A 63-year-old woman was referred to the neuro-ophthalmology service at the New England Eye Center for evaluation of 2 months of painless vision loss in the right eye.
Two months prior, the patient was in her normal state of health when, on a leisurely walk with her husband, she had sudden, painless monocular vision loss in the right eye. She did not have any other symptoms including flashes, floaters, double vision, pain with extraocular movement or jaw claudication.
The patient’s ocular history was notable for mild nonproliferative diabetic retinopathy and contact lens wear for myopia. Her medical history included multiple sclerosis, which was diagnosed in 1990 via neuroimaging after presenting to a neurologist with an episode of numbness in her extremities. She did not have any recurrences since her initial presentation and did not take medication for MS. Additional medical history included type 2 diabetes, hypertension, hyperlipidemia and two prior miscarriages. Her medications included metformin, sitagliptin, lisinopril, simvastatin, and vitamins D and B12. She had a family history significant for Alzheimer’s disease and type 2 diabetes in her father, type 2 diabetes and an unknown hypercoagulable disorder with deep vein thrombosis (DVT) in her mother, and Crohn’s disease in her sister. There was no known family history of ophthalmic disease, and she had no history of smoking, recreational drug use or alcohol use.
One day after her vision loss episode, she presented to her primary optometrist who urgently referred her to an ophthalmologist. A review of medical records revealed that visual acuity was count fingers with afferent pupillary defect but no evidence of retinal pathology or optic nerve edema. The outside ophthalmologist, concerned for a retrobulbar pathology, ordered MRI of the brain and orbits with contrast and fat saturation, which was read as “no acute findings or abnormal enhancement,” but because clinical suspicion remained high for optic neuritis, she subsequently received 5 days of high-dose IV steroids. She also completed a stroke workup, including carotid ultrasound and echocardiogram with bubble study, which was normal. Lab work, including complete blood count, basic metabolic panel and serology for several systemic diseases including sarcoidosis, was negative or within normal limits, except for a mild elevation of inflammatory markers (C-reactive protein, or CRP, 2.89 mg/dL; erythrocyte sedimentation rate, or ESR, 45 mm/hr). Given the elevated inflammatory markers, she had bilateral temporal artery biopsies, which were both negative for giant cell arteritis. Despite the steroid therapy, there was no improvement in vision on repeat evaluations, and her exam remained unchanged.
At the time of presentation to our neuro-ophthalmology department, 2 months after symptoms began, visual acuity was hand motion in the right eye and 20/30 in the left eye. The pupils were equal in size and briskly reactive to light, with a 2+ afferent pupillary defect in the right eye. IOPs were 15 mm Hg in both eyes. Visual fields to confrontation revealed generalized constriction in the right eye, with no visible color plates, including the control plate, on HRR color testing. The left eye was full on visual field to confrontation and had normal color testing. Extraocular motility was full and painless in both eyes.
External exam was unremarkable. Anterior segment exam of both eyes was unremarkable except for 1+ nuclear sclerosis and 1+ cortical cataracts. Posterior segment exam of both eyes demonstrated posterior vitreous detachment, normal caliber vessels, and flat and attached macula and peripheral retina. However, there was severe, diffuse pallor of the right optic nerve. The left optic nerve was pink and healthy. The cup-to-disc ratio of both nerves was 0.5.
Humphrey visual field (HVF) 30-2 showed generalized depression of the right eye and nonspecific changes of the left eye (Figure 1). OCT of the retinal nerve fiber layer thickness demonstrated superior and inferior thinning of the right eye and superior thinning with normal thickness of the left eye, changes consistent with the patient’s glaucoma suspect diagnosis. Ganglion cell layer demonstrated diffuse thinning of the right eye and algorithm failure but overall normal thickness of the left eye (Figure 2).
The patient’s initial presentation was notable for acute onset of painless vision loss with decreased color vision, afferent pupillary defect, no evidence of optic nerve head swelling, diffuse depression on HVF and thinning of the ganglion cell layer on OCT in the right eye, corresponding with unilateral optic neuropathy.
