Glaucoma is a disease characterized by the loss of ganglion cells and their axons and the consequent visual field loss. It is one of the leading causes of irreversible visual impairment, affecting more than 70 million people, 10% of whom are bilaterally blind.1,2 This prevalence is expected to increase in parallel with increasing life expectancies, to 111.8 million in the year 2040.3 Despite its significance, the underlying pathogenesis of glaucoma remains largely mysterious. Moreover, its diagnosis is often delayed, as a majority of patients remain asymptomatic until the late stages, and awareness among the general population is relatively low.4–7
In 1857, von Graefe8 first described a form of glaucoma manifesting optic nerve head damage and an open anterior chamber angle, but with an intraocular pressure (IOP) within the reference range; this is now known as normal-tension glaucoma (NTG). Although primary open-angle glaucoma (POAG) is the most common subtype of glaucoma, large numbers of patients with POAG have IOP within the reference range and are categorized as NTG, the proportions of which vary by ethnicity and study population. In Asian countries, higher prevalence rates of NTG, up to a maximum of 90%, have been reported than those in Western ones.6,7,9–18
Currently, the contentious question surrounding NTG is whether it should be regarded as a disease within the spectrum of POAG or as a distinctive disease entity. Nonetheless, NTG is associated with characteristic pathogenic risk factors, such as IOP-independent risk factors including vascular factors, systemic disease–associated factors, and myopia-related biomechanical factors, and shows structural and functional clinical features distinguishing it from POAG.19 Furthermore, NTG has distinctive progression-associated factors and a different overall progression rate with regard to clinical outcome. Over the years, amid constant debate, investigations have sought to resolve the pathomechanisms of NTG. In light of this, the present review aims to update the current knowledge on the prevalence, etiology, diagnosis, and monitoring of NTG and to outline future directions for investigations that it is hoped will lead to a better understanding of NTG.
Previous studies have reported various POAG prevalence rates ranging from 0.5%20 to 8.8%21 according to ethnicity, study design, and glaucoma definition. Normal-tension glaucoma constitutes the major proportion of POAG, which is common in Asian populations (Table 1).6,15,22 For this reason, the population-based studies that have investigated NTG proportions among POAG have been conducted mostly in Asia. The POAG prevalence in Asian populations is between 1.0%16 and 3.9%,6 with the proportion of NTG somewhere between 46.9%23 and 92.3%,6 whereas in white and African population studies, the POAG prevalence is between 1.1%24 and 8.8%,21 with NTG proportions ranging from 30.0%25 to 57.1%.26
In a recent review of population-based glaucoma prevalence, the calculated mean proportion of NTG was larger in Asia (76.3%) than in a white population (33.7%).27 To date, the highest NTG proportion reported was 92.0%, from the Tajimi Study6 conducted in Japan, and the lowest was 30%, from the Italian Egna-Neumarkt Study.25 The prevalence of POAG and proportion of NTG in population-based studies were as follows. In Asia, the estimated prevalence of POAG in Liwan District, Guangzhou, was 2.1%, and the proportion of NTG was 85.0%;10 the corresponding figures were 3.5% and 77.0% in the Namil Study from South Korea,9 2.5% and 85% in the Singapore Malay Eye Study,14 and 3.9% and 92% in the aforementioned Tajimi Study.6 For white populations, the prevalence of POAG and the proportion of NTG were 2.1% and 32.0%, respectively, in the Beaver Dam Eye Study,28 1.1% and 39.0% in the Rotterdam Study,24 and 2.9% and 39.0% in the previously noted Egna-Neumarkt Study.25 For African populations, the prevalence of POAG was 2.7%, with the proportion of NTG at 57% in Zululand.26
The prevalence of POAG is expected to increase with longer life expectancies and reach 111.8 million in 2040.3 In Asia, the number of people with POAG is projected to increase to 53.47 million by the same year,29 which would be nearly half of the worldwide prevalence. Exact estimates on future NTG prevalence have not yet been reported, although increasing trends in line with predicted POAG increases are expected.
