(Investigative Ophthalmology and Visual Science. 2007;48:3318-3323.)
© 2007 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.06-1526
Effect of Posture on the Diurnal Variation in Clinically Significant Diabetic Macular Edema
Antonio Polito,1
Giovanni Polini,1
Raffaella Gortana Chiodini,2
Miriam Isola,3
Franca Soldano,3 and
Francesco Bandello1
1From the Departments of Ophthalmology and
3Medical and Morphological Research, University of Udine, Udine, Italy; and
2IRCCS (Istituti di Ricovero e Cura a Carattere Scientifico), Fondazione G. B. Bietti per l’Oftalmologia, Roma, Italy.
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Abstract
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PURPOSE. To investigate the role of posture and other systemic factors in the diurnal variation of clinically significant diabetic macular edema (CSDME).
METHODS. Ten eyes of 10 diabetic subjects with CSDME underwent four OCT foveal thickness measurements with StratusOCT at 9 AM and 12, 3, and 6 PM consecutively on two different days, with the subject in an upright position on one and in a recumbent position on the other. For the "recumbent-position" measurements, the patients were admitted the night before and remained in bed during the entire day of testing. Clinical laboratory results at baseline included HbA1c, urinary albumin, and serum creatinine. Refraction and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity were also measured before each OCT measurement was taken. Variations in blood pressure, body temperature, plasma glucose, renin, aldosterone, and cortisol levels were measured and then correlated with macular thickness.
RESULTS. Foveal thickening decreased in all cases over the course of the day. The decrease, however, was significantly greater for the upright-position measurements (relative mean ± SD decrease of 20.6% ± 6.5% in the upright position and 6.2% ± 4.6% in the recumbent position). Visual acuity improved by at least 1 ETDRS line in three eyes in the upright position as opposed to only one eye in the recumbent position. There seemed to be no association between any of the systemic factors studied and foveal thickening, with the exception of cortisol.
CONCLUSIONS. The results support the hypothesis that posture and hydrostatic pressure play a major role in determining time-related shifts in CSDME and suggest that the forces of Starling’s law can in part, account for CSDME formation.
Clinically significant diabetic macular edema (CSDME) in diabetic patients may show substantial variability during the course of the day, with macular thickening being at its maximum on awakening and then tending to decrease throughout the day. The use of optical coherence tomography (OCT), which provides quantitative and reproducible measurements of macular thickness, has permitted an objective demonstration of these variations.1 Frank et al.2 found consistent decreases in macular thickness with OCT-1 over the course of a waking day in 4 of the10 diabetic subjects in the study and concluded that macular edema might decrease over the day. We found a similar decrease in 9 of 15 diabetic patients with CSDME and foveal thickness of 
300 µm in the morning.3 Two of these patients also showed better visual acuity over the day. A recent study by Larsen et al.4 confirmed an overnight increase in CSDME, which tended to be related to a concomitant reduction in visual acuity. Circadian fluctuations in both macular thickening and visual acuity were reported in 16 patients who reported blurred vision on awakening, due to post–central retinal vein occlusion. In these eyes, mean macular thickness was higher, and mean visual acuity was worse at 7 AM than at 7 PM, suggesting an overnight increase in macular thickness.5
Many factors have been postulated to explain these fluctuations in macular thickness. Our working hypothesis was that the change in macular edema is mainly influenced by postural changes. Variations in arterial blood pressure may also play a role in these observed changes throughout the day. Arterial blood pressure variations normally follow a circadian rhythm, showing typical decreases at night, and numerous diabetic patients have impaired nocturnal blood pressure regulation.6 7 Additional factors include temporal differences in blood glucose level, circadian secretion of specific hormones, body temperature, ambient light level, and retinal metabolism.
To test the "gravitational hypothesis," we evaluated the difference in diurnal variation in diabetic macular edema measured on two different days, during which patients were maintained in an upright and recumbent position, respectively. We also analyzed the correlation between retinal thickness variations and HbA1c; serum creatinine; albumin excretion rate at baseline; and diurnal variations in arterial blood pressure, body temperature, plasma glucose, aldosterone, and cortisol levels.
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Methods
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We examined 10 eyes of 10 diabetic patients with CSME (five men, five women) aged 53 to 79 years (mean, 67). The study was conducted according to the tenets of the Declaration of Helsinki, and all subjects gave informed consent on full description of the study.
