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| Antioxidant effects on | Clinical parameters to be measured | Rationale & method |
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| Refractive error and accommodation | (i) Best-corrected functional near and distant visual acuity | The effect of antioxidants on disease prevention also has an overall impact on vision. |
| (ii) The amplitude of accommodation and accommodative status | Bilberry extract influences the progression of myopia and changes in accommodation [83, 85]. |
| Visual fatigue | (i) Subjective measures: visual fatigue questionnaires
(ii) Objective measures of indices of visual fatigue: Accommodation parameters, critical flicker–fusion frequency (CFF), and blinking characteristics
(iii) Workplace ergonomics questionnaire | Bilberry extract may reduce visual fatigue symptoms [82, 83]. Questionnaires are frequently used to identify self-reported visual fatigue symptoms [94–97]. Workplace ergonomics should take into consideration visual fatigue assessment, as it is one of the biggest confounding factors. |
| Ocular surface and dry eye | Diagnostic tests to assess and monitor dry eye according to the Tear Film and Ocular Surface Society (TFOS) Dry Eye Workshop (DEWS) II report [92]:
(i) Subjective measurement of symptoms: questionnaires such as the Ocular Surface Disease Index (OSDI) | Reduction in dry eye symptoms has been reported with intake of oral antioxidants containing bilberry extract [84]. Questionnaire instruments are often self-administered by the patient or research subject without input from the clinician or researcher [98–102]. |
(ii) Tear film stability
(a) Tear film breakup time (TBUT)
(b) Noninvasive TBUT
(c) Fluorescein tear breakup time (FBUT) | TBUT measures tear film stability. It is defined as the interval of time that elapses between a complete blink and the appearance of the first break in the tear film. The noninvasive technique (NIBUT) is preferred over the fluorescein technique (FBUT) [103]. |
(iii) Tear volume
(a) Schirmer test
(b) Phenol red thread (PRT) test
(c) Quantitative tear meniscus height and volume | Tear volume is quantified with the Schirmer test. The Schirmer test without anesthesia is well-standardized, providing an estimation of stimulated reflex tear flow. It is performed by folding a Schirmer paper strip at the notch and hooking the folded end over the temporal one-third of the lower lid margin. The score is the measured length of wetting from the notch, after five minutes. It can be performed with (a measurement of basal tear volume) and without topical anesthesia (a measurement of basal plus reflex tear volume)
Alternatives to the Schirmer test are the phenol red thread (PRT) test. This test provides an indirect but realistic measure of the resting tear volume. The test is performed by hooking the folded end of the thread in the lower fornix for 15 seconds. When the phenol red meets the alkaline tears, it changes color from white to yellow-orange, yellow, and finally red. The thread is removed after 15 seconds and the red portion will be measured from the very tip regardless of the fold.
The quantitative assessment of the tear menisci is, at present, the most direct approach to studying the tear film volume. The tear menisci serve as reservoirs, supplying tears to the precorneal tear film. Tear meniscus may take the form of a height or a cross-sectional volume metric. |
(iv) Damage to the ocular surface
(a) Punctate staining of the ocular surface with topical sodium fluorescein | Punctate staining of the ocular surface is a feature of many ocular diseases and instilled dyes are used extensively in the diagnosis and management of dry eye. Ocular surface staining can be assessed using a slit-lamp biomicroscope following instillation of fluorescein dye and viewed under a cobalt blue filter. |
(v) Meibomian gland assessment
(a) Meibum quantity, quality, and expressibility | Meibomian glands secrete meibum, which contains components of the lipid layer of the tear film. Meibum quantity, quality, and expressibility are thought to reflect meibomian gland function. The superficial location of the meibomian glands in the tarsal plates permits their anatomic features to be quantified by meibography and confocal microscopy. |
(vi) Objective dry eye measurement
