Eye (1991) 5, 75-79

Antiphospholipid Antibodies in the Aetiology of Ischaemic Optic Neuropathy

M. T. WATTS, M. GREAVES,!. G. RENNIE, L. G. CLEARKIN Sheffield

Summary The involvement of anti phospholipid antibodies in the mediation of acute anterior ischaemic optic neuropathy (AION) was studied, in the light of recent associations between these autoantibodies and other vascular events. A strong association between IgG anticardiolipin antibodies and AION secondary to biopsy proven giant cell arteritis was identified, which did not exist with the 'non-arteritic', biopsy nega­ tive form of AION. The possible implications of this finding on the aetiology, diag­ nosis, and treatment of giant cell arteritis are discussed.

Anterior ischaemic optic neuropathy (AlaN) ity. Though success has been reported in iso­ results from compromise of the peripapillary lated cases, �O results of a prospective study of choroid and posterior ciliary artery vascular a series of such treatment are not yet supply to the optic nerve head.1,2 Extensive available. study of the condition has identified a number In an attempt to identify a common factor of contributory factors to such ischaemia,3A in the aetiology of ischaemic optic neuro­ and in particular, has identified giant cell pathy, we investigated the possible involve­ arteritis as a cause in a proportion of cases, ment of antiphospholipid antibodies in this and hence the opportunity to minimise second disease. eye involvement by the use of systemic steroid treatment in AlaN of 'arteritic' origin.s Materials and Methods Other than 'vascular insufficiency, how­ Nineteen consecutive patients presenting ever, no common factor has been identified in with acute AlaN were studied. This was the aetiology of AlaN, which may either definedas a sudden loss of either visual acuity, offer a diagnostic marker for the disease, or visual field, or both, in association with the suggest a line of management. appearance of a swollen optic nerve head in In recent years, a strong association has the affected eye(s) and peripapillary retinal been noted between the presence of antiphos­ haemorrhages, in the absence of any anterior pholipid antibodies and a number of vascular or posterior vitreous activity. Eleven patients events,6 such as arterial and venous throm­ were female and eight male. Patients were bosis/ recurrent fetal loss due to placental asked about systemic symptoms of giant cell vascular insufficiencl and thrombocytope­ arteritis, and a past medical history was taken, nia.9 Furthermore, identificationof such auto­ with particular attention paid to previous vas­ antibodies has suggested new modes of cular events, hypertension, connective tissue treatment of certain vascular disease, by disease, such as systemic lupus erythemato­ reduction of antiphospholipid antibody activ- sus, and spontaneous fetal loss. No patient

From: The Royal Hallamshire Hospital, Sheffield.

