Normal-tension glaucoma (NTG) was first described by von Graefe back in 1857.^(1,2) More than 160 years have passed since then, and NTG remains a diagnostic and therapeutic challenge for ophthalmologists. NTG, also known as normal or low-pressure glaucoma, is defined as a type of chronic open-angle glaucoma with a statistically normal intraocular pressure (IOP).⁽³⁾

While elevated IOP represents the main risk factor for progressive visual field loss in open-angle glaucoma, the progression of NTG involves diverse and multifactorial mechanisms, ultimately leading to the common final pathway of retinal ganglion cell loss. Several investigations have placed greater emphasis on the vascular theory over the mechanical theory, given that IOP falls within statistically normal ranges, with compromised blood flow being more pronounced in NTG compared to high-tension glaucoma.⁽⁴⁾ Low blood pressure, orthostatic hypotension, nocturnal hypotension, migraine, Raynaud phenomenon, and sleep apnea have been identified as risk factors for NTG.^(5-9) Other proposed non IOP-dependent mechanisms include metabolic and neurodegenerative alterations, excitotoxicity, oxidative stress, autoimmunity, and abnormal biomechanics of the lamina cribrosa.^(10,11)

IOP reduction remains a beneficial treatment for NTG.⁽¹²⁾ The Collaborative Normal-Tension Glaucoma Study (CNTGS) demonstrated that a 30% IOP reduction significantly decreased the risk of glaucoma progression in treated patients compared to untreated patients.^(12,13) However, ongoing research is exploring other treatment strategies that do not involve IOP reduction, including nutritional supplements and phytochemicals as adjunctive therapies.

Ginkgo Biloba extract (GBE), derived from a tree species native to China, Korea and Japan, is among the most commonly studied phytochemicals. It has been used for treatment of vascular and neurological disorders for hundreds of years and is considered one of the most widely used herbal supplements worldwide.⁽¹⁴⁾

GBE consists mainly of flavonoids and terpenoids, which have been proven to possess vasorelaxant, antioxidant, and neuroprotective effects.^(15-18) While there are no approved indications for GBE by the Food and Drug Administration (FDA), it has been used as adjunctive therapy for cardiovascular diseases,⁽¹⁹⁾ diabetes,⁽²⁰⁾ ischemic stroke,⁽²¹⁾ dementia,⁽²²⁾ psychiatric disorders,⁽²³⁾ vertigo,⁽²⁴⁾ tinnitus,⁽²⁵⁾ and vitiligo.⁽²⁶⁾ In ophthalmology, GBE has been used for age-related macular degeneration,⁽²⁷⁾ and glaucoma.⁽²⁸⁾ Preclinical studies have demonstrated that GBE exerts neuroprotective effects on retinal ganglion cells in rat models of chronic high-tension glaucoma.⁽²⁹⁾ However, the absence of available animal models for NTG presents a challenge. Nonetheless, several clinical studies have explored the impact of GBE treatment in NTG, with conflicting results.^(30-34) Therefore, the aim of this meta-analysis was to investigate the efficacy of GBE compared to placebo in the treatment of NTG.

This meta-analysis was performed according to the guidelines of the Declaration Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and the recommendations of the Cochrane Collaboration.⁽³⁵⁾ The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number (CRD42024548235).

Management of NTG could be more challenging than high-tension glaucoma, necessitating a greater reliance on non-IOP-dependent strategies to reduce the risk of glaucoma progression. This meta-analysis aims to help clinicians and patients in deciding whether to use the adjunctive treatment GBE alongside IOP-lowering medications. Given the few RCTs with limited sample sizes on the efficacy of GBE in NTG, our goal was to incorporate data from various study designs that compared the use of GBE versus placebo in the settings of NTG. The four studies we identified included a total of 285 eyes and allowed for a comparison between GBE and placebo in terms of changes in visual field MD, visual field PSD, and IOP, over a follow-up duration ranging from 1 month to 24 months. The present analysis suggests that use of GBE resulted in significantly better visual field MD in patients with NTG compared to the use of placebo. Additionally, the GBE group experienced no adverse events, indicating a strong safety profile. Changes in visual field PSD and IOP were similar between groups.

The main finding of the present analysis is that the visual field MD was significantly better in the GBE group compared to the Placebo groups, with a mean difference of 1.7 dB. Given that no significant changes in IOP were observed in the GBE group following treatment, these results suggest potential neuroprotective effects of GBE. These effects may be linked to its antioxidant and anti-inflammatory properties reported in previous studies.^(40-43) Additionally, since reduced optic nerve blood flow can contribute to glaucomatous visual field damage,⁽⁴⁴⁾ and considering that GBE can has been shown to improve ocular blood flow,^(33,45,46) this could explain the beneficial effect of GBE on the visual field. These mechanisms may help mitigate neuronal damage and preserve visual function, particularly in the context of NTG where IOP-independent factors play a crucial role in disease progression.⁽¹¹⁾

On the other hand, there were no significant differences between the GBE and placebo groups in terms of changes in visual field PSD. PSD measures the irregularity or variability in visual field sensitivity patterns.⁽⁴⁷⁾ The lack of difference in PSD between the GBE and placebo groups suggests that while GBE may improve the overall average sensitivity, as represented by visual field MD, it may not significantly affect the specific patterns of sensitivity loss in the visual field. The beneficial effect of GBE on visual field MD, attributed to its antioxidant, anti-inflammatory, and neuroprotective properties,^(40-43) may help maintain optic nerve function, reduce overall loss of visual sensitivity, and improve global measures of visual function. However, these effects may not extend to altering the localized patterns of damage that contribute to PSD.

The study carries several limitations. Firstly, it is based on a small number of studies involving a total of 285 eyes, which may limit the generalizability of the findings. Additionally, the studies included had relatively short treatment and follow-up durations, which restricts the ability to assess the long-term sustainability of the benefits observed with GBE. Moreover, there is a risk of publication bias, as unpublished studies, particularly those with negative results may not have been included, potentially skewing the overall findings. Other outcome measures such as changes in ocular blood flow or contrast sensitivity were not analyzed due to insufficient data availability. Lastly, studies were included regardless of their quality assessment to enable a thorough review of the available evidence. On the other hand, this study also has notable strengths; three out of four studies were RCTs, indicating a robust study design. Only one study was retrospective and had a moderate risk of bias, suggesting a generally high methodological quality among the included studies.