CHRONIC MYELOID LEUKEMIA DIAGNOSED IN A PATIENT WITH UNCONTROLLED PROLIFERATIVE DIABETIC RETINOPATHY Lígia M. Figueiredo, MD, Renata T. Rothwell, MD, Dália Meira, MD, Sofia Fonseca, MD

Purpose: To report a case of uncontrolled proliferative diabetic retinopathy as an initial manifestation of chronic myeloid leukemia. Methods: Case report. Patients: A 55-year-old man with moderate nonproliferative diabetic retinopathy who rapidly developed proliferative retinopathy and bilateral neovascular glaucoma despite good glycemic control. Conclusion: Other pathologies should be excluded in diabetic patients with a rapid and severe progression in their retinopathy despite adequate metabolic control. These patients should be treated promptly and aggressively until systemic disease is stable. RETINAL CASES & BRIEF REPORTS 9:210–213, 2015

acuity was 8/10 in the right eye and 10/10 in the left eye (Snellen equivalent) (Figures 1 and 2). In November 2012, he complained of blurred vision. On ophthalmological examination, his best-corrected visual acuity was 6/10 in the right eye and 4/10 in the left eye. Anterior segment findings showed angle neovascularization with no peripheral anterior synechiae. Intraocular pressure (IOP) with applanation tonometry was 16 mmHg in the right eye and 20 mmHg in the left eye. A dilated fundus examination revealed retinal ischemia with multiple intraretinal hemorrhages and cotton–wool exudates, but no definitive neovascularization was observed. In the right eye, there was no apparent macular edema, but temporal macular edema was visible in the left eye. Fluorescein angiography showed numerous microaneurysms and flame-shaped hemorrhages, areas of marked capillary nonperfusion, and leakage from small fronds of neovascularization bilaterally on the optic disk (Figures 3 and 4). At that time, he was normotensive, his hemoglobin A1c (HbA1c) was 6.5%, and he had no systemic complaints. He started treatment with panretinal photocoagulation (PRP). One week after his first laser session, he presented to the emergency department with complaints of vision loss and pain in the left eye. Ophthalmologic examination revealed acute NVG of the left eye with corneal edema and Grade 1 hyphema (occupying less than one third of the anterior chamber). He was treated with intravitreal bevacizumab injection, which resulted in rapid improvement of visual acuity (in 1 week), regression of neovascularization with marked decrease of IOP (from 50 to 18 mmHg), and clearing of the corneal edema and hyphema. He continued his laser treatment, but after 1 month (3 laser sessions), he had a similar episode of acute NVG in the other eye and he was also treated with intravitreal

From the Department of Ophthalmology, Centro Hospitalar Vila Nova de Gaia, Vila Nova de Gaia, Portugal.

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n patients with good glycemic control, the progression of moderate nonproliferative diabetic retinopathy to proliferative diabetic retinopathy in less than a year is very rare. The progression/evolution of the retinopathy can be accelerated by rare diseases that cause further retinal ischemia, leading to proliferative retinopathy.

Case Report A 55-year-old man with noninsulin-dependent diabetes mellitus diagnosed 19 years earlier had nonproliferative diabetic retinopathy and mild maculopathy that was treated with a single session of macular laser photocoagulation. Despite good glycemic control, he developed proliferative retinopathy (PRP) and bilateral neovascular glaucoma (NVG). He had been followed by a retina specialist for 5 years through half-yearly appointments. Until June 2012, his best-corrected visual None of the authors have any financial/conflicting interests to disclose. Reprint requests: Lígia M. Figueiredo, MD, Department of Ophthalmology, Centro Hospitalar Vila Nova de Gaia, Rua Conceição Fernandes, Vila Nova de Gaia 4430-502, Portugal; e-mail: ligia_fi[email protected]

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Fig. 1. Fluorescein angiography of both eyes taken in June 2012 shows multiple microaneurysms in 4 quadrants and intraretinal hemorrhages. Multiple microaneurysms are present near the fovea with minimal late leakage. Degree of capillary nonperfusion is minimal. OD, right eye; OS, left eye.

