Intraretinal Neovascularization in Diabetic Retinopathy FREE

The hallmark of proliferative diabetic retinopathy is neovascularization occurring at the vitreoretinal interface and in the vitreous,¹ although intraretinal neovascularization (IRNV) is also reported to be a common finding if repeated fluorescein angiography is performed.^{2 - 3} However, the appearance of the IRNV in routine histological sections has been reported only rarely.⁴ Herein, we describe the histological features of IRNV in both eyes of a man with chronic diabetes mellitus.

A 53-year-old man with chronic diabetes mellitus, hypertension, chronic kidney disease,coronary artery disease, and congestive heart failure fell out of bed. The next morning he was unresponsive; a computed tomographic scan disclosed a large right subdural hematoma with 3 cm of a right-to-left midline shift of the brain and uncal herniation. He had fixed and dilated pupils, a Glasgow Coma Scale score of 3, and no spontaneous respirations or evidence of brain stem function. The patient was declared brain-dead and died shortly after having the ventilator removed. There was no recorded ophthalmic history or eye examination.

Both eyes were enlarged, measuring 28 × 28 × 28 mm. On sectioning, both eyes had innumerable 0.1- to 1.0-mm-diameter retinal hemorrhages surrounding the macula. Microscopically, the neurosensory retina of both eyes had occasional thick-walled blood vessels and other vessels with occlusive fibrin microthrombi, some of which may have been an agonal event. Some arterioles with fibrin microthrombi had dual lumina typical of recanalization or intravascular endothelial proliferation. Other vessels exhibited vascular proliferation (Figure 1) with glomeruloid⁵ and angiomatoid⁶ appearances. Immunostains using antibodies to factor VIII–related antigen and CD34 confirmed the vascular identity (Figure 2). Widespread hemorrhages appeared throughout the neurosensory retina along with a few hemosiderin-laden macrophages around some retinal arterioles. Epiretinal membranes appeared in both eyes; the left retina had a few microinfarcts of the nerve fiber layer, cystoid macular edema, and serous exudates in the outer plexiform layer; and both eyes had low-lying serous detachments of the macular neurosensory retina as well as focal chorioretinal scars.

Takahashi et al³ noted IRNV in 54 of 94 eyes (57%) when repeated fluorescein angiography was used to examine patients with diabetes mellitus having nonperfused areas of retina.² The IRNV occurred as capillaries that budded from a venule and grew to form a network.³ The IRNV developed in eyes with nonproliferative diabetic retinopathy or developed concomitantly with or after the appearance of new blood vessels at the vitreoretinal interface.²

Despite the frequency with which IRNV is noted by fluorescein angiography, we found only 1 report of the microscopic features of this condition in human eyes in routine histological sections.⁴ Our histological findings were similar to those by Imesch et al,⁴ who examined the eyes from 5 individuals with diabetic retinopathy and noted intraretinal neovascular lesions consisting of “multiple microvascular lumina spaced closely together and enveloped by a thick perivascular cuff”⁴ containing collagen fibrils. The IRNV and preretinal neovascularization were sometimes contiguous.⁴

Vascular endothelial growth factor has been implicated in the pathogenesis of proliferative diabetic retinopathy,¹ and the histological appearance of the IRNV in these eyes is similar to that induced by intradermal injection of vascular endothelial growth factor in mice.⁵ The IRNV also resembles plexiform and angiomatoid lesions in lungs with pulmonary hypertension.⁶ Factors implicated in the pathogenesis of pulmonary plexiform lesions include overexpression of vascular endothelial growth factor, endothelin 1, and survivin; reduced expression of vascular antiremodeling mediators such as nitric oxide synthase and prostacyclin synthase; loss of expression of transforming growth factor β receptor 2 and proapoptotic Bax; and mutations in bone morphogenetic protein receptor 2, a component of the transforming growth factor β family.⁶ The similarity of IRNV with pulmonary plexiform lesions suggests potential avenues for investigating the pathogenesis of proliferative diabetic retinopathy.

Correspondence: Dr Proia, Department of Pathology, Duke University Medical Center, DUMC 3712, Durham, NC 27710 (proia001@mc.duke.edu).

Financial Disclosure: None reported.