All subjects underwent a complete eye examination before enrollment, including contact lens biomicroscopic funduscopy and visual acuity testing with refraction determined with the chart and protocol of the Early Treatment Diabetic Retinopathy Study (ETDRS). Inclusion criteria included diagnosis of diabetic retinopathy with retinal thickening involving the center of the macula exceeding 300 µm in thickness measured with OCT. Exclusion criteria included: history of focal-, grid-, panretinal-photocoagulation, and cataract surgery up to 6 months before; significant media opacities; and macular ischemia on fluorescein angiography. Patients were also excluded if they had chronic liver disease, clinical jaundice, chronic renal failure on dialysis, congestive heart failure, or cancer. We enrolled the first 10 eligible volunteers consecutively. All patients had type 2 diabetes with a mean duration of 15 years. All but three had nonproliferative diabetic retinopathy. Three patients had undergone grid laser photocoagulation, and two patients, panretinal photocoagulation, before entering the study.
Blood samples were taken at baseline to establish levels of glycated hemoglobin, lipids, cholesterol, albumin excretion rate, and serum creatinine. Repeat blood samples were taken at four different sessions during the day (9 AM and 12, 3, and 6 PM) on two different days, during which the patients were in the recumbent on one day and upright position on the other. Each session included ETDRS subjective refraction; best corrected visual acuity (BCVA); and, macular thickness measurements taken with the StratusOCT (Carl Zeiss Meditec, Oberkochen, Germany) Fast Macular Thickness mapping protocol (software ver. 2.0). Each subject was admitted to the hospital the evening before and strictly confined to bed on the day of the recumbent-position data collection. The patients were permitted to get up from bed only for visual acuity testing and OCT macular thickness measurements, which were taken within a 15-minute period. They were not hospitalized for the upright-position measurements and were allowed unrestricted ambulation between sessions on the day of testing. The upright-position measurements were taken within 7 days after the recumbent-position measurement day.
All macular thickness measurements were taken in nondilated eyes by the same experienced examiner with the StratusOCT Fast Mapping protocol that uses 6-mm scans. Correct positioning and absence of artifacts for each of the six radial scans were assessed before analysis according to criteria previously reported by our group.3 Foveal thickness was defined as the average value for the central 1-mm diameter area of the retina map. Foveal thickening was calculated by subtracting the measured foveal thickness from the average foveal thickness in normal subjects (defined as 209 µm, based on a sample of healthy eye measurements taken with our instrument).
To test the effects of body temperature, specific plasma hormones and blood glucose on macular thickness fluctuations, each upright-position session included taking the following readings: body temperature; blood glucose measurements with a test strip; and, renin, aldosterone, and cortisol blood levels. In addition, a noninvasive ambulatory 24-hour blood pressure monitoring device was used in evaluating the role of arterial blood pressure. Daytime mean arterial pressure [MAP = (systolic pressure + 2 diastolic pressure)/3] was based on the mean of 64 measurements recorded every 15 minutes between 7 AM and 11 PM. Nighttime MAP was based on the mean of 16 measurements recorded every 30 minutes between 11 PM and 7 AM. Arterial blood pressure for each time point was taken as the mean of the four measurements recorded between the hours of 8 to 9 AM, 11 AM to 12 PM, 2 to 3 PM, and 5 to 6 PM.
A general linear model (GLM) for repeated measures (univariate approach) was used to analyze temporal variations in observational parameters.8 Relative differences in variations between upright- and recumbent-position measurements were analyzed by using the same method (GLM). The assumptions that the vector of the measures followed a multivariate normal distribution (Shapiro-Wilk test) and that the variance-covariance matrices were circular in form (Mauchly’s test) were verified. Correlations between parameters were analyzed with the Pearson test. P < 0.05 was considered statistically significant (SPSS 13.0.1; Statistical Package for the Social Sciences; SPSS Inc., Chicago, IL).
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Results
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Patient demographics at baseline are listed in Table 1 . Foveal thickness variations at each session of the two testing days are shown in Figure 1 . Tables 2 and 3 list individual patient results obtained on the upright-position day of testing.
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FIGURE 1. Mean foveal thickness ± 1.0 SE for upright- and recumbent-position measurements plotted as a function of time. A significant decrease in mean macular thickness throughout the day was found for both study conditions by the GLM for repeated measures (P < 0.001).
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TABLE 2. Foveal Thickness and Foveal Thickening for Individual Patients on the Upright- and Recumbent-Position Days
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Recumbent-position measurements showed slight decreases in mean foveal thickness ± SD as the day progressed, with an initial mean of 549 ± 119 µm at 9 AM, that decreased to 540 ± 118, 531 ± 122, and 532 ± 122 µm at 12, 3, and 6 PM, respectively (P < 0.001). Upright-position measurements showed that mean foveal thickness markedly decreased from 547 ± 115 µm at 9 AM to 519 ± 114 µm, 491 ± 113 and 480 ± 109 µm at 12, 3, and 6 PM, respectively (P < 0.001). The average relative decrease in foveal thickening (9%, 17.5%, and 20.6%) at 12, 3, and 6 PM for upright-position measurements was significantly greater (P < 0.001) than corresponding recumbent-position values (3.7%, 5.9% and 6.2%, respectively).