injection of bevacizumab, resulting in improvement of signs and symptoms (IOP decreased from 46 to 30 mmHg) within 1 week. PRP was completed, but neovascularization of the angle recurred after 1 month of bevacizumab injections with IOP exceeding 21 mmHg in both eyes (with maximal topical antihypertensive treatment), so he started treatment with monthly injection of bevacizumab. Meanwhile, he underwent a thorough physical examination including carotid duplex scanning of cervical vessels, routine blood tests that included complete blood count, and hemoglobin electrophoresis. Laboratory analysis revealed leukocytosis (201,510 mm3), with increase of blast cells and normocytic normochromic anemia (hemoglobin = 9 g/dL). Hemoglobin electrophoresis excluded sickle cell disease or sickle cell trait. Bone marrow biopsy demonstrated the BCR-ABL translocation, confirming the diagnosis of chronic myeloid leukemia (CML). In April 2013, the patient started systemic treatment with hydroxyurea, allopurinol, and imatinib (Glivec, Novartis). After 6 months of treatment with imatinib (in October 2013), the patient presented with a normal hemogram and a good general clinical condition. After remission of the disease, there was complete regression of angle neovascularization in both eyes, and no further injections of bevacizumab were performed. However, IOP was not controlled with medical therapy because of formation of 270° peripheral anterior synechiae in the right eye and 180° in the left eye. Both

Fig. 2. Optical coherence tomography of both eyes (June 2012). OD, right eye; OS, left eye.

eyes underwent trabeculectomy with Ex-Press Glaucoma Shunt with control of IOP in the left eye, but in the right eye, the trabeculectomy failed 6 months postoperatively. He is currently waiting for Ahmed Glaucoma Valve implantation in the right eye. On the last visit (in April 2014), his best-corrected visual acuity was 3/10 in the right eye and 2/10 in the left eye, and IOP was 31 mmHg in the right eye and 14 mmHg in the left eye, with topical brimonidine, dorzolamide, timolol, and travoprost in both eyes. Fundus examination showed decreased retinal hemorrhages and no evidence of infiltrates or neovascularization in either eye.

Discussion Chronic myeloid leukemia is a myeloproliferative neoplasm characterized by the t(9;22) chromosomal translocation, or Philadelphia chromosome, that leads to the expression of BCR-ABL fusion protein. BCRABL acts as a constitutively active kinase, and the unregulated activity of this protein contributes to the malignant transformation of the disease by increasing proliferation and inhibiting apoptosis in hematopoietic progenitors.1 During the chronic phase of CML, some patients are asymptomatic, whereas others may present with fatigue and weight loss. Chronic myeloid leukemia is typically characterized by splenomegaly and leukocytosis with a prominent shift in the granulocytic series.2 Thrombocytosis and anemia are often observed. Marked leukocytosis (usually .200 · 103 mg) can increase blood viscosity, leading to hyperviscosity syndrome. Typical symptoms include peripheral vascular occlusions, cerebrovascular accident, venous thrombosis, and priapism. Fundus changes caused by leukostasis were first described as leukemic retinopathy in the 1806s by Liebreich. Although it is more frequent in patients with acute leukemia, it is also described in patients with CML.

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Fig. 3. Color fundus photographs of posterior pole of OD and OS taken in June 2012 demonstrate dilated and tortuous vein, dot–blot, and November retinal hemorrhages, and microaneurysms in both eyes and fluorescein angiography of both eyes show numerous microaneurysms and flameshaped hemorrhages, areas of marked capillary nonperfusion, and leakage from small fronds of neovascularization bilaterally on the optic disk. OD, right eye; OS, left eye.

