Clinical background
The idea that factors other than elevated intraocular pressure (IOP) contribute to the pathophysiological processes underlying glaucoma was formulated more than 150 years ago. Von Graefe was the first to recognize that glaucoma can occur despite normal IOP. Only 1 year later Jaeger proposed the vascular concept as cause for normal-tension glaucoma (NTG). The prevalence of NTG as estimated from different studies differs significantly. On average it is now assumed that 30–40% of all primary open-angle glaucoma (POAG) patients have normal IOP, a proportion that rises to 90% in Japan.
The fact that optic nerve head damage and loss of visual field are not related only to elevated IOP is also seen from other arguments. On the one hand a large number of subjects have elevated IOP without showing signs of glaucoma, a condition known as ocular hypertension. The rate of conversion from ocular hypertension to glaucoma is small. Therefore, a large proportion of ocular hypertensive patients never develop glaucoma. On the other hand several multicenter trials have shown that a large proportion of patients with glaucoma progress despite IOP-lowering therapy.
In this chapter the evidence that reduced blood flow plays a role in the glaucomatous process will be summarized. Unfortunately, measurement of ocular blood flow is difficult and currently available techniques are not suitable for clinical practice. This makes it difficult to discern whether a specific patient shows signs of vascular dysregulation ( Box 29.1 ) in the optic nerve head or retina. Hence, the diagnosis of vascular dysregulation in glaucoma patients largely relies on indirect evidence and a thorough evaluation of medical history plays a key role. Patients with vascular dysregulation often suffer from a history of cold hands. Migraine, a risk factor for the progression of NTG, can also be found in some glaucoma patients with vascular dysregulation. Obviously, measurement of systemic blood pressure is required in patients with potential vascular involvement. Ideally, a 24-hour ambulatory blood pressure profile is recorded together with a 24-hour IOP profile. This allows for identification of periods of nocturnal hypotension and low ocular perfusion pressure (OPP), which are likely associated with ischemic conditions at the level of the eye.
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Cold hands and feet, more frequently than the average person
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Raynaud’s syndrome
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Low blood pressure, especially at night
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Local vasoconstriction of conjunctival blood vessels
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Migraine
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Variant angina
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Vasospasm induced by cold, mechanical stress, or by emotional stress
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Reduced feeling of thirst
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Low body mass index
When discussing the potential therapeutic implications of ocular blood flow disturbances in glaucoma one first has to consider that lowering IOP, the hallmark of glaucoma therapy, has a vascular consequence in itself. Any reduction in IOP, whether achieved pharmacologically or surgically, induces an increase in OPP. In addition, a number of drug classes that may induce direct vasodilatation at the posterior pole of the eye have been identified. The best evidence is available for carbonic anhydrase inhibitors and calcium channel blockers. Given that reduced perfusion and vascular dysregulation are risk factors for glaucoma there is a clear rationale behind such treatment. On the other hand, results of large-scale clinical trials showing that improving ocular blood flow is associated with beneficial effects on visual fields are lacking. Is it conceivable to assume that vasodilator treatment is beneficial for glaucoma? At least some studies show that short-term improvements of visual fields in glaucoma are closely related to vasodilatation, particularly in vasospastic subjects. However, vasodilator therapy could also induce negative effects, including disturbance of autoregulatory mechanisms, increase of capillary hydrostatic pressure, or shunting of blood to other vascular beds. Hence, large-scale clinical trials are urgently required. At the moment any attempted vasodilator treatment in glaucoma patients needs to be done under careful monitoring of visual fields and drug-related adverse events, but may be tried in patients who progress despite optimal IOP reduction. It may currently be more fruitful to evaluate patients for nocturnal hypotension and to treat this, if present, in collaboration with other physicians.
Pathology
The specific tissue changes characteristic for glaucoma are covered in other chapters of this book. Clinical findings suggesting that vascular phenomena are important in glaucoma include the common finding of flame hemorrhages of the optic nerve head neuroretinal rim in open-angle glaucoma patients ( Figure 29.1 ). A flame hemorrhage is commonly followed by the appearance of a new nerve fiber layer defect and subsequent progressive visual field loss, suggesting that a vascular phenomenon is contributing to disease progression. These hemorrhages are interpreted as a sign of vascular strain in the optic nerve head, but their cause and mechanism are unknown. Arterial narrowing may also be seen overlying the disk in glaucoma. Beta-peripapillary atrophy is associated with glaucomatous optic nerve changes and is linked to glaucoma progression ( Figure 29.1 ). This atrophy is hypothesized to be vascular in origin, because it is characterized histologically as a loss of choriocapillaris ( Box 29.2 ).
Ocular
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Neuroretinal rim flame hemorrhages
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Local constriction of peripapillary retinal arteries
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Peripapillary chorioretinal atrophy
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Low ocular perfusion pressure
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Reduced perfusion of the ocular vasculature
Systemic
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Low blood pressure
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Nocturnal hypotension
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Cold hands and feet
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Migraine
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Cardiovascular disease
Attempts have been made to characterize specific phenotypes in optic disk appearance associated with the presence of vascular risk factors ( Box 29.3 ). According to this work glaucomatous optic nerve head appearance has been divided into four subtypes: (1) focal glaucomatous optic disk; (2) myopic glaucomatous optic disk; (3) senile sclerotic optic disk; and (4) generalized enlargement of the optic disk cup. The vast majority of glaucomatous disks, however, appear to have features of two or more of these disk types. However, some risk factors were associated with a higher prevalence of a specific disk appearance. Ischemic heart disease was more prevalent among patients with senile sclerotic glaucoma in comparison with the other groups. A suggestion of a greater prevalence of systemic hypertension in the senile sclerotic group and of migraine and vasospasticity in the focal glaucomatous group was also observed. Larger studies are required to characterize in more detail which risk factors are associated with specific optic disk appearance and patterns of visual field loss.