An elevated IOP has long been considered to have a primary role in the pathogenesis of open-angle glaucoma. However, the main question with regard to NTG might be the role of IOP-independent mechanisms. Studies have been conducted to reveal the extent to which IOP-dependent and -independent mechanisms are respectively responsible for glaucoma development. Still, the results are conflicting. Moreover, despite the emphasis on various IOP-independent etiologic aspects, both IOP-dependent and-independent mechanisms are central to the pathogenesis of NTG.
There has been histological evidence obtained by impression cytology and laser scanning in vivo confocal microscopy indicating that glaucomatous eyes exhibit conjunctival change induced by high IOP. Conjunctival epithelial microcysts have been found not only in eyes that have undergone trabeculectomy,32 but also in eyes with POAG or ocular hypertension that were affected by high IOP.33 Such findings were also seen in NTG patients similar to POAG patients, indicating that hyperbaric damage also plays a role even in eyes within the IOP reference range.34
Based on the multitude of epidemiologic studies (conducted in populations with large NTG proportions) reporting high IOP as a common risk factor15,16,22,35 and longitudinal studies reporting clinical treatment outcomes in NTG patients,36–39 it can be concluded that there is a protective effect of IOP-lowering treatment for NTG patients. Moreover, despite NTG patients having IOP within the reference range, epidemiological data have confirmed significantly higher IOPs than those of control subjects.6,9 In the Tajimi Study, the mean IOPs were 15.4 ± 2.8 and 14.5 ± 2.5 mm Hg in the right eyes of the POAG (92.3% of them being NTG) and control groups, respectively (P < 0.001),6 and in the Namil Study, they were 14.6 ± 3.3 and 13.3 ± 2.7 mm Hg in the NTG and control groups, respectively (P = 0.001).9 Similar differences were found in the Singapore Indian Eye Study40 and the Beijing Eye Study.41 All of these results indicate that, although NTG pressures are not as high as POAG ones, IOP still plays an important role in the pathogenesis of NTG. These data in fact provide the basis for the currently preferred IOP-lowering treatment for NTG eyes to slow progression.
Despite the impact of IOP on the pathogenesis of NTG, it is generally accepted that IOP is not the only causative factor in NTG. Based on the recent discoveries of IOP-independent processes, vascular factors are more likely than high-IOP POAG to be the major pathomechanisms of NTG. Still, prospective studies with large subject populations are needed to support current assumptions.
Questions have been raised about possible structure-related factors in NTG eyes that would increase the susceptibility to glaucomatous damage under “normal pressure” levels. Recent investigations conducted with Asian populations have reported high prevalence rates of myopia and its strong association with NTG,6,7,16,22,42,43 on which basis they have identified myopia as a notable risk factor for glaucoma.6,7,16,22,42–44 The Tajimi Study reported an association between myopia and NTG,35 and another study based on the Korea National Health and Nutrition Examination Survey database reported that more severe myopia was associated with greater odds of glaucoma.44 The structural thinning/stretching and inherent structural weakness resulting from axial elongation in myopic eyes can increase vulnerability to glaucomatous damage even within the IOP reference range. However, caution is needed when interpreting such associations, as glaucoma-like structural and functional damage can occur because of myopia alone. In this regard, recent studies have raised concerns about the need to distinguish myopia-related optic nerve head/retinal nerve fiber layer (RNFL) damage or visual field defect from true glaucomatous conditions.45,46
Other than myopia, various features in the lamina cribrosa of NTG eyes can be considered to be possible structural-biomechanical factors associated with NTG. Park and Park47 reported that NTG eyes exhibited thinner laminar thickness compared with high-IOP POAG eyes and that thin laminar thickness showed good diagnostic performance in detecting early glaucomatous changes in NTG eyes. Jung et al50 investigated the prelaminar thickness difference between high-IOP POAG and NTG eyes, concluding that an IOP-dependent mechanism played an important role in thinning the prelaminar tissue in both groups relative to the control subjects. However, based on thinner prelaminar tissue in high-IOP POAG eyes than in NTG eyes, they postulated that the IOP-dependent mechanism might be more strongly associated with high-IOP POAG than with NTG. Currently, only a limited number of studies are available on the characteristics of the lamina cribrosa in NTG eyes. Moreover, improved imaging devices or techniques to overcome the current limitations in the visibility of the lamina cribrosa are needed to confirm those hypotheses.