The most common findings of leukemic retinopathy are dilation and tortuosity of the veins, perivascular sheathing of retinal vessels, intraretinal hemorrhages, leukemic infiltrates, cotton–wool spots, and optic nerve infiltration. In rare cases, it progresses to proliferative retinopathy with neovascularization and/ or fibrovascular proliferation.3–5 Leukemia retinopathy is believed to be induced by retinal ischemia secondary to obliteration of the terminal retinal arteries. Leukocytosis increases blood viscosity, which can be aggravated by associated conditions such as anemia, thrombocytopenia, and intravascular sludging by large leukemic cells.6 The rapid progression of nonproliferative diabetic retinopathy to proliferative diabetic retinopathy in patients with good metabolic and tensional control and poor response to treatment is rare, and other diseases that can cause further retinal ischemia should be excluded.7 Our patient had good glycemic control (HbA1c of 6.5%) and progressed from nonproliferative diabetic retinopathy to proliferative diabetic retinopathy with bilateral NVG over a period of 6 months. Ischemic angiogenic stimulus plays a major role in the pathogenesis of diabetic retinopathy, leading to upregulation of vasoproliferative factors including vascular endothelial growth factor (VEGF). Interesting recent studies have shown that angiogenesis and VEGF levels are also increased in bone marrow cells and in the serum of patients with CML.8,9 We interrogate if in our case, retinal ischemia was not only due to the increased blood viscosity but also due to the increased VEGF levels caused by CML. Another possibility for the rapid progression is that PRP could have induced transient angle closure and further ischemia. However, the PRP treatment of this patient was undertaken in multiple sections, with no more than 500 burns per session, and on the patient’s

first acute glaucoma crisis, the anterior segment ultrasound showed no anterior rotation of the ciliary body (intense PRP treatment may rarely lead to ciliochoroidal effusion with anterior rotation of the body and iris root). Recent reports have demonstrated the use of intravitreal injections as an important adjunct for the treatment of NVG.10 Although the regression induced by bevacizumab was temporary in our patient and he needed monthly injections, it helped to control the levels of VEGF and IOP until the leukemia stabilized. After reaching remission of the disease, there was regression of the new vessels of the angle in both eyes not requiring further injections of bevacizumab, but IOP was not controlled because of the formation of peripheral anterior synechiae.

Conclusion Our case underlines the importance of the exclusion of other pathologies in diabetic patients with a rapid and severe progression in their retinopathy despite adequate metabolic control and the necessity of prompt and aggressive treatment with PRP and antiVEGF injections until their systemic diseases are stable.

Fig. 4. Optical coherence tomography of both eyes (November 2012).

PROLIFERATIVE RETINOPATHY AND LEUKEMIA

Key words: chronic myeloid leukemia, hyperviscosity syndrome, neovascular glaucoma, proliferative retinopathy. References 1. Deininger MW, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood 2000;96:3343– 3356. 2. Vardiman JW, Pierre R, Thiele J, et al. Chronic myelogenous leukaemia. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. Tumors of Haemotopoietic and Lympoid Tissues. Lyon, France: IARC Press; 2001:20–26. 3. Morse PH, McCready JL. Peripheral retinal neovascularization in chronic myelocyticleukemia. Am J Ophthalmol 1971;72:975–978. 4. Mandava N, Costakos D, Barlett HM. Chronic myelogenousleucemia manifested as bilateral proliferative retinopathy. Arch Ophthalmol 2005;123:576–577.

213 5. Huynh TH, Johnson MW, Hackel RE. Bilateral proliferative retinopathy in chronic mylegenousleukemia. Retina 2007;27:124–125. 6. Nobacht S, Vandoninck KF, Deutman AF, Klevering BJ. Peripheral retinal nonperfusion associated with chronic myeloid leukemia. Am J Ophthalmol 2003;135;404–406. 7. Melberg NS, Grand MG, Rup D. The impact of acute lymphocytic leukemia on diabetic retinopathy. J Pediatrichematoloncol 1995;17:81–84. 8. Sillaber C, Mayerhofer M, Aichberger KJ, et al. Expression of angiogenic factors in chronic myeloid leukaemia: role of the BCR/ABL gene oncogene, biochemical mechanisms, and potential clinical implications. Eur J Clin Invest 2004;34:2–11. 9. Aguayo A, Kantarjian H, Manshouri T, et al. Angiogenisis in acute and chronic leukemias and myelodysplastic syndromes. Blood 2000;96:2240–2245. 10. Moraczewski AL, Lee RK, Palmberg PF, et al. Outcomes of treatment of neovascular glaucoma with intravitrealbevacizumab. Br J Ophthalmol 2009;93:589–593.

Chronic myeloid leukemia diagnosed in a patient with uncontrolled proliferative diabetic retinopathy.

To report a case of uncontrolled proliferative diabetic retinopathy as an initial manifestation of chronic myeloid leukemia...
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