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Slide 1 |
Larissa Camejo, MD
Normal-tension glaucoma (NTG) refers to glaucomatous optic nerve head changes and corresponding glaucomatous visual field defects in the absence of elevated IOP. Glaucoma without high IOP was first described by von Graefe in 1857; however, NTG is a recently accepted diagnosis. NTG has been called pseudo-glaucoma and is interchangeable with the term low-tension glaucoma. The role of IOP in the pathogenesis of NTG has been dismissed. Evidence now suggests that IOP favorably alters the course of visual field progression in patients with NTG.1
NTG accounts for 30% of the glaucomas. Patients commonly affected by this condition are older women and patients who are Japanese.2 The mean age is 60 years and patients with NTG are generally 10 years older than patients with high-tension glaucoma.2,3
Among patients with NTG, an elevated prevalence of vasospastic diseases (primarily migraine and Raynaud's disease), ischemic vascular diseases, and hypotension is found.4 Evidence suggests a high prevalence of autoimmune diseases in patients with NTG compared to controls with ocular hypertension.5
The pathogenesis of NTG is multifactorial. Reduction in IOP of at least 30% from baseline diminishes the progression of disease. However, progression occurs in 12% of treated patients who obtain adequate IOP reduction. This supports the participation of pressure-independent factors in the etiology of NTG.1
NTG presents variable individual rates of progression. Therefore, efforts have been and continue to be made regarding the identification of risk factors that may make a patient more likely to have the disease, as well as those that may affect progression and those that may be related to a greater benefit from treatment.
In sub analysis work performed by the NTG study group, risk factors for prevalence included age and untreated levels of IOP. Risk factors for progression were migraine, female gender, and disc hemorrhages. Patients who benefited most from treatment were those who were female, patients without baseline disc hemorrhage, with family history of glaucoma, without family history of stroke or personal history of cardiovascular disease, and with mild disc excavation.6-8
As in any other type of glaucoma, patients with NTG may be asymptomatic or complain of reduced vision or other visual difficulties secondary to peripheral vision loss. Most patients are asymptomatic and NTG is detected by the ophthalmologist on a routine examination usually based on the optic nerve head appearance.
On examination, high cup-to-disc ratios and decreased neuroretinal rim are noted on evaluation of the optic nerve head. IOP, by definition, has to be within the normal range, less than 21 mm Hg measured by applanation tonometry. Geijssen defined four types of patients with NTG based on optic disc appearance9:
Specific patterns of optic nerve head appearance characteristic of NTG have been described in the literature. However, not all investigators agree on these specific disc changes being more characteristic of NTG.
The disc changes thought to be more likely to occur in NTG are more focal, deeper, and with more tendency of causing a notch than in other glaucomas. A thinner neuroretinal rim inferiorly and inferotemporally, compared to more diffuse rim thinning in chronic open-angle glaucoma, has also been described.10 The cumulative incidence of disc hemorrhages among all types of glaucomas is highest in NTG - approximately 33% versus 10% in patients with primary open-angle glaucoma and ocular hypertension.
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A disc hemorrhage is defined as an isolated hemorrhage seen on the optic disc or in the peripapillary retina usually extending to the disc rim Slide 1. Two causative theories are proposed. Bleeding may be secondary to vascular insufficiency causing ischemia or it may occur as a result of a mechanical shearing effect caused by the same IOP-induced distortion of the lamina cribrosa that is proposed for causing the death of retinal ganglion cell axons leading to glaucoma.
The presence of a disc hemorrhage should alert physicians to uncontrolled glaucoma in that patient. Alternative scenarios in which one could see a disc hemorrhage include diabetic retinopathy, ischemic optic neuropathy, papillitis, central retinal vein occlusion, and posterior vitreous detachment.
In a study of patients with NTG in which alternative pathologies were ruled out, correlation between the presence of a disc hemorrhage and visual field progression was found. Eighty-one percent of patients with a disc hemorrhage had progression versus only 45% of those without a disc hemorrhage. Also, patients with recurrent disc hemorrhages progressed. In the majority of cases, the disc hemorrhage preceded the field defect with an average delay of 1.5 years and a good location correlation in 65% of patients.11
In previous studies, disc hemorrhages were found to occur mostly inferotemporally followed by superotemporal location. Approximately 70% of recurrent hemorrhages occurred within the same quadrant and more than half recurred within 1 year.
Peripapillary atrophy has also been found to be prevalent among optic nerve heads in patients with NTG. Furthermore, peripapillary atrophy is seen more in eyes with NTG than in eyes with ocular hypertension, suggesting correlation of peripapillary atrophy with optic nerve damage and not high IOP.12,13 Patients with NTG tend to have less glaucomatous visual field defect for the same degree of optic disc glaucomatous change as compared to primary open-angle glaucoma.
Also, visual field defects tend to be focal, deeper and closer to fixation, especially early in disease.3 The majority of experts agree that it is virtually impossible to distinguish NTG and high-tension glaucoma solely on the appearance of the optic nerve head.