The differential diagnosis for this presentation falls into two main categories: ischemic and inflammatory (including autoimmune). From an ischemic etiology, nonarteritic anterior ischemic optic neuropathy (NAION), arteritic anterior ischemic optic neuropathy (AAION) and atypical ischemic optic neuropathy (ION) may present with unilateral, sudden painless vision loss. NAION presents with optic nerve head swelling and typically altitudinal visual field defect with corresponding ganglion cell thinning. Our patient was never found to have optic nerve head edema and additionally demonstrated diffusely depressed visual field and ganglion cell thinning on OCT. AAION presents with associated systemic symptoms such as headache, weight loss, fever, fatigue and jaw claudication, which the patient denied. She did have mildly elevated inflammatory markers, but both of her temporal artery biopsies were negative, reassuring against giant cell arteritis. Atypical ION is from ischemia of the optic nerve secondary to either vasculitis or an occlusion obstructing blood flow to the optic nerve. The patient had a positive family history of DVT, as well as a history of multiple miscarriages, concerning for a hypercoagulable state that could lead to optic nerve vascular occlusion. From an inflammatory/autoimmune etiology, the patient’s presentation may be secondary to typical or atypical optic neuritis. MRI of the brain and orbits, as interpreted by an outside radiologist, was concerning for this diagnosis. However, she denied any ocular pain, and there was no visual recovery because symptoms began 2 months prior, which is the expected course of typical optic neuritis, pointing more toward a diagnosis of atypical optic neuritis such as neuromyelitis optica (NMO) or myelin oligodendrocyte glycoprotein (MOG) optic neuritis. Finally, inflammatory optic neuritis may be secondary to a systemic disease such as sarcoidosis, but prior workup including serologic testing was negative.
The patient provided a copy of the previously obtained MRI of the brain and orbits, which demonstrated several hyperintense lesions above the ventricular system, consistent with a demyelinating disease (Figure 3). There was no optic nerve enhancement or signs of optic neuritis. Further laboratory workup revealed negative NMO and MOG serum markers. Due to the patient’s family history of DVT and history of multiple miscarriages, we were highly suspicious of a hypercoagulable disorder causing ischemic optic neuropathy and sent the appropriate lab workup, which returned with elevated factor VIII and beta-2-glycoprotein IgM.
Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by arterial, venous or small vessel thrombosis and/or recurrent miscarriages or stillbirths. APS affects women five times more commonly than men. APS can occur as a primary disease or secondary to a connective tissue disorder, most frequently associated with systemic lupus erythematosus. The antiphospholipid antibodies include lupus anticoagulant, anticardiolipin antibody, and beta-2-glycoprotein IgG and/or IgM. The pathophysiology, in brief, entails the binding of the antiphospholipid antibody to beta-2-glycoprotein on phospholipids, which causes increased binding stabilization. This activates endothelial cells, platelets, complement and cytokines (IL-1beta, IL-6 and IL-8), leading to a pro-inflammatory and pro-thrombotic state. The higher the level of antiphospholipid antibodies, the greater the risk and severity of thrombosis. Diagnosis of APS is based on the revised Sapporo classification criteria, which requires one or more clinical episode of a vascular thrombosis or an adverse pregnancy outcome, in addition to the presence of one or more specified antiphospholipid antibodies on two or more occasions that are at least 12 weeks apart.
The most common clinical manifestations include DVT, pregnancy morbidity and stroke. Other manifestations include rashes such as livedo reticularis, non-healing ulcers, thrombocytopenia, nephropathy, cardiac valve or coronary artery disease, and cognitive dysfunction. Interestingly, small ischemic strokes can occur in the white matter of the brain and spinal cord, which may result in lesions resembling demyelinating plaques seen in MS or demyelinating disease.
Ocular manifestations occur in 14% to 18% of patients with APS and can be found in both anterior and posterior segments of the eye. The most frequent is vaso-occlusive retinopathy including central or branch retinal vein and artery occlusion. Other retinal manifestations include amaurosis fugax, vasculitis and ophthalmic artery occlusion. Neuro-ophthalmic manifestations include optic neuropathy from optic neuritis or atypical ION from a thrombotic event, which is the most likely etiology of our patient’s unilateral vision loss.
Most patients who present with a thrombotic event due to suspected APS, such as our patient, have not undergone prior testing for antiphospholipid antibodies. These must also be performed at least 12 weeks after initial testing to confirm the diagnosis. Thus, the initial management for patients who present with a thrombotic event due to suspected APS is anticoagulation, with the initial choice — warfarin, low molecular weight heparin, direct oral anticoagulant and/or antiplatelet therapy — largely based on clinical suspicion for APS and whether the thrombotic event is venous or arterial. Prompt hematology and/or rheumatology referral is recommended for further evaluation. It is important to investigate APS as an etiology of optic neuropathy, particularly if the patient is younger in age and/or has a history of recurrent ischemic events. Ocular manifestations of APS are frequently the presenting sign of the disease, highlighting the important role of the ophthalmologist in the early detection and prevention of potentially life-threatening thrombosis.
The patient was referred to rheumatology for further evaluation. She was started on aspirin, with the decision to not initiate anticoagulation, as the risks outweighed the benefits. Of note, inflammatory markers (CRP and ESR) were repeated and were within normal limits. At her 6-month follow-up visit, vision in the right eye was count fingers at 1 foot, and her exam was stable. Repeat HVF 30-2 demonstrated a slight improvement in the inferotemporal visual field of the right eye (Figure 4).
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