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Show Journal of Neuro- Ophthalmology 21( 4): 260- 263, 2001. 1 2001 Lippincott Williams & Wilkins, Inc., Philadelphia Original Contribution Catastrophic Antiphospholipid Antibody Syndrome Manifesting as an Orbital Ischemic Syndrome Michael S. Vaphiades, DO, Wade Brock, MD, Harry H. Brown, MD, Gissur Petursson, MD, and Christopher T. Westfall, MD Painful bilateral ophthalmoparesis, marked proptosis, increased intraocular pressure, and blindness developed in a 29- year- old woman with protein C deficiency and catastrophic antiphospholipid syndrome. Magnetic resonance imaging of the orbits showed bilateral proptosis, globe tenting, and tethering of the optic nerves consistent with an orbital ischemic syndrome. Despite aggressive therapy for antiphospholipid syndrome, the patient died. The autopsy showed necrosis of orbital tissues. This is the first report of orbital ischemic syndrome from protein C deficiency and antiphospholipid syndrome. Key Words: Antiphospholipid antibody syndrome- Orbital ischemic syndrome. Antiphospholipid syndrome ( APS), first recognized in patients with systemic lupus erythematosus and later in patients without systemic lupus erythematosus or underlying autoimmune disease, is associated with venous and arterial thrombosis ( 1,2). Antiphospholipid syndrome may involve vital organs with life- threatening consequences (" catastrophic APS") ( 2). This report describes a patient with protein C deficiency and catastrophic APS in whom an orbital ischemic syndrome developed. CASE REPORT In 1993, a 29- year- old woman with deep- vein thrombosis, hematuria, and a history of two spontaneous abortions showed an increased anticardiolipin antibody immunoglobulin ( Ig) G level of 32.2 GPL (< 23) and IgM of 2.8 MPL (< 11). Antinuclear antibody test results were This work was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, New York. From the Departments of Ophthalmology ( MSV, WB, GP, CTW), Neurology ( MSV), and Pathology ( HHB), University of Arkansas for Medical Sciences, Little Rock, Arkansas. Address correspondence and reprint requests to Michael S. Vaphiades, DO, Harvey & Bernice Jones Eye Institute, Department of Ophthalmology, University of Arkansas for Medical Sciences, 4301 West Markham, Mail Slot 523, Little Rock, AR 72205- 7199; E- mail: mvaphiades@ uams. edu negative. She had no history of migraine, transient ischemic attacks, or joint pain. Skin necrosis developed after the patient was treated with warfarin, so this drug was withheld. She was treated instead with oral prednisone and subcutaneous heparin. Serum test results showed a low protein C activity of 22% ( 70- 160%) and a normal protein S activity of 80% ( 65- 140%). In 1998, the patient began to experience episodes of painful unilateral proptosis involving either eye without visual loss. She was treated successfully each time with intravenous and oral corticosteroids for a presumptive diagnosis of idiopathic inflammatory orbitopathy. In January 2000, a large, nonhealing ulceration developed on the patient's right lower extremity, and she was admitted to the hospital. Multiple erythematous skin lesions also developed. A skin biopsy of the right arm showed extensive vascular thrombosis and neutrophilic infiltrate around but not within blood vessels. During this time, right periocular pain and proptosis with substantial visual loss developed, and the patient again responded completely to corticosteroids. A gadolinium- enhanced orbital magnetic resonance imaging scan showed enhancement of the sclera, fat, and the optic nerve sheath in the right orbit. After being discharged from the hospital, the patient was treated with subcutaneous heparin and oral corticosteroids for maintenance. In March 2000, chronic renal insufficiency, hematuria, sepsis, and pneumonia developed, and the patient was admitted to the hospital. The right lower extremity ulceration was still present. She was treated with bladder irrigation and intravenous vancomycin for a diagnosis of enterococcus sepsis. Protein C activity was again low at 20% ( 70- 160%). Anti-( 32- glycoprotein I IgG and IgA levels were increased at 21.82 G units ( normal, < 20 G units) and 24.82 A units ( normal, < 20 A units), respectively. The anti-( 32- glycoprotein IlgM level was normal, as were antiphosphatidylserine test results. Antinuclear 260 CATASTROPHIC ANTIPHOSPHOLIPID ANTIBODY SYNDROME 261 antibody testing and anti- DNA testing yielded negative results. C3 complement level was increased at 101.9 mg/ dl ( 50- 100 mg/ dl), and C4 complement level was increased at 48 mg/ dl ( 12.5- 45 mg/ dl). Cryoglobulin testing yielded negative results. The patient was discharged from the hospital in May 2000, and subcutaneous heparin and a slow taper of oral corticosteroids were prescribed. In June 2000, the patient presented with bilateral painful proptosis and visual loss. She was drowsy but oriented. Her blood pressure was 153/ 94 mm Hg, her pulse was