Current evidence-based knowledge regarding NTG is available because of the collaborative Normal-Tension Glaucoma study. The follow-up of untreated patients allowed investigators to obtain information on the natural history of the disease. The study suggested that approximately half of the eyes with NTG showed recognizable progressive deterioration within 5 to 7 years.6
When progression occurs, it seems to be slower, even when visual field defects are close to fixation. Much variability has been encountered in the natural history of this disease with progression times ranging significantly among patients who progressed. Physicians are incapable of predicting the fast progressors from the slow progressors.
Baselines for treated and untreated groups were taken at different points in time. Those untreated had baselines taken at randomization while the baseline for those patients treated were obtained when the target 30% reduction was achieved, on average 7 months after randomization. Also, "intent to treat analysis" was performed and yielded no significant difference in progression between the two groups. The authors attribute this to the larger number of cataracts developed among the treated group, especially those who underwent surgery, as compared to the untreated group. The cataracts may have caused false progression on visual fields.
The patients included in the Normal-Tension Glaucoma study had unilateral or bilateral NTG (optic disc and/or visual field defect characteristic of glaucoma) with an IOP within normal limits. To further define an acceptable IOP, 10 baseline IOPs were taken, six of these between 8 o'clock am and 6 o'clock pm of 1 day and the other four taken on other days. No IOP value could be higher than 24 mm Hg in either eye, median IOP had to be 20 mm Hg or lower, and no more than one reading of 23 mm Hg or more was permitted.
Three good baseline tests were obtained within 1 month. Parameters included in the test were fixation losses and false positives of 15% or less and false negatives of 30% or less. Patients had five chances to test adequately enough to provide three baseline fields.
The differential diagnosis of NTG is extensive. Three major groups may be discussed. The first group would encompass patients with falsely normal or obscured high IOP. Thin central corneal thickness and low scleral rigidity can cause tonometric readings of falsely low IOP. A patient on systemic beta blockers can also have IOP falsely normal. The second group comprises patients who had at one or several points in time elevated pressures that caused undiagnosed optic nerve damage, but whose precipitating conditions are no longer present. Examples are intermittent angle-closure glaucoma, steroid-induced glaucoma, and uveitic and trauma-related glaucoma.
Other glaucoma entities with intermittent high pressures include pigmentary glaucoma and glaucomatocyclitic glaucoma. It is important to acknowledge the diurnal variation of IOP that can account for erroneously diagnosing true primary open-angle glaucoma as NTG. The third group would be the nonglaucomatous optic neuropathies.
Congenital anomalies such as colobomas and pits can be confused with focal damage of the neuroretinal rim. These case fields should be nonprogressive unless serous macular detachments occur. Also, compressive lesions, shock optic neuropathy, anterior ischemic optic neuropathy, optic nerve head drusen, and retinal disorders may occur.
A high index of suspicion must be kept to diagnose NTG. However, a number of factors should be considered and evaluated before diagnosing a patient with NTG.
History
Medical history including that of migraines, cardiovascular disease, and hypotension must
be assessed. Patients should be asked about neurological symptoms and, if present, these
must be studied further by a neuro-ophthalmologist or with a patient's primary care
physician. Past ocular history, mainly of refractive surgery that may limit reliable
tonometric readings or of events such as trauma or uveitis that could be the cause of
their glaucoma, is critical. History of glaucoma in a first-degree relative must be
obtained.
IOP
IOP should be measured with a tonometer at various times of the day to rule out diurnal
variation in the presence of primary open-angle glaucoma.
Central corneal thickness
Central corneal thickness should be measured. This helps address the true IOP and the
true target pressures needed for management. Clinicians must remember that patients with
thin corneas are at risk of progression in presence of ocular hypertension.14
Gonioscopy
Gonioscopy must reveal open-angles.
Stereoscopic disc exam
A stereoscopic disc exam should be performed, with emphasis on differentiating
glaucomatous disc appearance with nonglaucomatous changes and searching for those
changes described as characteristic of NTG.
Visual field
Visual field tests look for correlating glaucomatous field defects. The visual field
defect must correspond to the area of neuroretinal rim thinning. In the Normal-Tension
Glaucoma study, three good baseline visual fields were obtained within 1 month, the mean
of which was used as the baseline visual field.
Good fields were those with fixation losses and false positives of 15% or less and false negatives of 30% or less. If patient had 10% or less fixation loss then false negatives of up to 50% were tolerated. Then, a visual field defect was considered to exist when retinal sensitivity was decreased by at least 5 dB in three adjacent points on one side of the horizontal meridian, of which one point had decreased sensitivity by at least 10 dB.
Progression was defined as deepening or expansion of an existing scotoma, new, or expanded threat to fixation or a new scotoma. In the study, field progression was verified on two of three tests performed within 1 month and on two of three tests performed 3 months later. The study analyzed progression in two ways: by the protocol-defined endpoints and the 4-of-5 endpoints. Progression in advanced cases may be difficult to detect and therefore its identification may be aided by a central 10-2 visual field.
Retinal nerve fiber layer thickness
Retinal nerve fiber layer thickness can be measured by optical coherence tomography (OCT)
and/or scanning laser polarimetry (GDX) and optic nerve head imaging by Heidelberg retina
tomography (HRT) and/or OCT. Surgeons can obtain information on structural changes
secondary to glaucoma, which in the majority of patients precede visual field changes.