Correspondence to: M. T. Watts, Senior Registrar in Ophthalmology, Royal Hallamshire Hospital, Glossop Road, Sheffield. 76 M. T. WATTS ET AL. had any history consistent with previous optic artentIs, as confirmed by positive temporal neuritis. Exposure to steroid or phenothia­ artery biopsy histology, and 12 from a 'non­ zine drugs (which can produce a lupus anti­ arteritic' form of the disease. The clinical fea­ coagulant effectll) was sought. tures, past medical history, ESR on presen­ Ophthalmological and general medical tation, and biopsy histology are shown in the examinations were undertaken, the former Table, together with the results of the ELISA including assessment of best corrected visual assays for IgG and IgM anticardiolipin anti­ acuity and visual field assessment using Gold­ bodies. The presence of significantly elevated man perimetry in patients with acuity of 6/60 levels of IgG anticardiolipin antibody in all or better, and confrontation fields when patients with giant cell arteritis, but in only acuity was less than this. Temporal artery one of the patients with 'non-arteritic' disease biopsy was performed in all, a minimum of is highly statistically significant using chi­ 15 mm of artery being taken, which was exam­ squared test, with Yates' correction for con­ ined after paraffin sectioning at 200 fA. inter­ tinuity (pplatelets). ment and admitted to hospital (prior to await­ ing temporal artery biopsy histology). Discussion Coagulation tests including the Dilute Rus­ It is interesting to note that three of the sel's Viper Venom Time (DRV VT) with patients with giant cell arteritis mediated platelet neutralisation procedures (PNP) AION had none of the systemic features of were undertaken, this being among the most the disease, such as scalp tenderness, jaw sensitive tests for lupus anticoagulant activ­ claudication and malaise. Although one of ity.13 IgG and IgM antibodies to cardiolipin them had suffered premonitory amaurotic were measured using an enzyme linked immu­ episodes for three days prior to presentation, nosorbent assay. 14 All these assays were per­ the other two had experienced no symptoms formed on blood samples taken at the same at all prior to sudden visual loss. In one of time as the ESR on presentation, by staff with these patients, the ESR on presentation was no knowledge of the clinical features, and only 20 mm/hour, and, had temporal artery prior to the institution of any treatment. biopsy not shown active arteritic disease, Because of the skewed distribution of would have been considered to be suffering values in a normal population recognised in 'non-arteritic' AION. This highlights the high these assays, the upper limit of normality was index of suspicion of giant cell arteritis defined as mean + 3 Standard Deviations required, and may explain the relatively (mean determined in the study of 70 healthy higher proportion of giant cell arteritis sUbjects). This value was 8.0 IU/ml for IgG mediated disease in this series as compared to and 5.0 IU/ml for IgM antibody. Anti-dsDNA others, when temporal artery biopsy was not and anti-Ro antibodies were assayed to undertaken in all.16 exclude the presence of systemic lupus type The presence of IgG anticardiolipin anti­ disease. bodies in patients suffering an 'arteritic' AION, and their absence in patients with a Results 'non-arteritic' form of the disease, raises Of the 19 patients presenting with acute questions as to their possible involvement in AION, seven were suffering from giant cell the pathogenesis of giant cell arteritis. The ANTIPHOSPHOLIPID ANTIBODIES IN ISCHAEMIC OPTIC NEUROPATHY 77

Table I. Ocular and systemic features, age, sex, ESR on presentation, temporal artery biopsy histology and anticardiolipin antibody titres

Ocular features Anticardiolipin antibody (V:A. = best Temporal titres (IU/ml) corrected visual Past artery acuity in affected Systemic medical biopsy IgG (mean IgM (mean Patient Age Sex eye) features history ESR histology +3SD*

76 F VA. = H.M. None None of note 20 Negative 22.5 4.4 Central scotoma 2 74 F VA. = 6/6 None None of note 22 Negative 1.8 1.1 Central + inferior altitudinal scotoma 3 72 F VA. = 6-36 None Previolls 32 Positive 29.1 Generalised field central retinal constriction artery occlusion in fellow eye 4 70 F VA. = 6/24 Malaise, myalgia, None of note 60 Positive 45.1 Inferior temporal artery altitudinal tenderness, jaw scotoma claudication 79 M VA. = 6/24 Headache, scalp None of note 60 Positive 13.5 2.5 Inferior nasal tenderness quadrant scotoma 6 61 F VA. = N.P.L. None Hypertension 16 Negative 2.3 7 79 F VA. = 6/24 None None of note 12 Negative 1.0 Inferior arcuate scotoma 8 83 M VA. = H.M. None None of note 52 Positive 14.1 Generalised field constriction 9 76 M VA. = 2/60 None Hypertension 13 Negative 1.8 Central scotoma Myocardial inferior altitudinal infarct 10 77 F Bilateral visual· loss None None of note 20 Positive 9.6 VA. = N.P.L. right and left 11 76 F VA. = 6/36 Malaise Angina Negative 2.8 Generalised field constriction 12 64 M VA. = 6/60 None Previous 4 Negative 1.9 Central + inferior central retinal altitudinal scotoma vein occlusion in fellow eye 13 79 M V.A. = 5/60 None Hypertension 37 Negative 3.4 Inferior-nasal only remaining field 14 62 M VA. = 6/36 None Diabetes 15 Negative 4.4 Central scotoma mellitus 15 74 M VA. = H.M. None None of note 47 Negative 4.4 1.1 Small temporal island of field only remaining 16 69 F V.A. = P. L. None Hypertension 15 Negative 2.4 Generalised field Deep vein loss thrombosis 17 76 F VA. = 6/60 Headache Hypertension 8 Negative Central scotoma 18 74 F VA. = H.M. Malaise, scalp None of note 54 Positive 46.5 6.4 Generalised field tenderness, jaw constriction claudication 19 77 M VA. = H.M. Malaise, scalp Hypertension 14 Positive 11.5 58.6 Small temporal tenderness Myocardial island of field only infarct remaining

