Syndrome
Cristina Castañon and Pedro A. Reyes
Clinical associations of antiphospholipid antibodies (aPL) include venous and arte- rial thrombosis, recurrent fetal loss, blood cytopenias, thrombocytopenia, and multi-organ compromise [1–13]. Vessel occlusion is a hallmark of this association;
it may occur within the context of several diseases, mainly autoimmune disorders such as systemic lupus erythematosus (SLE), or it may be present without any recognizible disease, the so-called primary antiphospholipid syndrome or Hughes syndrome [14].
In the past there were isolated reports describing the eye involved in the primary antiphospholipid syndrome (APS) and serious ocular damage, like optic neuritis and ocular vaso-occlusive disease in patients with Hughes syndrome [15–17]. This association was challenged by Merry et al [18] based on the absence of aPL in a group of patients with ocular vaso-occlusive disease. However, Asherson et al [19]
found that the presence of ocular vaso-occlusive disease in patients with SLE was definitely related to the presence of antiphospholipid autoantibodies and several studies agree on a high prevalence of vasculopathic eye disease in subjects with Hughes syndrome [20–25]. Maybe the different appreciation reflects both a selec- tion bias (the presence of ocular disease was the inclusion criterion in some studies) and a low prevalence of Hughes syndrome among patients with ocular vaso-occlu- sive disease of miscellaneous origin.
At present, some cases or some series [26–48] which describe ocular findings in the presence of aPL, or associated to other diseases, are added to our clinical observa- tions, and confirm that the eye is frequently affected. Also, they confirm that the damage is predominant in the posterior segment, as retinal or choroidal vaso-occlu- sive diseases, which can be arterial, venous, or both. A higher number of studied cases has made it possible to identify, in the literature, a more frecuently anterior segment damages. Anterior and posterior scleritis, related to aPL, were also reported.
However, in our APS ocular disease experience, we have not seen yet this manifesta- tion. Besides this, there is nothing new to be added to our clinical study at present.
Clinical Study
We performed and reported a cross-sectional ophthalmology study [49] on 28 con- secutive patients (18 women, 10 men; median ages, 30.5 and 40 years, respectively)
147
with APS, all of them were seen at the Instituto Nacional de Cardiología Ignacio Chávez from 1987 to 1996. Irrespective of visual symptoms, 27 patients were evalu- ated prospectively by the ophthalmologist in an equivalent search effort. One patient had visual symptoms, and primary antiphospholipid antibody syndrome (PAPS) was subsequently identified. The diagnosis was based on proposed clinical criteria [5]. SLE was ruled out clinically and serologically over a 48-month follow up. Anticardiolipin antibodies (aCL) were detected by enzyme-linked immunosor- bent assay according to Gharavi et al [50], with some modifications by the authors [51]. Test for serum lipid profile, fluorescent antinuclear antibodies, rheumatoid factors, syphilis (VDRL, fluorescent treponemal absorbed antibody), and a clotting profile were performed in every patient using standard laboratory techniques.
The eye examination included a survey of ocular symptoms; tests for visual acuity, ocular movements, and intraocular pressure; and slit-lamp biomicroscopy to evaluate the anterior segment and the fundus. Twenty-four patients agreed to a standard retinal fluorangiography [52].
All patients (Table 14.1) had high titer [>5 standard deviations (SD) above the mean] IgG aCL in at least two determinations. No other non–organ-specific anti- bodies nor lipid abnormalities were detected. In 14 out of 17 patients, a prolonged phospholipid-dependent clotting assay (PTT) was identified. In the remaining 11 patients, the test was not performed because the patients were receiving anticoagu- lant drugs. A false-positive VDRL test was present in 11 patients. Nine patients had thrombocytopenia, 1 more case had persistent leukopenia. Four out of 9 patients at risk in whom the test was done presented a positive lupus anticoagulant (LA) test.
Ocular Findings
As shown in Table 14.2, 19 (68%) patients had visual symptoms. Transient visual disturbance (transient blurred vision or amaurosis fugax) was present in 16 eyes (8 patients), decreased vision in 7 (4 patients), transient diplopia in 8 (4 patients), and transient field loss associated with headache and photopsy in 8 (4 patients). Visual acuity with or without correction was 20/20 to 20/ 40 in 46 eyes, 20/60 to 20/100 in 3
148 Hughes Syndrome
Table 14.1. Primary antiphospholipid syndrome: clinical and laboratory findings.
Clinical findings No. Laboratory findings No.
Ocular disease 24/28 IgG aCL 28/28a
Recurrent fetal loss 8/10b PTT > 10 14/17
Venous thrombosis 16/28 False-positive results of VDLR 11/28
Arterial occlusion 10/28d Lupus anticoagulant 4/9b
Migraine 11/28 Cytopenia 10/28c
Livedo reticularis 7/28 FANA (low titer) 3/28
Leg ulcers 3/28
Chorea 1/28
PTT = partial thromboplastin time; FANA = fluorescent antinuclear antibodies.
aMore than 5 SD above the mean value.
bSubjects at risk or those in whom the test was done.
cThrombocytopenia, 9; leukopenia, 1.
dSeven of these 10 patients had brain infarction demonstrated by computed tomography.
