James Tsai, MD
New York City
M.A. Karim, MD
Chittagong, Bangladesh

There is considerable debate in the literature whether normal tension glaucoma (NTG) represents a dis­tinct entity or is simply primary op­en-angle glaucoma with intraocular pressure within the normal range. Since IOP is a continuous variable with no definite dividing line be­tween normal and abnormal, some have questioned whether the term NTG is misleading.1 In our view, the de­finition of NTG should be based on characteristic glaucomatous optic disc cupping and associated visual field defects in eyes with intraocular pressure in the statistical norm and the absence of ocular or systemic features contributing to other forms of optic neuropathy.



Normal Tension Glaucoma is a disease of elderly persons, and the mean reported age in clinical studies generally is in the 60s; myopic patients with this disease are significantly younger. On average, in population-based surveys, 30 to 40 percent of patients diagnosed with glaucomatous visual field defect have normal IOPs.2,3 In Japan, NTG accounts for the majority of pa­tients diagnosed with primary open-angle glaucoma.4 The relatively high prevalence of NTG may in part be explained by findings that more than 50 percent of patients with glaucoma have been pre­viously undia­g­nosed in population-based, cross-sectional studies.5

Patients with NTG may be asymptomatic and present when they already have extensive visual field loss. A high index of suspicion is required for the diagnosis of the disease. In patients with NTG, the optic disc rim may be significantly thinner, especially inferiorly and inferotemporally (compared to that observed in POAG patients).6 Optic disc hemorrhages and parapapillary disc atrophy (particularly in zone beta) may be more commonly ob­served in patients with NTG.7 More­over, the visual field defects tend to be more focal, deeper, and closer to fixation.8 It is not unusual for a patient with NTG to present initially with a dense paracentral scotoma encroaching on fixation.

The pathogenesis of NTG remains unclear. Some have hypothesized that the presence of a progressive optic neu­ropathy in the context of normal IOPs suggests an underlying vascular insufficiency.9 A variety of cardiovascular and hematologic abnormalities have been described in patients with NTG including hemodynamic crisis, hypercoagulability, reduced diastolic ophthalmodynamometry, nocturnal systemic hypotension, increased blood and plasma viscosity, elevated blood cholesterol and li­pids, carotid artery disease, slowed pa­ra­papillary, cho­roid­­al and retinal circulation and mi­graine.10 In addition, studies have suggested an association of immune-related diseases with NTG, including an in­creased incidence of paraproteinemia and autoantibodies.11


Clinical Evaluation

The most important part of the di­agnostic workup for NTG is a careful and comprehensive ocular and systemic history and examination. Ques­tions should be posed regarding any previous episodes of IOP elevation, ocular trauma/inflammation, use of med­ications (e.g., steroids), sleep-related breathing disorders (e.g., sleep apnea), and nocturnal blood pressure dips. In particular, obstructive sleep apnea may be a significant risk factor for NTG, and thus it is important to take a sleep history from patients with NTG.12

A recent study also reported that marked circadian fluctuation in mean ocular perfusion pressure (associated with nocturnal blood pressure reduction) may be a significant risk factor for the development of NTG.13 The clinician should also inquire about any history of hemodynamic crisis including episodes of blood loss, hypotension, anemia, syncope, blood transfusions and falls. Neurological symptoms such as weakness in extremities, dizziness, headache, loss of consciousness and diplopia should be noted. If elicited, the presence of neurological symptoms may indicate the need for neuro-ophthalmological evaluation to rule out neurological diseases that may masquerade as NTG.

The comprehensive ocular examination should include slit-lamp examination, color vision and pupillary reaction testing, central corneal thickness measurement, diurnal IOP assessment, gonioscopy, perimetry (if indicated), and stereoscopic optic disc examination. As an example, careful slit-lamp evaluation can rule out burned-out pigmentary glaucoma as a potential diagnosis by looking for pigment dispersion on corneal endothelium, iris transillumination defects, and in­creased pigmentation in the an­terior chamber angle. Diurnal variations in IOP must be ruled out, since previously undetected POAG with large swings in diurnal IOP values is on the differential diagnosis.

Gonioscopy should be performed to rule out angle closure, angle re­cession, increased pig­mentation (suggestive of pseudoexfoliation or pigmentary dispersion), or evidence of previous intraocular in­flammation. Careful stereoscopic optic disc evaluation is essential to exclude other congenital or acquired disc anomalies such as optic disc coloboma, drusen and a physiologically enlarged cup. Struc­tural evaluation of the optic disc and retinal nerve fiber layer may prove helpful for the early detection of NTG prior to the development of discernable visual field defects.

The diagnosis of NTG is made only after a comprehensive assessment has been performed (i.e., it is a diagnosis of exclusion). Confirmation of the disease requires repetitive and diurnal IOP measurements to rule out ocular hypertension and/or POAG. Acquired loss (not hereditary) of color vision may indicate a neurological condition as the cause of the optic neuropathy. The presence of a relative afferent pupillary defect may indicate a neurologic defect. Correspondence of the glaucomatous optic disc cupping/neuroretinal rim changes with the visual field defect may be reassuring for a glaucomatous process (though not always). Identification of potentially causative vascular factors (e.g., mi­graine, vasospasm) is important in making the diagnosis; further diagnostic workup may include measurement of the cold response of the nail fold capillaries, ambulatory blood pressure measurement to identify noc­turnal dips, and also color Dop­pler imaging of the common carotid artery to rule out blood flow abnormalities.10 The differential diagnosis also includes neurologic lesions and conditions. A brain scan and/or additional neurological investigation may be indicated if any disparity arises between the optic disc appearance (e.g., extent of cupping, neural rim loss) and the visual field defect. The differential diagnosis is extensive and requires thoughtful consideration (See Table).


