Gingko Biloba as an adjuvant to Timolol in Moderate Primary Open Angle Glaucoma

INTRODUCTION

Glaucoma is a major cause of irreversible blindness in the world.¹ It has been noticed that blood flow is decreased in glaucoma patients in different tissues of the eye.² Primary open-angle glaucoma (POAG), is a chronic, progressive neurodegenerative disease characterized by cupping of optic disc and loss of visual field.³ In addition to increased Intraocular Pressure (IOP); there are more risk factors like genetic factors, decreased intracranial pressure, systemic diseases and neurodegenerative diseases associated factors  like oxidative damage, mitochondrial dysfunction, microglial activation and excitotoxicity, can also contribute in the glaucomatous damage of optic nerve.⁴

Despite these variable causes; the only proven treatment is decreasing IOP using medical, laser, or surgical procedures, that reduce vascular resistance thus increase mean vascular flow. FDA has only approved calcium channel blockers as a treatment dealing with the vascular risk factors but there are doubts about their efficacy. This is why, new treatments are needed to be discovered to deal with those biochemical, genetic, cell biological, and pathophysiologic mechanisms.⁴

Chinese traditional medicine has used Ginkgo Biloba for about 5000 years.⁵ Currently, its extraction is utilized in multiple medical conditions like concentration difficulties, confusion, depression, anxiety, dizziness, headache and tinnitus.⁶ It has been proven that Ginkgo has a neuroprotective and anti- oxidative properties. It also causes vasodilation and reduction of blood viscosity thus increases blood flow. These characteristics suggest that Gingko Biloba could be a proficient adjuvant treatment in glaucoma.⁷ Several studies were done to examine the role of Ginkgo Biloba in Normal Tension Glaucoma (NTG), they showed that Ginkgo Biloba has increased the retinal blood flow and improved preexisting visual field damage.^{4, 8-11}

This study was done to assess the safety and the efficacy of using Ginkgo Biloba capsules with Timolol eye drops in the treatment of patients with moderate POAG.

PATIENTS AND METHODS

Patients

This randomized comparative clinical trial was conducted between May and December 2021 at “The Department of Ophthalmology in El-Huseein & El-sayed Galal Al-Azhar University Hospitals, Cairo, Egypt”.

Ethical Consideration

We received the approval for this study from The Ethics Board of Al-Azhar University, Cairo, Egypt and the Medical Research Ethical Committee of the National Research Centre, Cairo, Egypt under the number “41022022”. Before starting the study; we collected a written informed consent from each participant. The study followed the principles specified in the Declaration of Helsinki.

Inclusion Criteria

Patients with moderate POAG aged 30 to 50 years old of both genders. IOP should only be controlled by Timolol. Patients should have the mental and physical capacity to give informed consents and follow the instructions. If a patient is on medication that affects blood flow then there should be no alteration in the dose or direction of medication for at least 2 months before starting the study. No vitamin supplements for 1 month before starting the study & during the study.

Moderate stage POAG was defined according to (the Glaucoma Severity Staging System Classification)³ that has the following characteristics; Humphery MD score = -5.01 to -12.00 AND regarding probability plot/pattern deviation; points below 5% should be 19-36 and points below 1% should be 12-18 OR regarding dB plot; point(s) within the central 5° with sensitivity of 1 and point(s) within the central 5° with sensitivity ofOR Points(s) with sensitivity

Exclusion Criteria

Visual acuity of 6/12 or less, Anisometropia >1 D, Central Corneal Thickness < 500 µm in either eye, lens opacities more severe than C2, N2, P2 according to lens opacities classification system III criteria, previous ocular and systemic disorder that could affect optic disc appearance and VF test (e.g. high myopia, tilted disc, DM), history of ocular surgeries, history of having ocular inflammation or infection in the 3 months before trial, hypersensitivity to Gingko Biloba, pregnancy or breastfeeding women, addiction or alcoholism, use of other ocular medications that might affect IOP, use of other similar systemic medications (e.g., ergoloid mesylate derivative: a vasodilator agent) and contact lens wearers.

