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Chapter 10

Rapid progression of diabetic retinopathy in eyes with posterior uveitis Judie Knol1 MD, Bram van Kooij1 MD, Harold de Valk2 MD, PhD, Aniki Rothova1 MD, PhD. 1FC Donders Institute of Ophthalmology, and Department of Internal Medicine,2 University Medical Center Utrecht The Netherlands. (American Journal of Ophthalmology, in press)

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Abstract Purpose To report on two patients, who developed rapid progression of asymmetric diabetic retinopathy (DRP) in eyes affected by posterior uveitis, in contrast to their fellow eyes not affected by uveitis. Design Observational case report. Methods Two patients with diabetes mellitus (DM) and unilateral uveitis underwent repeated ophthalmologic examinations and fluorescein angiography. Results Two patients with DM and unilateral posterior uveitis developed proliferative DRP in eyes with previous uveitis within 3 months after the uveitis subsided. In contrast, the retinal findings of non-uveitic eyes remained unchanged on the follow-up of several years. Conclusions Since the pathogenesis of intraocular inflammation and diabetic retinopathy acts through similar biochemical mediators and pathways, it is feasible that posterior uveitis accelerates the progression of diabetic retinopathy. Our results support this hypothesis and point out a risk for rapid retinopathy development in eyes affected with posterior uveitis.

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Introduction The pathogenetic agents involved in the development of DRP are not entirely clarified. In addition to hyperglycemia and retinal hypoxia a number of vasoactive factors promote pathologic changes in the microvasculature. This paper reports on rapid progression of asymmetric DRP in 2 patients with posterior uveitis. Figure 1. Left eye of patient 1, four weeks (Left panel) and 4 months (Right panel) after the onset of toxoplasmic retinitis. Left panel, old hyperpigmented scar in satellite formation to an active yellowish toxoplasmic lesion located adjacent to optic disc. Associated inflammation of arterial wall is visible. No signs of diabetic retinopathy or neovascularizations are present. Right panel, 3 months later, extensive neovascular membrane radiating from optic disc and associated with preretinal hemorrhages has developed.

Case 1 A 27-year-old female presented in with toxoplasmic chorioretinitis OS. Patient had diabetes mellitus type I since the age of 19 years and was treated with insulin. She had no chronic complications of her diabetes, co-morbidity or co-medication. Ocular examination OD was without abnormalities. Patient was treated with multiple antiparasitic drugs and within 6 weeks the lesion became scarified; visual acuity returned to 20/16 and no DRP was visible. Three months later vitreous hemorrhage

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and optic disc neovascularizations developed (Figure 1 and 2). Despite continuous laser treatment, vitreous bleeding with retinal traction recurred. Visual acuity dropped to light perception despite pars plana vitrectomy with silicone oil injection, retinotomy and endolaser treatment. After the follow-up of 8 years she still had full visual acuity OD and no manifest DRP changes. Figure 2. Retinal photographs of patient 1, four months after the onset of toxoplasmic retinitis in the left eye. Left, retina of the right eye not affected by toxoplasmic retinitis exhibits no signs of diabetic retinopathy, and severe proliferative diabetic retinopathy in the left eye associated with old retinal scar adjacent to optic disc and preretinal hemorrhage (right).

Case 2 A 58-year-old male presented with acute retinal necrosis in OD caused by a herpes zoster infection. This patient had an insuline-requiring type II diabetes mellitus of 18 years’ duration complicated by clinical polyneuropathy. He was known with a minimal background diabetic retinopathy in both eyes. The infection in OD was treated with intravenous acyclovir and his retinal lesions scarified and visual acuity increased to 20/60. However, after this initial favorable reaction, the patient developed severe proliferative DRP with multiple

