Ocular and systemic risk factors associated with glaucomatous visual field defect in normal tension glaucoma

INTRODUCTION

One of the leading causes of preventable blindness worldwide is glaucoma.^[1] A class of eye conditions known as glaucoma is defined by optic neuropathy, which is frequently accompanied by high intraocular pressure (IOP) and can cause irreversible damage to the optic nerve. Because the disease is frequently asymptomatic in its early stages, it is often diagnosed only after significant and irreversible visual loss has occurred.^[2] Primary open-angle glaucoma patients are categorized as normal tension glaucoma (NTG) in one-third of cases.^[3]

NTG is characterized by cupping of the optic disc and abnormalities in the visual field, as well as an IOP of <21 mmHg on applanation tonometry.^[4,5] Even though IOP is thought to be the most important one, several other factors have also been reported to influence the development and progression of NTG.

The pathophysiology of NTG remains poorly understood. Recent research has shed light on a complex interplay of factors that may contribute to the disease process, ranging from vascular insufficiency and abnormalities in the flow of blood in the optic nerve head to genetic predisposition and systemic conditions that affect ocular health. Furthermore, environmental and lifestyle factors such as stress, hypotension, and sleep disturbances have also been implicated in exacerbating the condition.^[6] Understanding these multifactorial risk factors is crucial for improving early detection, monitoring, and management strategies to preserve vision in individuals with NTG.

Despite several studies evaluating ocular and systemic risk factors in NTG, most available data are derived from nonBangladeshi populations, particularly from East Asia and South India. Regional variations in genetic predisposition, systemic comorbidities, and healthcare access may influence both the presentation and progression of NTG. Moreover, the relationship between certain systemic conditions, such as thyroid disorders, and the severity of glaucomatous visual field damage remains inadequately explored.

Therefore, this study aims to evaluate both ocular and systemic risk factors associated with NTG and to assess their correlation with the severity of glaucomatous visual field defects in a Bangladeshi population.

MATERIAL AND METHODS

A cross-sectional analytical study was conducted at the Department of Ophthalmology at a tertiary-level hospital over a 1-year period. The study population comprised 67 patients in total. Patients either from inpatient or outpatient premises at the Department of Ophthalmology were included in this study. A consecutive type of sampling technique was applied to enroll the patients. The inclusion criteria included open angles on gonioscopy, typical optic disc alterations, distinctive visual field abnormalities, and a mean IOP ≤21 mmHg (Goldmann applanation tonometry). Patients with opacity of the cornea, prior intraocular surgery, contact lens users, corneal edema, other diseases of the optic nerve, intracranial disease, and secondary causes of optic neuropathy (angle recession glaucoma, steroid-induced glaucoma, and inflammatory glaucoma) were excluded. A thorough eye examination was performed on each of them, including visual acuity, slit-lamp biomicroscopy, and IOP using a Goldmann applanation tonometer. Normal value is 10–21 mmHg, gonioscopy (with the help of Zeiss 4 mirror lens and anterior chamber was designated as open on the basis of Shaffer grading system grade 2 or more, i.e., posterior Trabecular meshwork visible at least 270°) and fundoscopy (done with the slit lamp via the help of Ocular +78 D condensing lens). We observed peripapillary atrophy, focal notching, nerve fiber layer abnormalities, laminar dot sign, neuroretinal rim thinning, disc hemorrhage, and optic disc cupping. A detailed history of systemic disease was taken. The Humphrey field analyzer was used for field evaluation. Anderson’s criteria were used to examine and grade visual field problems. Statistical analysis was conducted using the Statistical Package for the Social Sciences 27.0 software.