(a) Oculus Keratograph® 5M corneal topographer (Germany) | The Oculus Keratograph® 5 M corneal topographer is an advanced corneal topographer with a built-in real keratometer and a color camera. This permits optimized external imaging. Unique features of this instrument include examining the meibomian glands, NIBUT, and the tear meniscus height measurement and evaluating the lipid layer (source: https://www.oculus.de/us/ products/topography/keratograph-5m/oculus-keratograph-5m/). Parameters such as tear film stability, tear meniscus height, blink rate, and meibography can be recorded with this instrument. It provides a quick yet reliable dry eye analysis giving a more accurate clinical diagnosis. |
| Retinal structure, function, and microcirculation | (i) Optical coherence tomography (OCT) of the macula (non-invasive) | The literature indicates that antioxidant supplements with lutein, zeaxanthin, saffron, and beta-carotene have a reasonable probability of slowing the progression of retinal diseases [15–35, 38–45, 47–49, 53, 54, 66, 67, 69, 86]. OCT of the macula can display a cross-section of the macula, making it an invaluable noninvasive tool to objectively screen, diagnose and monitor AMD. |
| (ii) OCT angiography (noninvasive) | OCT angiography is a newer imaging modality using the OCT platform. Real-time scanning of blood corpuscle movements in the retinal vessels produces 3-dimensional images of the macula and optic nerve head vasculature. In pathological conditions characterized by damage to blood vessels such as AMD and DR, this imaging technique also carries the potential for diagnosis, screening, and monitoring. While its advantages include no requirement for peripheral venous canulation and invasive dyes, its effectiveness as compared to conventional angiography is still being investigated. |
| (iii) Fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA) (invasive) | The advantages of conventional dye angiography over OCTA include the ability to determine leakage. While the OCTA can show abnormal vasculature progression, the FFA and ICGA are still necessary to determine the presence of leakage and diagnose polyps in polypoidal choroidal vasculopathy, a subset of AMD. However, it must be used with caution among patients with renal impairment, those who are pregnant or have a history of anaphylaxis. |
| (iv) Multifocal electroretinogram (mfERG) | mfERG is an objective test for retinal function by measuring retinal conduction. mfERG can be performed according to guidelines from the International Society for Clinical Electrophysiology of Vision (ISCEV) [104]. The recording is performed with full correction for near vision and dilated pupils. The standard measurement for mfERG amplitude and timing is the amplitude measured from the trough of N1 (first negative deflection) to the peak of P1 (positive peak after N1), and the peak time of P1, respectively. |
| Optic nerve assessment for structure, function, microcirculation, and risk factor for damage. | (i) Tonometry for IOP measurement | The IOP should be measured as the saffron extract has been reported to cause IOP reduction in glaucoma patients [68]. The IOP is influenced by various factors, including the patient’s position during measurement, central corneal thickness, corneal diameter and curvature, the rigidity of the cornea, and the cornea’s state of hydration. At present, the gold standard of IOP measurement is the Goldmann applanation tonometry (GAT). Several new devices for IOP measurement have been developed, including noncontact tonometry, the Tono-Pen (Reichert, US), the ICare tonometer (Finland), dynamic contour tonometry (Ziemer, Switzerland), TGDc-01 tonometry (Rjazan State Instrument Making, Russia), and the ocular response analyzer (Reichert, US). |
| (ii) Structural test: OCT of the optic nerve | OCT of the peripapillary retinal nerve fiber layer (RNFL) is also useful to diagnose glaucomatous optic neuropathy by virtue of the characteristic loss of the RNFL thickness, particularly at the superior and inferior quadrants of the disc. It is also useful to monitor the progression of optic nerve damage in early to moderate glaucoma. It is less useful in advanced glaucoma, being better monitored by automated perimetry at more advanced stages. |
| (iii) Automated perimetry, e.g., Humphrey visual field analyzer (Carl Zeiss Meditech, US) | Automated perimetry is an objective test to map out the visual field defect sustained from various types of optic neuropathy, including glaucoma. Apart from eliciting the characteristic visual field defects, it is also used for characterizing glaucoma into mild, moderate, and severe stages. This allows appropriate and customized treatment of the disease. |
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