• Normal = <[mean + 3 Standard Deviations] determined in study of 70 healthy normals. 78 M. T. WAITS ET AL.

absence of such an association with the IgM ation with antiphospholipid antibodies, using antibody is in agreement with previous work corticosteroid treatment to reduce antibody on antiphospholipid antibodies mediating levels,22 and plasmapheresis has also found other vascular events, when the IgG anti­ success.23 Such studies may explain the mech­ bodies have been shown to correlate best with anism of action of steroids in treatment of clinical disease.17 However, the absence of giant cell arteritis; reduction of an immune other autoantibodies, such as anti-dsDNA, response which therefore reduces second eye anti-Ro, and those responsible for the lupus involvement. They also make suggestions as anticoagulant effect identifies the patients to possible new techniques in management. with giant cell arteritis mediated AION as a As long as the basic mechanism of action of group with a highly specific antibody. In other antiphospholipid antibodies remains obscure, disease states with antiphospholipid mediated a number of questions must remain vascular events, a more diffuse range of auto­ unanswered. However, the association of IgG 8 antibodies has been identified.1 anticardiolipin antibodies with giant cell The mechanism by which antiphospholipid arteritis mediated AION suggests new direc­ antibodies mediate thrombosis remains tions in which to look for an understanding of undefined, and similarly their precise role in this enigmatic disease, and offers a new diag­ giant cell arteritis is obscure. It may be that nostic marker. the antibodies are part of a humorally Keywords: Antiphospholipid antibodies; giant cell mediated immune response, and indeed, the arteritis; ischaemic optic neuropathy. presence of immunoglobulins on the walls of References 1 arteries affected by giant cell arteritis has Hayreh SS and Baines JAB: Occlusion of the pos· . 0 been well documented.1 9 2 Alternatively, the terior ciliary artery III. Effects on the optic ncrve antibodies may initiate a microvascular head. Br J OphthalmoI1972, 56: 754-64. 2 Hayreh SS: Anterior ischaemic optic neuropathy 1. thrombosis in the posterior ciliary arteries and Terminology and pathogenesis. Br J Ophthalmol peripapillary choroidal vasculature, as they 1974, 58: 955-6 3. do in the plancental microvasculature in cases 3 Hayreh SS: Anterior ischaemic optic neuropathy. of recurrent fetal 10ss.21 The possibility that New York: Springer-Verlag, 1975. 4 the antibodies are merely an epiphenomenon Hayreh SS and Zahoruk RM: Anterior ischaemic optic neuropathy VI. In juvenile diabetics. Oph· also exists, since in certain situations they may thalmologica1981, 182: 13-28. be a consequence of tissue damage, for 5 Jennings GH: Arteritis of the temporal vessels. Lan· example after myocardial injury. However, cet19 38, 1: 424-8. 6 their absence in the patients with 'non-arter­ Hughes GRV: Thrombosis, abortion, cerebral disease and the Lupus anticoagulant. Br Med J itic' AI ON, and presence in three patients 198 3, 287: 1088-9. with AION secondary to giant cell arteritis, 7 Harris EN, Asherson RA, Hughes GRV: Antiphos­ but without systemic involvement, argues pholipid antibodies-autoantibodies with a against this. difference. Ann Rev Med 1988, 39: 261-71. " Derue GJ, Englert HJ, Harris EN et al: Fetal loss in Although the numbers are as yet relatively systemic lupus: association with anticardiolipin small, the results of IgG anticardiolipin assay antibody. J Obstet Gynaecol1985, 5: 207-9. have so far provided a sensitive (100%) and " Harris EN, Asherson RA, Gharavi AE et al: Throm­ specific (91%) test to distinguish between bocytopenia in SLE and related autoimmune dis­ orders: Association with anticardiolipin 'arteritic' and 'non-arteritic' AION, as antibodies. Clin Exp Rheumatol1984, 1: 47-51. 10 defined by conventional criteria. The distinc­ Cortelazzo S, Galli M, Barbui T: Intravenous gam· tion is often not easy to make, and this addi­ maglobulin in patients with antiphospholipid anti­ tional marker of the disease may be of benefit. bodies and thrombocytopenia. Clin Exp Rheumatol1990, 8: 224. The recognition of the importance of anti­ II Zarabbi MH, Zucker S, Miller et al: Immunologic phospholipid antibodies in the aetiology of and coagulation disorders in chlorpromazine certain vascular events has directed attention treated patients. Ann Int Med 1979, 9: 194-9. 12 to their treatment using techniques aimed at Ellis ME and Ralston S: The ESR in the diagnosis and management of the polymyalgia rheumatical their elimination. For example, successful giant cell arteritis syndrome. Ann Rheum Dis pregnancies have been achieved in patients 198 3,42: 168-70. 1 with a history of recurrent fetal loss in associ- 3 The Lupus Anticoagulant Working Party. Detection ANTIPHOSPHOLIPID ANTIBODIES IN ISCHAEMIC OPTIC NEUROPATHY 79

