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Diabetic retinopathy is one of the leading causes of blindness in the world. From the data collected from nationwide studies, trends show that Diabetes mellitus is on the increase and seems to be emerging as a major public health problem (1). The problem we now face in India is that despite modernisations and implementing western cultures leading to an increase in sedentary life style and consumption of high fat foods, knowledge about the disease and early diagnosis is still lacking. In addition, Asians certainly have unique clinical and biochemical abnormalities like , greater abdominal adiposity, lower adiponectin levelsand increased insulin resistance. (2) Western literature have shown that 20 years after the start of diabetes, majority of patients with type I diabetes (insulin-dependent) and more than 60% of those with type II diabetes (non-insulin dependent) will have a degree of retinopathy.(3)
Just as Asians have certain phenotypical predispositions for developing Diabetes, this concept can be carried to other physiological characteristics such as haemodynamics, in particular our topic of interest, which is ocular blood flow and its regulation both in disease and health. A great deal of research and resource has been poured into identifying the pathogenesis of Diabetic retinopathy. The blood supply to the outer retinal layers is from the choroidal vessels and the inner retinal layers are supplied by the retinal capillaries which are supplied by the central retinal artery. Damaging effects of chronically elevated glucose on the retinal capillary endothelial cells and pericytes and also focal ischemia as pathogenetic factors in progression of disease have been well studied (4). The cellular and biochemical mechanisms that cause diabetic vasoconstriction and vasodilation are also beginning to be ascertained. However there are very few studies that have looked at choroidal blood flow as a prognostic or pathogenetic factor in the development and progression of Diabetic Retinopathy.
The study of the choroid is being looked into as an attempt to answer some of the questions regarding the pathogenesis of diabetic retinopathy and how these changes are brought about in the retina. The pulsatile ocular blood flow (POBF) and ocular pulse amplitude (OPA) are indirect indicators of choroidal blood flow. Though inferences have been made from the few studies that have been done on choroidal blood flow, conclusions based on each study have been contradictory to each other. With the advent of new and more accurate measurement tools, more reliable data can be obtained regarding the choroidal circulation and its perfusion.
Ocular blood flow can be indirectly measured non-invasively with the pneumotonometer, which measures the pulsatile ocular blood flow and more recently, the Dynamic Contour Tonometer which measures the ocular pulse amplitudes. These instruments provide the clinician with data that can be used to interpret the choroidal blood flow, which actually supplies 80% of the retina.(5)
Dynamic contour tonometry (DCT) is a non-invasive technique of checking the intraocular pressure. It also measures the ocular pulse amplitude of the eye being studied simultaneously. Ocular blood flow varies with systole and diastole. The pulsatile ocular blood flow (POBF) shows a peak during systole. The difference in the minimum and maximum values of the pulsatile wave contour during systole and diastole gives us the ocular pulse amplitude (OPA).
In this study, we focused on documenting ocular pulse amplitudes, and indirectly the choroidal blood flow, in diabetic patients with various stages of Diabetic retinopathy. We also wanted to observe the effect of hypertension on choroidal blood flow in Diabetic patients. By carrying out this study, we may determine whether changes in choroidal blood flow play a role in either prognosticating diabetic retinopathy, or whether it proves to be a factor able to predict progression of diabetic retinopathy.
To document the ocular pulse amplitudes in patients with various stages of Diabetic retinopathy
1. To document any difference in Ocular Pulse Amplitudes with increasing severity of Diabetic retinopathy
2. To document any difference in Ocular Pulse Amplitudes between Diabetics with and without systemic Hypertension
Review of literature
Burden of Diabetes Mellitus:
According to WHO, 346 million people in the world have diabetes.(1) The number may grow to 438 million by 2030, which is 7.8% of the adult population. In 2004, around 3.4 million people died from complications related to diabetes mellitus(1). More than 80% of diabetes deaths occur within low- and middle-income countries. The World Health Organisation (WHO) says that diabetes deaths will double between 2005 and 2030. Non-communicable diseases, which includes diabetes, account for 60% of all deaths worldwide.(1) While the global prevalence of diabetes is 6.4%, WHO projects that the prevalence varies from 10.2% in the West to 3.8% in Africa.(1) 70% of the current cases of diabetes occur within low- and middle income countries. With an estimated 50.8 million people living with diabetes, India has the world's largest diabetes population, followed by China with 43.2 million.
In developing countries, for every patient who is diagnosed with Diabetes, there is one patient who has the disease but has not been screened for it (3). Without timely diagnoses and adequate treatment, complications and morbidity from diabetes will rise exponentially.
80% of type 2 diabetes is preventable by increasing physical activity, changing diet and improving the surrounding environment. Yet, the incidence of diabetes is likely to rise globally(1).
Economic burden of disease:
The financial burden caused by people with diabetes and their families depends on the economic status and the insurance policies of their countries. In the poorest countries, people with diabetes and their families bear the whole cost of the medical care they can afford.
Diabetic retinopathy in India:
The prevalence of Diabetic Retinopathy in the Chennai Urban Rural Epidemiology (CURES) Eye Study in South India was 17.6 per cent where 1715 diabetic subjects studied. This was a population based study from 10 zones in Chennai, which included a representative sample of the population of 26,000 individuals. Diabetes was diagnosed based on the past medical history, medications for diabetes. The study showed that the systemic risk factors for onset and progression of Diabetic Retinopathy are mainly duration of diabetes, degree of glycaemic control and hyperlipidaemia. (6) Among the 1715 known Diabetics, the overall prevalence of Diabetic retinopathy was 20.8 per cent, while among the newly diagnosed diabetic subjects 5.1 per cent had retinopathy. Higher frequency of all the grades of retinopathy (overall, NPDR and PDR) was observed in known diabetic subjects compared to newly detected cases. Prevalence of Diabetic macular edema in the total diabetic population was 5.0 per cent and in the known diabetic subjects it was 6.3, 1.1 per cent among the newly diagnosed diabetic subjects. (6)
In another study, R P Agrawal et al (7) found that 1176 patients (28.9%) had evidence of Retinopathy out of 4067 patients with Diabetes who presented to an outpatient diabetic clinic. Out of this, there were 938 (79.8%) patients of non proliferative diabetic retinopathy (NPDR), 68 (5.8%) patients of maculopathy and 172 (14.6%) patients of proliferative diabetic retinopathy.(8)
R Raman et al. (9) did a multicentric random sampling of the population in Chennai for screening for diabetic retinopathy. The sample size was 5900. They found the prevalence of Diabetes to be 28.2% and the prevalence of diabetic retinopathy to be 3.5%. (9)
Ramachandran A et al (9) conducted a study among 3010 subjects (M:F 1892:1118, Mean age 52 +/- 9.7 years) attending an outpatient diabetic clinic. The study sample resembled the population sample. Retinopathy was diagnosed in 23.7% (nonproliferative retinopathy in 20.0% and proliferative in 3.7%). (10)
Pathophysiology in Diabetic retinopathy:
Diabetic retinopathy is essentially a microangiopathy in which there is leakage in the blood retinal barrier, resulting from damage to the walls of the arterioles supplying the retina. Hyperglycaemia leads to a wide variety of microvascular and macrovascular abnormalities, including abnormal autoregulation. (9) As described by Ciulla et al. , chronic hyperglycemia leads to altered retinal vasoregulations. This increases bulk retinal blood flow with progressive retinopathy, perifoveal capillary dropout. In turn, there are retrobulbar hemodynamic abnormalities, including choroidal, central retinal arterial flow changes and ophthalmic arterial flow alterations.(9) Having said that, the factors that link raised glucose levels to capillary dropout, vascular cell dysfunction, and tissue hypoxia have not been elucidated.
