Ocular manifestations of Antiphospholipid Syndrome
Basic Ophthalmology Review
Tittle: Ocular manifestations of Antiphospholipid Syndrome Author: S. Hernández/MS4 UAG
Antiphospholipid syndrome (APS) is a disorder of the immune system characterized by the presence of auto-antibodies that are directed to different phospholipids through the body, which are known as antiphospholipid antibodies (aPL). Phospholipids comprise the membranes of cells which enclose organelles and serve as barriers. Disruption of this barrier, triggers a cascade of events in which hypercoagulability becomes and plays a critical role. APS, is clinically highly characterized by features of venous or arterial thrombosis and recurrent pregnancy loss or morbidity 1. Antiphospholipid antibodies (aPLs) are directed against anionic or negatively charged phospholipids and phospholipid binding proteins, which in turn lead to stimulation of procoagulant factors and inhibition of the fibrinolytic pathways 2. The aPL’s that have been characterized are: Anticardiolipin antibodies (aCL), which based on physician reports are detected approximately in a 23% to 44% of patients, Lupus anticoagulants (LA); detected in approximately 34% of patients and Anti-β2-glycoprotein-I antibodies (Anti-β2GPI); detected in a 20% of patients. All of them of either IgG or IgM isotypes.
The pathophysiology of APS is based on the action of those characterized antibodies and their different targets, although the most studied aspect has been the propensity for pro-coagulation and thrombi formation 6. “Platelet, endothelial cell and monocyte activation occurs in conjunction with disruption of natural anticoagulant and fibrinolytic systems in response to aPLs resulting in a procoagulant phenotype in APS patients 8. The etiology is not well understood, but it is believed that it is genetic and environmental in origin. “Some APS-positive families exist, and human leukocyte antigen (HLA) studies have suggested associations with HLA DR7, DR4, and Dqw7+Drw53” 2. There are reports that had shown that many infections are the most prominent environmental trigger for not only the production of aPLs, but the development of APS manifestations 6. Some of these infectious agents associated with APS are CMV, Varicella Zoster(VZV), parvovirus B19, Human Immunodeficiency Virus (HIV), Hepatitis B and C Viruses and Human T-cell Lymphoma/leukemia virus (HTLV) 7-9. Patients or groups that are at risk for APS are mostly young to middle aged adults. Physicians should be aware of women in reproductive age with multiple and recurrent miscarriages and suspect or rule out APS, since 10% to 15% of these women have present with the pathology 6. Other underlying pathologies that are risk factors or increase the probability of developing APS are Systemic Lupus Erythematosus (SLE), vascular or collagen disorders and other autoimmune disorders like rheumatoid arthritis (RA), Sjögren’s syndrome, Behçet’s syndrome, primary immune thrombocytopenia also known as idiopathic thrombocytopenic purpura) and AIDS 2.
APS, can present as a primary pathology or as secondary to different systemic, autoimmune and rheumatic diseases. As a primary pathology, it can affect the whole body involving all organ systems, causing a variability of features depending on the affected organ 3. “Apart from the well-recognized arterial and venous thrombotic events typical of APS, these patients can also present with a variety of ‘non-criteria’ manifestations which include thrombocytopenia, nephropathy, livedo reticularis, cardiac valve disease, skin ulcers, diffuse pulmonary hemorrhage and neurological manifestations such as chorea, epilepsy, cognitive dysfunction and transverse myelopathy” 4-5.
