7.3 Physiology

A useful framework for understanding the pathophysiology of diabetic macular edema is the oxygen theory.24 According to this theory, hyperglycemia over prolonged periods leads to reduction in perfusion of the inner retina and decrease in inner retinal oxygen tension. The autoregulatory response of the retinal arterioles is dilation which leads to increased hydrostatic pressure in the intraretinal capillaries and venules as specified by Poiseuille’s law

(Box).54 The elevated intravascular pressure experienced by the capillaries may itself damage them.24,54

Concomitantly, the decrease in retinal oxygen tension leads to an increase in synthesis of VEGF and probably other permeability factors, which cause the microvasculature to become leakier. Besides

increasing microvascular permeability, VEGF can also directly induce retinal venous dilation, a synergistic effect exacerbating extracellular edema.57 By Starling’s Law (Box), increased intravascular pressure and increased vascular permeability imply net flow of water, ions, and macromolecules from the intravascular space into the extravascular space. Extracellular fluid exits by reentering the retinal vessels further downstream or out into the choroid via the pumping action of the RPE. The relative contributions of these two pathways to the egress of macular extracellular fluid have not been quanti-

tated. Clinical observations that retinal arteriolar dilation precedes DME fit well with this theory.24,58

Fig. 7.11 (a) Development of hypotony with associated maculopathy (choroidal folds) in the presence of nonproliferative diabetic retinopathy inducing recurrent DME. (b) Midphase frame from the fluorescein angiogram showing leaky microaneurysms, old focal laser scars, and pigmented linear RPE scars from previous choroidal detachment subsequent to

a mitomycin C trabeculectomy. (c) Late frame from the fluor escein angiogram showing late diffuse hyperfluorescence in the macula. (d) Recurrence of macular thickening as depicted in the macular false color map associated with onset of hypotony. (e) Radial line scans showing intraretinal cysts in the presence of the recurrent DME

Many variables have suspected importance in the breakdown of the blood–retina barrier. The duration of diabetes and the integrated elevation of

blood glucose reflected in the HbA1C have proven pathophysiologic importance. Retinal neurons and glial cells increase their production of VEGF

in diabetes, even before ophthalmoscopic evidence of capillary loss, and this is associated with increased

occludin phosphorylation and reduced occludin content in capillary endothelial tight junctions.35,60,61 Vitr-

eous levels of VEGF are higher in eyes with DME than in diabetic eyes without retinopathy.62 The diabetic retina shows leukostasis, accumulation of macrophages, intercellular adhesion molecule-1 activation, and prostacyclin upregulation which indicates a state of inflammation and is associated with capillary non-

perfusion and breakdown of the blood–retina barrier.52,63 Inflammatory cytokines such as tumor necro-

sis factor-beta and interleukin-1b may be important mediators of increased vascular permeability.35,64,65 Pigment epithelium-derived growth factor, an antiangiogenic and possibly permeability decreasing cytokine, is lower in eyes with DME than diabetic eyes without retinopathy.62 Many other small molecules and growth factors, including insulin-like growth factor, hepatocyte growth factor, and histamine, may be important in the mechanisms underlying DME,

although the details of the pathways are incompletely understood.64–68 High lipid levels may cause endothe-

lial dysfunction and increased vascular permeability through a local inflammatory response, release of vascular permeability promoting cytokines, and higher levels of advanced glycation end products.14,69

Alterations in retinal and choroidal blood flow have been reported in diabetic retinopathy that may influence DME. Patients with diabetes have impaired retinal vascular reactivity to oxygen tension that worsens with retinopathy severity.70,71 Retinal vascular autoregulation is impaired in diabetes with more severe dysfunction associated with more severe retinopathy.55 The local factors primarily responsible for vascular autoregulation are nitric oxide and endothe- lin-1.72 Vitreous nitric oxide concentration does not differ from vitreous concentrations in macular hole patients used as controls, but vitreous endothelin-1 concentration is significantly lower in DME than levels found in these controls.72 It is possible that this loss of autoregulatory function may explain refractoriness of certain patients with DME to treatments that are effective in eyes retaining autoregulation. Reported decreases in foveal choroidal blood flow in type 2 diabetic patients with retinopathy may be relevant in the pathophysiology of DME as well, although the techniques for assessing choroidal blood flow have greater uncertainty. Eyes with DME have

been reported to have a greater decrease in choroidal blood flow than eyes without DME, leading to suggestions of relative hypoxia of the RPE and outer retina and possible increased permeability of the outer blood retinal barrier on this basis.31

