Bilateral frosted branch angiitis as the presenting sign of antiphospholipid antibody syndrome
Discussion
Ito et al. [1] first coined the term frosted branch angiitis in 1976 where they reported the appearance of thick perivascular sheathing in a 6-year-old boy’s fundus recalling imagery of frosted tree branches during an icy winter. Frosted branch angiitis may be idiopathic or associated with various systemic conditions including SLE [2, 3], Behcet’s disease [4], Crohn’s disease [5], cytomegalovirus (CMV) retinitis [6], herpes simplex type 2 infection [7], mycobacterium tuberculosis infection [8], T. gondii infection [9], various other viral and bacterial infections [10], aseptic meningitis [11], and blood dyscrasias such as leukemia [12] and lymphoma [13]. Additional retinal findings may include intraretinal hemorrhages, hard exudates, and serous exudative detachments of the macula and periphery. A proposed mechanism of retinopathy involves immune complex deposition in retinal vessels causing vasculitis [14]. Patients may complain of sudden onset of blurred vision, central scotomas, floaters, and photopsias, and most patients respond to systemic corticosteroid therapy with good recovery of visual acuity.
Antiphospholipid antibody syndrome (APS) is an acquired thrombophilic disorder in which autoantibodies are produced against a variety of phospholipids and phospholipid-binding proteins. Diagnostic criteria for APS include one clinical event and one laboratory finding. Clinically, a suspected patient must have suffered either vascular thrombosis (which may be venous, arterial, or small vessel) without significant evidence of inflammation in the vessel wall or have suffered pregnancy morbidity (fetal death after 10 weeks gestation, premature birth before 34 weeks associated with eclampsia, pre-eclampsia, or placental insufficiency, or three or more spontaneous abortions before the tenth week of gestation). Regarding the laboratory finding, the patient must have elevated levels of one of the following autoantibodies in serum or plasma on two or more occasions measured at least 12 weeks apart: lupus anticoagulant (LAC), anti-cardiolipin of IgG and/or IgM isotype (aCL), and/or anti-?2 glycoprotein I (a?2GPI) antibody assays. These autoantibodies, collectively referred to as antiphospholipid antibodies (aPL), may arise from multiple mechanisms, including molecular mimicry between human B2GPI (a plasma protein that binds to negatively charged phospholipids and regulates coagulation) and similar molecules on pathogenic bacteria, as a reaction against certain medications (phenytoin and hydralazine among many), and other theorized mechanisms [15]. Generally, aPL may activate platelets, endothelial cells, and monocytes, leading to the inhibition of the fibrinolytic system, activation of the coagulation cascade, and possibly activation of the complement system [16]. The end effect of these pathways may lead to the thrombosis or fetal demise that is seen clinically in APS. The ophthalmic manifestations of APS are typically the result of vessel thrombosis as well, with vaso-occlusive disease involving the choroidal and retinal vasculatures as the most common locations for ocular involvement. Other findings such as anterior segment inflammation, episcleritis, scleritis, keratoconjunctivitis sicca, cranial nerve palsies, and ischemic infarcts of the visual pathway have been reported but are relatively uncommon [17].
In order to be diagnosed with definite SLE, the American College of Rheumatology has recommended that at least four of the 11 diagnostic criteria must be met. These criteria include (1) malar rash; (2) discoid rash; (3) photosensitivity; (4) oral or nose ulcers that are usually painless; (5) non-erosive arthritis in two or more joints; (6) cardiopulmonary involvement such as pericarditis or pleuritis; (7) neurologic disease including seizures or psychosis; (8) renal disease which may manifest as proteinuria or urine casts; (9) hematologic disorders including hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia; (10) immunologic disorder showing the presence of antibodies such as Anti-DNA, Anti-SM, and/or antiphospholipid antibodies (lupus anticoagulant (LAC), anti-cardiolipin of IgG and/or IgM isotype (aCL), and/or a?2GPI); and (11) having a positive anti-nuclear antibody test (ANA) [18]. Following consultation with rheumatology, our patient demonstrated three clinical criteria and thus did not meet the full diagnostic criteria for SLE.