Current Treatment

The treatment for NTG has been the subject of intense debate for many years. Current treatment modalities are aimed at controlling IOP, a widely accepted risk factor in the progression of NTG. The Collaborative Nor­mal Tension Glaucoma Study reported that ag­gressive IOP reduction of at least 30 percent from baseline levels re­duced the ex­tent of progressive visual field loss.14,15 In that study, therapy was initiated in patients with NTG with visual field loss threatening fixation, disc hemorrhage, and documented visual field or optic nerve progression. The study results showed that aggressive IOP re­duction with medications and/or sur­gery de­creased the risk of progression from 35 percent to 12 percent over a five-year period.14

However, a substantial percentage of the untreated patients (65 percent) did not progress, thereby demonstrating the extremely variable clinical course observed in NTG. Moreover, the favorable effect of IOP reduction on progression of visual change was only noted after the impact of cat­aracts on visual field progression, produced largely by surgery, was re­moved. Since not all untreated pa­tients with NTG progress, the clinician must consider the natural history of the disease (as well as whether there is risk of serious visual loss) be­fore embarking on IOP reduction therapy.15 A faster rate of progression occurs in women (risk ratio=1.85), in patients with migraine headaches (risk ratio=2.58), and in the presence of disc hemorrhages (risk ra­tio=2.72).16

Before initiating treatment of NTG, the clinician must first determine whether the affected patient is at risk for progression (i.e., progressive vs. non-progressive form). If the patient is judged to have the progressive form of the disease, then it is very helpful to determine a target pressure level. For example, if the untreated IOPs have been in the high teens, then a target level of 14 mmHg or less (with a minimum 30-percent re­duction) seems a reasonable place to start. If the un­treated IOPs have been in the mid-teens, then the clinician should aim for pressure reductions in the 10 to 12 mmHg range. Once the target IOP levels have been achieved, IOP measurements should be taken at different times of the day to rule out diurnal fluctuation. The target pressure may need to be reset (and therapy changed) if fluctuation in diurnal IOP and/or progression of optic nerves/visual fields are ob­served.

A common initial approach in treating NTG is medical therapy. It may be helpful to initiate a unilateral trial of the medication so that the contralateral eye can be used as a control to assess the drug's therapeutic and side-effect profile. If medical therapy is in­sufficient and/or intolerable in reach­ing the target IOP level, laser trabeculoplasty may be considered. In certain instances, glaucoma filtering surgery is indicated to obtain IOP control.17 Use of antifibrotic agents such as mito­mycin-C or 5-fluorouracil may im­prove the overall success rate of filtration surgery.


Future Treatment

Despite apparent adequate IOP lowering, some patients still have progression of their disease. As mentioned above, a number of other risk factors besides IOP have been implicated in the pathogenesis of glaucoma (particularly NTG) including vascular, mechanical and genetic aspects, as well as myopia, endocrine abnormalities and autoimmune phenomena.18 Di­urnal variations in the microcirculation of the optic nerve head may play a role in the progression of NTG in patients with vascular dysregulation, leading to both low perfusion pressure and impaired autoregulation.19 This, in turn, may lead to unstable ocular perfusion and resultant ischemia and re­perfusion damage. Thus, some have advocated therapy with vasodilator drugs such as calcium-channel blockers in select NTG patients with visual field damage and vasospastic propensity.18 For example, brovincamine, a re­latively selective cerebral vasodilator used to improve cerebral circulation and metabolism, has been shown to retard visual field deterioration in certain patients with NTG.20 Nimodipine, another selective calcium-channel blocker, has been reported to improve performance in visual field and color vision testing in NTG patients.21

In the future, neuroprotection therapeutic modalities will likely be considered in the treatment regimen for patients with NTG. Memantine, a po­tential neuroprotective agent that blocks excessive NMDA-type glutamate receptor activity without disrupting normal activity, has been ap­proved for the treatment of Alz­hei­mer's disease.22 Clinical studies evaluating the safety and efficacy of mem­an­tine in glaucoma are currently under way. Ginkgo biloba has also been reported to improve visual field indices in NTG patients in a prospective, randomized, placebo-controlled, double-masked crossover study.23 Thus, further research is required to improve our un­derstanding of the pathogenesis, diagnosis, and treatment of this challenging disease.


Dr Tsai is an associate professor of ophthalmology and director of the Glaucoma Division at the Edward S. Harkness Eye Institute, Columbia University College of Physicians and Surgeons. Contact him at 212-305-9535, or jct2002@columbia.edu.

Dr. Karim is a consultant in the Glau­coma Service at Chittagong Eye Infirmary and Training Complex, Pahartali, Chittagong-4000 Bang­la­desh. Phone: 88-031-659018-9; e-mail: drkarim20@hotmail.com,  Web: eyeinfirmary.org.


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