A 30 year old woman with gradual vision loss OU
Digital Journal of Ophthalmology 2005
Volume 11, Number 15
August 15, 2005
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Darren J. Bell | University of Tennessee
Joseph Mastellone | University of Tennessee
Edward Chaum MD PhD | Univ. of Tennessee Memphis

A 30 year-old Caucasian woman with a history of Type I diabetes for 29 years presented for initial consultation regarding decreasing vision over the previous month. Her past ocular history included previous macular grid laser treatment OU performed by a local general ophthalmologist. There was no history of hypertension.

Her visual acuity was 20/30 OD and 20/40 OS. The anterior segment examination and intraocular pressure were normal. There was no rubeosis iridis. Dilated fundus exam and fluorescein angiography revealed cystic appearing clinically significant macular edema (CSME). Concentric grid laser scars were present in both maculae (Figures 1,2). The fluorescein angiogram (FA) showed extensive areas of poor capillary perfusion and non-perfusion in the retinal periphery with late staining of the retinal vessels; however, no proliferative retinopathy was seen in either eye (Figures 3, 4). Her CSME was initially treated with periocular injections of Kenalog (40mg) with subsequent improvement in visual acuity to 20/25 in both eyes. Panretinal photocoagulation was planned pending improvement in the macular edema.

Figure 1a
Red free images of right (1a) and left (1b) maculae and discs at the time of presentation. Concentric grid laser scars and cystic edema are present in both eyes. There is no apparent neovascularization.

Figure 1b

Figure 2a
Fluorescein image of the right (2a) and left (2b)maculae and discs at the time of presentation. Macular edema is evident in both eyes.

Figure 2b

Figure 3a
Fluorescein image of right (3a) and left (3b) retinal peripheries at the time of presentation. Peripheral retinal ischemia without neovascularization is evident in both eyes.


Figure 4a
Red-free image of right (4a) and left (4b)maculae and discs 3 months later, at the time of diagnosis with leukemia (CML). Proliferative retinopathy and one disc area of neovascularization at the disc is seen in both eyes. Extensive intraretinal hemorrhages are also seen.

Figure 4b

Ancillary Testing
Radiographic Studies
Three months later she presented to her primary care provider complaining of fatigue and dehydration. Laboratory studies revealed a white blood cell count of 157,000 with blasts present on peripheral smear, a hematocrit of 30.9, and a platelet count of 346,000. A bone marrow aspiration was performed and cytogenetic studies revealed a reciprocal translocation between chromosomes 9 and 22 (Philadelphia chromosome), consistent with the diagnosis of chronic myelogenous leukemia (CML). A repeat dilated fundus exam at that time showed extensive intraretinal hemorrhages, neovascularization of both optic discs, and development of PDR with HRC (Figure 5, 6). There was severe ischemia of the peripheral retina in both eyes with widespread dropout of the peripheral retinal capillary bed (Figure 7, 8).

Figure 5a
Fluorescein image of right (5a) and left (5b) maculae at the time of diagnosis with CML. Neovascularization of both discs (with HRC) is evident. There is global capillary dropout encroaching on the left macula.

Figure 5b

Figure 6a
Fluorescein images (a-c) of right and left retinal peripheries at the time of diagnosis with CML. Severe retinal ischemia with global infarction of the peripheral capillary bed is seen in both eyes. See also Figure 5b.

Figure 6b

Figure 6c

She was subsequently treated with bilateral panretinal photocoagulation.

Differential Diagnosis
The literature on the epidemiology of diabetic retinopathy demonstrates a generally slow progression of nonproliferative diabetic retinopathy (NPDR) and preproliferative disease to the development of proliferative diabetic retinopathy (PDR) in diabetic patients (1). This patient with newly diagnosed chronic myelogenous leukemia (CML) progressed from NPDR to bilateral PDR with high-risk characteristics (HRC) over a period of 3 months. Possible contributing factors and reasons for progression include atypically rapid progression of underlying diabetic retinopathy, other factors such as hypertension or anemia, or rapid progression due to the leukemia.

Diagnosis and Discussion
Epidemiological studies of the progression of diabetic retinopathy by Klein et al. showed that only 10.5% of patients under the age of 30 with NPDR at baseline progress to proliferative retinopathy after a period of 4 years. Of those patients with preexisting PDR at the time of the initial examination, only 13.8% progressed to PDR with HRC after 4 years of follow up (2). However, patients with rapid progression of retinopathy were observed in the ETDRS studies (3). Development of PDR with HRC was seen at 1-year in 0.8% of patients with mild NPDR (level 35) at baseline and in 3.3% of patients with moderate NPDR (level 43, no IRMAs) at baseline as seen in this patient.
The progression to bilateral PDR with HRC in only 3 months; however, is striking in this case. Melberg et al. described a patient with acute lymphocytic leukemia who progressed from background diabetic retinopathy to severe proliferative diabetic retinopathy over a period of six months (4). The authors concluded that the accelerated course of progression was attributable to moderate anemia related to the leukemia and its treatment. In our patient, there was also severe retinal ischemia; however, we propose an alternative hypothesis and mechanism for the accelerated progression to proliferative disease.
Leukoembolization of the retina with resulting ischemia from infarction of the retinal capillary bed is seen in numerous conditions manifesting as Purtscher’s-like retinopathy (5). The mechanism of microvascular occlusion in these diseases is generally believed to be leukocyte aggregation resulting from activation of complement factor C5a. We suggest that the unusually rapid progression of her disease was exacerbated by a similar mechanism, i.e. granulocyte aggregation with secondary microvascular occlusion due to severe leukocytosis. Aggregation of stimulated granulocytes has been proposed as a mechanism of microvascular occlusion, as well as pressure-dependent plugging of vessels and endothelial cell damage by toxic leukocyte products (6). This aggregation hypothesis is supported by evidence of increased blood viscosity and leukostasis in the vasculature of brains of patients who have died from leukemia (7). The clinical presentation of severe peripheral retinal ischemia in our patient may have been due in part to unrecognized leukoembolization of the retinal vasculature prior to her diagnosis of CML. The progressive retinal ischemia may have exacerbated the secretion of angiogenic factors in the diseased retina and led to accelerated development of neovascular disease.
Interestingly, recent studies have found that systemic blood plasma concentrations of angiogenic factors, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are significantly increased in patients with CML, compared to healthy controls (8,9). Extravascular leakage of circulating VEGF and bFGF from incompetent vessels into the compromised retina may also act to increase the local tissue levels of these angiogenic factors and accelerate the clinical course of proliferative disease. Increased amounts of circulating VEGF, produced independently of underlying retinal ischemia in patients with CML, could also provide a synergistic mechanism for the rapid development of PDR with high risk characteristics observed in our patient.

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