There was a slight statistically significant increase in mean ETDRS score (P = 0.009) as the day progressed on the upright-position day (62.2 ± 11, 63.3 ± 9, 64.8 ± 10, and 64.9 ± 9, respectively). This trend was not observed in recumbent-position measurements (60.7 ± 11, 61.9 ± 10, 62.6 ± 10, and 61.7 ± 11, respectively, P = 0.063). BCVA improved by one ETDRS line at 12 PM in three eyes on the upright-position day (patients 5, 7, and 9), as opposed to only one eye on the recumbent-position day. Changes in refraction were not observed in any of the subjects throughout the entire period of the study. A negative correlation was found between foveal thickness and visual acuity at all time points (r = –0.516, P = 0.001; Fig. 2 ).
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FIGURE 2. Correlation between ETDRS visual acuity (y-axis) and foveal thickness (x-axis) for all measurements (r = –0.516, P = 0.001).
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No correlations were found between changes in macular thickness and baseline parameters (HbA1c, lipids, cholesterol, creatinine, albumin excretion rate; P = 0.818, 0.187, 0.113, 0.126, and 0.174 respectively). The same could be said for correlations with variations in body temperature (P = 0.522), blood glucose (P = 0.256), aldosterone (P = 0.110), and renin (P = 0.360) levels throughout the day. The change in foveal thickening, however, showed a positive correlation with variations in plasma cortisol levels (r = 0.699, P = 0.024; Fig. 3 ).
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FIGURE 3. Relative diurnal changes in foveal thickening versus relative changes in cortisol. The diurnal decrease in foveal thickening increased in proportion to the decrease in plasma cortisol levels (r = 0.699, P = 0.024).
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Changes in arterial blood pressure throughout the day, including differences between day- and nighttime readings, were not statistically significant. (Table 4) . Fluctuations in foveal thickening measurements on the upright-position day did not show any correlations with arterial blood pressure measurements at 9 AM (P = 0.19), blood pressure changes during the day (P = 0.563), and variations between night and day measurements (P = 0.747). Sequential OCT scans in patient 5, taken on separate days, serve as examples in Figures 4 and 5 .
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FIGURE 4. Macular thickness maps obtained on the recumbent-position day for patient 5. Each part of the figure shows a cross-sectional image with: retinal boundaries identified by the software (white lines); a color-coded retinal thickness map; and a numeric map with retinal thickness measurements, for each of the nine ETDRS-regions. (A) 9 AM scanning session; (B) 12 PM scanning session; (C) 3 PM scanning session; (D) 6 PM scanning session. Foveal thickness decreased by 4% at 6 PM BCVA was 20/125 throughout the day.
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FIGURE 5. Macular thickness maps obtained on the upright-position day for the same patient as in Figure 4 at each scanning session (A, 9 AM; B, 12 PM; C, 3 PM; D, 6 PM). Foveal retinal thickness decreased by 21% at 6 PM. BCVA improved from 20/125 at 9 AM to 20/80 at 6 PM.
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Discussion
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Our findings suggest that posture plays a role in the diurnal variation of CSDME. All the patients in our series showed minimal foveal thickness variations on the day in which they were strictly confined to bed (supine position), while showing a significantly greater decrease in foveal thickness on the day when they maintained an upright posture. Moreover, three patients with a significant decrease in foveal thickening during the upright-position day also had an increase in visual acuity versus one patient on the recumbent-position day.
Our present finding of an average decrease in mean foveal thickening of approximately 20% on the upright-position examination day independently confirms our previous OCT study that showed a similar diurnal decrease (of 21%) in nine diabetic patients with a foveal thickness of 300 µm in the morning.3 These results are also in agreement with the study of 12 diabetic patients with fovea-involving diabetic macular edema by Larsen et al.4 that showed an overnight increase in macular thickness of an average of 6.3%, with measurements varying from 316 µm in the evening to 376 µm in the morning (with concomitant reduction in visual acuity). In contrast, The Diabetic Retinopathy Clinical Research Network (DRCR.net) has recently reported a lower diurnal decrease in relative foveal thickening of 8% in 32 eyes having similar baseline foveal thickness measurements (>450 µm).9 Although this discrepancy may be explained by the larger number of patients examined in the DRCR.net study, differences in the protocols for maintaining posture in the DRCR.net study and our own study may partly account for the differing results.
