Evaluation of the Effect of Religious Fasting on Retinal Vessel Density and Retinal Thickness Using Optical Coherence Tomography Angiography

ABSTRACT

We conducted this study to assess the effect of religious fasting on intraocular pressure (IOP) as well as retinal parameters and retinal thickness during Ramadan using optical coherence tomography angiography (OCTA) performed on a spectral domain device. All the participants ate a pre-dawn meal and drink, and then fasted for at least 15 hours. We assessed a total of 61 eyes from 31 healthy volunteers with a mean age of 32.87 ± 8.07. A significant decrease was found in the median IOP after fasting at 10.00 mmHg in comparison with the pre-fasting value of 12.00 mmHg (p < .0001). Retinal peri-papillary capillary (RPC) whole image, RPC inside disk, and RPC mean values showed significant decreases after fasting (p = .011, .012, and .032 respectively). RPC whole vessel density (VD), RPC inside VD, and RPC VD mean values also showed significant decreases after fasting period (p = .025, <.0001, and .003, respectively). Religious fasting during the warm season could decrease IOP. It could also reduce the blood flow of the retina, specifically the macula, and the retinal peri-papillary VD.

Introduction

Nearly one billion Muslims fast every year during the month of Ramadan.¹ They refuse to drink, eat, or smoke during the fasting time. Due to the difference between the lunar and solar calendars, religious fasting time can range from 11 to 17 hours per day.^2,3 This prolonged abstinence from food and water provides an opportunity to investigate different aspects of fasting on the human body. It is reported that fasting, through different mechanisms, alters ocular functions including intraocular pressure (IOP),^4–7 ocular biometrics,^4,6,7 and even tear secretion.^4,6,7 It is not completely understood how fasting has these effects on the eye.⁸ Nevertheless, depending on the duration of fasting, different effects may occur in the eye. These effects may vary from choroidal and retinal blood flow changes to alteration in their vascular density.² Hypovolaemia, which is caused by reduced water uptake during fasting, reduces cardiac output and pulse pressure. Such decrease may alter the perfusion pressure of the eye through changes of sympathetic baroreceptors activity.⁹ Reduction in perfusion may affect the intense vascular structures in the eye including the choroid.⁸ In a study by Sherwin et al. it was reported that retinal vascular disease may be associated with dehydration.¹⁰

Fasting may also alter sleep patterns and eating habits.¹¹ In an animal study by Uyar et al., hypoglycaemia was reported to be associated with decreased retinal responses and an increase in retinal cell death. However, the effects of hypoglycaemia on human retinal function are still unknown. Optical coherence tomography angiography (OCTA) is a non-invasive method that provides both blood flow and structural information on retinal and choroidal layers.¹² This new imaging modality establishes its clinical value in the management of many eye diseases, such as glaucoma¹³ and age-related macular degeneration.¹⁴ OCTA provides rapid and detailed views of the retinal vasculature using the signals of blood flow on B-scan images.^12,15 However, OCTA is still a new technique, and further studies are required to completely determine its potential uses in the clinical setting. To our knowledge, only a few studies have evaluated the effect of fasting on the retina.¹⁶ Regarding the paucity of the data on the effects of fasting on vascular structures of the eye and the novelty of OCTA, we conducted this study to evaluate the effect of religious fasting on vascular structures of the macula using OCTA.

Material and methods

Participants and study design

We enrolled 31 healthy volunteers from Khatam-al-Anbia Eye Hospital (Mashhad, Iran) during the month of Ramadan. After providing detailed information on the study objectives and procedures, informed consent was obtained from all of them. Participants fasted about 15 hours during the day and had a pre-dawn meal and drink. All measurements were obtained by a single experienced technician with one device. Measurements for each subject were performed between 08:00 to 09:00, and 18:00 to 19:00. The first examination was conducted about 3 to 4 hours after the pre-dawn meal and it represents the non-fasting time. The second examination was conducted in the evening, about 15 hours after fasting. The subjects underwent a full ophthalmological examination including visual acuity, pupillary reaction, IOP, slit-lamp bio microscopy, and body weight measuring. IOPs were measured by an ophthalmologist using Goldmann applanation tonometry (AT900, Haag-Streit) and imaging signal quality of > 0.60 was considered acceptable. Blood pressure and blood oxygen saturation were obtained in the fasting and non-fasting states. This study was approved by the Ethics Committee of Mashhad University of Medical Sciences with code number of IR.MUMS.MEDICAL.REC.1397.540 and conducted according to the principles of the Helsinki Declaration.

