Table of Contents

Introduction

Elevated intraocular pressure (IOP) is currently the only major risk factor being treated in the management of glaucoma. However, despite lowering of IOP, some patients continue to experience progressive visual field loss leading to irreversible loss of vision and ultimately blindness. On the other hand, some patients with higher than normal IOP remain stable with no visual field deterioration.

Progression despite IOP reduction: populationbased studies

Several large population-based studies have emphasized that although IOP reduction may be beneficial, it may not be sufficient to prevent disease progression. The Ocular Hypertension Study (OHTS)1 was designed to determine the efficacy of topical ocular hypotensive medications in preventing or delaying the onset of POAG in patients with ocular hypertension (OHT). Ocular hypertension is defined as an intraocular pressure greater than 21 mmHg in one or both eyes as measured by applanation tonometry on two or more occasions without visual field or optic nerve changes. In this randomized clinical trial, 1636 subjects with IOP greater than or equal to 24 mmHg but less than or equal to

32 mmHg in at least one eye, IOP greater than or equal to 21 but less than or equal to 32 mmHg in the fellow eye and no evidence of glaucomatous optic nerve or visual field damage were randomized to either observation or treatment with topical ocular hypotensive medication. During the course of the study, IOP was reduced by 22.5% (± 9.9%) in the treatment group compared to 4.0% ( ± 11.6%) in the observation group. This reduction reduced the risk of developing glaucoma at five years by about half, from 9.5% in the observation group to 4.4% in the treatment group. Although clearly beneficial, the clinically significant reduction of IOP did not stop progression to glaucoma in a large proportion of patients.

The Early Manifest Glaucoma Trial (EMGT)2 also compared the effect of lowering the IOP on the progression of newly diagnosed OAG. In this clinical trial, 255 patients with early glaucoma were randomized to argon laser trabeculoplasty plus the topical ocular hypotensive betaxolol or observation. Over four years of follow-up, the IOP was reduced by an average of 5.1 mmHg, or 25%, in the treatment group, compared to no change in the control group. Disease progression was lower in the treatment

group (45%) compared to the control group (62%). Nevertheless, this again demonstrates a significant number of subjects who continue to experience visual loss and disease progression despite IOP reduction.3 The Collaborative Normal Tension Glaucoma

Study (CNTGS),4 examined the effectiveness of a 30% reduction in IOP on the course of the disease progression as measured by visual field deterioration. One hundred and forty-five patients with NTG were randomized to either a control group or a treatment group. Although visual field progression was reduced by 14.5% through IOP reduction, 12% still deteriorated.

The Advanced Glaucoma Intervention Study (AGIS)5,6 further analyzed the association between control of IOP after surgical intervention and visual field deterioration. Despite the maintenance of an IOP of less than 18 mmHg, visual fields of 14.4% of subjects had still deteriorated after seven years. In order to further evaluate factors associated with visual field progression, the Collaborative Initial Glaucoma Treatment Study (CIGTS)7 enrolled 607 newly diagnosed glaucoma patients. An IOP reduction of 48% and 35% was achieved through surgical and medical interventions, respectively. At the eight-year follow-up examination, 21.3% and 25.5% of the initial surgical and medicine groups, respectively, developed a substantial worsening in their visual fields from baseline.

These aforementioned studies demonstrate that in a significant number of patients, glaucomatous deterioration of visual fields continues despite IOP

control through both surgical and medical management. This evidence suggests that although elevated IOP may contribute to the pathophysiology of glaucoma, it may not explain the disease process in its entirety, and other contributing factors may exist.

Other risk factors for glaucomatous optic nerve progression have been identified, some of which are actually risk factors for IOP increase and thus risk factors for glaucoma progression such as age, smoking, dislipidemia, systemic hypertension, male sex and obesity. Others may be additional non-IOP related risk factors such as cup-to-disc ratio and pattern standard deviation (PSD) although a cause and effect has not been established fully and they may actually be the effect of the glaucomatous optic neuropathy and not the risk factors. A few more risk factors have been described such as central corneal thickness (CCT), and pseudoexfoliation syndrome (Table 1).