Frank et al.2 were the first to demonstrate that time-related shifts in CSDME, using quantitative OCT measurements, do occur. Diurnal decreases in macular edema that may result from postural changes were first suggested, however, by Sternberg et al.10 in 1982 as a possible hypothesis to explain their observations. Our study was based on this hypothesis and specifically designed to investigate the effect of postural changes on fluctuations in macular edema. Our protocol was designed to assure that all patients were kept supine on the recumbent-position data collection day, permitting limited ambulation only for OCT and visual acuity testing. Our findings support the theory of what may happen on postural changes, in that the increase in orbital venous pressure after the positional change from upright to recumbent may increase the hydrostatic pressure in retinal capillaries and favor water-flux movement from the vascular compartment into the tissue interstitial compartment in accordance with Starling’s law. Conversely, in moving from a supine to an upright position, the decrease in retinal capillary intravascular pressure may reduce fluid leakage and lessen the degree of edematous thickening. This mechanism has also been proposed as one of the major factors influencing macular edema and visual acuity fluctuations in patients with central retinal vein occlusion.5 Studies by Anarsson and Stefansson11 12 have also suggested that macular edema follows the principles of Starling’s forces. The upright posture may also induce a decrease in foveal thickening by favoring a gradual downward displacement of the intraretinal fluid from the uppermost to the lowermost macular zones, with no change in the total macular volume over time. However, the retinal thickness variations of the inner and outer four ETDRS regions of the OCT retina map from both our previous3 and current (data not shown) studies show a "generalized" retinal thickness reduction over the course of the day, with no differences between the superiormost and inferiormost macular zones. These results may be indicative of a reduction in entire macular volume over time.
The second objective of our study was to investigate the role of variations in arterial blood pressure, body temperature, plasma glucose, renin, aldosterone, and cortisol levels. Our analysis also included baseline HbA1c, plasma lipids, cholesterol, urinary albumin, and serum creatinine levels.
It is well known that macular edema can be aggravated by high systemic blood pressure and that a tight control of hypertension can significantly reduce the risk of CSDME.13 14 Diabetic patients usually have an impaired retinal autoregulatory capacity, and increases in blood pressure may cause an increased vascular pressure in the capillary bed.15 Studies have shown correlations between arterial blood pressure levels at night and the severity of macular edema in both diabetic patients and subjects who have macular edema secondary to central retinal vein occlusion.4 5 In contrast, our patients did not show any effects of arterial blood pressure variations. Although this may be explained by the small number of patients considered in our study, we are in agreement with Larsen et al.4 in that other "chronic" mechanisms independent of "acute" changes in arterial blood pressure are involved in the maintenance of diabetic macular edema and may counteract the effect of circadian blood pressure changes, which include severity of the breakdown of the blood retinal barrier, osmotic pressure gradients, retinal tissue compliance, and cohesiveness. Moreover, variations in retinal metabolism and in retinal and choroidal blood flow that are yet to be uncovered could also be relevant in influencing short-term macular thickness changes.
Our study did not show any correlations with HbA1c, plasma lipids, cholesterol, urinary albumin, and serum creatinine levels. This was also true of diurnal fluctuations in plasma glucose and of the circadian rhythms of hormones that are involved in volume homeostasis and vascular permeability, such as renin and aldosterone. The number of subjects in our study was limited, and thus definite conclusions regarding the influence of these parameters on the process of edema formation cannot be drawn. Surprisingly, decreases in foveal thickening seemed to correlate with decreases in diurnal plasma cortisol. It has been well established that cortisol secretion follows a circadian rhythm and that plasma levels fluctuate throughout the day, showing higher levels in the morning and lower levels in the evening.16 Considering that cortisol is directed at maintaining endothelial integrity, vascular permeability and the distribution of total body water within the vascular compartment, we expected an opposite trend toward smaller decreases in foveal thickening with decreasing concentrations of cortisol. Although our findings could be explained by chance alone based on the small number of patients, another hypothesis may be put forth to explain these results. Considering that corticosteroid-related effects are mostly mediated by intracellular genomic regulations that require several hours after corticosteroid exposure, the patterns in macular thickness changes and cortisol secretions may be shifted temporally by several hours and not act in a parallel manner. If this is the case, a greater decrease in cortisol secretion during the day could correlate with a greater overnight increase in macular edema and, consequently, a greater decrease during the day. Further studies with a larger group of subjects are needed to determine the role of cortisol secretion in circadian variations of macular edema.