Inclusion and exclusion criteria

We included individuals without any: (1) previous history of systemic diseases including diabetes and hypertension; (2) abnormalities in blood pressure or blood oxygen saturation; (3) topical and systemic drug uses; (4) ophthalmological pathologies; (5) previous ocular surgery procedures or trauma; or (6) pathological finding in the anterior or posterior segments of the eye. Since no amount of gaining weight is acceptable during fasting time, individuals with an increase in body weight after the fasting time were excluded. We also excluded subjects who could not co-operate with the examination or if their second examination was not performed.

Optical coherence tomography data acquisition and processing

We used a spectral domain device to perform OCTA (AngioVue Software Version 2017.1.0.151, Optovue, Fremont, CA, USA). Employing the split spectrum amplitude-decorrelation angiography (SSADA) algorithm and a wavelength of 840 nm (with a range of 50-micron band), this device obtains two volumetric raster scans. The scans consist of a horizontal priority (x-fast) and a vertical priority (y-fast). Volunteers were asked to fix their gaze on the internal fixation target, and we used a standard fundus view for fundus imaging area assessment. Optic nerve head (ONH), papillary and peri-papillary area perfusion were also measured.¹⁷ Using AngioAnalytics (Version 2017.1.0.151) software on the AngioVue OCTA system, 3 × 3 and 4.5 × 4.5 mm high-definition angiograms for the macula and optic nerve head were obtained. We also analysed the radial peri-papillary capillaries (RPC). We defined the peri-papillary vascular density (VD) in percentage terms as the area between two concentric circles, 1.5 and 3.4 mm in diameter. RPC vascular and capillary densities were analysed using AngioAnalytics software.¹⁷ Overall, hemispheric and eight sectoral averages were provided by the AngioAnalytics software for the RPC VD parameters. For macular VD measurement, en face OCTA was performed on a 3 × 3 mm region centred on the macula. Automated thresholding and a measuring algorithm method using the AngioAnalytics software for foveal blood flow and VD were applied. Thicknesses of the macula and the peri-papillary retinal nerve fibre (RNFL) were also measured during OCT scanning. Since there was no need for pupil dilation during the retinal examination and imaging we did not use any mydriatic medication.

Statistical analysis

Statistical analysis was performed using SPSS software version 16.0 (SPSS Inc., Chicago, USA). We used the Kolmogorov–Smirnov test to check the normality of the sample distribution and paired sample t-test or Wilcoxon test for group comparison, accordingly. A p-value of <.05 was considered significant.

Results

We assessed a total of 61 eyes from 31 healthy volunteers (21 men and 10 women) with a mean age of 32.87 ± 8.07, ranging from 23 to 54-years-old. Due to the low quality of imaging in one eye of one of the participants, the data from one eye are missing.

Table 1 summarises the result of IOP and vascular OCTA parameters before and after fasting. Significant decreases were found after fasting in the median IOP, mean macular flow area, and all RPC mean parameters compared with the morning pre-fasting values.

Table 1.

Intraocular pressure and vascular retinal measurements of subjects during the non-fasting and fasting periods

	Pre-fast Mean ± SD/Median (25th, 75th percentiles)	Post-fast Mean ± SD/Median (25th, 75th percentiles)	p-value
IOP (mmHg)	12.00 (11.00,13.00)	10.00 (10.00,11.00)	<.0001**
Macular flow area (mm2)	0.766 ± 0.388	0.576 ± 0.334	<.0001*
RPC whole image capillary (%)	49.35 ± 2.53	48.62 ± 3.01	.011*
RPC whole vessel density (%)	55.50 ± 3.01	54.84 ± 3.64	.025*
RPC inside disk capillary (%)	49.82 ± 3.54	48.43 ± 4.89	.012*
RPC inside disk vessel density (%)	59.33 ± 3.54	57.57 ± 5.03	<.0001*
RPC peripapillary capillary (%)	51.79 ± 3.28	51.09 ± 3.24	.032*
RPC peripapillary vessel density (%)	58.13 ± 3.60	57.13 ± 3.89	.003*

IOP = Intraocular pressure

RPC = Retinal peri-papillary capillary

SD = Standard deviation

Paired sample t-test Paired sample t-test Paired sample t-test Paired sample t-test

** Wilcoxon test

The structural OCT measures of RNFL thickness and macular thickness did not change significantly after fasting (Table 2).

