Large diurnal intraocular pressure fluctuations may be a significant risk factor for disease progression.

In a study of 64 glaucoma patients (105 eyes), those with wide diurnal intraocular pressure fluctuations were found to be at a greater risk of visual field loss than those with more stable intraocular pressure levels throughout the day. 1

Because functional damage from a high intraocular pressure is exponential, even transient elevations in intraocular pressure may cause significant glaucomatous damage. Patients who have periodic or sporadic pressure spikes can lose visual field due to cumulative effects. An important goal of therapy therefore should be to prevent transient intraocular pressure elevations and achieve a low stable intraocular pressure throughout the day and night.

The Target Pressure

The discussion till now indicates that past efforts to lower intraocular pressure in the ‘normal' range of 21 mm Hg or lower may be inadequate and that “control” really means an intraocular pressure of less than 15 mm or 16 mm of Hg especially in advanced glaucoma. 2

Target pressure may be defined as a pressure, rather a range of intraocular pressure levels within which the progression of glaucoma and visual field loss will be delayed or halted. The goal should be to lower the intraocular pressure to a level that is ‘safe' for that particular eye. Because individuals vary in their susceptibility to IOP independent damage, there is no ‘Safe' intraocular pressure that can be guaranteed to prevent further glaucomatous damage. 2 The optic nerve that has already been damaged appears to be more susceptible to pressure mediated injury, so patients with advanced glaucomatous neuropathy may require very low target pressure to halt the disease.

Ocular pressure (mmHg) Percent with nerve damage

In determining the appropriate target pressure for an individual, the ophthalmologist must take into account several major factors 1,2,4 : the IOP level at which the nerve damage occurred, the extent and rate of progression of glaucomatous damage, if known; the presence of other risk factors for glaucoma; and the patient's age, expected life span, and medical history.

Specific IOP ranges may be recommended as a starting point. The AAO guidelines suggest 1 :

For patients with mild damage (optic disc cupping but no visual field loss), the initial target pressure should be 20-30% below baseline.

For patients with advanced damage, the target pressure range may be a reduction of 40% or more from baseline.

For patients with NTG, a 30% reduction is recommended.

A target intraocular pressure that is appropriate when you first see a patient may not be a safe pressure 10 years later when he/she may have developed systemic hypertension, diabetes or some other condition, that may affect the person's susceptibility to glaucomatous progression. The clinician should always revaluate each glaucoma patient at regular intervals to determine if the target intraocular pressure originally selected is still valid.

Conclusion:

In the current scenario of changing concepts of glaucoma diagnosis and management, after many rounds of debate about its significance, IOP still remains an important risk factor and the sole variable that can be controlled among a host of probable mechanisms.

Guidelines for management include:

1. Target IOP should be individualized as per patient and should be a flexible ever changing variable varying with the progression of the disease. 1,2

2. Early manifest glaucoma should be treated aggressively; studies show a substantial decrease in risk of progression with treatment. 6~7

3. Target pressures in advanced glaucoma should be set at a level to ensure visual field stability and to halt further optic nerve changes and ganglion cell loss -- this may be a much lower level than was conventionally thought adequate. 1,3,8,9,10

4. Normal Tension Glaucoma should be treated with a target to achieve a 30% reduction IOP. 11,12

5. Ocular Hypertension should be treated according to the merits of the situation. Central corneal thickness should be a mandatory investigation in the work up of ocular hypertensives. 5,13,14

1. Goldberg I: Relationship between Intraocular Pressure and Preservation of Visual Field in Glaucoma. Surv Ophthalmol 48 (Supp 1): S3—7, 2003.
   
   
2. Stamper R L, Leiberman MF, Drake M V: Becker and Schaffers Diagnosis and Therapy of Glaucomas. Seventh edition: 2-9; 414—429, 1999.
   
   
3. Brubaker R F: Three Targets of Glaucoma Therapy. Ocular Surgery News: 3, September 15, 2002 .
   
   
4. Brubaker R F: Introduction: Three Targets for Glaucoma Management. Surv Ophthalmol 48 (Supp 1): S 1—2, 2003.
   
   
5. Kass M A, Heur DK, Higginbotham D J et al: The Ocular Hypertension Treatment Study; A randomized trial determines that topical hypotensive medication delays or prevents the onset of Primary Open Angle Glaucoma. Arch Ophthalmol 120: 701—713, June 2002.
   
   
6. Leske C, Heijl A, Hyman L et al: Early Manifest Glaucoma Trial; Design and Baseline Data. Ophthalmology 106:2144—2153, Nov 1999.
   
   
7. eijl A, Leske M C, Bengtsson B et al: Reduction of Intraocular Pressure and Glaucoma Progression; Results from the Early Manifest Glaucoma trial. Arch Ophthalmol 120: 1268—1372, Oct 2002.
   
   
8. The Advanced Glaucoma Intervention Study Investigators: Advanced Glaucoma Intervention Study 2. Ophthalmology 101: 1445—1455, Aug 1994.
   
   
9. he AGIS Investigators: The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of Intraocular Pressure and Visual Field Deterioration. Am J Ophthalmol 130: 429-439, Oct 2000.
   
   
10. Beck A D: Review of recent publications of the Advanced Glaucoma Intervention Study. Curr Opin Ophthalmol 14: 83-85, 2003.
    
    
11. Collaborative Normal Tension Study Group: The Effectiveness of Intraocular Pressure Reduction in the Treatment of Normal-Tension Glaucoma. Am J Opthalmol 126:498-505, Oct 1998.
    
12. Anderson D R: Collaborative Normal Tension Glaucoma Study. Curr Opin Ophthalmol 14: 86-90, 2003.
    
13. Lee B L, Wilson M R: Ocular Hypotension Treatment Study (OHTS) commentary. Curr Opin Ophthalmol 14: 74-77, 2003.
    
    
14. Gordon M O, Beiser J A, Brandt J D et al: The Ocular Hypertension Treatment Study: Baseline Factors that Predict the onset of Primary Open Angle Glaucoma. Arch Ophthalmol 120: 714-720, June 2002.