DME remains the leading cause of visual loss among patients with diabetes mellitus. Among the various patterns of DME, NSD under the fovea has been reported in 3–31% of patients. The pathogenesis of NSD is linked not only to the limitations of the draining vascular system, but also to impairment in the function of the RPE. Kang et al. reported that in diabetic eyes, the incidence of CME and NSD increasd with the existence of retinal vascular hyperpermeability and the pathology of these two phenomena might share a common pathogenesis in this regard .
Various systemic factors have been associated with increased incidence of DME like severity of diabetic retinopathy, poor glycemic control and duration of diabetes. Hypertension, proteinuria, dyslipidemia, uncontrolled renal parameters, and PRP for PDR (causing acute choroidal ischemia), have also been associated with increased risk of DME. Although all these factors are known to correlate with increased incidence of DME, very few studies have correlated the presence of uncontrolled systemic disease and biochemical parameters with increased incidence of NSD in DME. Poor control of systemic factors could be related to increased leakage from the capillaries with loss of vascular integrity as well to an impaired function of RPE. One study demonstrated the presence of high HbA1c levels in the patients with diabetic CME and NSD, compared to those with diabetic CME and no associated NSD . In our study, we did not find a significant association between HbA1c and presence of NSD. Instead, only high mean systolic and diastolic blood pressures were found to be independent and significant risk factors for NSD in DME.
Increased blood pressure has been implicated, through the effects of increased blood flow, to cause damage to the retinal capillary endothelial cells in eyes of diabetic patients . Elevated blood pressure also alters the retinal arteriolar hemodynamics, causing a reduction in the compliance (i.e., an increase of vascular rigidity) of the arteriolar circulation with increasing risk of DME . Hypertension is a well recognized cause of NSD preferentially affecting the macular region, although NSD is more commonly accompanied with malignant hypertension [24, 25]. The occurrence of NSD in DME can be secondary to excessive leakage in retina or to a poorly functioning RPE. Raised blood pressure can lead to increased retinal leakage as well as ischemic damage to RPE. Another possibility is that diabetes may have caused subclinical choroidal vascular damage in diabetic subjects, rendering the circulatory system more susceptible to further ischemic insult by raised blood pressure.
Choroidal vascular damage causes ischemic damage to the RPE and leads to breakdown of the blood-retinal barrier with transudation of fluid into subretinal space. Hayreh observed that the presence of NSD was correlated to the degree of choroidal circulation disruption. Fluid overload has also been implicated as a cause of NSD .
Anemia is another known risk factor for DME. Low hemoglobin levels can occur in diabetic patients secondary to renal disease or can occur independently. However, the renal disease as measured by serum urea and creatinine was not found to be associated with NSD in this study. Futhermore, anemia was not found as an independent risk factor for formation of NSD. Low hemoglobin has been described as an independent baseline risk factor in the EDTRS for the development of DME and severe visual loss . Other studies have corroborated this finding  and have also found improvement in the DME status following correction of anemia [28–30]. Correction of anemia (and also supplementation of erythropoietin) was noted to decrease the effects of retinopathy with structural improvement, possibly through improved oxygenation of the macula . Singh et al. noted spontaneous closure of microaneurysms in diabetic retinopathy with treatment of co-existing anemia . Friedman et al. reported that increased hematocrit may improve visual acuity due to resolution of macular edema in diabetic retinopathy . Over the past few years, growing evidence supports the hypothesis that hypoxia contributes to progression of tissue injury in diabetic individuals . In our study, although the patients with NSD had lower hemoglobin, none of them had significantly low hemoglobin levels which could be clinically called as anemia. This could be the reason why we were unable to find any significant effect of anemia on NSD.