Table 2.

Retinal nerve fibre layer, inner macular, full macular, central macular, and para-foveal thicknesses

	Pre-fast Median (25th, 75th percentiles)	Post-fast Median (25th, 75th percentiles)	p-value**
RNFL mean thickness (μm)	106.00 (97.5,112.5)	106.00 (99.00,112.00)	.640
Inner macular thickness (μm)	48.00 (45.00,52.5)	48.00 (44.50,53.50)	.600
Full macular thickness (μm)	253.00 (241.50,266.50)	253.00 (241.50,263.50)	.827
Central macular thickness (μm)	249.00 (241.00,266.00)	250.00 (240.50,266.00)	.671
Para-foveal thickness (μm)	327.00 (319.50,336.00)	326.00 (319.00,335.00)	.119

RNFL = Retinal nerve fibre layer

** Wilcoxon test

Discussion

In a recent study, Esa et al. found that the mean values of IOP among healthy volunteers aged between 20 to 25 years, decreased significantly after fasting compared with the non-fasting period.¹⁸ They discussed that such reduction may be caused due to the changes in fluid consumption, as they observed significant fluid intake reduction among the participants. In another study by Idu et al., healthy volunteers showed significant decreases in IOP after 18 hours of refraining from drinking water.¹⁹ They also evaluated and reported a significant elevation in the plasma osmolality and arginine vasopressin (AVP) concentration after dehydration among the subjects. An increase in plasma osmolality forces water out into the plasma, resulting in in reduction of IOP.²⁰ AVP, a nano-peptide also known as antidiuretic hormone (ADH), is stored in the posterior pituitary gland and secreted into the blood in response to elevations in blood osmolality.²¹ Both dehydration and elevation in osmolality increase the secretion of AVP.²² During dehydration, AVP is able to decrease the mean atransporting water through epithelial membranerterial blood pressure and increase vasoconstriction,transporting water through epithelial membrane and accordingly reduce the flow of the major ocular arteries, including the ophthalmic, central retinal, and temporal short ciliary arteries. Consequently, this reduction could lead to the reduction of the IOP.^20,23 Dehydration could negatively affect the non-pigmented ciliary epithelium and decrease the secretion of aqueous humour. It is noteworthy that the aquaporin 1 (AQP 1) on ciliary body epithelium plays important roles in transporting water through the epithelial membrane and out of the plasma, and aqueous secretion. Nevertheless, the effect AVP on AQP 1 is still unknown.^19,20,24 It has also been reported that the limited intake of the dietary fat and thus the depletion of fat storage during fasting is a stimulus for prostaglandin secretion.²⁵ IOP is balanced within normal ranges by the rate of inflow (secretion) and outflow of the aqueous humour.¹⁹ There is evidence that prostaglandin analogues are able to increase the aqueous humour outflow through relaxing the ciliary muscle, which results in a reduction of IOP.²⁶ We also showed that IOP reduced significantly after fasting. In a recent study by Beyoǧlu et al. on 100 healthy volunteers, IOP decreased significantly in the fasting group in comparison with the non-fasting group.²⁷ Their study was conducted also during the northern hemisphere summer (May and June). However, in a recent cross-sectional study on healthy volunteers, IOP values did not change significantly after fasting.²⁸ This could be justified by the fact that we evaluated the acute effect of fasting on IOP by re-examining our subjects in the same day. Yet, Uysal et al. re-evaluated their participants 1 month after the end of the Ramadan. In another study by Kayikçioğlu et al., which was conducted in the northern hemisphere winter in January, IOP changes were not considerable.²⁹ As it may be expected, fasting could result in higher stages of dehydration during warm seasons,³⁰ like in our study which was conducted during summer. However, Kayikçioğlu et al. followed up their participant 1 month after Ramadan, which could tamper with the acute effects of fasting on IOP.²⁹ Some other studies discussed the effect of a drinking water test on increasing IOP both in healthy subjects and glaucomatous patients.^31,32 Nonetheless, there are few studies thaHowever, in a recent study, Nilforushan et al.t have evaluated the elevation of IOP during fasting in accordance with sympathetic pathway hyperactivation.^33,34 Elevation of serum cortisol levels as a result of sympathetic hyperactivity is reported to be harmful to the trabecular meshwork.³⁵ Altogether, long-term IOP changes could permanently damage the lamina cribrosa. In a recent meta-analysis, it was stated that a 1 mmHowever, in a recent study, Nilforushan et al.Hg increase in IOP increases the chance of glaucoma progression by 10%.³⁶ Regarding IOP fluctuation being the risk factor in glaucoma progression,³⁷ fasting should be carried out with caution and with regular ophthalmic examinations in both glaucomatous patients and in the pre-glaucoma stages.