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neovascularizations and massive vitreous hemorrhage in the OD within 3 months, while the minimal background retinopathy in OS remained unchanged (Figure 3). Despite panretinal laser photocoagulation and vitrectomy combined with retinal cryocoagulation, the progression of the DRP failed to stop and his useful visual acuity OD was lost to light perception. However, his OS remained stable and exhibited unchanged features of mild background DRP. Figure 3. Asymmetric development of diabetic retinopathy in patient 2 affected by Acute Retinal Necrosis (ARN) in the left eye. Left panel, right eye not affected by ARN and no visible diabetic retinopathy in contrast to severe background diabetic retinopathy, which developed within 3 months after the initial beneficial response to ARN treatment. Note the extensive capillary non-perfusion and start of laser coagulation treatment in the lower area of the retina (right panel).

Discussion We report on 2 patients with a rapid progression of DRP in the eyes affected by posterior uveitis in contrast to fellow non-uveitic eyes which remained stable on long-term follow-up. Diverse modifying ocular factors related to asymmetric development of DRP were previously described and included presence of endophthalmitis, carotid occlusive disease and cataract surgery.1-4 On the contrary, protective factors against DRP consisted of optic atrophy, extensive chorioretinal scarring, high myopia and retinitis pigmentosa.2 Contradictory reports examined the effect of intraocular inflammation on the development of DRP and

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included a study of rapid progression of DRP following endophthalmitis in contrast to two patients with unilateral chronic uveitis without DRP manifestations and severe DRP in their fellow eyes without uveitis.3,5,6

The rapid course of the unilateral DRP progression and the stable disease in the fellow eyes suggest that the asymmetric DRP may have occurred due to the effects of inflammatory mediators on retinal vasculature. Multiple biochemical mechanisms have been proposed to explain the pathogenesis of DRP. A major factor consists of VEGF, which is known to be a potent pro-angiogenic and permeability factor and has been implicated in the development of retinal neovascularizations.7 The expression of many inflammatory cytokines is increased in ocular fluid of patients with DRP. Likewise, high intraocular levels of VEGF were found in eyes with uveitis.7 Because intraocular inflammation and DRP may act through similar biochemical mediators and pathways, it is possible that the elevated levels of VEGF in uveitis might have provoked the rapid development of DRP in our patients. In addition, the vascular wall changes in the retina in posterior uveitis associated with increased leakage might have also contributed to the aggressive development of DRP. Further studies are needed to clarify our findings and hypotheses.

To conclude, our results support the hypothesis that inflammation can accelerate progression of diabetic retinopathy and point out a risk for rapid retinopathy development in eyes affected with posterior uveitis.

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References 1. Dogru M, Inoue M, Nakamura M, Yamamoto M. Modifying factors related to

asymmetric diabetic retinopathy. Eye 1998; 12:929-933. 2. Browning DJ, Flynn HW, Blankenship GW. Asymmetric retinopathy in patients

with diabetes mellitus. Am J Ophthalmol 1988; 105:584-589. 3. Dev S, Pulido JS, Tessler HH, et al. Progression of diabetic retinopathy after

endophthalmitis. Ophthalmology 1999 Apr; 106:774-781. 4. Hauser D, Katz H, Pokroy R, Bukelman A, Shechtman E, Pollack A. Occurrence

and progression of diabetic retinopathy after phacoemulsification cataract surgery. J Cataract Refract Surg 2004 Feb; 30:428-432.

5. Murray DC, Sung VCT, Headon MP. Asymmetric diabetic retinopathy associated with Fuchs’ heterochromic cyclitis. Br J Ophthalmol 1999 Aug; 83:988-989.

6. Scialdone A, Menchini U, Pietroni C, Brancato R. Unilateral proliferative diabetic retinopathy and uveitis in the fellow eye: report of a case. Ann Ophthalmol 1991; 23:259-261

7. Vinores SA, Youssri AI, Luna JD, et al. Upregulation of vascular endothelial growth factor in ischemic and non-ischemic human and experimental retinal diseases. Histol Histopathol 1997 Jan; 12:99-109.

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