The discussion of progression in glaucoma is particularly challenging in patients with normal-tension disease. Most patients understand the connection between glaucoma and elevated eye pressure and thus explaining how glaucoma can worsen despite good or even excellent IOP is challenging. In my clinics, I use these moments to discuss the interaction between systemic factors and glaucoma and try to work with my patients to optimize those factors that are relevant to them.

The diagnostic evaluation of normal-tension glaucoma (NTG) should always begin with a thorough medical history and review of systems. It is not uncommon for patients with NTG to communicate a history of cold extremities, migraine headaches, systemic hypotension, or other signs of vascular dysregulation when asked. A complete history may also be helpful in alerting the ophthalmologist to the possibility of nonglaucomatous causes of optic neuropathy. Although a multitude of systemic factors may contribute to glaucoma progression (ie, sleeping position and other behaviors, history of blood loss, anemia, or even diabetes), this article will focus on blood pressure, vascular dysregulation, and vascular occlusive disease.

Blood Pressure

Many studies have demonstrated a correlation between both arterial hypertension and arterial hypotension and glaucoma.¹ Most experts believe, however, that the treatment of hypertension is the culprit in resulting NTG and optic nerve ischemic damage. Exaggerated nocturnal hypotension, or dips in blood pressure at night, which may compromise susceptible capillary beds, has been implicated in optic nerve head ischemia and glaucoma progression, in the setting of well-controlled IOP. As a result, NTG patients on blood pressure medication who show progression despite low IOP have been encouraged to talk to their PCPs about taking their medication in the morning. Evening dosing with antihypertensive therapy has historically been recommended, but recent studies have challenged those assumptions.

The TIME, or Treatment in Morning vs Evening study, a prospective, randomized trial recently performed in the United Kingdom, looked at the association of morning vs evening dosing of antihypertensive medication on cardiovascular events, and found no difference.² The authors of the study concluded that patients can take their regular antihypertensive medications at a convenient time that minimizes any undesirable effects. Thus, morning dosing of antihypertensive agents in NTG patients who are showing progression despite low IOP may be considered.

The class of blood pressure medication used in NTG may also be important. Studies have shown that calcium channel blocker use may slow visual field progression in NTG, potentially by reducing vascular resistance.³ Conversely, systemic beta blockers have been associated with a higher frequency of disc hemorrhages as well as progression in patients with NTG.⁴

Vascular Dysregulation

Vasospasm has also been found to be associated with NTG. Blood perfusion to the optic disc is affected by the integrity of the autoregulatory system, and in the presence of vasospasm this is impaired. Primary vascular dysregulation syndrome, or Flammer syndrome, describes a complex of clinical features caused mainly by dysregulation of the blood supply. Symptoms can include cold extremities, low blood pressure, reduced thirst, and increased pain sensitivity. A comprehensive questionnaire has been developed to better screen patients for this syndrome.⁵

Flammer syndrome is believed to increase the risk for NTG, particularly in younger patients. Treatment of this syndrome consists of lifestyle modifications such as avoidance of cold, stress, and extreme exercise; nutritional recommendations such as increasing consumption of antioxidants, taking magnesium supplements, and increasing evening salt intake in the case of extreme hypotension; and medical therapy including use of calcium channel blockers.⁶

Silent Cerebral Infarcts

Silent cerebral infarcts are defined as brain infarcts resulting from vascular occlusion that are found incidentally by magnetic resonance imaging or computed tomography in the absence of clinically detectable focal neurologic signs. This is a relatively common finding, seen in 1 of 4 patients over the age of 80, and is a risk factor for further stroke. Multiple studies have found evidence of frequent vascular insults in patients with NTG and it has been suggested that prevention of silent cerebral infarcts may ultimately slow visual field progression in these patients.⁷ The American Heart Association now recommends following stroke prevention guidelines in this subset of patients, including optimizing a patient’s underlying medical conditions, encouraging a Mediterranean diet, and avoiding smoking.⁸ Patients with NTG, especially those who show progression, can also be encouraged to follow these guidelines.

Neuroimaging

Though studies have shown that routine neuroimaging for NTG has a low sensitivity for detecting mass lesions, there are certain factors that should prompt consideration for neuroimaging. Young patients with visual acuity less than 20/40, or patients with vertically aligned field defects, optic nerve pallor in excess of cupping, unilateral disease, or rapidly progressive disease despite well-controlled IOP, should be considered for neuroimaging to rule out CNS pathology.⁹

Conclusion

Evaluating systemic factors in patients with NTG is critical, especially in those who are progressing despite excellent IOP. Taking a thorough history and review of systems is critical, because many patients with normal-tension disease suffer from a host of other conditions. GP