Leske MC, Wu SY, Hennis A, Honkanen R, Nemesure B; BESs Study Group. Risk factors for incident open-angle glaucoma: the Barbados Eye Studies. Ophthalmology. 2008;115(1):85–93.

Retinal vein occlusion

Patients with central retinal vein occlusion (CRVO) may present with elevated IOP and glaucoma. They may have preexisting POAG or other types of glaucoma. After CRVO, patients may develop angle-closure glaucoma or, at a later stage, neovascular glaucoma. Glaucoma and OHT are risk factors for the development of CRVO. In susceptible individuals, eyes with elevated IOP are at risk of developing CRVO. In OHTS, the occurrence of vein occlusions was higher in the observation group than in the treatment group; however, the difference did not reach statistical significance. OHTS was insufficiently powered to detect a treatment effect, given the apparent relative risk and low incidence of CRVO. Thus, consideration should be given to treating elevated IOP in patients with a history of CRVO, the aim being to reduce the risk of CRVO in the fellow eye. As the pathophysiology of hemicentral retinal vein occlusion is similar to that of CRVO, the association with glaucoma in these 2 conditions should be similar.

Other associated conditions

Sleep apnea, thyroid disorders, hypercholesterolemia, migraine, and Raynaud phenomenon have variously been identified as risk factors for the development of glaucoma in some studies. Further research is required in order to clarify the significance of these systemic conditions in patients with POAG and their relationship to glaucoma, if any.

Prognosis

Most patients with POAG will retain useful vision for their entire lives. The prevalence of bilateral blindness among persons with OAG has been estimated at 8% in black persons and 4% in white persons. The patients who are at greatest risk of blindness have visual field loss at the time of diagnosis of glaucoma.

Treatment with medication, laser surgery, or incisional surgery to lower IOP has been shown to significantly reduce the risk of progression of the disease. Many clinical trials have compared various treatments at different points in the clinical course and have confirmed the efficacy of IOP reduction. In the Early Manifest Glaucoma Trial (EMGT), a mean IOP reduction of 25% reduced the risk of progression of OAG from 62% to 45% of patients at 6 years’ follow-up. In the CIGTS, initial medical therapy and initial surgical therapy for OAG resulted in relatively equivalent outcomes after 5 years, with significant visual field progression in only 10%–13% of participants. For further details, see Clinical Trials 4-1 through 4-4 at the end of this chapter.

The AGIS Investigators. Advanced Glaucoma Intervention Study (AGIS): 4. Comparison of treatment outcomes within race: sevenyear results. Ophthalmology. 1998;105(7):1146–1164.

The AGIS Investigators. Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol. 2000;130(4):429–440.

American Academy of Ophthalmology Glaucoma Panel. Preferred Practice Pattern Guidelines. Primary Open-Angle Glaucoma. San Francisco: American Academy of Ophthalmology; 2010. Available at: www.aao.org/ppp.

Leske MC, Heijl A, Hyman L, Bengtsson B, Dong L, Yang Z; EMGT Group. Predictors of long-term progression in the Early Manifest Glaucoma Trial. Ophthalmology. 2007;114(11):1965–1972.

Oliver JE, Hattenhauer MG, Herman D, et al. Blindness and glaucoma: a comparison of patients progressing to blindness from glaucoma with patients maintaining vision. Am J Ophthalmol. 2002;133(6):764–772.

Quigley HA, Vitale S. Models of open-angle glaucoma prevalence and incidence in the United States. Invest Ophthalmol Vis Sci. 1997;38(1):83–91.

Wilson MR, Brandt JD. Update on glaucoma clinical trials. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 2003, module 9.

Open-Angle Glaucoma Without Elevated IOP (Normal-Tension Glaucoma,

Low-Tension Glaucoma)

Controversy remains about whether normal-tension glaucoma represents a distinct disease entity or whether it is simply POAG with IOP within the average range. Because glaucoma can develop at any IOP level within the range of pressures observed in the general population, IOP is a continuous risk factor for the development of glaucoma, and any cutoff between “normal” and “abnormal” IOP is arbitrary. Accordingly, many authorities believe the terms low-tension glaucoma and normal-tension glaucoma should be abandoned.