regular at 80 beats/ minute, and she was afebrile. She had no light perception vision OU, and the pupils were fixed at 5 mm OU. She had total ophthalmoplegia bilaterally and bloody epiphora from extensive hemorrhagic chemosis. Trigeminal and facial nerve function was intact. Marked corneal edema prevented detailed visualization of the anterior chamber, and there was no view of the fundus. Tonopen intraocular pressures were 39 mm Hg OD and 47 mm Hg OS. She had no weakness or numbness of the extremities. A large, nonhealing ulceration was present on the right lower extremity. A magnetic resonance imaging scan of the brain and orbits showed bilateral proptosis and tethering of the optic nerves, such that both globes were oval ( tented) ( Fig. 1). There was no enhancement of orbital tissues, presumably because of necrosis. The brain appeared to be normal. Intravenous methylprednisolone, 125 mg four times daily, was initiated. Bilateral canthotomy and cantholysis reduced the intraocular pressures to 22 mg Hg OD and 23 mm Hg OS without improvement in vision. The patient underwent an endoscopic bilateral medial and inferior orbital wall decompression with further improvement of the intraocular pressures but no change in visual acuity. Under the surgical microscope, shallow chambers and microhyphemas were visible OU. An echocardiogram showed a 3 x 2- cm thrombus in the right atrium. A carotid Doppler study yielded normal results. A diagnosis of orbital ischemic syndrome secondary to catastrophic APS and protein C deficiency was made. Plasmapheresis treatment was rejected because of high risk in view of the cardiac thrombus, and intravenous Ig treatment was rejected as too nephrotoxic, considering the patient's renal insufficiency. Later, in June 2000, the patient experienced acute respiratory arrest and hypotension. She underwent intubation and was transferred to the intensive care unit. Vasoconstrictors were initiated. Endoscopy showed a gastric ulcer without hemorrhage. An abdominal computed tomography scan showed a large subcapsular hematoma of the liver. Computed tomography of the brain showed bilateral proptosis but no intracranial abnormality. A ventilation/ perfusion scan showed a low probability for a pulmonary embolism. The hemoglobin and hematocrit levels continued to decrease. Complete renal failure developed. Dialysis caused a further decrease in blood pressure. The patient died several days later, presumably of multiorgan failure. FIG. 1. Axial T2- weighted magnetic resonance imaging scan of the orbits, showing bilateral proptosis and tenting of globes. Autopsy showed a massive intra- abdominal hemorrhage with 4 L of blood and clot, a large hematoma of the liver, and infarctions of the lung, pancreas, and bladder. The adrenal glands were atrophic. The kidneys showed glomerulosclerosis and interstitial nephritis. The heart had a large right atrial thrombus. Gross examination of the orbital tissues showed marked enlargement and hemorrhage of the extraocular muscles. The conjunctiva was markedly hemorrhagic and edematous, and the corneas were diffusely cloudy. The eyes were opened vertically in an anteroposterior direction, revealing an enlarged lens with opacification, cloudy, hemorrhagic vitreous fluid, and sloughing of the retina and retinal pigment epithelium. The globes were conical in shape because of flattening postequatorially ( Fig. 2). Microscopic examination showed near- complete coagulative necrosis of all intraocular tissues, with vascular congestion and intravascular fibrin thrombi ( Fig. 3). The retinas were almost entirely necrotic, with a single peripapillary focus of retained nuclear architecture. The extraocular muscles showed marked vascular congestion, hemorrhage, coagulative necrosis, and intravascular fibrin thrombi. DISCUSSION Antiphospholipid syndrome manifests as recurrent fetal loss thrombocytopenia and as venous and arterial FIG. 2. Pathologic gross specimen of the conical right eye, showing cloudy, hemorrhagic vitreous fluid and sloughing of the retina. J Neuro- Ophthalmol, Vol. 21, No. 4, 2001 262 M. S. VAPHIADES ET AL. FIG. 3. Microscopic section of the right eye, showing near-complete coagulative necrosis of the sclera ( bottom) and of the retina ( top). The choroid shows vascular congestion and intravascular fibrin thrombi. thrombosis of the skin, brain, retina, heart, lungs, liver, and kidneys ( 1,2). Patients have increased titers of an-tiphospholipid antibodies, a heterogenous group of IgM and IgG autoantibodies against protein and phospholipid complexes ( 3). The thrombotic tendency is paradoxical because in vitro, there is prolongation of phospholipid-dependent coagulation assays ( 3). In primary APS, there are no associated autoimmune diseases, such as systemic lupus erythematosus ( 1), as in our patient. Catastrophic APS denotes a potentially life-threatening course over days to weeks ( 2). A seminal paper by Asherson et al. ( 2) in 1998 outlined key points about catastrophic