Ocular blood flow response to hyperglycemia:
With regard to the macrovascular pathophysiology, Bursell et al (9) found that chronic hyperglycaemia is associated with a decrease in retinal blood flow, but the retina is still capable of autoregulating this by increasing retinal blood flow according to the acute elevations in blood glucose. Their study with video fluorescein angiography (n=60) suggest that as compared to normal ocular blood flow, there is a decrease in ocular blood flow in diabetic patients without Diabetic retinopathy. When patients had been exposed to acute increase in glucose levels, there was an increase in retinal blood flow within one hour. The retinal blood flow with progressively increasing sugar levels were as follows: with the glucose clamp at 100 mg/dl , the retinal blood flow was 16.3 3.8 AU (arbitrary units); with the Glucose clamp at 200 mg/dl: 21.5 4.7AU, with the glucose clamp at 300 mg/dl : 25.9 8.8 AU and in the Random diabetic group, it was 19.4 4.6 AU. In the non diabetic group: 28.7 6.4 AU. They suggest that chronic hyperglycaemia is associated with reduced retinal blood flow, but that the retina is still capable of responding to increased metabolic rates associated with acute changes in blood glucose by increasing retinal blood flow.
Retinal blood flow studies:
Different studies have found different results of increased, decreased or no changes in the ocular blood flow in different stages of retinopathy.
Kohner et al (11) studied retinal blood flow in 9 normal volunteers and 36 diabetic patients using video fluorescein angiography. Measurement of the mean transit time of flourescein in the superior temporal quandrant of the retina and estimation of the vascular volume by measuring vessels diameters was done. The results showed that patients with mild or no retinopathy had significantly increased volume flow compared with normals, those with moderate retinopathy had a slight but not significant increase and those with severe retinopathy had blood flow similar to that found in normals.
Clermont et al (12) showed that the retinal blood flow increased as the stage of retinopathy increased. In this study, 48 diabetic and 22 nondiabetic patients had their diabetic retinopathy levels determined from fundus photographs according to Early Treatment Diabetic Retinopathy Study (ETDRS). Fluorescein angiograms were recorded from the left eye by video fluorescein angiography. Retinal blood flow decreased 33% in patients with mild retinopathy compared with control patients (P = .001) and increased sequentially in more advanced stages of retinopathy, with a strong correlation between retinal blood flow and retinopathy level (r2 = 0.434, P = .001)
The increase in total retinal perfusion during pre-proliferative retinopathy probably arises from thickening of the capillary basement membrane leading to occlusive angiopathy and tissue hypoxia that increases bulk blood flow demands. (13)(14) There is also considerable evidence that the retinal autoregulatory capacity for hyperoxic vasoconstriction is blunted in diabetic subjects (15,16)
Grunwald et al (15) showed in a study using LASER Doppler Velocimetry ,(n=77) that 100% oxygen breathing reduced bulk retinal blood flow by 61% in normal eyes, total flow fell only 53% in diabetic eyes without retinopathy, 38% in eyes with background retinopathy, and only 24% in eyes with proliferative retinopathy. This loss of the normal autoregulatory response to elevated PO2 suggests that the capacity to reduce bulk retinal flow in response to increased oxygen delivery, as mediated primarily through the actions ET-1 on pericytes is progressively extinguished as the disease advances.(16)
Rassam et al (17) studied the effect of hypertension on retinal haemodynamics and the autoregulatory capacity of the retinal circulation under conditions of normoglycaemia and hyperglycaemia. Retinal blood flow was measured before and after raising the systemic blood pressure in 10 normal control subjects, 10 diabetic subjects with blood glucose < 10 mmol 11 and 10 diabetic subjects with blood glucose > 15 mmol/l'. Laser Doppler velocimetry was used. Results showed that with a 40 % increase in mean arterial blood pressure (MAP), there was a significant increase in retinal blood flow of 32.9 + 7-1 % in non-diabetic controls. In diabetics at the low blood glucose level, the increase in retinal blood flow was significant at 30% increase in MAP (23.6 + 87 %, P = 0-032) and at 40 % increase (49-9 + 12-03 %, P = 0-004). Diabetics with high blood glucose failed to autoregulate at any of the increased levels of MAP (15 % increase, 27 0 + 11 1 %; 30 % increase, 66.9 + 19.8 %; and 40 % increase, 101 9 + 21 4 %; P < 0.022). The coefficients of autoregulation showed that in non-diabetic controls, retinal vascular autoregulation broke down with increases in MAP of between 30 and 40 %. In diabetic subjects, it broke down between 15 and 30 % in normoglycaemia and at less than 15 % in hyperglycaemia. They hypothesised that there was an impairment in retinal vascular autoregulation in response to raised systemic blood pressure in diabetic subjects, more so at an elevated blood glucose level.
Schemetter et al. (18) showed that the beta-adrenergic sensitivity of the ocular vessels of diabetic patients is lower than that of control subjects. LASER interoferometry was used. (18) The eyes (n = 214) were divided into four groups according to the modified Airlie House classification. Fundus pulsation amplitudes were significantly smaller in group 4 than in the control group (P < 0.027) Local fundus pulsations in the macula are reduced in proliferative diabetic retinopathy, which is compatible with previous findings of reduced choroidal blood flow in late stages of the disease.
Evans et al. (19) studied eleven patients with early diabetes with minimal or no retinopathy and 11 healthy controls were evaluated for retrobulbar blood flow velocity using colour Doppler imaging for the ophthalmic and central retinal arteries. Patients and subjects were tested while breathing room air and again under conditions of hyperoxia. They found that hyperoxia induced a significant change in the central retinal artery end diastolic velocity (EDV) (p = 0.008) and resistance index (RI) (p = 0.032) in normal subjects, but not in diabetic patients. Consequently, during hyperoxia, the diabetic patients were significantly higher for EDV (p = 0.006) and significantly lower for RI (p = 0.002) compared with normal controls. They concluded that hyperoxia significantly reduces central retinal artery end diastolic velocity and significantly increases the resistance index in healthy but not in diabetic subjects.(19)
Patel et al. (20) 24 non-diabetic controls and 76 diabetic subjects were studied Of the diabetic subjects, 12 had no diabetic retinopathy, 27 had background retinopathy, 13 had pre-proliferative retinopathy, 12 had proliferative retinopathy, and 12 had had pan-retinal photocoagulation for proliferative retinopathyIn comparison with non-diabetic controls (9.52 microliters/min) and diabetic patients with no diabetic retinopathy (9.12 microliters/min) retinal blood flow was significantly increased in all grades of untreated diabetic retinopathy (background 12.13 microliters/min, pre-proliferative 15.27 microliters/min, proliferative 13.88 microliters/min). They concluded that retinal blood flow is significantly increased in diabetic retinopathy in comparison with non-diabetic controls and diabetic subjects with no retinopathy.