Study Design

We initially enrolled 90 patients with moderate POAG with IOP being normalized by Timolol alone. The study extended for 6 months (180 days). Patients were divided into two groups; a case group of 45 patients who continued on Timolol with addition of Ginkgo Biloba capsules (40mg capsule 3X/day for a total of 120mg/day) and a control group of 45 patients who continued using Timolol eye drops alone.

Methods

Each patient was subjected to the following at the beginning of the study then every 2 months; full history taking, coagulation tests that included bleeding time (BT), activated partial thromboplastin time (aPTT), prothrombin time (PT/ INR) and thrombin time (TT) and ocular examination that included slit lamp examination, gonioscopy, angle examination, retinal and optic disc evaluation, measuring visual acuity and IOP.

Visual field (VF) examination was done at the beginning and at the end of the study. We used “Humphrey Field Analyzer 3; Carl Zeiss Meditec Inc, Dublin, Ca, USA” with Central 24-2 Threshold Test and the “Swedish Interactive Threshold Algorithm (SITA)” was set to fast. Visual Field Index percent (VFI %) and Mean Deviation dB (MD) are global indices that were used to assess the results.^{12, 13}

Optical coherence tomography angiography (OCTA) was done at the beginning and at the end of the study. We used “AngioPlex Cirrus HD-OCT device (model 5000, Carl Zeiss Meditec, Inc., Dublin, USA)”. We applied a scanning area of 6 × 6 mm² centered on the ONH and a scanning area of 4.5x4.5 mm² centered on the macula. The outer region of ONH contains the radial peripapillary capillary (RPC). For OCTA of ONH; we used two parameters in assessment; perfusion density % and flux index. For OCTA of Macula; we used perfusion density % and vessel density parameters that were defined in the “Early treatment of diabetic retinopathy study (ETDRS)”.^{14, 15}

Statistical Analysis

It has been done using IBM SPSS statistics (Statistical Package for Social Sciences) software version 26.0, IBM Corp., Chicago, USA, 2019. Data were expressed as mean ± SD (standard deviation), then compared using independent t-test (groups comparisons) and paired t-test (times comparisons). Differences between groups were expressed as Mean ± SE (standard error) and 95% confidence interval. P value was considered to be significant if < 0.05.

RESULTS

Of a total of 90 cases that were initially enrolled in this study, only 82 cases completed the study whom were distributed as 42 patients (77 eyes) in the case group, and 40 patients (70 eyes) in the control group. The other eyes were excluded due to poor image quality caused by media opacities like “vitreous floaters”, motion artifact or blink artifact.

Regarding Age and gender; the differences were not significant among the two groups (Table 1).

Non-significant (NS) if P-value > 0.05, Significant (S) if P-value < 0.05., • Independent t-test, * Chi-square test.

Table 1: Comparison regarding demographic characteristics

Regarding coagulation tests (BT, aPTT, PT/INR and TT), visual acuity and IOP; there were no significant differences between the follow up levels and baseline level in both groups and the differences were not significant between them at the baseline and the follow up levels.

Regarding VFI%; there was a significant improvement “▲7.7%” at the end of the study in the case group (Mean difference = 6.73±10.80; p= 0.014) with non-significant change in the control group (Mean difference = 1.42±5.88; p= 0.306). The difference between the case and control groups was not significant regarding baseline level but at the study end the difference was significant (93.63±10.12 vs 87.36±11.64; p = 0.001). (Table 2), (Fig. 1)

CI: Confidence interval, # Independent t-test, SE: Standard error, *Paired t-test, Non-significant (NS) if P-value > 0.05, Significant (S) if P-value < 0.05

Table 2: Comparison regarding VFI (%)

Fig. 1: Comparison regarding VFI (%)

Regarding MD; there was a significant improvement “▲13.5%” at the end of the study in the case group (Mean difference = 1.17±1.95; p= 0.018) with non-significant change in the control group (Mean difference = 0.24±1.16, p = 0.378). The difference between the two groups was not significant regarding the baseline level but at the study end the difference between them was significant (-7.44±2.53 vs -8.46±2.44; p = 0.014). (Table 3), (Fig. 2)