Table 14.2.Ocular vaso-occlusive disease in primary antiphospholipid syndrome. Case no.12345678910111213141516171819202122232425262728Total no. eyes Ocular findings visual symptoms (18/28) Decreased visionR/LLR/LR/L7 Transient blurringR/LR/LR/LR/LR/LR/LR/LR/L16 Transient diplopiaR/LR/LR/LR/L8 Transient field lossR/LR/LR/LR/L8 PhotopsyR/LR/LR/LR/L6 Ocular findings anterior segment (9/28) Conjunctival R/LR/LR/LR/LR/LR/L12 telangiectases Conjunctival R/LR/LR/LR/LR/LR/L12 microaneurysms Simple episcleritisR/L2 Limbal keratitisR1 Corneal opacityR1 Ocular findings eye fundi (24/28) Vitreous hemorrhageRLL3 Preretinal R/L2 hemorrhage Swelling optic discRLRR4 Venous tortuosityR/LR/LR/LR/LR/LR/LR/LR/LR/LR/LR/LR/LR/LR/LR/LR/LR/LR/LR/L38 Vascular sheathingR/LR/L*L*L*R/L*LR10 Rarefacción y R/L2 Rectificación Pigment abnormalitiesR/LLR/LRR/LR9 Flame-shaped R/LLLLR/L7 hemorrhages Cotton-wool spotsRR2 MicroaneurysmsLLLL4 Macular serous L1 detachment IRMAsL1 Peripheral druscenR/LR/L4 R = right eye; L = left eye; IRMAs = intraretinal microvascular abnormalities. *Peripheral vessels.
eyes, and 20/400 or worse in 7 eyes (4 patients). All patients had normal intraocular pressures (12–18 mm Hg), except for a case with cerebrovascular disease and 20 mm Hg intraocular pressure in both eyes who had an inferior temporal quadran- tanopia, due to an obstruction of a branch of retinal artery.
Anterior segment abnormalities were mild and relatively uncommon: conjuncti- val telangiectases or microaneurysms were present in 12 eyes (6 patients), simple episcleritis in 2 (1 patient), and limbal keratitis in 1. The latter two abnormalities resolved with local corticosteroid treatment. One patient had a monocular post- traumatic superficial corneal opacity since childhood.
Posterior segment abnormalities were found in 24 patients (86%; Table 14.2).
Tortuosity of first-order venous vessels or peripheral terminals in 38 eyes (19 patients) was the most common finding. Swelling of the optic disc was found in 4 eyes (cases 1, 12, 13, and 24). Vitreous hemorrhage occurred in 3 eyes (cases 1, 12, and 24; Fig. 14.1); vitreous bands adherent to the optic disc subsequently developed in 2 of these eyes (case 12, 24) after the hemorrhage. One of these (case 1) fully recovered under treatment. Serous detachment at the macula with preretinal hem- orrhage was observed in one eye (case 13) . Other patient, had segmental dilatation of capillary vessels, microaneurysms, and intraretinal microvascular abnormalities in 1 eye (case 8). There were cotton-wool spots in two eyes (cases 1 and 13), flame- shaped hemorrhages in 8 eyes (cases 1, 8, 9, 12, 13, and 24), microaneurysms in 3 eyes (cases 8, 9, and 14); sheathing of first-order veins in 2 eyes (case 1), arterial sheathing in 1 additional patient (case 25). Equatorial and peripheral hypopigmen- tation was noted in 2 eyes (case 3), and reticular pigment clumps around the tempo- ral vascular arcade of both eyes, associated with widespread areas of atrophy, were seen in case 10. Two eyes (case 26) presented grayish lines extended radially on tem- poral retina from optic disc, with an hypertrophic scar in the temporal aspect of the macula in the right eye. One eye had minor irregular clumps of pigment near supe- rior temporal vessels (case 28).
Retinal fluorescein angiography was performed in 24 patients (Table 14.3) and it was abnormal in 18 eyes (12 patients, 50%). Although in general the procedure
150 Hughes Syndrome
Table 14.3. Ocular vaso-occlusive disease in primary antiphospholipid syndrome*
Case no. 1 3 8 9 10 12 13 20 24 25 26 28 Total no. eyes
Abnormalities 12/24
Vitreous Hemorrhage R L L 3
Choroidal Blocked fluorescence R/L L R R 5
Window defects R/L L R/L R/L 7
Vascular Tortuosity R/L R/L R/L R/L R/L R/L L L 14
Microaneurysms R/L L R/L 5
Capilar ectasis R/L L R/L L 6
Leakage R/L L L L 5
Noncapillary perfusion R/L L L L L R/L L 9
Obstruction* R/L L L L R/L L R 9
Neoformation L 1
Retinal Hemorrhages R/L L L R/L 6
Cotton-wool spots R R 2
Optic disc Leakage R R R 3
R = right; L = left.