of Lupus-like anticoagulant: current laboratory 19 Liang GC, Simkin MD, Mannik M: Immunoglobu­ practice in the UK. J Clin Patho11990, 43: 73-5. lins in temporal arteries. An immunofluorescent 14Harris EN, Gharavi AE, Patel SP, Hughes GRV: study. Ann Int Med 1974, 81: 19-24. 20 Evaluation of the anti cardiolipin antibody test: Wells KK, Folberg R, Goeken JA, Kemp JD: Tem­ report of an international workshop held on 4th poral artery biopsies. Correlation of light micro­ April 1986. Clin Exp Immunol1987,68: 215-9. scopy and immunofluorescence microscopy. IlTan EM, Cohen AS, Fries JF et al: The 1982 revised Ophthalmology 1989, 96: 1058--64. criteria for the classification of SLE. Arthritis 21 Hughes GRV and Khamashta MA: Anticardiolipin Rheum1982, 25: 1271-7. antibody: a cause of a tendency to thrombosis. Br 16Hayreh SS: Anterior Ischacmic Optic Neuropathy. Med J 1989 , 299: 1414. Eye1990, 4: 25-41. 22 McCartey GA, Lister KA, Thurnau GM, Altshuler 17 Gharavi AE, Harris EN, Asherson RA, Hughes G: Successful treatment of recurrent fetal loss in a GRV: Anticardiolipin antibodies: isotype distri­ woman with prepartum normalisation of anti­ bution and phospholipid specificity. Ann Rheum Dis1987, 46: 1--6. phospholipid antibodies and normal placenta. .Clin Exp Rheumatol1990, 8: 221. 18 Asherson RA, Merry P, Acheson JF, Harris EN, 2 3 Hughes GRV: Antiphospholipid antibodies: a Frampton G, Cameron JS, Thorn M, Jones S, Raf­ risk factor for occlusive ocular vascular disease in tery M: Successful removal of antiphospholipid systemic lupus erythematosus and the 'primary' antibody during pregnancy using plasma antiphospholipid syndrome. Ann Rheum Dis exchange and low-dose prednisolone. Lancet 1989, 48: 358-61. 1987,2: 102 3-4.