Diabetic Macular Edema

DIABETIC MACULAR EDEMA
Pathophysiology
Diabetic macular edema is a microvascular complication of diabetes mellitus with serious
implications for vision loss. The central pathophysiologic event is retinal capillary incompetence
and leakage. Several biochemical hypotheses exist to explain the damage to retinal capillary
constituents in diabetes mellitus. Prolonged hyperglycemia has been implicated in direct injury to
retinal capillary endothelial cell and pericytes and to a decline in cell division (Engerman 1987).
Cells in the body produce energy from the metabolism of glucose. The sorbitol (or polyol)
pathway concurrently employs aldose reductase to reduce unused glucose to sorbitol (Brownlee
2001). Under normal circumstances cells metabolize glucose primarily via glycolysis,
particularly because at a physiologic serum concentration, aldose reductase has a low affinity for
glucose. However, high serum glucose concentrations can saturate the glycolysis pathway,
making excess glucose molecules available for reduction to sorbitol by the avidly-binding aldose
reductase. Excessive activation of the sorbitol pathway in hyperglycemia results in an
accumulation of sorbitol in the intracellular space which has been considered toxic to cells, in
particular to retinal capillary endothelial cells and pericytes (Brownlee 2001).
Retinal capillary walls normally consist of a succinct network of endothelial cells and mural
pericytes, which exist in a deliberate one-to-one ratio. In the 1950s, Kuwabara and Cogan
developed Trypsin digest studies in retinal tissue of diabetic human subjects, which made
possible the close examination of the retinal vasculature by light microscopy (Kuwabara 1960).
These retinal digest studies were the first of their kind to demonstrate the key pathologic events
of diabetic retinopathy. The biochemical derangements of diabetes mellitus cause a preferential
loss of pericytes, identified histologically as empty balloonlike spaces or ghost cells along
retinal capillary walls (Kuwabara 1960). Immunologic studies have demonstrated that mural
pericytes contain properties that make them structurally analogous to the smooth muscle layer of
larger scale blood vessels. The contractile nature and tonus of pericytes contribute to the
structural integrity of the retinal capillary wall (Herman 1985). Therefore, a loss of mural
pericytes may cause focal weakening and saccular dilatation of retinal capillaries, identified
biomicroscopically as microaneurysms. Microaneurysms are readily detected on close
fundoscopic examination and by fluorescein angiography and are one of the earliest signs of
nonproliferative diabetic retinopathy (Freidenwald 1950). They are visually indistinguishable
from dot intraretinal hemorrhages and thus represent areas of focal retinal vasculature
incompetence.
The breakdown of the inner blood retinal barrier at the level of the retinal capillary endothelial
cells likewise contributes to capillary incompetence. This breakdown largely occurs with an
opening of tight junctions, or zonulae occludentes, between adjacent endothelial cells (Green
1985). The pathophysiologic outcome of inner blood retinal barrier compromise and abnormally
permeable microaneurysms is an unchecked leakage of erythrocytes, plasma, and lipoproteins

into the retinal interstitium. Retinal edema results once this fluid leakage overwhelms the
capacity of the retinal pigment epithelial pump to remove it. The sequelae of vascular
incompetence and retinal edema include (1) precipitation of serum lipoproteins in the retinal
interstitium, causing a disruption of the delicate retinal architecture and (2) retinal arteriolar
closure, resulting in focal retinal ischemia (Ryan 1989).
Retinal arteriolar closure characterizes a more advanced stage of nonproliferative retinopathy and
carries more serious implications for widespread retinal ischemia and progression to proliferative
disease (Ryan 1989). Several mechanisms of arteriolar occlusion have been hypothesized,
implicating both intraluminal and extraluminal forces. Firstly, erythrocyte and platelet
agglutination and defective fibrinolysis may cause intraluminal occlusion of arterioles (Little
1981) Endothelial cell basement membrane thickening, a general histologic characteristic of
diabetes mellitus, potentially causes luminal narrowing and occlusion. The accumulation of
interstitial fluid and protein leads to increased tissue oncotic pressure and tissue turgor which
may cause vascular closure by means of direct compression (Ryan 1989). Macular ischemia
resulting from closure of retinal capillaries and arterioles may exacerbate concurrent macular
edema.
Deformational macular edema caused by tractional membranes on the retinal surface is often
observed in diabetic retinopathy either alone or in the presence of underlying diabetic macular
edema (Clarkson 1977). Epiretinal membranes and a taut posterior hyaloid are the most common
examples of tractional membranes. Epiretinal membranes are fibrocellular membranes caused by
the migration and proliferation of retinal glial cells along the retinal surface. Their origin can be
idiopathic or as a consequence of diabetic retinopathy or retinal vascular disorders. Depending
on their severity, epiretinal membranes can cause retinal distortion and tractional retinal edema
that is evident on both fundoscopy and fluorescein angiography (as cystoid macular edema).
Epiretinal membranes can thus exacerbate underlying DME. The posterior hyaloid face of the
vitreous can likewise cause deformational macular edema by exerting antero-posterior forces on
the macula, as observed in the vitreomacular traction (VMT) syndrome. This is an idiopathic
condition characterized by abnormal adhesion of the posterior hyaloid to the macula. As seen
with epiretinal membranes, there may be tractional edema causing leakage in the macula and
from the optic nerve head on fluorescein angiography (Hikichi 1995). Several hypotheses have
attempted to explain the VMT syndrome: (1) Glycation of the vitreous: abnormal crosslinking of
cortical vitreous in systemic hyperglycemic with tractional adherence to the macula causing a
secondary deformation of retinal architecture (Dillinger 2004); (2) sequestration of proinflammatory factors or compounds in the pre-macular area by the posterior hyaloid that increase
vascular permeability (Dillinger 2004); (3) frank, idiopathic contraction of the posterior hyaloid
face with resultant deformational edema (Figueroa 2008).
The metabolic derangements of diabetes mellitus take a serious toll on the smallest constituents
of the retinal vasculature. These early changes eventually manifest themselves on a macroscopic
level, causing a generalized dysfunction of the blood retinal barrier, pathologic retinal edema,
retinal vascular compromise and closure, tissue ischemia, and the potential for serious loss of
visual acuity.

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DIABETIC MACULAR EDEMA

permeable microaneurysms is an unchecked leakage of erythrocytes, plasma, and lipoproteins

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