*Ocular findings, retinal fluorescein angiography (12/24).
confirmed the funduscopic findings, it showed unsuspected occlusion of the peri- macular arteriole in 1 eye (case 9), focal late hiperfluorescence, and leakage of retinal capillaries superior in 1 eye (case 20), and pigment epithelial window defects considered to be secondary to choriocapillary vessels obstruction in 2 eyes (case 3).
In case 10, early hyperfluorescence of atrophic areas around pigment clumps created a window effect, which was interpreted as reticular degeneration of the pig- mentary epithelium. Two eyes (case 26) showed fluorescence in the arterial phase which persisted after the dye had disappeared from retinal veins; these angioid streaks did occur in absence of systemic evidence of pseudoxanthoma elasticum.
This patient also had vessel occlusion inferior to macula and hipertrophic scar in right eye. Case 24 had hyperfluorescence and poor arterial filling because of retinal central artery occlusion in right eye with vitreous hemorrhage and vaso-occlusive retinopathy in left eye.
A generalized vaso-occlusive retinopathy with fluorescein leakage and areas of hypoperfusion was noted in 5 eyes (cases 1, 12, and 25). In another patient, a macular serous detachment was present (case 13). Of particular interest were the angiographic findings in one eye (case 8), including focal occlusion of temporal arterioles and venules near the macula, areas of capillary hypoperfusion, fluorescein leakage, and retinal neovascularization. Emergency photocoagulation treatment was used on this patient; 4 years later the recurrence on these vessels required further treatment.
Follow Up
Six patients were lost: 2 died and 4 left the hospital. Ophtalmologic follow up from 5 to 9 years has been completed in 8 patients, 11 more were followed from 1 to 3 years, and 3 for less than a year. All cases were treated with chronic anticoagulants, with international normalization radio (INR) between 2 and 3, as well as chronic low dosage of acetilsalycilic acid, except case 19, who had an associated clotting defect, von Willebrand disease, which prevent the use of anticlotting measures.
Most patients recovered and stay visually asymptomatic for long periods, up to 9 years. Some of them required photocoagulation therapy, usually once, but one of them required a second treatment. A patient (case 13) with extensive bilateral arter- ial and venous ocular obstruction developed a neovascular glaucoma and right-eye ptisis bulbi in a 2-year period; the left eye conserved a corrected 20/50 vision
Table 14.4. Retinal vascular obstruction 12/56 eyes.
Case No. CRA RA branch CRV
1 – – R/L
8 – – L
9 – L –
12 – – L
13 R – R/L
24 R – L
25 – L –
26 – L –
CRA = central retinal artery; RA branch = retinal artery branch; CRV = central retinal vein.
without further problems. Another patient (case 18) developed retinal microa- neurysms and hemorrhages in both eyes which disappeared in a year.
In summary, ocular vaso-occlusive disease is a common finding in APS; it is easy to identify this complication by systematic eye exam. Prompt recognition and anticlotting therapy limits organ damage and usually achieve sustained improvement.
Discussion
Since the first edition of this book was published in 2000, growing evidence has confirmed eye morbidity as part of the clinical expression of PAPS. Authors from all over the world have made contributions, case reports, case series, and case-control studies describing many different forms of eye vasocclusive disease in PAPS patients and some forms of inflammatory disease which may be linked to focal ischaemia due to arterial or venous occlusions.
The posterior pole, mainly venous or arterial retinal vessels, are the most com- monly affected vessels; venous engorgement and tortuosity, occluded central vein and arterial involvement with sheathered vessels appearing as white lines in fundus- copy, hemorrhage due to wall damage, and abnormalities in fluorangiography are frequent findings in one or both eyes in these patients. Sometimes central nervous system damage in specific nuclei manifested as eye abnormalities such as oculomo- tor nerve palsy.
Vitreous hemorrhage and choroidal vessel involvement has been described, in one case, as the first manifestation of eye compromise in PAPS.
Occasionally an inherited defect on clotting mechanisms, such as Leiden or pro- thrombin G20210A mutations, homocysteine levels, or abnormal S or C proteins, coincides with aPL; however, in most cases the antibody alone is the culprit of the eye disease. All these pathogenic mechanisms may explain eye symptoms such as blurred vision, scotoma, transient ischemic attacks with visual loss, progressive loss in visual acuity, and sudden blindness, which are frequent in PAPS patients or may occur as presenting manifestation. In such case it is necessary a complete physical exam and laboratory work up.
Anterior segment symptoms are also common. Telangiectasis at conjunctival vessels, keratitis limbal, or filamentary and neovascular glaucoma were sometimes reported, but in many patients the anterior segment was completely normal in spite of serious posterior segment severe disease.
Differential diagnosis should consider diabetic retinopathy, sarcoid, and hemato- logical neoplasia as well as stroke and accelerated artheriosclerosis and, of course, systemic rheumatic diseases such as SLE, Sjögren syndorme, or systemic progres- sive sclerosis and some infections. These cases are considered, of course, secondary APS.
Increased medical awareness has made it possible to recognize more cases.
Reports on eye disease linked to aPL have become frequent in the literature. Aspirin and long-term anticoagulation help many patients and it is common to achieve significant visual improvement and stop visual loss progression and vasocclusive disease with minimal adverse effects.
152 Hughes Syndrome
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