Central retinal vein occlusion in a pediatric patient with SLE and antiphospholipid antibodies without anti-cardiolipin or anti-β2 glycoprotein I antibodies

Background Antiphospholipid antibody syndrome is characterized by venous and/or arterial thrombosis, and is found in patients with systemic lupus erythematosus. Its diagnosis requires the presence of both clinical and laboratory findings, such as positive anti-cardiolipin and anti-β2 glycoprotein I antibodies and lupus anticoagulant. However, cardiolipin is a minor component of the vascular endothelial cells in human, and phosphatidylcholine and phosphatidylethanolamine are major components. Case presentation A 15-year-old female suddenly developed massive left intraretinal hemorrhaging due to central retinal vein occlusion. She also had a butterfly rash, and her laboratory findings revealed positive serum anti-nuclear antibodies and decreased serum complement. During this episode, she was diagnosed with systemic lupus erythematosus. Although she was negative for serum anti-cardiolipin IgG and anti-β2 glycoprotein I antibodies as well as lupus anticoagulant, her serum anti-phosphatidylcholine, anti-phosphatidylethanolamine, anti-phosphatidylinositol and phosphatidylserine IgG antibodies levels were increased. Conclusion Pediatric cases of central retinal vein occlusion are rare. Even in patients without anti-cardiolipin or anti-β2 glycoprotein I antibodies and lupus anticoagulant, there is the potential for the development of antiphospholipid antibody-related thrombosis.


Background
Antiphospholipid antibody syndrome (APS) is characterized by venous and/or arterial thrombosis and recurrent fetal loss, and is found in patients with systemic lupus erythematosus (SLE) [1]. A diagnosis of APS requires the presence of both clinical and laboratory findings, such as positive anti-cardiolipin (CL) and anti-β2 glycoprotein I antibodies and lupus anticoagulant. However, CL is a minor component of phospholipids in humans [2]. This report describes central retinal vein occlusion (CRVO) in a pediatric patient with SLE and antiphospholipids antibodies without anti-CL antibody.

Case presentation
A female patient was born without any perinatal problems and her psychomotor and growth development had been normal. Her father had Crohn's disease and her elder brother had atopic dermatitis. She developed allergic conjunctivitis when she was around 10 years old and was administered betamethasone eye-drops. She also developed a butterfly rash and photosensitivity at the age of 14. And then, she suddenly developed a left visual disturbance without any premonitory sign at the age of 15. Her visual acuity (left: 0.04, right: 1.2) showed asymmetry. Her eye fundus examination showed massive left intraretinal hemorrhaging due to CRVO (Figure 1). Her blood pressure was 100/70 mmHg and she had not history of any cardiovascular disorders or diabetes.
Intravenous low-molecular weight heparin of reviparin was initiated, and she received steroid pulse therapy, oral fexofenadine and levocabastine eye-drops. The intraretinal hemorrhaging gradually improved, and the patient was treated with warfarin, aspirin, prednisolone and tacrolimus. Her anti-CL IgG antibody titer was examined four times every two weeks, however, all of evaluations showed negative results (2/3/1/1 U/ml). The second examination of the anti-β2 glycoprotein I antibody titer also showed a level less than 1.3 U/ml.
After informed consent was provided by the patient and parents, we examined the patient for other antiphospholipid antibodies according to the Guidelines of the European Consensus described the development of the antiphospholipid IgG antibody ELISA assay, as described previously [3]. Briefly, 1 ml of whole blood was drawn twice at an interval of 12 weeks. Microtitre plates were coated with 50 μg/ml phosphatidylcholine (PC, Nacalai tesque, Kyoto, Japan), phosphatidylethanolamine (PE, Sigma, St. Louis, USA), phosphatidylinositol (PI, Nacalai tesque, Kyoto, Japan) and phosphatidylserine (PS, ChromaDex, Inc, California, USA) and were incubated overnight. On the following day the plates were incubated with triplicate serum at a 1/10 dilution for one hour. After wash, the plates were incubated with goat antihuman IgG (Santa Cruz Biotechnology, Inc, California, USA) at a 1/2,000 dilution for one hour. Using substrate of o-phenylenediamine (Sigma, St. Louis, USA), the absorbance was read at 450 nm with ELISA reader. Agematched three patients with APS with anti-CL IgG antibody, four patients with SLE and eight patients with non-collagen disease controls were also enrolled as disease controls. The positive cut-off value was defined as two standard deviations above the mean in the controls subjects. Since there were no positive control antiphospholipid antibodies, we calculated the optical density (OD) according to the method used in previous reports [3].

Conclusion
CRVO in pediatric patients is rare and has been described to be caused by cardio-vascular disorders, such as hypertension, heart failure, diabetes, atherosclerosis and APS [4]. APS may be considered present in a patient with thrombotic events and positive antiphospholipid antibodies such as anti-CL and anti-β2 glycoprotein I antibodies and lupus anti-coagulant titer that is verified on at least two occasions at least 12 weeks apart [1].
Von Schieven et al. [7] found no significant difference in the prevalence of anti-anti-β2 glycoprotein I between SLE children with or without thrombosis. Berard et al. [8] reported that 15 patients with anti-PE antibodies without anti-CL antibodies developed thromboembolic episodes. Bertolaccini ML et al. [9] also showed that anti-PS/prothrombin antibodies also act as risk factor for thrombosis. Moreover, Kuksis et al. [10] described that decreased plasma levels of the PC is an indicator of atherosclerosis. These previous reports indicated that anti-PC, −PE, and -PS increases the risk of thrombosis and atherosclerosis even in patients without anti-CL antibody.
The examination of patients for anti-CL and anti-β2 glycoprotein I antibodies and lupus anticoagulant is insufficient to understand the essential pathology of antiphospholipid antibody-related thrombosis. Even in patients without anti-CL and anti-β2 glycoprotein I antibodies or lupus anticoagulant, there is the potential for the development of antiphospholipid antibody-related thrombosis.

Consent
Informed consent was obtained from the patient and her parents for publication of this case report. A copy of the consent form is available for review from the Editor of this journal.