Systemic and Ocular Vascular Risk Factors
The vascular theory is one of the main theories considered in seeking to elucidate the pathogenesis of glaucomatous optic neuropathy in NTG. Systemic and ocular vascular factors such as migraine, cold hands/feet, primary vascular dysregulation, peripheral arterial stiffness, high or low systolic and diastolic blood pressures, and reduced ocular perfusion pressure have presented direct or indirect associations with NTG.19
Migraine is more common in patients with glaucoma than in control subjects, especially in patients with NTG.48,49 As the underlying mechanism of migraine is presumed to be associated with vascular dysregulation,49,51 patients with migraine could have poor blood flow at the optic nerve head, leading to an increase in the susceptibility to glaucomatous damage.52
Primary Vascular Dysregulation
Autoregulation, an intrinsic vascular ability to maintain relatively constant blood flow over a large range of pressure while fulfilling the metabolic demand of the tissue, is the main mechanism maintaining retinal blood flow in healthy eyes.53 However, in subjects with primary vascular dysregulation, this ability to maintain sufficient blood flow is diminished despite the absence of causative diseases or anatomical factors. Normal-tension glaucoma patients are reported to have decreased autoregulation capacity to preserve proper blood flow compared with healthy subjects, which relative incapacity is presumed to be associated in some cases with primary vascular dysregulation.54,55
Flammer syndrome is a phenotype characterized by the presence of a cluster of systemic and ocular symptoms (eg, cold hands and/or feet, long sleep onset time, reduced feeling of thirst, increased sensitivity) and signs (eg, blood pressure drop at night, abnormal nailfold capillaroscopy, reduced capacity to autoregulate ocular blood flow) of primary vascular dysregulation.56 Although its prevalence is low, and despite the fact that most subjects with Flammer syndrome are in the subclinical status, it can increase the likelihood of glaucomatous damage, especially in NTG eyes, and can also increase the risk of disc hemorrhage.56
The systemic and diastolic blood pressures play dominant roles in regulating ocular blood flow and IOP, and both increased and decreased statuses are possibly associated with glaucomatous optic neuropathy. The question of which is more important, increased or decreased blood pressure, remains unresolved. A recent meta-analysis reported a 1.2-fold increase in the risk of POAG among hypertensive patients but with different strengths of association depending on the study design, being stronger in cross-sectional studies than in case-control and longitudinal studies.57 In addition, in that study, the pooled average increase in IOP associated with a 10–mm Hg increase in systolic blood pressure was 0.26 mm Hg (95% confidence interval, 0.23–0.28), and the average increase associated with a 5–mm Hg increase in diastolic blood pressure was 0.17 mm Hg (95% confidence interval, 0.11–0.23). This blood pressure increase and at least its correlation with IOP have been considered as possible underlying mechanisms for glaucoma, despite ongoing debate among studies.
In contrast, excessive blood pressure lowering due to the use of antihypertensive medication or nocturnal hypotension in NTG patients might be linked with decreased ocular perfusion pressure, causing insufficient oxygen and nutritional support to the optic nerve head and subsequent ischemic injury. The possible causal relationship between low blood pressure and glaucoma development requires more evidence, although recent studies have obtained positive results on the role of low level blood pressure as a risk factor for progressive visual field loss in glaucoma.58,59 Despite ongoing debates and the need for more evidence, high and low blood pressures both have shown an association with glaucoma in different studies. Both can cause greater damage in NTG eyes, which are more vulnerable to vascular ischemic insult.