Mendivil et al. (21) compared 25 eyes of 25 patients with proliferative diabetic retinopathy before and 6 months and 1 year after panretinal photocoagulation with a matched control group of 30 eyes of 30 healthy volunteers. The ophthalmic artery, short posterior ciliary artery, central retinal vessels, and vortex veins of all patients were examined, and the systolic, diastolic, and mean arterial velocities were measured. Panretinal photocoagulation was performed with these parameters: 800-1000 spots, 0.1 second, 500 mW. The blood velocity was significantly lower in diabetic patients than in normals in the ophthalmic artery and the central retinal artery. After treatment, blood-flow velocities were significantly lower than before photocoagulation in the ophthalmic artery, the central retinal artery and the central retinal vein. Eyes with proliferative diabetic retinopathy showed lower ocular perfusion velocities than normals in the ophthalmic artery and the central retinal artery. Photocoagulation resulted in a reduction in ocular blood-flow velocities in the ophthalmic artery, the central retinal artery and the central retinal vein; these values did not change significantly during 1 year of follow-up
Feke et al. (22) used laser Doppler technique and monochromatic fundus photography to measure retinal circulatory parameters in 39 patients with type 1 diabetes with duration of diabetes between 7 and 20 years and 13 age-matched controls without diabetes. Blood pressure, intraocular pressure, and heart rate were measured in all subjects. Glycosylated hemoglobin was measured in the patients. Retinopathy was assessed using standardized color fundus photography and fluorescein angiography. They concluded that the retinal circulation of patients with type 1 diabetes with no retinopathy or background retinopathy is characterized by dilated major arteries with reduced blood speeds.
Effects of diabetes on retrobulbar blood flow:
As the retina is supplied by the central retinal artery, we would expect some changes in the central retinal artery hemodynamics in patients with diabetes. Guven et al. (23) showed in seventy-three eyes in 37 patients with diabetes that the CRA maximum blood flow velocity levels were significantly higher in the pre-retinopathy group (9.8 +/- 2.1 cm/second) than in the non-PDR group (8.1 +/- 2.2 cm/second). Color Doppler imaging was used to quantitate peak systolic blood flow velocities of the central retinal artery (CRA). (n=37) In addition, the CRV maximum blood flow velocity levels were significantly higher in the pre-retinopathy group (5.7 +/- 0.9 cm/second) than in both the PDR group (4.8 +/- 1.5 cm/second) and the PRP group (4.9 +/- 1.7 cm/second)
Goebel et al. (24), using color Doppler imaging, studied 61 eyes with proliferative, 59 eyes with nonproliferative, and 26 eyes with preproliferative diabetic fundus changes with a matched control group of 70 patients without diabetes (128 eyes). He showed that proliferative retinopathy strongly correlated with reduced flow velocities in the retrobulbar vessels, mainly the central retinal artery. These findings only tell us that there is change in the retrobulbar blood flow. Whether these changes in the retrobulbar circulation are partly a cause of retinopathy or an effect of dysfunctional autoregulation is not clear.
Choroidal changes in Diabetes- Diabetic choroidopathy:
Increased tortuosity, focal vascular dilatations and narrowings, vascular loops and microaneurysm formation, dropout of choriocapillaries and sinus-like structure formation between choroidal lobules in the equatorial area have been documented in the choroidal vasculature of Diabetic retinopathy patients. High resolution histological analysis of the human choroidal vasculature revealed areas of capillary dropouts, beaded capillaries, and neovascularisation. Fluorescein angiography showed delayed choroidal perfusion, and electroretinograms with abnormal oscillatory potentials in the same diabetic patients. (25)
Analyzing the association between the presence of abnormal choroidal lesions evident on ICG angiography and several risk factors, one study found that some of the risk factors for developing choroidopathy were the severity if diabetic retinopathy, degree of diabetic control and stringency of diabetic treatment regimen. (26)
Studies on choroidal blood flow :
Upto 80% of the aerobic metabolism of the retina is supplied by the choroid.(5)( Retinal blood flow represents only about 4 percent of total ocular blood flow. The choroidal blood flow on the other hand ranges from 500 to 2000 ml/min/100g tissue. The mechanisms controlling ocular blood flow are of different types: systemic, local, neural, endocrine, paracrine. Not all operate in the various beds. Since the retinal and choroidal arterioles do not possess sphincters, blood flow in these tissues is only a function of the muscular tonus of the arterioles and possible the state of contraction of the pericytes. Vessels tonus is modulated by the interacted of multiple control mechanisms: myogenic, metabolic , neurogenic, and humoral, which are mediated by the release of vasoactive molecules by the vascular endothelium or by the glial cells surrounding the vessels.
We know that there is retinal autonomic dysregulation in diabetic retinopathy. We also know that the choroid is regulated by the autonomic nervous system. What has not been studied to a great extent though is whether there is any autonomic dysregulation of the choroidal blood flow in Diabetic patients. (9) In normal individuals, the choroid has a linear relationship with the pulse pressures. This indicates a lack of autoregulation capacity of the choroid in response to increased pulse pressures. In the choroid, an increase in arterial pressures causes the sympathetic nervous system to increase the peripheral resistance.(5)
Due to the recent advance in tools to measure choroidal blood flow, a great deal has been learnt about how the blood flow within the eye occurs and how it changes with various stresses in the body. POBF and OPA are indirect indicators of choroidal blood flow can be measured by techniques like laser interferometry, colour Doppler imaging, laser Doppler flowmetry and pneumotonometry.
Polska et al (23) found these various techniques reproducible in healthy individuals. Laser interferometry assesses fundus pulsation amplitude. Colour Doppler imaging assesses blood velocities in the ophthalmic and posterior ciliary arteries. Laser Doppler flowmetry assesses choroidal blood flow, volume, and velocity using fundus camera.