Clinical Features

As previously emphasized, glaucoma is a multifactorial disease process for which elevated IOP is just one of several risk factors. The other risk factors may play a more important role in normal-tension glaucoma than they do in POAG with higher IOPs. Many authorities have hypothesized that local vascular factors may have a significant part in the development of this disorder. Some studies have suggested that patients with normal-tension glaucoma show a higher prevalence of vasospastic disorders such as migraine headache and Raynaud phenomenon, ischemic vascular diseases, autoimmune diseases, and coagulopathies compared with patients who have high-tension glaucoma. However, these findings have not been consistent. Vascular autoregulatory defects have also been described in studies of eyes with normal-tension glaucoma.

The condition is characteristically bilateral but often asymmetric. Studies have indicated that in glaucomatous eyes with normal but asymmetric IOP, worse damage usually occurs in the eye with the higher IOP.

Optic disc hemorrhages are more common among patients with normal-tension glaucoma, compared to those with POAG and higher IOPs. Some authorities have separated normal-tension glaucoma into 2 groups based on disc appearance:

a senile sclerotic group with shallow, pale sloping of the neuroretinal rim (primarily seen in older patients with vascular disease)

a focal ischemic group with deep, focal notching of the neuroretinal rim

The visual field defects in normal-tension glaucoma tend to be more focal, deeper, and closer to fixation, especially early in the course of the disease, compared with those commonly seen in POAG. A dense paracentral scotoma encroaching on fixation is not an unusual finding as the initial defect. Although many reports have described these differences between groups of patients with normaltension glaucoma and those with POAG, others have failed to confirm them. In any individual patient, there is no characteristic abnormality of the optic disc or visual field that distinguishes normaltension glaucoma from POAG with higher IOPs.

Cartwright MJ, Anderson DR. Correlation of asymmetric damage with asymmetric intraocular pressure in normal-tension glaucoma (low-tension glaucoma). Arch Ophthalmol. 1988;106(7):898–900.

Collaborative Normal-Tension Glaucoma Study Group. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol. 1998;126(4):487– 497.

Differential Diagnosis

Normal-tension glaucoma can be mimicked by many conditions, as summarized in Table 4-1. Several of these conditions can cause visual field defects similar to those seen in glaucoma, and some may be

progressive. Great care must be taken to distinguish normal-tension glaucoma from a nonglaucomatous optic neuropathy, angle-closure glaucoma, optic disc anomalies, and retinal disease because appropriate treatment may vary greatly.

Table 4-1

Diurnal IOP measurement may be useful for determining peak IOP, which can aid in determining the target IOP but does not capture possible nocturnal peaks. Elevated IOP can be obscured in patients taking systemic medication, particularly systemic β-blockers. Some patients with apparent normaltension glaucoma may have artifactually low tonometry readings caused by, for example, reduced scleral rigidity or low CCT. Decreased corneal thickness in patients who have undergone refractive surgery may be associated with underestimation of IOP and an erroneous diagnosis of normaltension glaucoma in these patients. From a clinical standpoint, for eyes with normal-tension glaucoma and a low CCT, the clinical management should be unchanged in that the ophthalmologist should carefully determine the baseline IOP prior to initiation of therapy, with a typical target pressure 30% below baseline, to be adjusted as necessary based on the patient’s unique circumstances.

Many patients with myopia may have anomalous discs or myopic visual field changes, further complicating the diagnosis of glaucoma. Other conditions to consider in the differential diagnosis include normalized IOP in an eye with previously elevated IOP and previous corticosteroid-induced or other secondary glaucoma.

Diagnostic Evaluation

It is difficult to know how often glaucomatous damage occurs with IOP in the normal range. Population-based epidemiologic studies have suggested that as many as 30%–50% of eyes with POAG may have IOP below 21 mm Hg on a single reading. Repeated testing would undoubtedly have detected elevated IOP in many of these eyes. The prevalence of normal-tension glaucoma appears to vary among different populations. Studies have suggested that among Japanese patients, a particularly high proportion of OAG occurs with IOP in the normal range.