Ocular Perfusion Pressure
Decreased ocular perfusion pressure in glaucomatous eyes is suggested as an important pathomechanism, particularly in NTG eyes. A low diastolic ocular perfusion pressure was indeed a risk factor of NTG in the Rotterdam Study.60 In a study by Plange et al,58 a prolonged arteriovenous passage time, reflecting impaired autoregulation, was found in NTG patients compared with healthy individuals, and it was correlated with low mean arterial blood pressure and low ocular perfusion pressure. In addition to low ocular perfusion pressure, a large fluctuation of ocular perfusion pressure was suggested as a risk factor for NTG development.62 On the contrary, conflicting results have been reported by Mroczkowska et al,63 specifically that NTG patients exhibited increased nocturnal systemic blood pressure variability, peripheral arterial stiffness, carotid intima-media thickness, and reduced ocular perfusion pressure, although these changes were similar to those of high-IOP POAG patients.
The association between NTG and metabolic syndrome or its components is still debatable. The Tajimi Study35 found no relationship between glaucoma and obesity or hypertension, whereas Kim et al64 reported that hypertension and impaired glucose tolerance were associated with increased risk of NTG in a population that underwent health screenings. A meta-analysis of population-based studies showed that systemic hypertension increased the risk of developing POAG, but that this relation was not definite in NTG patients.64 The literature to date has not established any significant association between diabetes mellitus and NTG other than its relationship with bilateral involvement of NTG in 1 retrospective study by Kim and Kim.65 In a population-based study using Korea National Health and Nutrition Examination Survey data, a fasting capillary glucose level of 200 mg/dL or greater was a significant risk factor for NTG in a Korean population between 19 and 39 years of age.64 A positive association between diabetes and IOP, furthermore, was noted in the Tajimi66 and Kumejima67 studies, but not with glaucoma.
Obstructive sleep apnea (OSA) has been posited as playing a role in glaucoma development and also in NTG.68,69 Studies have reported that people with OSA tend to have increased IOP values, possibly related to increased body mass index and RNFL thinning with visual field defect. The proposed pathogenesis of OSA in NTG seems to be multifactorial, mainly mechanical and vascular factors. The mechanical factors include increased IOP at night related to the supine position70 and obesity71 and elevated intracranial pressure.69 The vascular factors include recurrent hypoxia with increased vascular resistance or dysregulation and subsequent reperfusion injury, all leading to increased levels of oxidative stress and inflammation, decreased perfusion pressure, and prolonged ischemia, ultimately damaging the optic nerve.69 However, more direct evidence supporting the associations among these various factors and OSA is needed.
Translaminar Pressure Difference
Increased translaminar pressure difference has been investigated as a potential risk factor in glaucoma pathogenesis.72 Translaminar pressure was reported to have a positive association with visual field loss73 and cup-to-disc ratio74 and a negative association with neuroretinal rim area.73 Studies have also reported that intracranial pressure is lower in patients with NTG than in those with POAG or normal subjects.72,74–76 Low intracranial pressure in the context of normal IOP levels might in fact lead to an abnormally large translaminar cribrosa pressure difference, thereby increasing the probability of glaucomatous damage. Jonas et al,41 utilizing data from the Beijing Eye Study, reported that translaminar pressure difference (calculated with body mass index, diastolic blood pressure, and age) showed a better correlation with the extent of glaucomatous damage than did IOP, indicating its potential role as a biomarker for open-angle glaucoma. However, the relationship between translaminar pressure difference and glaucoma is complex and can be affected by various factors such as body mass index, body position, blood pressure, and displaced lamina cribrosa. Therefore, further investigations aiming to uncover the influence of such systemic or ocular variables on translaminar pressure difference are needed to expand our knowledge of its link with NTG.