The eyes are not exempt of being affected due to these antibodies. “It includes a broad spectrum of ocular manifestations from the anterior and posterior segment or presence of neuro-ophthalmologic features” 3. Some of the anterior segment features are known to be conjunctival microaneurysms, iritis, telangectasias, episcleritis, uveitis and filamentary keratitis/dry eye 10. Posterior segment manifestations include retinal detachment, vitreitis, venous tortuosity, posterior scleritis, retinal vein occlusion, cilioretinal artery occlusion, bilateral choroidal infarction, cotton-wool spots and retinal hemorrhages. Monocular or bilateral vision loss, ischemic optic neuropathy, progressive optic nerve atrophy and transient visual field loss are the neuro-ophthalmologic features observed 10. According to different studies, anterior eye segment manifestations of all APS patients have a prevalence of 76% and any changes of the eyelid like erythema, telangiectasia or purpura are important to start raising suspicion for the diagnosis. Patients with secondary APS due to SLE have a common ocular manifestation known as punctuate epithelial keratopathy. Additional changes found on corneal periphery can be asymptomatic noninfectious marginal thinning, marginal infiltrates and marginal ulcerations with infiltration and vascularizations. Physicians have observed that more than the 45% of patients that present with scleritis, have an underlying systemic disease, with or without APS 12. The most prominent or common presentation in the posterior segment are vascular retinal thromboses (unilateral or bilateral), either in primary or secondary APS 13. Small arterial occlusions are more associated with secondary APC. “In these cases, ophthalmologic examination reveals torqued and dilated veins, cotton-wool exudates and hemorrhages most frequently on the periphery of the fundus oculi”
- 11. An 84% of APS patients have been reported to have posterior eye segment changes of which 60% are retinal vasculitis, 38% vitreitis, 15% retinal detachment, 7%posterior scleritis and 7% central retinal artery occlusion 11.
The ophthalmologist’s examination must be thorough and should include visual acuity, measurement of intraocular pressure (ICP), biomicroscopic examination, motility of eye and examination of fundus with direct and indirect ophthalmoscopy 15. Diagnosis of APS mostly relies on phospholipid- dependent coagulation tests to detect Lupus Anticoagulant (LA) or/and immune tests that can detect
anticardiolipin, other anionic phospholipids as well as antibodies to phospholipid-binding protein cofactors, β-2 glycoprotein I (β2-GPI), and proteins C and S 11.
There are few clinical trials for the treatment or other therapeutic options for APS. The treatment is mostly aimed to inhibit thrombosis or thromboprophylaxis. The latter is achieved primarily using antiplatelet agents or anticoagulants. Although, recent publications have shown an increase in number of successfully treated APS patients due to new therapeutic strategies including IVIG administration, application of recombinant tissue plasminogen activator and plasmapheresis 11.
Since APS can be primary or secondary, it is important for physicians to be aware of the ocular manifestations that have been seen in APS. The latter is important since ocular changes have been diagnosed in a 15%-88% of patients weather it is primary or secondary 11. Also, it has been pointed out by different studies the need of screening for antibodies of APC (aPLs) in patients with visual decline, complaints and systemic diseases of the connective tissue or autoimmune disorders. Finally, there is very little information about if ocular manifestations could be a prevailing sign of APS. Based on this motivation, efforts of the department of medicine with the research lab of internal medicine of the medical school of Thessaly, Greece conducted different observations with three rare cases of ocular manifestations. Efforts were carried out with the referral of three patients with “unexplained” ocular manifestations after extensive workups and proper investigations. Past medical history, appropriate laboratory work and step guided protocols didn’t yield any revealing results 3. With further highly sensitive testing, cases showed either one or two of the aPLs (IgG/IgM-aCL, IgG/IgM-aLA and IgG/IgM-aβ2-GPI). Patients showed high titters of aPLs after the highly sensitive tests and after six (6) month follow up 3. These patients were all started on anticoagulant therapy and demonstrated great improvement and efficacy. After two (2) year follow up, the three patients, still in anticoagulant therapy with great treatment efficacy, no side effects with visual acuity of 20/20 and no neovascularization 3. This showed, that in some or rare cases, ocular manifestations of antiphospholipid syndrome can be the first or prevailing sign. For this reason, ophthalmologists and clinicians in general, should try to screen for aPLs on routine eye examination with “unexplained” ocular manifestations to uncover underlying autoimmunity and preserve visual acuity or further damage.
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