RESULTS

In this cross-sectional study, the mean age of participants was 59.3 ± 10.4 years, ranging from 31 to 75 years. Seven patients (10.4%) were aged between 30 and 45 years, 27 (40.3%) patients were aged between 46 and 60 years, and 33 (49.3%) patients were aged from 61 to 75 years. There were 39 male patients, who constituted 58.2% of the cohort. Seventeen (25.4%) patients had a family history of glaucoma. IOP ranged from 8 to 21 mmHg (mean: 15.3 ± 3.2 mmHg), with most patients (55.2%) in the 15–21 mmHg range. As shown in Table 1, the mean CD ratio was 0.69 ± 0.13, with 50.7% of participants having a CD ratio between 0.51 and 0.79. The average central corneal thickness (CCT) was 525.8 ± 44.7 µm, with most patients (50.7%) in the 501–550 µm range. Systemic comorbidities included hypertension (71.6%), diabetes mellitus (49.3%), dyslipidemia (43.3%), smoking (28.4%), ischemic heart disease (19.4%), and Alzheimer’s disease (3%). Visual field changes were predominantly early stage (35.8%) or pre-perimetric (31.3%), while 22.4% had advanced-stage changes. Optic disc findings included neuroretinal rim thinning (47.8%), disc hemorrhage (14.9%), and pale discs (3%) [Figure 1]. No significant associations were found between age, gender, diabetes, hypertension, or dyslipidemia and glaucomatous changes, except for thyroid disorders (P = 0.038). Ocular factors showed a significant association between CD ratio and glaucomatous changes (P = 0.045) [Table 2]. As shown in Table 3, glaucomatous visual field changes had a weak positive correlation with age (ρ = 0.248, P = 0.043) and a moderately positive correlation with CD ratio (ρ = 0.364, P = 0.002).

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Figure 1: Distribution of systemic co-morbidities in normal tension glaucoma patients (n=67).

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DISCUSSION

In our study, the demographic and clinical profile of the study population was consistent with typical NTG cohorts, with a predominance of older individuals and a slight male preponderance. Systemic comorbidities such as hypertension, diabetes mellitus, and dyslipidemia were commonly observed, reflecting the known association between vascular risk factors and NTG. Most patients presented with early or preperimetric visual field changes, highlighting the importance of early detection in this condition. Optic disc findings were predominantly characterized by neuroretinal rim thinning and occasional disc hemorrhage, which are well-recognized features of glaucomatous optic neuropathy. In our analysis, conventional systemic risk factors such as age, gender, diabetes, hypertension, and dyslipidemia did not show a significant association with the severity of glaucomatous visual field defects. However, thyroid disorders demonstrated a significant association, suggesting a potential role of systemic endocrine factors in disease progression [Table 4]. Among ocular parameters, the cup-to-disc (CD) ratio was the only factor significantly associated with the severity of glaucomatous damage and showed a positive correlation with visual field defects. In contrast, IOP and CCT did not demonstrate significant correlations, consistent with the pressure-independent nature of NTG [Tables 2 and 3]. The mean age of our participants was in the late fifties, with a higher proportion of patients in the older age group. This is consistent with previous studies by Leung et al. which also reported a higher prevalence of NTG in older individuals, supporting the association between increasing age and NTG.^[7] However, Krishnan et al. reported a relatively younger study population, suggesting possible regional variations in the age of presentation.^[9] These findings reinforce age as an important risk factor in NTG, although regional differences in demographic profiles may influence the age of presentation.

Male patients constituted the majority of our study population. In contrast, Kosior-Jarecka et al. reported a female predominance, suggesting possible regional or demographic variations in gender distribution among patients with NTG.^[10]

A quarter of the individuals had a family history of glaucoma. Krishnan also demonstrated a high correlation between future NTG development and family history.^[9]

Systemic comorbidities were common in our cohort, with hypertension (71.6%) and diabetes mellitus (49.3%) being the most prevalent, followed by dyslipidemia (43.3%) and smoking (28.4%). These findings are consistent with previous studies by Leung et al. and Krishnan et al., which also highlight the role of vascular and metabolic risk factors in NTG.^[7,9] In addition, vascular dysregulation, including arterial hypotension, has been emphasized by Leung et al., while Kosior-Jarecka et al. reported associations with conditions such as migraine, cold extremities, and systemic hypotension.^[7,10] Neurological comorbidities, including stroke (4.5%) and Alzheimer’s disease (3%), were also observed in our study population. Prior studies, such as those by Chen et al. and Ho et al., have reported an increased association between NTG and neurodegenerative disorders, with evidence suggesting a higher risk of Alzheimer’s disease among NTG patients.^[8,11] These associations support the hypothesis that impaired vascular regulation and neurodegenerative mechanisms may contribute to the pathogenesis of NTG.