In the last years, alterations in ocular blood flow and abnormal vascular autoregulation are emerging as key components of the disease process of glaucoma. Clinical trials have demonstrated deficiencies of blood flow in patients with OAG in the retinal,8 choroidal,9 and retrobulbar10-13 circulations. Ischemia has been shown to regionally correspond with areas of visual field loss in patients with glaucoma.14 Abnormalities in ocular perfusion pressure15,16 and blood pressure,17 as well as

References

1.Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: A randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary openangle glaucoma. Arch Ophthalmol 2002; 120: 701-713.

2.Leske MC, Heijl A, Hyman L, Bengtsson B. Early Manifest Glaucoma Trial: Design and baseline data. Ophthalmology 1999; 106: 2144-2153.

3.Heijl A, Leske MC, Bengtsson B, et al, Early Manifest Glaucoma Trial Study Group. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol 2002;

120:1268-1279.

4.Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am J Ophthalmol 1998; 126: 498-505.

5.The Advanced Glaucoma Intervention Study (AGIS): 4. Comparison of treatment outcomes within race. Seven-year results. Ophthalmology 1998;

105:1146-1164.

6.The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration.The AGIS Investigators. Am J Ophthalmol 2000; 130: 429-440.

7.Musch D, Gillespie B, Lichter P, et al. Visual field progression in the Collaborative Initial Glaucoma Treatment Study: The impact of treatment and other baseline factors. Ophthalmol 2009; 116: 200-207.

8.Chung HS, Harris A, Kagemann L, Martin B: Peripapillary retinal blood flow in normal tension glaucoma. Br J Ophthalmol 1999; 83: 466-469.

9.Yin ZQ, Vaegan, Millar TJ, et al. Widespread choroidal insufficiency in primary open-angle glaucoma. J Glaucoma 1997; 6: 23-32.

10.Butt Z, McKillop G, O’Brien C, et al. Measurement of ocular blood flow velocity using colour Doppler imaging in low tension glaucoma. Eye 1995;

9:29-33.

nocturnal hypotension,18 aging of the vasculature,19 optic disc hemorrhage,20 migraine,20 and diabetes20 have also been associated with OAG.

The purpose of this book is to focus on these vascular abnormalities that have been implicated as risk factors for disease progression and as such to try and advocate an additional route in the pathogenesis of glaucomatous optic neuropathy.

11.Galassi F, Sodi A., Ucci F, et al. Ocular haemodynamics in glaucoma associated with high myopia. Int Ophthalmol 1998; 22: 299-305.

12.Harris A, Sergott RC, Spaeth GL, et al. Color Doppler analysis of ocular vessel blood velocity in normal-tension glaucoma. Am J Ophthalmol 1994;

118:642-649.

13.Rojanapongpun P, Drance SM, Morrison BJ. Ophthalmic artery flow velocity in glaucomatous and normal subjects. Br J Ophthalmol 1993; 77: 25-29.

14.Breil P, Krummenauer F, Schmitz S, Pfeiffer N. [The relationship between retrobulbar blood flow velocity and glaucoma damage.] (In German) Ophthalmologe 2002; 99: 613-616.

15.Bonomi L, Marchini G, Marraffa M, et al. Vascular risk factors for primary open-angle glaucoma: the Egna-Neumarkt Study. Ophthalmology 2000;

107:1287-1293.

16.Tielsch JM, Katz J, Sommer A, et al. Hypertension, perfusion pressure, and primary open-angle glaucoma. A population based assessment. Arch Ophthalmol 1995; 113: 216-221.

17.Leighton DA, Phillips CI. Systemic blood pressure in open-angle glaucoma, low tension glaucoma, and the normal eye. Br J Ophthalmol 1972; 56: 447-453.

18.Hayreh SS, Zimmerman MB, Podhajsky P, Alward WL. Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol 1994; 117: 603-624.

19.Harris A, Sergott RC, Spaeth GL, et al. Color Doppler analysis of ocular vessel blood velocity in normal-tension glaucoma. Am J Ophthalmol 1994;

118:642-649.

20.Drance S, Anderson DR, Schulzer M. Risk factors for progression of visual field abnormalities in normal-tension glaucoma. Am J Ophthalmol 2001;

131:699-708.