CI: Confidence interval, # Independent t-test, SE: Standard error, *Paired t-test, Non-significant (NS) if P-value > 0.05, Significant (S) if P-value < 0.05

Table 3: Comparison regarding MD (dB)

Fig. (2): Comparison regarding MD (dB)

Regarding Outer region perfusion % of ONH; there was a significant improvement “▲2.6%” at the end of the study in the case group (Mean difference = 1.21±1.54; p = 0.003) with non-significant change in the control group (Mean difference =0.05±0.74; p= 0.740). The difference between the two groups was not significant regarding the baseline level but at the study end the difference between them was significant (47.93±1.42 vs 46.4±1.87; p < 0.001). (Table 4) and (Fig. 3, 4)

CI: Confidence interval, # Independent t-test, SE: Standard error, *Paired t-test, Non-significant (NS) if P-value > 0.05, Significant (S) if P-value < 0.05

Table 4: Comparison regarding (4.5x4.5 mm Outer Region Perfusion % of ONH)

Fig. 3: Comparison regarding (4.5x4.5 mm Outer Region Perfusion % of ONH)

Fig. 4: OCTA change analysis report of ONH of left eye (a sample report from our study).

Regarding outer region flux index of ONH; there was a significant improvement “▲4.6%” at the end of the study in the case group (Mean difference = 0.02±0.03; p = 0.009) with non-significant change in the control group (Mean difference =0.01±0.03; p = 0.083). The difference between the two groups was not significant regarding the baseline level but at the study end the difference between them was significant (0.45±0.03 vs  0.44±0.03; p = 0.045). (Tables 5) and (Fig. 4, 5)

CI: Confidence interval, # Independent t-test, SE: Standard error, *Paired t-test, Non-significant (NS) if P-value > 0.05, Significant (S) if P-value < 0.05

Table 5: Comparison regarding (4.5x4.5 mm Outer Region Flux index of ONH)

Fig. (5): Comparison regarding (4.5x4.5 mm Outer Region Flux index of ONH)

Regarding full perfusion density % of Macula; there was a significant improvement “▲6.4%” at the end of the study in the case group (Mean difference = 2.56±5.44; p = 0.049) with non-significant change in the control group (Mean difference = -0.05±0.6; p= 0.687 The difference between the two groups was not significant regarding the baseline level but at the study end the difference between them was significant (42.59±4.9 vs 39.46±6.82; p = 0.002). (Tables 6) and (Fig. 6, 7)

CI: Confidence interval, # Independent t-test, SE: Standard error, *Paired t-test, Non-significant (NS) if P-value > 0.05, Significant (S) if P-value < 0.05

Table 6: Comparison regarding (ETDRS 6x6mm Full Perfusion Density % of Macula)

Fig. 6: Comparison regarding (ETDRS 6x6mm Full Perfusion Density % of Macula)

Fig. 7: OCTA change analysis report of Macula “Perfusion Density” of left eye (a sample report from our study)

Regarding full vessel density of Macula; there was a significant improvement “▲6.5%” at the end of the study in the case group Mean difference = 1.07±1.63; p = 0.008) with non-significant change in the control group (Mean difference = -0.09±0.44; p = 0.382). The difference between the two groups was not significant regarding the baseline level but at the study end the difference between them was significant (17.49±1.84 vs 16.16±2.5; p < 0.001). (Tables 7) and (Fig. 8, 9)

CI: Confidence interval, # Independent t-test, SE: Standard error, *Paired t-test, Non-significant (NS) if P-value > 0.05, Significant (S) if P-value < 0.05

Table 7: Comparison regarding (ETDRS 6x6mm Full Vessel Density of Macula (mm/mm²))

Fig. (8): Comparison regarding (ETDRS 6x6mm Full Vessel Density of Macula (mm/mm²))

Fig. (9): OCTA change analysis report of Macula “Vessel Density” of right eye (a sample report from our study).