Pulsatile ocular blood flow (POBF) can be measured with the pneumotonometer OBF (ocular blood flow) system. (28) By means of a pneumatic applanation tonometer, the system assesses changes in IOP that are caused by the rhythmic filling of the intraocular vessels. The maximum IOP change during the cardiac cycle is called pulse amplitude (PA). Based on a theoretical eye model, the POBF is calculated from the IOP variation over time. This hydrodynamic model is based on the assumption that venous outflow from the eye is nonpulsatile. Moreover, the ocular rigidity, which is used to derive ocular volume changes from changes in IOP, is assumed to be equal in all subjects. The calculation of POBF is automatically derived from the five pulses that are closest to each other in IOP beat-to-beat variation. (28)
Studies on POBF:
Savage et al. (29) conducted a study using the Langham pneumotonometry on patients with Non Proliferative Diabetic retinopathy. 77 diabetic subjects, including 13 with mild or no retinopathy, 36 with moderate to severe retinopathy, and 28 with proliferative diabetic retinopathy (PDR), previously treated with pan retinal photocoagulation (PRP) were selected. 56 non-diabetic control subjects served as the comparison group. Patients with moderate to severe non-proliferative diabetic retinopathy (NPDR) had POBF 18% higher than the control (mean OBF, 943 L/min). Among PRP-treated subjects with PDR, ocular blood flow was 22% below the control (mean OBF, 619 L/min), and 34% less than moderate to severe non-proliferative diabetic retinopathy. Diabetic patients with no retinopathy or mild NPDR had OBF indistinguishable from the control (785 vs. 797 L/min). Differences between the four groups were statistically significant by ANOVA (P < 0.0001). He showed that POBF is unaffected early in diabetic retinopathy, but increases significantly in eyes with moderate to severe NPDR. POBF is decreased in eyes with laser-treated PDR .(29)
McKinnon et al, (30) using an adapted pneumotonometer attached to a slit lamp, studied 82 age-matched subjects divided into 4 groups: non-diabetic controls (n = 22); diabetics with no clinical retinopathy (n = 20); background diabetic retinopathy (n = 20); pre-proliferative /proliferative diabetic retinopathy(n = 20). The mean pulsatile ocular blood flow values were found to be increased in all grades of diabetic retinopathy (no retinopathy 818 l/min, background 1015 l/min, pre-proliferative/proliferative 1097 l/min) compared to the control group (644 l/min). These pulsatile ocular blood flow values were significantly higher (p<0.05) in tbe background and pre-proliferative /proliferative retinopathy groups compared to controls. They found that the pulsatile ocular blood flow was found to be higher in diabetics compared to controls and appears to increase as the severity of retinopathy progresses. (30)
Dimitrova et al. (31) studied choroidal circulatory changes in diabetic patients with and without background diabetic retinopathy (BDR) by measuring the retro bulbar circulation with colour Doppler imaging (CDI). End-diastolic velocity (EDV) in the posterior ciliary artery (PCA) was decreased (2.55 0.80 cm/s) and resistivity index (RI) in the PCA was increased (0.70 0.08) in BDR patients compared with the control patients' EDV (3.23 1.08 cm/s,P = 0.01) and RI (0.62 0.06, P = 0.0003). RI in the CRA was significantly higher in the BDR group (0.74 0.09) than in the control group (0.68 0.08, P = 0.006). RI in the OA was significantly higher in the BDR group (0.87 0.06) compared both with the NDR group (0.83 0.07) and with the control group (0.81 0.06; p = 0.007, P = 0.004). NDR patients had a significantly higher RI in the PCA (0.67 0.08) than control patients (0.62 0.06, P = 0.01, while the CRA RI (0.71 0.09) did not show significant differences from the control group (0.69 0.08, P = 0.32). Decreased EDV in the CRA was detected in NDR patients (2.16 0.76 cm/s) compared with the controls (2.72 0.92 cm/s, P = 0.007). They concluded that choroidal circulation is affected in NDR and BDR patients.
Langham et al. (32) found that choroidal blood flow decreases with the severity of the retinopathy in diabetes due to increased vascular resistance and a decreased ocular perfusion pressure. In a group of 19 healthy volunteers the mean ophthalmic arterial pressure and the ocular pulsatile blood flow were calculated.
Nagoka et al (33) used Laser Doppler flowmetry to determine the Choroidal blood flow in the foveal region in 70 patients with type 2 diabetes and 36 age and sex matched healthy subjects (control group). 33 patients with no diabetic retinopathy (NDR) , 20 patients with non-proliferative diabetic retinopathy and no macular oedema (NPDR-MO) and 17 patients with non-proliferative diabetic retinopathy and macular oedema (NPDR +MO). Optical coherence tomography was also used to measure the foveal thickness. The group averaged choroidal blood flow values were 13.5 (4.9), 9.4 (2.5), 10.8 (4.8), and 5.6 (2.0) (arbitrary units) in the control, NDR, NPDR/MO-, and NPDR/MO+ groups, respectively. The group averaged CBF values in the NDR group decreased (30.2%; p<0.01) compared with the control group. The average CBF value in the NPDR/MO+ group was also significantly lower (48.2%; p<0.01) compared with that in the NPDR/MO- group. They concluded that the CBF in the foveal region significantly decreases in patients with diabetes, especially those with macular oedema.
LASER interferometry studies on fundus pulsation magnitude have been done and these fail to show any significant difference in choroidal blood flow in diabetics compared to normals. (18,34) Guven et al. showed that flow velocities in the posterior ciliary arteries feeding the choroid are also changed by the disease. (23)
Studies done on ocular pulse amplitudes:
Schmidt et al(25) studied OPA, using the Langham ocular blood flow (OBF) pneumotonometer system . OPA was measured in patients with insulin dependent diabetes mellitus (IDDM) with no (DR-0, n = 22) non-proliferative (DR-1, n = 24), and proliferative (DR-2, n = 18) diabetic retinopathy. He concluded that choroidal circulation remains unaffected as diabetic retinopathy advances.
Geyer et al. (35)studied pulse amplitude (PA) and pulsatile ocular blood flow (POBF) were measured with a pneumotonometer (OBF). The eyes were grouped: (a) normal control, n=26, (b) diabetes with no observable diabetic retinopathy (NDR), n=18, (c) mild to moderate non-proliferative diabetic retinopathy (NPDR), n=20, and (d) very severe pre-proliferative and proliferative diabetic retinopathy (PPDR/PDR), n=12. He found that the PA and POBF values were lower than normal values in the earliest stage (NDR). The POBF increased but was still below normal levels at the NPDR stage, and then increased to an above normal level in the PPDR/PDR stage of diabetic retinopathy. The PA was at normal levels in these later two stages. Results showed that there was an initial dip in the pulsatile ocular blood flow during early stages of Diabetic retinopathy and then in more severe stages, there was an increase in the pulse ocular blood flow.(35) Geyer observed that the ocular pulse amplitude was lower in diabetics with no retinopathy as compared to normal subjects and participants with documented diabetic retinopathy. They also found that the ocular blood flow increased as the progression of diabetic retinopathy increased. They hypothesized that the low POBF in the non-diabetic-retinopathy patients correlated with the histological features of chorio-capillaris degeneration and basal lamina deposits. In proliferative retinopathy, they hypothesise that the choroid also has an analogous condition- Diabetic choroidopathy.
Geyer et al. showed the following in their study on OPA with the Langham OBF system
Control NDR NPDR PDR
NUMBER 26 18 20 12
PULSE AMPLITUDES 2.8 (1.0) 1.8 (0.7) 2.7 (0.8) 2.9 (0.9)
Significance compared to ndr P<0.001 P=0.55 P=0.83
Pulse ocular blood fow (ul/sec) 13.7 (4.5) 8.8 (3.4) 11.7 (2.1) 18.3 (3.8)
Significance compared to control P< 0.001 P=0.054 P=0.003
The above mentioned studies of on OPA, the OPA has been measured using the pneumotonometer. Dynamic contour tonometer (DCT) , a relatively newer instrument used to measure IOP can be also be used to measure OPA (more details elaborated later). To date there are no studies of OPA in diabetics as measured by DCT.