The IOP in our study ranged from 8 to 21 mmHg, with a mean of 15.3 ± 3.2 mmHg, and most patients had IOP within the upper normal range. These findings are comparable to those reported by Krishnan et al., who observed a similar mean IOP, reinforcing the characteristic feature of NTG. Slight variations in mean IOP across other studies, such as those by Kosior-Jarecka et al. and Asaoka et al., may reflect differences in study populations and measurement settings.^[10,12] Overall, these observations support the concept that IOP remains within the statistically normal range in NTG, despite the presence of glaucomatous damage.

The mean CD ratio in our study was 0.69 ± 0.13, with the majority of patients falling within the moderate cupping range. This is comparable to previous studies, including those by Krishnan et al. and Kosior-Jarecka et al., which reported similar distributions of CD ratio, supporting its role as a key structural indicator in NTG.^[7]

The mean CCT was 525.8 ± 44.7 µm, with most participants within the mid-normal range. These findings are consistent with earlier reports, including those by Krishnan et al., Kosior-Jarecka et al., and Asaoka et al., suggesting that CCT in NTG patients generally falls within the normal range and may not independently influence disease severity.^[9,12]

Visual field defects in our study were predominantly in the early and pre-perimetric stages, with a smaller proportion of patients presenting with advanced disease. This highlights the importance of early detection in NTG, where structural damage may precede significant functional loss. Optic disc evaluation revealed that neuroretinal rim thinning and disc hemorrhage were the most common findings, consistent with characteristic features of glaucomatous optic neuropathy. Similar patterns have been reported in previous studies, including those by Krishnan et al. and Kosior-Jarecka et al., although variations in the frequency and type of visual field defects and disc changes may reflect differences in study populations and disease stages at presentation.^[9,10]

Our findings are broadly comparable to those reported by Krishnan et al. (2018) from South India,^[9] who also evaluated ocular and systemic risk factors in NTG. Similarities were observed in terms of mean IOP, CCT, and distribution of CD ratio.^[8] However, our study provides additional insights by evaluating these associations in a Bangladeshi population, where epidemiological and systemic risk profiles may differ.

Notably, thyroid disorders demonstrated a statistically significant association with glaucomatous visual field changes in our study, a finding that has not been consistently emphasized in earlier regional studies. This suggests a possible role of systemic endocrine dysfunction in influencing disease severity, warranting further investigation. This finding is supported by Park et al. (2021), who highlighted the role of systemic factors, including metabolic and vascular dysregulation, in the development of NTG in the South Korean population. Such associations suggest that NTG may not be solely an ocular condition but part of a broader systemic disease process affecting optic nerve perfusion.^[13]

In our study, glaucomatous changes showed a weak positive correlation with age and a moderate correlation with CD ratio, while no significant correlation was observed with IOP or CCT. These findings suggest that structural optic nerve parameters may be more closely associated with disease severity than pressure-related factors in NTG.

Previous studies have reported variable associations between CCT, IOP, and glaucomatous damage. While some authors, including Krishnan et al., have described weak correlations between CCT and optic nerve parameters, these associations were not consistently statistically significant.^[9] Similarly, other studies have found no significant relationship between IOP and CCT across different glaucoma subtypes, although moderate correlations have been observed in ocular hypertension.^[14,15]

The lack of a significant relationship between IOP and disease severity in our study further supports the concept that NTG is largely independent of elevated IOP. In addition, the known influence of CCT on Goldmann applanation tonometry measurements may partly explain inconsistencies in reported associations. Overall, our findings reinforce the importance of structural assessment, particularly the CD ratio, in evaluating disease severity in NTG.

This study has several limitations. The cross-sectional design limits the ability to establish causal relationships between risk factors and disease progression. The relatively small sample size and single-center setting may affect the generalizability of the findings. In addition, the lack of longitudinal follow-up restricts the assessment of temporal changes in glaucomatous damage. Important vascular factors such as ocular perfusion pressure and nocturnal hypotension were not evaluated. Furthermore, some systemic data were based on patient-reported history, which may introduce recall bias.

CONCLUSION

NTG can range from asymptomatic disease to progressive visual loss and may mimic other optic neuropathies, requiring careful evaluation. In addition to IOP-lowering therapy, systemic factors such as cardiovascular disease, diabetes, hyperlipidemia, and thyroid disorders should be addressed. A multidisciplinary approach is essential to reduce disease progression and prevent irreversible vision loss.