Before making a diagnosis of normal-tension glaucoma, the clinician should measure the patient’s IOP by applanation tonometry at various times during the day. Gonioscopy should be performed to rule out angle closure, angle recession, or evidence of previous intraocular inflammation or pigment dispersion. Careful stereoscopic disc evaluation is essential to rule out other congenital or acquired disc anomalies, such as optic nerve coloboma, drusen, and physiologically enlarged cups. The clinician must also consider the patient’s medical history, particularly any record of cardiovascular disease and low blood pressure caused by hemorrhage, myocardial infarction, or shock. Visual field loss consistent with glaucoma has been noted after a decrease in blood pressure following a hypotensive crisis. However, damage secondary to such a

specific precipitating event tends to be stable and does not progress once the underlying problem has been corrected. Similarly, a previous episode of prolonged, elevated IOP, such as that related to the use of topical steroids in susceptible individuals, may result in optic nerve damage that later mimics normal-tension glaucoma but is not progressive.

In the setting of atypical findings such as unilateral disease, decreased central vision, dyschromatopsia, young age, the presence of a relative afferent pupillary defect, neuroretinal rim pallor, or visual field loss not consistent with the optic disc appearance, additional medical and neurological evaluation should be considered, including tests for anemia, carotid artery insufficiency, syphilis, certain vitamin deficiencies, and temporal arteritis or other causes of systemic vasculitis. Auscultation and palpation of the carotid arteries should be performed, and noninvasive tests of carotid circulation may be helpful. Evaluation of the optic nerve and chiasm with computed tomography or magnetic resonance imaging may be warranted in some cases to rule out compressive lesions, especially if the visual field loss is at all suggestive of a neurological defect (see also BCSC Section 5, Neuro-Ophthalmology).

Greenfield DS, Siatkowski RM, Glaser JS, Schatz NJ, Parrish RK II. The cupped disc. Who needs neuroimaging? Ophthalmology. 1998;105(10):1866–1874.

Prognosis and Therapy

The Collaborative Normal-Tension Glaucoma Study (CNTGS) found that lowering IOP by at least 30% reduced the 5-year risk of visual field progression from 35% to 12%, confirming that IOP has a clear role in this disease. However, because some patients did progress despite the reduction in IOP, other factors may be operative as well. It should be noted that the protective effect of IOP reduction was evident only after adjusting for the effect of cataracts, which were more frequent in the treated group.

Based on the findings of the CNTGS, treatment of normal-tension glaucoma is generally initiated unless the optic neuropathy is determined to be stable. This study demonstrated that in some patients (65%), the glaucoma did not progress over the length of the study despite the lack of treatment, whereas in others (12%) the disease progressed despite successful IOP reduction. The rate of visual field progression was highly variable but slow in the majority of those with visual field progression. Treatment benefit was lower among patients with a baseline history of disc hemorrhage. The potential role of neuroprotective agents is experimental and remains under investigation.

The initial goal of therapy should be to use currently available treatments to achieve an IOP level that is approximately 30% below a carefully determined baseline, with appropriate adjustments of the target pressure that take into account the baseline severity of the optic nerve damage, the risks of therapy, and other relevant factors, such as life expectancy and comorbid conditions. Target pressure should be reassessed and adjusted as needed during follow-up visits in order to maintain visual function.

As with POAG, topical medical therapy is the most common initial approach in the management of normal-tension glaucoma. In addition to their IOP-lowering effect, some glaucoma medications may have neuroprotective properties or may improve ocular circulation. These potential benefits have not been proven clinically, however.

Medications, laser trabeculoplasty, and glaucoma filtering surgery may be indicated in an attempt to achieve the target IOP range. An antifibrotic agent, either mitomycin C or 5-fluorouracil, may be used to improve the success rate of filtering surgery. In the EMGT, the combination of betaxolol and argon laser trabeculoplasty (ALT) had little pressure-lowering effect on eyes with baseline IOPs of 15 mm Hg or lower, suggesting that in such eyes incisional surgery and medications other than β-