Factors affecting ocular blood flow
Effect of Pan Retinal Photocoagulation on ocular blood flow:
Pan retinal photocoagulation reduces both retinal and retro bulbar blood flow. Blood flow in the ophthalmic artery and the central retinal artery and vein are reduced for at least 2 years after photocoagulation therapy. Photocoagulation therapy may also affect choroidal perfusion since destruction of the choriocapillaris reduces the amplitude of ocular pressure pulsations. (20)(21)(29)(36)(37)
Effect of age on ocular blood flow:
The blood flow into the eye decreases with age.(38) Also, the pulse ocular blood flow decreases as the intraocular pressures increase. (38) Having said that, in primary open angle glaucoma, the pulse ocular blood flow was shown to decrease. (39)
Effect of gender on pulsatile ocular blood flow:
Gekkieva et al. (40) observed in their study comparing the ocular pulse amplitudes and ocular blood flow in men and women. They found significantly increased POBF (722.6 152.8 in females versus 647.8 1164.9 in males p=0.056) and OPA(2.3 0.7 in females versus 2.0 0.6 mm Hg in males) in females as compared to males.
Ocular Blood flow and Hypertension:
Blood pressures do not seem to affect the ocular pulse amplitude. (41) (42) These studies were done among normal subjects. They hypothesized that this lack of significant change in OPAs were due to the regulatory mechanisms of the baroreceptors in the carotid system before blood reached the choroidal circulation.(41) Also, in another study, POBF was found to be lower in diabetics without hypertension compared to the controls. Such a presence of systemic hypertension may increase the choroidal blood flow in diabetics.(43)
Ocular blood flow and pulse amplitude studies in India:
The Ocular pulse amplitude has not been studied extensively within the Indian population. In New Delhi, Agarwal et al. found that the pulse ocular blood flow in normal Indian individuals was higher than that of the Caucasian population(7) 95 normal subjects were selected. 41 males and 54 females. The pneumotonometer OBF system was used for all the measurements. The mean pulse amplitude obtained among the normal subjects was 3.41.46 mm Hg.
There is no published data on the normal range of ocular pulse amplitudes among the Indian subcontinent, nor any on the ocular pulse amplitudes of diabetic patients using the Dynamic Contour Tonometer. With this study we aim to document the above in the context of the Indian subcontinent.
Ocular pulse amplitudes in Glaucoma:
The variations of OPA in glaucoma has been well studied. Most studies show that there is a reduction in the ocular pulse amplitudes in patients with primary open angle glaucoma. (44)
In normal eyes in which the intraocular pressures were mechanically raised, with the raise in Intraocular pressures, the ocular pulse amplitudes increase. There is a direct relationship between the ocular pulse amplitudes and the ocular rigidity. (45)
Relationship of ocular pulse amplitudes and axial length:
Similarly, the variations of OPA in normal subjects have shown that OPA varies with the axial length of the eye. (46)(47) Kaufmann showed a negative correlation between OPA and axial length (0.27 mm Hg/1 mm of length; P<.001) (48)
Ocular pulse amplitudes in Retinitis Pigmentosa patients:
OPA measures by the ocular blood flow system showed a significant decrease in the OPA with increasing severity of Retinitis Pigmentosa. (49) The study was done to see if there was a decrease in choroidal perfusion in patients with increasing severity of Retinitis Pigmentosa. Therefore, in the conducted study, patients with Retinitis Pigmentosa were not selected to be enrolled in the study.
Ocular pulse amplitude in patients with age related macular degeneration:
In early ARMD, there is an increase in the choroidal blood flow, and in advancing severity of age related macular degeneration, there is a reduction in the choroidal blood flow and volume. (34)
Mori et al. (50) in their work showed that the POBF and PA in the patients with exudative AMD are lower than in the patients with non-exudative AMD and normal subjects. They recruited 10 patients with non-exudative AMD, 11 patients with exudative AMD, and 69 age matched controls. The significance of difference in pulse amplitudes between the exudative AMD group (PA=1.2 mm Hg) and non-exudative AMD (PA=2.2mm Hg) was p= 0.04. Similarly, the significance of difference between the exudative AMD group and the controls (PA= 2.0mm Hg) was p=0.01. They concluded that decreased choroidal blood flow may have a role in the development of choroidal neovascularisation in AMD.
Ciulla et al. (51) analysed 25 subjects with non exudative age- related macular degeneration and compared them with 25 age-matched control subjects in studies of flow velocities in several retro bulbar vessels. Colour Doppler imaging was done in his study which showed that subjects with non-exudative age-related macular degeneration showed a consistent trend toward lower peak systolic and end-diastolic velocities in the posterior ciliary arteries. They hypothesises that the reduced peak systolic velocity, and reduced end diastolic velocity, is consistent with reduced bulk flow within these vessels, probably suggesting that choroidal perfusion is abnormal in non-exudative age-related macular degeneration.
Dynamic Contour Tonometry:
Dynamic contour tonometry (DCT) is a new non-invasive technique of checking the intraocular pressure. It also simultaneously measures the ocular pulse amplitude of the eye being studied. Ocular blood flow varies with systole and diastole. This pulsatile ocular blood flow (POBF) shows a peak during systole. The difference in the minimum and maximum values of the pulsatile wave contour during systole and diastole gives us the ocular pulse amplitude (OPA). The OPA is an indirect indicator of the choroidal perfusion.(42)(52)
The Pascal DCT is one such device which can be installed into the optical axis of a slit lamp. The tonometer head piece consists of a cylindrical head with a surface contour which comes into contact with the corneal surface and becomes equal to the contour of the cornea when the pressures on both sides are equalized. The sensitive part of the head is only 0.25mm2. The Pascal software measures the intraocular pressure and its variation with every heart beat- the ocular pulse amplitude. The values are shown on an LCD display. The signals are stored in a computer via a wireless unit and the results are thus displayed and stored for further data analysis.
The intraocular pressures measured by the PASCAL dynamic contour tonometer are more accurate than the Goldmann applanation tonometer. The intra observer and inter observer variability was about 0.65 and 0.44 for the DCT and 1.11 and 2.38 mm Hg for the Goldmann applanation tonometer. This accuracy of the DCT can be accounted by the fact that the readings are electronic. (53) They also found that with DCT, the intraocular pressures reduced from the first to sixth readings. This is due to the repeated pressure over the eye as the readings are taken. Similarly, we suspect that there may be changes in the ocular pulse amplitudes of patients when repeated readings are taken, therefore an average of 3 readings are taken, with quality index 1 or 2. (54)
Studies using dynamic contour tonometer:
Kaufmann et al (48) found a median value of 3.0mmHg among the 223 eyes studied. The OPA readings ranged from 0.9 to 7.2 mm Hg (median, 3.0 mm Hg; 1.8-4.3 mm Hg). He found that the OPA readings were not affected by central corneal thickness (P = .08), corneal curvature (P = .47), anterior chamber depth (P = .80), age (P = .60), or sex (P = .73). There was a positive correlation between OPA and intraocular pressure (0.12 mm Hg/1 mm Hg of intraocular pressure; P<.001) and a negative correlation between OPA and axial length (0.27 mm Hg/1 mm of length; P<.001)
Hoffmann et al described a mean SD OPA value of 3.08 0.92 mmHg. (55) a total of 19 eyes were examined by DCT. The study was conducted in Germany..