APS. Spontaneous fetal abortions were present in 24% of patients. Sixty- six percent were women, and 56% had primary APS. Fourteen percent had nonhealing lower extremity skin ulcerations, and 78% had kidney involvement. Cardiac involvement was present in 50%, 2% of which had an intracardiac thrombus. Central nervous involvement was present in 56%. Fourteen percent of patients had retinal vascular involvement. Ophthalmologic involvement in APS includes transient monocular blindness ( 4), vaso- occlusive retinopathy ( cotton wool spots with or without retinal hemorrhages), branch retinal artery, central retinal artery or central retinal vein occlusion ( 5), and choriocapillary vessel occlusion ( 1). Iritis, scleritis and keratitis, vitreitis, retinal detachment, and posterior scleritis ( 6) occipital ischemia and migraine- like disturbances have also been reported ( 7). Confusion in diagnosis of APS may arise because coagulation studies can be influenced by treatment with warfarin or heparin. For example, protein C and S values are both decreased in patients receiving warfarin but are not influenced by heparin. Antithrombin III is decreased in patients receiving heparin but not warfarin. Lupus anticoagulant test results can be falsely positive after warfarin or heparin therapy; anticardiolipin antibody values are not influenced by either drug ( 8). Of the anticardiolipin antibody isotypes, IgG confers the greatest risk of thrombosis when compared with IgM, and some authors believe thrombocytopenia is an important risk factor ( 9). Our patient had increases of both anticardiolipin antibody isotypes and a low protein C level at a time when she was not being treated with warfarin. Proposed pathophysiologic mechanisms of APS vary and include stimulation of platelet aggregation, damage to vascular endothelial cells, and interference with protein C or antithrombin III pathways ( 10). Another theory states that thrombogenesis may rely on an anionic phospholipid called annexin- V. This protein has potent anticoagulant activity and exists on phospholipid surfaces at the vascular- blood interface. It plays a thrombo-regulatory role by preventing anionic phospholipids from complexing with circulating coagulation proteins. There is some experimental evidence that annexin- V is reduced in patients with antiphospholipid antibodies ( 10). However, this theory has been debated ( 11) and disputed experimentally ( 12). In addition to antiphospholipid antibodies and protein C deficiency, our patient also tested positive for antibodies to ( 32- glycopro-tein I, a phospholipid- binding protein. Patients with APS have autoantibodies that react to phospholipids on ( 32- glycoprotein I ( 13). The presence of this antibody is significantly associated with features of APS and thrombosis ( 14). ( 32- Glycoprotein acts as a phospho-lipid- bound natural anticoagulant by clearing anionic procoagulant phospholipids from the circulation. Interference with ( 32- glycoprotein I leads to a hypercoagulable state ( 13). Fifty percent of patients with catastrophic APS die ( 2). Treatment with a combination of anticoagulation, corticosteroids, plasmapheresis, or intravenous Ig allows recovery in 70% of patients ( 2). Our patient is unique in having orbital involvement. Orbital ischemic syndrome has been reported with orbital trauma ( 15), carotid dissection ( 16), subperiosteal abscess ( 17), giant- cell arteritis, and mucormycosis ( 18). The globe tenting noted on our patient's orbital magnetic resonance imaging scan ( Fig. 1) is a well- recognized sign of increased orbital tension. If the angle of the posterior pole tenting is less than 120°, as in our patient, emergent surgical decompression is recommended ( 17). Perhaps the episodes of previous presumed orbital pseudotumor in our patient were a milder form of orbital ischemia from the hypercoagulable state. The additive effects of the protein C deficiency and antiphospholipid antibodies increased the risk for thrombosis. To our knowledge, this is the first description of an orbital ischemic syndrome resulting from a combination of primary APS and protein C deficiency ( 1- 18). In summary, an orbital ischemic syndrome may result from a combination of APS and protein C deficiency. A patient with an orbital inflammatory syndrome, even if reversible, may suffer from this multiple hypercoagulable state. Globe tenting on cranial neuroimaging may be indicative of orbital ischemia from APS. If APS is diagnosed, early treatment may avoid catastrophic consequences. / Neuro- Ophthalmol, Vol. 21, No. 4, 2001 CATASTROPHIC ANTIPHOSPHOLIPID ANTIBODY SYNDROME 263 REFERENCES 1. Castanon C, Amigo MC, Banales JL, et al. Ocular vaso- occlusive disease in primary antiphospholipid syndrome. Ophthalmology 1995; 102: 256- 62. 2. Asherson R, Cervera R, Piette JC, et al. Catastrophic antiphospholipid syndrome: clinical and laboratory features of 50 patients. Medicine 1998; 77: 195- 207. 3. 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