Focal ischemic
Focal notch or acquired pit of the optic nerve head, some peripapillary atrophy
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Vasospasm
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Cold hands and feet
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Migraine
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Rim flame hemorrhages
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Two-thirds are female
Senile sclerotic
Shallow saucerized cupping, peripapillary atrophy around most of the disk
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Older age
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Systemic cardiovascular disease
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Hypertension
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Reduced blood flow in the ophthalmic artery
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Slower rate of progression
Myopic disk
Tilted disk with a crescent of peripapillary atrophy
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Younger age
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Some vasospasm
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Myopia
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Two-thirds are male
Concentric cupping
Round, concentric cup without localized rim thinning
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Younger age
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Markedly elevated intraocular pressure
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Low prevalence of vascular risk factors
Etiology
A number of vascular risk factors for the prevalence, incidence, and progression of POAG have been identified.
Low systemic blood pressure
Systemic blood pressure has been closely linked to prevalence of open-angle glaucoma. Epidemiologic studies indicate a markedly increased prevalence of glaucoma in people with lower diastolic OPP. In the Baltimore Eye Study, there was a sixfold increased risk of OAG in subjects having the lowest diastolic OPPs ( Figure 29.2 ). These findings were confirmed in different populations in the Egna-Neumarkt Eye Study and the Rotterdam Eye Study. The Barbados Study of Eye Disease subsequently observed an elevated incidence of OAG in subjects with low OPP and low blood pressure. The Early Manifest Glaucoma Trial demonstrated an increased risk of glaucoma progression in patients with low OPP. Low OPP appears to be the most important vascular risk factor for POAG.
High blood pressure
While in general lower blood pressures and OPPs are associated with glaucoma, epidemiological evidence suggests that systemic hypertension may play a role as well, particularly in older patients. This association is hypothesized to result from a breakdown of vascular autoregulation in longstanding hypertension. One needs, however, to consider that there is a correlation, albeit weak, between IOP and systemic blood pressure.
Vasospasticity and migraine
Vasospasticity or vascular dysregulation is associated with POAG. In the Collaborative Normal Tension Glaucoma Study, there was a 2.5-fold risk of visual field progression in patients reporting a history of migraine ( Figure 29.3 and Box 29.4 ). Schulzer et al defined two populations of glaucoma patients: those with predominantly atherosclerotic workups and those with peripheral vasospasm ( Figure 29.4 ). While there was no correlation between the maximum known IOP and the degree of visual field damage in the atherosclerotic group, there was a strong positive correlation in the vasospastic group. The authors interpreted their findings to suggest that, while in atherosclerotic patients optic nerve damage might be IOP-independent, in vasospastic patients the IOP damage was IOP-dependent. Hafez et al subsequently demonstrated that, in OAG, there exists a correlation between the degree of vasospasticity and the amount of change of neuroretinal rim blood flow upon IOP reduction. In other words, neuroretinal rim blood flow may be more sensitive to changes in IOP in vasospastic patients than in nonvasospastic patients.
Greater rate of progression in:
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Migraineurs
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Patients with disk hemorrhages
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Women (vascular mechanism?)
Lesser response to intraocular pressure therapy if:
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History of disk hemorrhage
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Family history of stroke
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Personal history of cardiovascular disease
Anticardiolipin antibodies
Anticardiolipin antibodies (ACA) are present in acquired prothrombotic syndromes and are linked to ischemic stroke, myocardial infarction, and systemic lupus erythematosus, but it is not known if they are causal or merely a sign of ongoing vascular inflammatory disease. A recent prospective clinical trial found a strong association between positive ACA and progression of open-angle glaucoma, although the prevalence of positive ACA was low in the study population. This suggests that vascular inflammatory factors may be linked to OAG, although at this time it is impossible to know whether they are causal or secondary to neurovascular damage.
Ocular blood flow and visual field progression
In order to prove definitively that abnormal ocular blood flow contributes to the pathophysiology of glaucoma a prospective large-scale clinical trial is required. Such a trial would test the hypothesis that reduced blood flow is an independent risk factor for glaucoma. There are some small-scale studies that examined this. In a prospective study of 44 newly diagnosed OAG patients, a lower diastolic velocity and higher resistivity index in the ophthalmic artery were associated with markedly greater risk of visual field progression over a 7-year follow-up. This is in good agreement with other data showing that reduced diastolic velocity in the central retinal artery is associated with progression of the disease. Martinez and Sánchez also studied OAG patients prospectively and found that patients with subsequent visual field progression had significantly greater resistance indexes in the ophthalmic artery at baseline. Another small-scale study suggested that patients with the smallest improvements in optic nerve head blood flow in response to initial IOP reduction had the greatest risk of visual field progression over 4.5 years ( Box 29.5 ).