In NTG patients, increased titers of serum antibodies against retinal or optic nerve proteins were found, indicating that retinal ganglion cell (RGC) degeneration can be accelerated by an imbalance of immune regulation between the proapoptotic and antiapoptotic pathways.19,77 Patients with NTG also showed increased antiphosphatidylserine antibodies compared with POAG patients and control subjects.78 These antibodies bind to phosphatidylserine molecules, which are shifted from the inner to the outer leaflet of cell membranes. This process activates the coagulation cascade and thus can cause thrombosis. This might explain the higher frequency of thromboembolism in NTG patients and suggests a strong association of apoptosis or circulatory disturbances and NTG.78 However, in another study investigating the association between NTG and autoantibodies detected in rheumatic disease, NTG patients did not show elevated levels of such antibodies, but only a higher level of antiprothrombin antibodies relative to the POAG group.79 The possible pathogenic role of Helicobacter pylori in increased autoimmunity has been raised as a secondary aggravating factor for NTG. Although more direct evidence is required, possible hypotheses are the release of proinflammatory and vasoactive substances, platelet activation and aggregation, production of reactive oxygen species, or antibodies against H. pylori cross-reacting with RGC, thus inducing their degeneration.80
Glaucoma is presumed to be a complex and multifactorial disease that is caused by an interaction of genetic (hereditary) and environmental factors. As a positive family history has been found to be a significant risk factor for glaucoma, genetic and/or familial factors are considered to play important roles in glaucoma development.81 A number of genes [eg, optineurin (OPTN), myocilin (MYOC), WD repeat-containing protein 36 (WDR36), endothelial type receptor, optic atrophy 1 (OPA), Toll-like receptor 4 (TLR4) genes], gene mutations, and genetic variants of NTG have been investigated actively despite conflicting evidence of their associations with NTG. Still, further analyses to find genes pathognomonic to NTG and subsequent analyses on the functions and weights of candidate genes in the development of glaucoma need to be pursued.
Currently, the standard diagnostic criteria for NTG consist of glaucomatous structural changes in the optic nerve head/RNFL and functional changes on visual field, the same as those established for POAG. In addition, for definitive diagnosis, IOP measurements by Goldmann applanation tonometry should consistently be 21 mm Hg or less, which is within the 95th percentile of the normal distribution of IOP measurements for the healthy population.82 Screening and diagnosis are important for early detection and treatment of NTG, because of its lack of apparent symptoms until advanced stages. Hence, recent studies have focused on more effective structural and functional measurements for obtaining early NTG diagnosis.
Characteristics of Structural Damage
Several features of optic nerve head and RNFL damage in NTG have been reported. Localized RNFL defect patterns in NTG eyes, for example, were closer to the fovea and wider than in high-IOP POAG eyes.83 This finding was supported by another study, which found that in NTG eyes visual field defects were more localized and central than in high-IOP POAG eyes.84 Also, NTG eyes showed larger cupping, smaller rims, and thinner RNFL than high-IOP POAG eyes by Heidelberg Retina Tomograph (Heidelberg Engineering GmbH, Heidelberg, Germany).85 In line with this, inferotemporally narrower optic disc rims and larger cups might be 2 of the possible explanations for the greater significance of paracentral scotoma in early NTG.86
Other than NTG and POAG eyes, studies also have compared the patterns of structural damage in different subgroups of NTG eyes. In a comparison between NTG eyes with low-teen and high-teen baseline IOP, localized RNFL defects were closer to the center of the macula in those with low-teen baseline IOP, whereas no significant difference was found in the width of the defects.87 Kim et al88 reported that localized RNFL defects were wider and closer to the fovea in NTG eyes with high myopia than in those with low to moderate myopia or emmetropia.
Use of Spectral-Domain Optical Coherence Tomography
High-resolution imaging devices have been developed to supplement clinical assessment, thereby improving glaucoma diagnostic performance. Among such ancillary imaging devices, the most commonly used is probably spectral-domain optical coherence tomography (SD-OCT). Numerous studies have highly praised SD-OCT for its objective and accurate peripapillary RNFL thickness, optic nerve head, and macular ganglion cell–inner plexiform layer (GCIPL) measurements, which can also be effective for diagnosing NTG.89,90
When forming judgments on glaucomatous structural damage, myopic eyes can be significantly challenging because of the following structural hurdles: tilted optic disc, large peripapillary atrophy, and myopia-induced retinal thinning. Even disc and RNFL photography cannot provide much information on highly myopic eyes with degenerative retinas. For myopic eyes with NTG, peripapillary measurements and diagnostic classifications based on the internal normative database of SD-OCT could have a high possibility of presenting false-positive results.91,92 A number of efforts to overcome these limitations have been made over the years. Approximately 50% of RGCs are concentrated within 4.5 mm of the fovea with less interindividual variability.93 Thus, recently updated papers are suggesting the potential of macular ganglion cell layer thickness as a useful diagnostic parameter for eyes with concurrent glaucomatous and myopic damage. In support of this contention, macular ganglion cell complex94 and GCIPL thickness95 measurements have shown good diagnostic performance comparable to RNFL measurements in myopic and highly myopic eyes. Moreover, Nakanishi et al,96 applying a normative database of macular ganglion cell complex thickness obtained from highly myopic eyes, found an improvement in the specificity for detection of early glaucoma in highly myopic eyes. A combination of effective SD-OCT parameters or application of a new normative database for myopic eyes is expected to synergistically enhance diagnostic power for myopic eyes with NTG.