Pourjavan et al (42), carrying out a prospective study including 52 eyes of 28 normal subjects with Goldmann applanation tonometry (GAT) IOPs<22 mmHg found a mean OPA was 2.2 +/- 0.7 mmHg (range: 1-3.4 mmHg). The mean amplitude of diurnal OPA fluctuations was 0.4 mmHg. There was no significant difference in the mean OPA values at each time of the diurnal curve. Neither blood pressure nor age had a significant bearing on the readings of OPA. OPA values of both eyes of the same individual were highly correlated (r = 0.89, P < 0.0001).
To date there are no studies of OPA in diabetics as measured by DCT-. We conducted this study to look at the OPA in varying grades of diabetic retinopathy and if presence of hypertension could affect the OPA in these patients.
Materials and Methods:
Study Design: observational study
1) Patients diagnosed to have diabetes in the Medicine/ endocrinology department of CMCH and referred to the Department of Ophthalmology, CMCH for evaluation for diabetic retinopathy.
2) Known diabetics and are undertaking treatment in the Department of Ophthalmology, CMC Vellore.
3) Patients who are not known diabetes who presented either to our outpatient facility or camp facility were screened for diabetes and were included in the diabetic/ no diabetic group as per the blood results (the inclusion criteria as given below).
Institutional Review Board clearance: The study was cleared by the institutional ethics and research committee of the Christian Medical College, Vellore. Ref. No: (appendix1)
Location: Department of Ophthalmology, CMC Vellore.
Patients were enrolled into the study if they belong to the following criteria:
1. For group 1 (No DM), patients had no history of Diabetes or having taken medications for Diabetes in the past. TO confirm absence of Diabetes Mellitus, based on the American Diabetic Association guidelines for Diabetes diagnosis 2011 (49) . HbA1C levels were done for all patients that were enrolled for the study (HbA1C of more than equal to 6.5 mg/dl were diagnosed as diabetics). Therefore, All patients with A1C levels of < 6.5 mg /dl were selected under this group
2. For group 2 (DM with no DR), they required one of the following criteria before being enrolled into the study:
a. Chronic history of Diabetes, on oral hypoglycemic medications
b. Recently diagnosed Diabetics ( based on ADA guidelines)
3. For group3 (DM with DR), they required presence of diabetic retinopathy to be enrolled in to the study.
Hypertension was diagnosed based on the Joint National Committee - 7 report as patients who had blood pressure readings of more than equal to 140/90 mm Hg in two or more readings*.
1. Active retinal pathology other than diabetic or hypertensive retinopathy
2. Any intraocular surgery in the past 1 year in the eye chosen to be examined
3. No clear view to the fundus
4. History of cerebro-vascular event
5. History of connective tissue disorders and hematological disorders
6. Patients with proven glaucoma
7. Ocular hypertensives (those with corrected intraocular pressures more than 24mm Hg)
8. Suspicious discs (suggestive of glaucoma)
9. History of any chronic topical ocular medications being used.
10. Corneal disease which prevents DCT measurement.
In addition , presence of HbA1C>6.5 mg/dl was an exclusion criteria for group 1 (No DM)
Participants who consented to take part in the study were divided into 3 sub-groups based on their clinical presentation: No diabetes (No DM group) , Diabetics with no retinopathy (DM with no DR group), Diabetics with retinopathy (DM with DR group). For each patient, the right eye was chosen by default unless the right eye had a contraindication for the same.
Patients without Diabetes (No DM) were mostly in-patients who were planned on being operated for cataract surgery the following day. For all patients without Diabetes, blood was sent for serum HbA1C levels on the same day, irrespective of whether an AC/PC was done in the recent past. Blood samples were taken in the ward for the admitted patients by trained nursing staff or by the primary investigator. For the few patients who were selected with consent from the outpatient department, blood was withdrawn at the laboratory in the Eye Hospital, CMC Vellore. All the blood samples were tested in the Biochemistry Laboratory under the Department of Biochemistry, CMC Hospital Vellore. Funding for the blood test was by the research fund. A/c no 22X873 (appendix) Patients who were found to have HbA1C levels above 6.5 were discontinued from the study.
Patients with Diabetes, with or without retinopathy were approached through the out-patient department in the Eye Hospital, CMC Vellore.
Diabetic patients (with or without Diabetic retinopathy) were identified by doctors in the outpatient department and referred to the principal investigator for further evaluation after orienting each patient briefly on what the study involved.
The patients were then explained in detail about what the study involved, the minimal risks involved, and the possible benefits from the study. If they were willing for the same, they were recruited.
Having given consent for participation in the study, the participants again underwent a dilated fundus examination by the principle investigator (Dr. Ashish Kuruvilla) using a 90 D condensing lens assisted by a Haag Streit slit lamp in order to confirm absence of exclusion criteria. This also enabled uniformity in the protocol in checking ocular pulse amplitudes after dilatation, as there are possible effects of mydriatics on the autonomic regulation of blood flow within the eye.
Patients with Diabetic retinopathy were classified based on the modified Airlee staging standard photographs into mild , moderate, severe and very severe non proliferative diabetic retinopathy and proliferative diabetic retinopathy.
Based on the clinical findings, patients underwent OCT and FFA where indicated based on the protocol followed in the department of Ophthalmology, CMC Vellore.
Once all the exclusion criteria were eliminated, the patients underwent blood pressure measurements by trained staff in the department of Ophthalmology. Blood pressures were checked in the sitting position, after 10 minutes of waiting, in the right arm, except in those who had a contraindication for the same. The BP cuff and the sphygmomanometer were placed approximately at the level of the heart. If the blood pressures were recorded to be more than equal to 140/90 mm Hg, they were rechecked after an hour. If the blood pressures were still more than 140/90 mm Hg , the patients were either referred to department of Medicine, CMC Vellore (if affordable) or the Low Cost Effective Care Unit CMC Vellore, for further management.
Once all the exclusion criteria were eliminated, patients underwent Ocular Pulse Amplitude measurements using the PASCAL Dynamic Contour Tonometer after entering preliminary information about the patient on the proforma sheet.(appendix2)
Once the PASCAL DCT unit was attached to the Haag Streit slit lamp, a drop of topical paracaine 1% was instilled. Having confirmed that the patient was comfortably seated and not straining to place his or her chin on the chin rest, the head was kept leaning on the head rest. The sensor tip of the DCT unit was then brought close to the cornea, with the patient fixing on a target straight ahead with the left eye. A darkened area in the centre of the sensor tip cover (approximately half of the diameter of the visualised sensor tip area) represented the area in contact with the eye. Visualisation was with the left eye piece, using the right eye of the observer. Three values of either quality score 1 or 2 were taken and entered in the proforma (appendix 2). Intraocular pressures (which were automatically displayed on the screen along with the Ocular Pulse Amplitude values) were also noted down to confirm absence of ocular hypertension, which has been hypothesised to affect the pulse ocular blood flow and therefore the ocular pulse amplitude.