They can aid in the diagnosis of glaucoma and provide a baseline to which follow-up
tests can be compared.
Neuroimaging
Routine head computed tomography or magnetic resonance imaging head scans are not
recommended. Although intracranial tumors are on the differential, it is unlikely for
them to solely produce a visual field defect with absence of symptoms or neurological
signs.
In a retrospective study, none of the patients diagnosed with glaucoma had neuroradiologic evidence of a mass involving the anterior visual pathway. Furthermore, patients with glaucoma compared to control patients (patients with compressive lesions) as being of an older age, having better visual acuities, greater vertical loss of neuroretinal rim tissue, more frequent disc hemorrhages, less rim pallor, and more field defects aligned at the horizontal midline.15
Researchers may conclude that routinely performing neuroimaging on patients with NTG is not cost effective. A neurological workup should be pursued in patients with unexplained reduction of visual acuity, color vision loss without advanced visual field loss, visual field loss out of proportion to optic nerve damage or atypical for glaucoma, including those respecting the vertical meridian, optic nerve pallor in excess of cupping, and presence of neurological symptoms.
In a review on NTG interventions, three studies were selected as valuable. The Collaborative Normal-Tension Glaucoma study group proved a beneficial effect was obtained when lowering IOP, but only after data were corrected for cataract development. Two other studies showed a beneficial effect of brovinvamine (a calcium channel antagonist).
Although IOP does not seem to be the sole causative factor of NTG, it is the one easily measurable variable that we can modify and lower with treatment. Researchers know that it will halt or slow the progression of disease in at least some cases of NTG, as evidenced in several studies, particularly the Normal-Tension Glaucoma study.
As with high-pressure glaucoma, it is important to establish the target pressure to prevent the progression of glaucomatous damage. The goal may be to achieve these target pressures or to reduce IOP lowering medications, laser trabeculoplasty and/or filtration surgery.
As in primary open-angle glaucoma, medical treatment is the initial approach in reaching this goal. A 30% reduction in IOP was achieved and maintained in almost half of the patients randomized to treatment in the Normal-Tension Glaucoma study with only topical drugs, or laser trabeculoplasty, or both.1
Today numerous topical pressure-lowering drugs are available that were either not used or not available at the time of this study. No established algorithm for first-line drugs in NTG treatment exists.
A school of thought suggests that the initial drug of choice should be brimonidine (alpha 2 agonist). Brimonidine has a pressure-lowering effect that averages 20% to 27%. It acts by decreasing aqueous humor production and increasing uveoscleral outflow. Furthermore, it has neuroprotective properties in laboratory studies, as it increases the resistance of retinal ganglion cells (RGC) to chronic stress, crush and ischemic injury in animal models.
Another study suggested this neuroprotective effect to be mediated by upregulation of a brain-derived neurotrophic factor in the RGCs. It is unfortunate that neuroprotection is yet to be proven in humans but there are ongoing clinical trials.16,17
On the other hand, if a surgeon's goal is to lower IOP by 30%, then the prostaglandin analogs are the best at achieving that effect because they usually have a lowering effect of 27% to 35%. Because patients with NTG have open angles, laser trabeculoplasty (LTP) is often a good option before proceeding with incisional surgery. Filtration surgery should be undertaken if the target pressure under which no progression is thought to occur cannot be reached by other means.
Currently, the role of neuroprotective agents is controversial. Available options are calcium channel blockers and alpha 2 agonists. The reasoning behind the use of calcium channel blockers is the ability to increase capillary perfusion to the optic nerve head and to block calcium channel mediated apoptosis. Calcium channel antagonists block cell-membrane-bound calcium channels and inhibit calcium influx. They cause the vascular wall smooth muscle to relax and decrease vascular resistance and improve blood flow. One study showed less visual field progression in patients with NTG when brovincamine (calcium channel antagonist) was given.18,19
Calcium channel blockers are not used commonly by ophthalmologists because of certain risks. Although the beneficial effects seem appealing, it must be understood that by acting as an antihypertensive these agents can also further compromise the optic nerve head perfusion in an already susceptible patient. Their use should be restricted to those cases in which a strong link to vasospastic disease is present and is thought to be the most important causative factor in those specific cases of NTG. Consulting an internist is advised and caution should be practiced when combining these with beta blockers to avoid dangerous bradycardia.
Glaucoma is treated when structural or functional optic nerve damage or progression of disease is evidenced. In the NTG study, patients with NTG were immediately randomized and therefore exposed to the possibility of treatment when a fixation threatening visual field defect was noticed or when recent progression on visual fields was documented. Otherwise, patients were examined every 6 months and randomized if a disc hemorrhage was evidenced or if progression was noted on an optic nerve head examination or visual fields.
Finally, genetic therapy may someday play a role in the treatment of glaucoma. Currently two optineurin sequence variations associated with NTG have been identified - the Glu50Lys OPTN associated with familial NTG and the Met98Lys change associated with a fraction of NTG in patients of Japanese ethnicity.20