In summary, this study demonstrates that postural changes play an important role in determining circadian fluctuation in CSDME. The findings suggest that orthostatic variations in venous blood pressure may influence hydrostatic pressure gradients across the blood–retinal barrier and contribute to water movement and CSDME formation, according to the principles of Starling’s law.
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Footnotes
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Presented in part at the 16th Annual Meeting of the EASD Eye Complication Study Group EASDec, Aarhus, Denmark, May 26–28, 2006.
Submitted for publication December 22, 2006; revised February 19 and March 7, 2007; accepted May 14, 2007.
Disclosure: A. Polito, None; G. Polini, None; R.G. Chiodini, None; M. Isola, None; F. Soldano, None; F. Bandello, None
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 
1734 solely to indicate this fact.
Corresponding author: Antonio Polito, University of Udine, Department of Ophthalmology, Piazzale S. Maria della Misericordia, 33100 Udine, Italy; apolito32{at}yahoo.it.
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References
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- Polito A, Del Borrello M, Isola M, Zemella N, Bandello F. Repeatability and reproducibility of fast macular thickness mapping with the Stratus OCT. Arch Ophthalmol. 2005;123:1330–1337.[Abstract/Free Full Text]
- Frank RN, Schulz L, Abe K, et al. Temporal variation in diabetic macular edema measured by optical coherence tomography. Ophthalmology. 2004;111:211–217.[CrossRef][Web of Science][Medline][Order article via Infotrieve]
- Polito A, Del Borrello M, Polini G, Furlan F, Isola M, Bandello F. Diurnal variation in clinically significant diabetic macular edema measured by the Stratus OCT. Retina. 2006;26:14–20.[CrossRef][Web of Science][Medline][Order article via Infotrieve]
- Larsen M, Wang M, Sander B. Overnight thickness variation in diabetic macular edema. Invest Ophthalmol Vis Sci. 2005;46:2313–2316.[Abstract/Free Full Text]
- Paques M, Massin P, Sahel JA, et al. Circadian fluctuation of macular edema in patients with morning vision blurring: correlation with arterial pressure and effect of light deprivation. Invest Ophthalmol Vis Sci. 2005;46:4707–4711.[Abstract/Free Full Text]
- White WB. Relevance of blood pressure variation in the circadian onset of cardiovascular events. J Hypertens. 2003;21(suppl 6)S9–S15.[Medline][Order article via Infotrieve]
- Spallone V, Maiello MR, Cicconetti E, et al. Factors determining the 24-h blood pressure profile in normotensive patients with type 1 and type 2 diabetes. J Hum Hypertens. 2001;15:239–246.[CrossRef][Web of Science][Medline][Order article via Infotrieve]
- Tabachnick BG, Fidel LS. Using Multivariate Statistics. 2001; 4th ed. Allyn & Bacon Needham Heights, MA.
- Diabetic Retinopathy Clinical Research Network. Diurnal variation in retinal thickening measurement by optical coherence tomography in center-involved diabetic macular edema. Arch Ophthalmol. 2006;124:1701–1707.[Abstract/Free Full Text]
- Sternberg P, Jr, Fitzke F, Finkelstein D. Cyclic macular edema. Am J Ophthalmol. 1982;94:664–669.[Web of Science][Medline][Order article via Infotrieve]
- Arnarsson A, Stefansson E. Laser treatment and the mechanism of edema reduction in branch retinal vein occlusion. Invest Ophthalmol Vis Sci. 2000;41:877–879.[Abstract/Free Full Text]
- Stefansson E. The therapeutic effects of retinal laser treatment and vitrectomy: a theory based on oxygen and vascular physiology. Acta Ophthalmol Scand. 2001;79:435–440.[CrossRef][Web of Science][Medline][Order article via Infotrieve]
- UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:703–713.[Abstract/Free Full Text]
- Vijan S, Hayaward RA. Treatment of hypertension in type 2 diabetes mellitus: blood pressure goals, choice of agents, and setting priorities in diabetes care. Ann Intern Med. 2003;138:593–602.[Abstract/Free Full Text]
- Ciulla T, Harris A, Latkany P, et al. Ocular perfusion abnormalities in diabetes. Acta Ophthalmol Scand. 2002;80:468–477.[CrossRef][Web of Science][Medline][Order article via Infotrieve]
- Czeisler C, Khalsa SBS. The human circadian timing system and sleep-wake regulation. Kryger MH Rogh T Dement WC eds. Principles and Practice of Sleep Medicine. 2000; 3rd ed. WB Saunders Philadelphia.
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Abstract
Methods