New Technologies in Use
Along with extensive technological improvements, OCT angiography has been developed as a noninvasive method to sensitively quantify microcirculation in the optic nerve head by combining high-speed OCT and the split-spectrum amplitude-decorrelation angiography algorithm.97 It revealed decreased optic disc perfusion status in glaucoma patients compared with normal subjects, indicating an association between focal optic disc ischemia and glaucoma.97 Using the same device, reduced disc flow index and vessel density in glaucoma patients were found, which were associated with glaucomatous structural severity as represented by ganglion cell complex thickness.98 Nonetheless, more results on the optic disc perfusion characteristics distinctive to NTG or the difference between POAG and NTG patients are anticipated. In addition, swept-source OCT uses the light source of a wavelength-sweeping laser centered at 1050 nm, which enables visualization of deeper structures such as the lamina cribrosa, choroid, and sclera.99 Unknown glaucomatous changes occurring in these deep structures have been explored by swept-source OCT along with SD-OCT in the enhanced depth imaging mode.100,101 Using new technologies, we expect additional NTG-specific features will be discovered.
According to recent reports on clinical outcomes for NTG patients, the rate of glaucoma progression and the proportion of blindness in NTG patients seem to be low. In a hospital-based study by Sawada et al,102 after 20 years of follow-up, 9.9% ± 1.9% and 1.4% ± 0.8% of NTG patients, respectively, developed unilateral and bilateral blindness. Choi et al103 reported that the cumulative risk of visual impairment (low vision or blindness) in at least 1 eye was 2.8% at 10 years and 8.7% at 15 years. The rates were somewhat different among studies, but they were relatively lower than those reported for POAG patients, the bilateral blindness of whom has been reported to range between 9%104 and 42.7%105 at 20 years. Despite relatively slow progression in NTG patients, the glaucomatous visual field does develop or progress in approximately half (or more than half, depending on the study) of patients during follow-up.36,37,39 Therefore, regular follow-up and examinations for detection of structural and functional change are needed, and additional caution and care should be extended to those with high-risk factors for progression.
Monitoring of Structural and Functional Progression
Follow-up with balanced judgment on structural and functional glaucomatous change in reference to the established baseline is essential for monitoring progression in glaucoma. For appropriate monitoring of functional progression, standard automated perimetry, which is still the criterion standard for monitoring functional change, should be regularly used. Currently, event and trend analysis by guided progression analysis software is being widely adopted in clinical practice for the detection of visual field progression in glaucoma. An adequate number of perimetries and standardization are advised to improve comparability. Although there is as yet no best answer on the appropriate number of perimetries for evaluation of progression, the suggested numbers are 2 to 3 examinations per year, depending on the patient’s stage and progression rate.106 In the course of NTG, not all patients follow the same progression pattern, although studies have uncovered some helpful consistencies. Ahrlich et al107 found that NTG eyes progressed more often within the paracentral visual field compared with eyes with exfoliative high-tension glaucoma. Cho and Kee,108 comparing the rate of visual field progression (using mean thresholds) in NTG eyes with different locations (superior, inferior, and both) of visual field defects at baseline, found the fastest rate of progression in those with superior hemifield defect.