The measured data was then transferred to a devoted computer via a blue tooth device.
All the ocular pulse amplitude readings were taken by the principal investigator.
Contact details were not obtained for all patients as they did not require follow up visits. As all the patients examined had a CMC hospital number, the Patients who were found to be Diabetic based on HbA1C levels were advised to get an OPD check up in the Low Care Effective Care Unit/ department of general medicine or Endocrinology, Christian Medical College Hospital Vellore.
Each proforma was stored in a file for future reference with date. Age and sex were documented along with the date of testing. History of Hypertension and whether on medications was also noted. The details of medications which the patients was on was also noted as some antihypertensives had a intraocular pressure lowering effect and therefore may have had an effect on the ocular pulse amplitude.
Sample size calculation:
Based on results of Orna- Geyer et al,(35) on ocular blood flow and ocular pulse amplitude using pneumotonometry, there was a significant difference in ocular pulse amplitudes between diabetics with no retinopathy and normals. Non proliferative and proliferative retinopathy did not show to have any significant difference from the normal mean. They found a mean difference of 1.0 between the normal (2.8 mm Hg; SD=1.0) and diabetics with no retinopathy (NDR= 1.8 mm Hg; SD 0.7).
Taking this data, with alpha error of 5% and power of 80%, we calculated the sample size required in each subgroup and found it to be 12. We then decided to club all diabetic patients that showed some features of Diabetic retinopathy into one group, diabetics with no retinopathy into another and lastly having the normal as the third group. 50 participants in each group would be adequate to get accurate inferences while doing univariate analysis. Also, this would ensure that atleast 12 patients with mild, moderate, severe non proliferative and proliferative retinopathy were in the Diabetics-with-retinopathy arm. We thought that these numbers (three times the required sample size in each arm) would be sufficient to analyse any new subgroups which we may observe during the course of the study.
The sample size was calculated based on hypothesis testing for 2 means, using the formula:
n= 2sp2[Z1-alpha/2 + Z1- beta]2 / ud2
Where sp2 =( s12 + s22 ) / 2
S12 : standard deviation in the first group
S22 : standard deviation in the second group
Ud2 : mean difference between the samples
Alpha: significance level
In the analysis, all data was analysed using SPSS software version 20.0, along with Microsoft Excel 2010. To assess the clinical significance of each statistical question asked, t-test for equality of means was used.
The total number of participants included in the study was 172. 3 Patients, who were screened to be selected in the No DM arm, who were found to have raised HbA1c (>6.5 mg/dl) were taken out of the study and referred to Department of Medicine, CMC Vellore.
4 patients enrolled were not able to sit by the slit lamp for the period of time required and therefore the quality index was not 1 or 2 in these participants. Therefore, they were taken out of the study.
One of the patients had a neck ailment and mechanically found it difficult to place her chin on the chin rest on the slit lamp. Though not mentioned in the criteria, she was not selected in the study for obvious reasons.
3 patients refused to undergo blood tests to confirm absence of Diabetes. All three were women. Two of them felt that they were too anaemic for blood tests and the third did not want to be poked repeatedly after the trained nursing staff failed to get a vein in two attempts. Therefore, these 3 women were not included in the study.
Mean OPA among patients with no Diabetes or Hypertension:
The total number of patients with no Diabetes group was 53. The mean ocular pulse amplitudes in this group was 2.83 0.94 . This represents the ocular pulse amplitudes among the normal population, with no systemic illnesses.
Gender-wise number of patients:
Out of these 172, the number of males were 83 and the number of females were 89. All the patients were from South India. One patient was originally from West Bengal but was living in Vellore during examination.
Figure No.1 Gender distribution
Table No.1: Comparison between OPA of males and females
sex N Mean OPA SD
Male 83 2.65 0.96
Female 89 2.60 0.95
OPA in mm Hg.
The mean OPA of men was 2.647 and for women was 2.60. It failed to show a significant difference in OPA with p=0.769 .
Subgroup analysis was done comparing significance of difference between mean OPA among men and women. None of the 3 sub-group analysis had any significant difference. (Table No.2)
Table No.2: Comparison of males and females in various subgroups
No DM number Mean OPA SD T-test significance (comparing males and females)
males 29 2.630.90
females 24 3.050.94
DM NO DR (n=66)
Males 22 2.680.96
females 44 2.460.73
DM +DR (n=53)
Males 32 2.310.88
Females 21 2.871.34 0.069
Age wise distribution:
The age of patients enrolled in the study ranged from 40 to 79 years. The decade wise distribution of participants is shown in Figure 2. Majority of the patients were in the 5th decade with almost similar number s in the 4th and 6th decade. There were only 5% of participants in the 71- 80 year age group. The graph below shows the distribution of the number (in absolute numbers) of participants in each group.
Table No. 3: Mean OPAs among patients grouped by decade
Age yrs number Mean PA SD
40-50 48 2.631.07
51-60 71 2.600.89
62-70 45 2.620.90
71-80 8 2.841.19
mean 172 2.630.95
OPA in mm Hg.
The mean OPA was almost the same in all the groups being considered. The mean OPA among the 172 population considered was 2.625. We took the subgroup 71-80 and cross tabulated with the mean OPA to see if the difference was significant. There was no significant difference seen ; p= 0.54.
Table No. 4: Significance of difference in OPA between groups based on age
Sum of Squares Df Mean Square F Sig.
Between Groups .405 3 .135 .146 .932
Within Groups 155.413 168 .925
Total 155.817 171
ANOVA was done to see if there was any significant difference between any of the sub groups. The table above shows the same. The test failed to show any significant difference between the four groups. P=0.932
SUB GROUP ANALYSIS:
Analysis between the 3 major sub groups:
As described in the methodology, there were 3 subgroups that we had selected. Group 1 was No DM, group2 DMwith no DR, and Group 3, DM with DR. Given below is the distribution of these 3 subgroups.
Figure No. 2 Percentage of patients without DM, with DM and no DR, with DM and DR
Table No.5: Analysis between the 3 major subgroups
number Mean OPA SD t-test (compared to controls)
No DM 53 2.83 0.94
DM no DR 66 2.54 0.81 0.068
DM and DR 53 2.53 1.11 0.13
OPA in mm Hg.
Comparison of the groups DMnoDR with DM+DR:
There was no significant difference between the two groups. P= 0.972 .
Distribution of patients in each stage of Diabetic retinopathy:
Out of the 53 in the Diabetics with retinopathy arm, 14 were with mild non proliferative diabetic retinopathy, 18 with moderate retinopathy and 21 with severe non proliferative and proliferative diabetic retinopathy.