The vitreous has a role in the pathogenesis of DME. The diabetic vitreous differs from normal, and the increased cross-linking and glycation of the diabetic vitreous may explain the tendency to develop tangential macular traction, which may in turn induce or exacerbate DME.42,44 Besides the direct effect of traction causing leakage from blood vessels or macular elevation with subretinal fluid, vitreous adherent to the macula may loculate chemical mediators of increased vessel permeability in proximity to macular capillaries and may impede oxygenation of the retina causing venous dilation and increased edema via Star-

ling’s Law or by upregulation of vascular endothelial growth factor.45,58,73–75 Mean blood flow velocity in

perifoveal capillaries increases after vitrectomy in eyes of diabetics with vitreous adhesion, which might be associated with improved macular oxygenation and lessened leakage.76

With all of the components that influence DME identified, we can consider the net economy of salt and water transport in subclinical and clinical DME. Figure 7.12 shows that the passive flux of salt and water out of retinal vessels and into the retinal interstitium increases monotonically as one traverses from the state of health to diabetic retinopathy without edema to subclinical DME and finally to clinically significant macular edema (CSME). Passive permeability increases 12-fold in going from health to CSME.54 Correspondingly, the active transport of salt and water outward through the RPE increases, although less steeply, through the first three stages, but then falters going into CSME, such that active transport increases only twofold as one traverses from health to CSME.54 The primary problem in DME, therefore, is the increase in passive permeability and not the RPE pumping mechanism.54

This account of the pathophysiology of DME informs our current understanding of how treatments for DME work and how nondiabetic factors can modulate severity of DME (Fig. 7.13). Pharmacologic blood pressure reduction reduces passive permeability of the inner blood–retinal barrier.54 The beneficial effects of grid laser are thought to arise from the increase in oxygenation of the inner retina

Fig. 7.12 Passive permeability primarily of the inner blood– retina barrier increases 12-fold in going from the state of health through the state of clinically significant macular edema. In contrast, active transport of salt and water outward via the RPE pump increases only doubles. P = passive permeability. T = active transport. Reproduced with permission from Lund-Andersen54

both by reduction in oxygen-consuming photorecep-

tors and by a shorter diffusion pathway to the inner retina for oxygen originating in the choroid.24,77,78

Focal photocoagulation presumably works by directly destroying leakage sources such as microaneurysms. Focal/grid laser may also improve RPE pumping of salt and water outward toward the choroid.24,79 In a rabbit model, focal/grid laser photocoagulation caused reduced expression of protein kinase C alpha, a regulatory protein for phototransduction and signal transmission in rod bipolar cells and increased labeling for glial fibrillary acidic protein in Muller cells throughout the retina, not just locally in the areas photocoagulated, implying more than a local effect of focal/grid laser treatment.80 The macular thinning effect of focal/grid photocoagulation precedes significant documented closure of microaneurysms on fluorescein angiography suggesting that

the grid effect begins immediately and the focal effect somewhat later. Eighty-nine percent of leaking microaneurysms have been reported to be closed by 12 weeks after a session of focal/grid laser, but less than 1% by 2 weeks post laser.27 Anti-VEGF drugs work by blocking the permeability inducing effects of VEGF.36 Although somewhat controversial, there is some evidence that corticosteroids reduce expression of the VEGF gene, thus reducing VEGF levels, and differentially regulate expression of the various VEGF receptors.81,82 Corticosteroids may have other, non-VEGF-mediated effects resulting in reduction in permeability of retinal microvessels such as decreasing leukocyte recruitment and production of intercellular adhesion molecule-1.83–85 Oral protein kinase C-b inhibitors such as ruboxistaurin block the biochemical pathway upregulated by VEGF binding to its receptor on retinal vascular endothelial cells.86 Statins reduce serum lipid levels, possibly decreasing microvasculature leukostasis and secondary inflammation.69,87 Vitrectomy may work by increasing intravitreal and secondarily inner retinal oxygen levels, leading to downregulation of VEGF synthesis and resulting in a decrease in permeability of microvessels.24,78,88 In addition, vitrectomy may open up compartments of loculated

cytokines and relieve traction exerted on the macula by an altered vitreous.48,88,89 Peribulbar and intravi-

treal corticosteroids may exert beneficial effects on DME by blocking VEGF-mediated increases in retinal vascular permeability and through influences on non-VEGF-mediated pathways.90 Endophthalmitis and other forms of uveitis that may coincidentally occur with diabetic retinopathy may exacerbate DME because inflammatory mediators increase microvasculature permeability.91

Our discussion of DME to this point has concerned extracellular edema, also called vasogenic edema. In addition to extracellular edema, a concept

of intracellular edema exists which may be relevant for DME, although it has been less studied.39,92

Water transport out of the retina occurs via retinal pigment epithelial active transport of potassium and chloride and passive co-transport of water across aquaporin1 channels. Less recognized, however, is transport of water into retinal microvessels via Muller cells. Muller cells possess a unidirectional potassium channel called Kir2.1 that allows extracellular potassium derived from neuronal firing to pass into