When monitoring structural progression, changes in the optic nerve head (eg, enlargement of cup-to-disc ratio, increased neuroretinal rim thinning, rim notching) and RNFL (eg, increased width or depth of RNFL defect, appearance of new RNFL defect) should be carefully evaluated as in open-angle glaucoma. Red-free RNFL photography can be highly sensitive in detecting signs of RNFL progression.109 However, it might be of limited value because of subjective and qualitative data on RNFL and in white populations with less pigmented retinas. To compensate for such limitations, OCT has been widely used as an additional effective means of monitoring glaucoma progression.110,111 However, when evaluating progression using OCT, caution is necessary to properly differentiate intersession variability from progression. In reference to the long-term reproducibility data of various OCT devices, thickness change exceeding the cutoff variance of each OCT parameter can be regarded as progression and as such should be distinguished from intersession variability. For instance, when using Cirrus OCT (Carl Zeiss Meditec Inc, CA, USA), changes in the average RNFL thickness exceeding 6.5 μm112 and in the average GCIPL thickness exceeding 4.0 μm113 are more likely to be signs of progression rather than of long-term test-retest variability.
Risk Factors for Progression
Not only should structural and functional examinations be performed on a regular basis, but also NTG eyes with risk factors for progression should be followed up with caution. With the therapeutic effect of IOP reduction well established since the Collaborative Normal-Tension Glaucoma Study,114 no one can deny the importance of lowering IOP to slow down the progression rate in NTG patients. With regard to IOP-related parameters in NTG patients, insufficient IOP reduction36,38,113 and large IOP fluctuation39 were found to be significant risk factors for progression. Therefore, major therapeutic goals for NTG patients include achievement of a large extent of IOP reduction and maintenance of low and stable IOP. However, NTG patients with low IOP have a narrow therapeutic range, and thus, it is not always easy to achieve a sufficient extent of IOP reduction for them.
Some NTG patients show continued progression despite maximal IOP-lowering therapy or maintenance of very low IOP.115 In such patients, IOP-independent risk factors, such as autonomic dysfunction,116 low nocturnal blood pressure,59 low ocular perfusion pressure,117 and large fluctuation of ocular perfusion pressure,118 can play more dominant roles in the disease course. Patients with NTG having systemic vascular risk factors, including autonomic dysfunction with sympathetic predominance (lower heart rate variability)116 or low nocturnal blood pressure, especially pressure that is 10 mm Hg lower than daytime mean arterial pressure,59 are reported to be at greater risk of progressive visual field loss. Lower mean ocular perfusion pressure increased the risk of progression in a low-pressure glaucoma treatment study,117 and unstable ocular perfusion pressure with large fluctuation was the most consistent prognostic factor for central visual field progression in an investigation by Sung et al.118 However, care should be exercised when interpreting ocular perfusion pressure: as blood pressure and IOP are its main determinants, their statuses should not be overlooked.
Disc hemorrhage, prevalent in 20% to 35% of NTG patients,119 is considered to be 1 of the significant risk factors associated with progression.37–39,120–122 Despite lingering questions on whether disc hemorrhage is an indicator of progression or a risk factor for progression, there is no doubt that it has a significant impact on glaucoma progression.
Controversy also persists on the issue of myopia as a risk factor for visual field progression. Sakata et al123 demonstrated that myopia extent was a significant prognostic factor for visual field progression in the upper paracentral area (in non–highly myopic eyes), whereas other studies found that myopia did not show any significant association with the NTG progression rate under medical treatment.124,125 Likewise, in an evidence-based review, myopia was not a significant risk factor for progression in NTG patients.121 The current data indicate that myopia might be more associated with the development of glaucoma than with its progression, but further studies are needed for confirmation.
Glaucoma is a multifactorial and mysterious disease that still requires large-scale, prospective investigations to find answers to unresolved questions. Current data on NTG demonstrate that NTG shares similar pathophysiology and mechanisms with POAG, but at the same time has many of its own distinctive features. It would be of great interest to discover additional in-depth information on the relevant IOP-dependent and -independent risk factors for both the development and progression of NTG and their cause-and-effect relationship. We believe that delineation of the pathomechanisms of NTG would lead to improvements in early detection and effective treatment, not only for NTG patients but also for POAG patients.
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