While retinal vasculitis is well observed in SLE, frosted branch angiitis has been described in only two patients with SLE [2, 3]. Both patients had previously met full diagnostic criteria for SLE without APS and presented with markedly decreased vision associated with prominent frosted branch periphlebitis. One patient received 1 g of IV methylprednisolone per day for 4 days, 2 units of packed erythrocytes, and 6 months of oral steroids and achieved marked visual improvement from HM OU to 20/60 OU. The other was treated with 500 mg of IV methylprednisolone daily for 3 days, followed by 3 weeks of 75 mg of prednisone along with 100 mg of azathioprine (patient’s chronic medication) daily, achieving nearly total remission of retinal lesions in 3 weeks with return of vision from 5/400 OU to 20/20 OU.
There exists a relationship between SLE and APS and clinically, patients may fall along a spectrum of disease. Patients with APS may have SLE. However, if patients with APS do not meet the American College of Rheumatology criteria for SLE diagnosis, they are diagnosed as having primary APS, as was the case in our patient. Gomez-Puerta et al. [19] found that that after median disease duration of 8.2 years, only 8 % of patients with primary APS developed SLE, with Coombs positivity conferring a statistically significant risk for the subsequent development of SLE. Montehermoso et al. [20] further solidified the relationship between SLE retinal vasculitis and APS, showing that 77 % of patients with SLE and retinal involvement had positive aPL titers, while only 29 % of SLE patients without retinal disease had positive titers. Stratified further, aPL antibodies are strongly associated with vaso-occlusive disease in SLE, a condition known as Hughes’ syndrome, and CNS manifestations of SLE [21]. Such patients should be initiated on lifelong anticoagulation therapy in concordance with APS management.
While SLE retinal vasculitis appears to be associated with the presence of aPL, frosted branch angiitis is very rare in the setting of aPL, and has not been previously described in APS. Abu El-Asrar et al. [22] reported two cases of retinal periphlebitis resembling frosted branch angiitis associated with non-perfused CRVO and positive aPL, but they did not meet the diagnostic criteria for APS. Despite systemic corticosteroid therapy, 80 mg/day of aspirin, and full panretinal photocoagulation, both patients developed rubeosis iridis and profound visual loss associated with neovascular glaucoma in one patient. Our patient, in contrast, had better visual and anatomical outcomes presumably due to the fact that we were able to identify and treat the retinopathy prior to the onset of widespread retinal ischemia and neovascularization.
The recommended primary treatment for APS is prevention of recurrent thrombosis or fetal morbidity with anticoagulation, and a discussion between the patient and physician should revolve around this decision. Once a patient has a proven thrombosis associated with aPL, lifelong anticoagulation is advisable. Many alternatives to Coumadin now exist, and the exact choice of anticoagulation should be tailored to the patient.
Hydroxychloroquine (HCQ) has also been shown to be protective against thrombosis in aPL-positive patients [23], and as in our patient, it may be reasonable to recommend HCQ for thrombosis prevention in APS as an add-on or alternative treatment option in cases resistant to other treatment modalities. While the drug is desirable for its steroid-sparing properties, a treatment period of roughly 6 months is required to reach steady state levels [24], and thus systemic immunosuppression with corticosteroids is often used in the acute setting.
In summary, to our knowledge, this is the first case of frosted branch angiitis seen in association with antiphospholipid antibody syndrome. With prompt treatment with corticosteroids, visual prognosis can be good. In these cases, long-term immunosuppression and additional anticoagulation may be beneficial to prevent recurrence. Appropriate consultations to hematology and rheumatology services are recommended. Ophthalmologists, rheumatologists, and hematologists should be aware of this possible association.