Figure no.3: Distribution of patients in each stage of Diabetic retinopathy
The average Ocular pulse amplitude among the 3 groups are as shown:
Table No.6: Mean OPA of patients in various stages of retinopathy
Group number Mean OPA SD t-test (compared to controls)
No diabetes (controls) 53 2.83 0.94
Diabetes with no retinopathy 66 2.54 0.81
Mild NPDR 14 2.70 1.51 0.69
Moderate NPDR 18 2.66 0.93 0.50
Severe NPDR , PDR 21 2.31 0.95 0.034
OPA in mm Hg.
There was a significant decrease in mean OPA in those with severe pre-proliferative and proliferative diabetic retinopathy.
Comparison of LASER therapy on values of OPA among severe NPDR- PDR groups:
Out of the 21 patients with severe non proliferative + proliferative diabetic retinopathy subgroup, 11 had had no LASER therapy and the rest of the patients had LASER .
Table No.7: Comparison of patients with and without LASER in patietns with severe NPDR/ PDR
Severe NPDR/PDR n Mean OPA* SD
No LASER 11 2.33 0.86
LASER 10 2.28 1.09
*OPA in mm Hg
Hypertension among Non-Diabetics and Diabetics:
Though Hypertension was not an exclusion criteria for selection of participants with no Diabetes, it was found that patients with Hypertension without Diabetes were very few. Also, there were 2 patients in whom Diabetes was found on doing HbA1c , both of whom claimed that they had Hypertension but no Diabetes.
The pie chart illustrates the point that the total percentage of patients with Hypertension but no diabetes was rare.
On the other hand, out of the patients with Diabetes, 42% had Hypertension, all of them were on medications. The rest of them underwent blood pressure checks and were found not to be Hypertensives.
Figure no.4 Percentage of non diabetics with Hypertension
Figure no. 5 Percentage of Hypertensives among Diabetics
The OPA in the various categories of patients in the presence and absence of hypertension is depicted in table 8
Table No.8: Comparison of Hypertension among various subgroups:
N(number in each category) Mean OPA` SD t-test analysis
No DM , No HTN 48 2.80 0.91
No DM, HTN + 5 3.14 1.18 0.44
DM , No HTN 69 2.40 0.93
DM , HTN + 50 2.73 0.96 0.06
DM , no DR, HTN+ 30 2.61 0.67
DM, no DR, no HTN 36 2.48 0.91 0.53
no HTN 33 2.30 0.95
DM, DR+, HTN+ 20 2.90 1.28 0.056
OPA in mm Hg.
Among the diabetic patients who had retinopathy, lower OPA was found in those patients who had no hypertension as compared to those who were hypertensive. (p= 0.05). It was significantly lower OPA as compared to controls as well. (p=0.02 )
Type of anti Hypertensives taken by those with Hypertension:
Anti-Hypertensive medications taken by these patients were also documented. All the patients were only on one antihypertensive. The results are as follows:
Table No. 9: Antihypertensive medications
Medications Number Percentage among Hypertensives (%)
Beta Blockers 9 18
Calcium channel blockers 2 4
ACE inhibitors 19 38
Angiotensin Receptor blockers 1 2
thiazides 6 12
Not on therapy 13 26
The above table shows a significant percentage of patients who were not on treatment despite being on medications for Diabetes and knowing that they had Hypertension. It was beyond the scope of the study to determine why these participants were not on antihypertensives despite knowing they had Hypertension.
Figure No.6 Patients on Antihypertensive medications in percentages
The numbers were not adequate to compare between Hypertensives with various antihypertensives. ANOVA done with the above data showed a significance of only 0.159.
Table No.10: Mean OPA among Hypertensives on antihypertensives
Antihypertensive used N Mean OPA SD
Beta blockers 9 2.310.46
Calcium channel blockers 4 2.160.99
ACE inhibitors 19 3.100.75
Angiotensin receptor blockers 1 3.57
Thiazides 6 2.600.88
Not on therapy 11 2.590.39
OPA in mm Hg
ACE inhibitors trended to show increased ocular pulse amplitudes as compared to the other antihypertensives used.
Various ocular perfusion abnormalities at micro and macrovascular levels as well as defects in autoregulation occur in diabetics. Changes in the retinal capillary endothelium and pericytes, causing various manifestations of diabetic retinopathy have been well established. Choroidal changes have also been documented in diabetics(26,4)
Different studies on ocular blood flow and OPA have shown varying results. The varied results could be due to 1) the different methods used to study the ocular blood flow. It is possible that some methods measure the flow in the smaller choroidal vessels and some probably measure the flow in the larger choroidal vessels. 2) The fact that the POBF could vary with the duration of diabetes, ( ref Kono et al 1996 iovs) with diabetics of shorter duration having higher POBF as compared to those with longer duration of diabetes(ref Kono). This could explain the varied results of POBF in the category of patients with DM but no DR with some studies showing no change (49)and other studies showing decreased blood flow (32,35). 3) Acute changes in the blood sugar levels can lead to varied ocular blood flow. Bursell et al found that acute hyperglycemia resulted in increased retinal blood flow in diabetics with no retinopathy.(57) 4) Most studies of ocular blood flow and OPA in diabetics have not looked at the confounding effect of co-existing hypertension. Hypertension causes increased retinal perfusion pressure as well as altered choroidal perfusion. Whether this will result in increased OBF will depend on the extent of change in the intraocular vessels, both choroidal and retinal, as well as the state of the general circulation. Simple extrapolation of haemodynamic principles make it possible to theorise that increased blood pressure could result in increased tissue blood supply or, paradoxically, a decreased blood supply when the vessels are grossly narrowed. Thus, the effect of hypertension on ocular blood flow can be highly variable and dependant on individual factors in the local circulation which may not be possible to measure and assess.
In our study, the mean OPA in the control group (non-diabetic, non-hypertensive , n= 48) was 2.80 0.91 mm Hg which is comparable to the OPA as measured by DCT in other studies- Kaufmann et al(53) found a median value of 3.0mmHg, Hoffmann et al (55) 3.08 0.92 mmHg among normals.
Though some studies have shown a gender difference in OPA (39,40) , in our study the mean OPA was similar in males( n= 83; 2.65 0.96 mmHg) and females (n= 89; 2.60 0.95 mmHg) [ p=0.77] . Notwithstanding this, we looked for any difference in the distribution of males and females in the three subgroups (No DM, DM without DR, and DM with DR) since it could have a confounding effect on the results. There was no statistically significant difference in any of the three subgroups(p> .05 in all three subgroups). (Table no. 2)
The age of patients included in our study ranged from 40 to 79 years with fewer patients (5%) in the 7th decade(fig. 2 ). This was because many patients in this age group had dense cataract which precluded a clear view to the fundus, and hence were excluded or because some of them could not cooperate for examination.
The OPA was similar in the three subgroups Group1: no DM ( 2.83 0.94mmHg), Group 2: DM no DR( 2.54 0.81 mmHg) , Group 3: DM + DR ( 2.53 1.11 mHg).
Some studies (32,35) have shown a decrease in POBF and OPA in patients with diabetes without retinopathy as compared to controls whereas few other studies(29) (49) have shown no difference. Our study did not show any differe