NORMAL TENSION GLAUCOMA

Signs and Symptoms

Inferiorly located disc hemorrhage in NTG.

Like most chronic forms of glaucoma, symptoms do not manifest in normal tension glaucoma (NTG) until very late in the disease when the patient suffers from a nearly extinguished visual field. The patient is typically elderly, and there is a female preponderance. It is not clear if there is a hereditary component, thus there is a variable family history. Many patients with NTG also possess vasospastic conditions, such as migraine and Raynaud's phenomenon. There appears to be an increased prevalence of known systemic autoimmune diseases in association with NTG.¹ Examination will reveal glaucomatous atrophy of the optic disc similar to that seen in other forms of chronic glaucoma, open anterior chamber angles, and occasionally disc hemorrhages emanating from the superior temporal or inferior temporal aspect of the disc in the nerve fiber layer. The visual field defects observed are similar to those seen in primary open-angle glaucoma (POAG), though they tend to be deeper, steeper sided, and more often threaten or split fixation.^2,3 However IOP exceeding a statistically normal range (in most reports, 21mm Hg) cannot be documented.

Pathophysiology

The pathophysiological process underlying NTG is unclear and is, at best, speculative. For quite some time, it was unclear if IOP played a role in the pathogenesis of NTG or whether IOP reduction benefited patients with the condition. However, results of the Collaborative Normal Tension Glaucoma Study (CNTGS) indicated that IOP played at least a role in the development of NTG, and IOP reduction without causing cataracts could benefit a number of patients at risk of progression.^4,5 Patients determined to be more at risk of progression included females, migraine suffers (many of whom were female), and those manifesting a disc hemorrhage.⁶ Interestingly, older age, higher average IOP, and field loss threatening fixation were not seen as risk factors for progression.⁶

While there has been some thought that NTG was a vascular perfusion problem, new research seems to indicate a potential autoimmune involvement in pathogenesis. Patients with NTG may have increased prevalence of monoclonal paraproteinemias.⁷ Paraprotein-emias have been seen in patients with peripheral motor and sensory neuropathies and are considered causative agents in several peripheral neuropathies in which antineuronal targets of these proteins have been identified.⁸ Kremmer and associates found greater incidence of antiphospholipid antibodies (particularly IgG anticardiolipin antibodies) in patients with NTG compared to those with POAG and age-matched control patients.⁹

Wax and associates¹⁰ and Tezel and associates¹¹ found that serum from patients with NTG contained high titers of antibodies against retinal proteins, including rhodop-sin and heat shock proteins (HSP). HSPs are a family of cellular chaperone proteins considered neuroprotective because their expression is induced in neurons to ameliorate damage caused by various stress conditions, such as ischemia and excitotoxicity. Heat shock proteins are significant autoantigens and have been implicated in a number of human autoimmune diseases.

Management

Before embarking on any therapeutic management of patients suspected of having NTG, remember that many other conditions can be confused with and misdiagnosed as NTG. These include congenital nerve anomalies such as tilted disc and morning glory syndrome, chronic angle closure, compressive lesions, and undiscovered POAG. The thorough examination includes gonioscopy to eliminate angle closure as a possibility and pachymetry to identify thin corneas (which by themselves may offer increased risk as well as the possibility that they may cause falsely lower IOP measurements). If the disc is unusual, a second opinion may be warranted to identify possible congenital anomalies.

Should NTG be strongly suspected, early treatment may not be prudent. Results of the CNTGS have shown that NTG is slowly- or non-progressive in the majority of cases. Thus, those patients destined to be slowly progressive or non-progressive derive no benefit from treatment, only risks. It is advocated that patients with NTG be observed for a period to establish the rate of progression or stability in each individual patient.⁶ Patients who manifest risk factors for progression such as migraine and disc hemorrhage may need to be monitored more closely. When progression has been conclusively demonstrated, IOP-lowering therapy may be initiated. However, should fixation be split or threatened, early treatment may be employed, though the CNTGS has shown that these patients are at no greater risk of progression. A 30% reduction in IOP from the mean baseline is advocated by most. Medications that have been typically avoided are the beta-blockers and alpha-adrenergic agonists, mostly due to a fear of diminishing perfusion to the optic nerve. It is interesting to note that the CNTGS avoided these medications. Brimonidine, however, has been used recently due to a perceived (though not clinically proven) neuroprotective effect. Prostaglandins have been recently advocated in the management of NTG, as they have the potential to lower IOP within the statistically normal range demonstrated in NTG. Pressure reductions of 15% to 30% have been seen in NTG in response to prostaglandin therapy.^12,13

Clinical Pearls

• Pachymetry should be done to differentiate those patients with POAG masked by a thin cornea from those patients with NTG.
• Patients younger than 50 years, those with markedly asymmetric presentations, and those with rapidly progressive disease should be considered for neuroradiologic imaging in order to rule out the possibility of a mass lesion masquerading as NTG. However, routine imaging on every NTG suspect is not advocated.
• Carefully rule out masqueraders such as tilted disc syndrome, megalopapillae, secondary glaucomas, angle-closure glaucoma, and undiscovered POAG prior to diagnosing any patient with NTG.
• It has been seen that NTG is frequently slowly progressive and even non-progressive. It is crucial to follow these patients for a period of time to establish the rate of progression in each individual case. Those not demonstrating progression do not benefit from pressure reduction and should be treated with close observation instead.
• Do not rush to make a diagnosis and initiate treatment.

Other reports in this section

• Phacomorphic Glaucoma
• Phacolytic Glaucoma
• Normal Tension Glaucoma
• Primary Chronic Angle Closure Glaucoma
• Iridocorneal Endothelial Syncromes (ICE)