Using OCTA, we also evaluated the effect of religious fasting on different aspects of vascular structure of the retina in healthy normal eyes. We recorded a significant decrease in RPC peri-papillary capillary and VD percentage mean values. This may contribute to the reduction of the retinal blood flow after fasting. We also found that the RPC whole image capillary and VD mean percentages decreased significantly. Moreover, the RPC inside the disk capillary and the VD mean percentages also significantly decreased after fasting. However, in a recent study, Nilforushan et al. reported opposite results.¹⁶ They discussed that, because of the mechanical effect of IOP reduction on ocular blood vascular structures, an increase in peri-papillary RPC density is expected. However, it seems more logical to expect a reduction of VD because of the autoregulation mechanism within blood vessels.³⁸ This pivotal mechanism ensures the provision of sufficient blood flow during changes in systemic blood pressure and IOP fluctuations.³⁹ Nonetheless, despite being statistically significant, such small changes are not considered clinically significant. Due to the paucity ofevidence, we encourage fellow researchers to further investigate this matter. We showed that macular flow area mean values significantly decreased after fasting for 15 hours. In a recent study by Karaküçük et al. on fasting healthy subjects a significant reduction was also found in superficial retinal, deep retinal, and chorio-capillaris flow areas.⁴⁰ Due to the dehydration and the autoregulation mechanism effect as a result of the reduction in IOP, a reduction in macular flow seems reasonable. In a recent study by She et al. a positive correlation between VD and RNFL thickness was observed among healthy subjects.⁴¹ In another study on healthy volunteers, RPCs’ distribution and volume also showed a significant relationship with RNFL thickness.⁴² Nilforushan et al. reported a significant reduction in RNFL mean thickness after fasting.¹⁶ However, we showed that mean RNFL thickness changes were not significant, which could be contributed to by the short-time assessment in our study. We also showed that the, inner, full, and central macular thickness, and para-foveal thickness medians did not change significantly after the fasting period. Karaküçük et al. also reported that CMT changes were not significant after Ramadan, compared with a pre-fasting period.⁴⁰ We think that due to the neuronal nature of these layers, dehydration and decreased blood flow do not affect these layers.

Limitations

We recommend that future studies are performed to further evaluate the effect of fasting during different seasons. As we mentioned, this study was conducted during the summer, which will not be representative of the whole year. We also were not able to obtain a larger sample size due to the short period of Ramadan and few volunteers. Additionally, studies with a wider age range and analysis based on genders could be beneficial in order to assess the effect of fasting more precisely. Finally, it is necessary to evaluate the possible effects of fasting in patients with ischaemic ophthalmological diseases or systemic diseases, which affect the eye, especially those with ocular vascular complications.

Conclusion

In this study, we demonstrated that fasting could potentially lead to a reduction in IOP and blood flow to the retina. These rather short-term fluctuations in IOP are potentially harmful in patients with glaucoma. Consideration is also needed as to whether fasting should also be monitored in patients with underlying ischaemic diseases and diabetic and hypertensive retinopathies.

Funding Statement

The study was funded by Mashhad University of Medical Sciences.

Author contributions

Conceptualisation, S.S.R and N.S.; methodology, S.S.R., N.S. and M.G.N.; analysis, E.B.; writing and original draft preparation, M.G.N; supervision, S.S.R. and N.S.; project administration, S.S.R., M.G.N. and N.S.; all the authors have read and approved the final manuscript.

Declaration of interest statement

No potential conflict of interest was reported by the author(s).

Statement of ethics

The study was carried out ethically in compliance with the Helsinki Declaration of the World Medical Association and was approved by the Ethics Committee of Mashhad University of Medical Sciences with code number of IR.MUMS.MEDICAL.REC.1397.540.