The Investigation of Patients with Retinal Vascular Occlusion

Eye (1990) 4, 464-468

ELIZABETH M. GRAHAM London

Summary The investigation of patients with retinal artery occlusion, retinal vein occlusion and cotton wool spots is discussed. The majority are due to either emboli or atheroma and occur in elderly patients. A full clinical history and examination remain the essential part of the investigation but the ophthalmologist must select patients in whom further investigation is warranted. The recent recognition of the importance of antiphospbolipid antibodies and natural anticoagulant deficiency states in the pathogenesis of thrombosis has identified a group of young people in whom specific therapy may be indicated.

Every ophthalmologist encounters the unfor examination accompanied by a thorough oph tunate patient with sudden visual loss due to a thalmic examination frequently identify the recent retinal vascular occlusion. Two cause of the occlusion without resorting to immediate questions arise: Firstly, can any special investigations. Salient features in the thing be done to improve or preserve vision? history are age, general health, family history Secondly, what was the cause of the occlusion of vascular disease, diet, drug and smoking and are any practical precautions available to habits. General examination should include prevent a further attack? In the majority of measurement of pulse, blood pressure in both cases substantial visual recovery is unusual arms, auscultation of the heart and carotids and therefore the second question is vitally and urinalysis for sugar and protein. important. The ophthalmologist who firstsees _ The eye examination is often diagnostic and such a patient is responsible for identifying important things to look for are: the cause of the occlusion, and consequently (i) evidence of local ocular disease, eg, arranging appropriate referral for further episcleritis or scleritis, anterior seg management. This paper addresses the inves ment inflammation, arteriolar loop, tigation of patients presenting to the ophthal drusen of the optic nerve. mologist with either retinal artery occlusion, (ii) evidence of generalised retinal vascular retinal vein occlusion or an isolated cotton disease, hypertensive or diabetic wool spot. retinopathy. (iii) presence of emboli and the nature of Retinal Artery Occlusion the embolus-white and calcific, The majority of both central retinal artery refractile (cholesterol) or pale fibrin occlusions and branch retinal artery occlu platelet plaques. sions are due to either emboli or atheroma Special investigations are directed towards and occur in patients with generalised arteri the cause of the vascular disease and the func osclerosis and hypertension. tion of the heart (Table I). Essential tests in all A pertinent general medical history and patients are a full blood count, ESR, blood

Correspondence to: Dr. E. M. Graham, Medical Eye Unit, St Thomas' Hospital, London SE1 7EH. THE INVESTIGATION OF PATIENTS WITH RETINAL VASCULAR OCCLUSION 465

Table Ia Investigation of embolic retinal artery occlusion Table Ib Investigation of non embolic retinal artery TYPE OF CALCIFIC FIBRIN PLATELET CHOLESTEROL occlusion EMBOLUS Pulse

ORIGIN aOr!ic or hear! valve or neck vessels Blood pressure mitral valve neck vessels Carotid bruit ! Smoking habits / � Urinalysis ! Pulse WHAT TO DO Pulse Blood glucose Blood Pressure in both arms Blood lipids Blood Pressure ESR Carotid Bruit VDRL TPHA Auscultation Ophthalmodynometry Echocardiogram Blood Lipids Electrocardiogram ! Smoking Cardiology Referral ! Consider Neurology Referral

Consider Digital Subratction Angiography

Trial of Aspirin

glucose and lipid screen. Several points are Isolated Cotton Wool Spot worth remembering. Calcific retinal emboli Cotton wool spots are commonly seen as part originate from either the aortic or mitral of a diabetic or hypertensive retinopathy. An valve. 1,2 An urgent opinion from a cardiol isolated cotton wool spot is unusual, and even ogist should be sought as frequently early though it is often an incidental finding it may valve replacement is the best treatment. herald severe systemic disease. The cotton In young patients retinal artery occlusions wool spot is produced by occlusion of the pre are often due to emboli from the heart, capillary arterioles and is a reflection of the although mitral valve prolapse has been breakdown of retrograde and orthograde axo 3 incriminated in the past. A recent study of plasmic flow: the axoplasmic debris accumu amaurosis fugax and retinal artery occlusion lates at the junction of healthy and anoxic in people under 45 years of age found the inci retina and causes a dense white fluffy appear dence of mitral valve prolapse was 6·5% in ance. 7,s The presence of a cotton wool spot both the patient group and in the general therefore indicates blockage of a retinal arte population4 casting doubt upon the previous riole which may be due to abnormalities of the assumption that mitral valve prolapse is of vascular endothelium, blockage by abnormal pathogenetic significance. erythrocytes or unusual emboli (see Ta ble II). In elderly patients giant cell arteritis must The macroscopic and microscopic features of never be forgotten as 20% of patients who a cotton wool spot are always the same lose vision do so from central retinal artery regardless of its cause. 9 occlusion; the remaining 80% suffering from The patient who presents with an isolated posterior ciliary artery occlusion,s In young patients with 'negative' history cotton wool spot requires the same general and examination a systemic vasculitis (PAN medical history and examination as the or SLE) should be suspected. Retinal artery patient with the retinal artery occlusion. occlusion associated with migraine is well However, the isolated cotton wool spot is documented. 6 However, the assumption that unlikely to be due to an embolic phenomenon migraine is the cause of the occlusion is but more likely to be due to arterial disease, dangerous and this diagnosis should stand particularly a systemic vasculitis. The inves only when all other possibilities have been tigations are summarised in Table III. Giant excluded. cell arteritis is usually easy to diagnose clini- 466 E. M. GRAHAM

Table II Causes of cotton wool spots have vaso-occlusive retinopathy associated 2, with antiphospholipid antibodies. 1 13 Abnormalities of Arteriosclerosis The diagnosis of PAN is made on clinical vascular endothelium Diabetes mellitus Hypertension grounds and the pathological confirmationof a Systemic vasculitis vasculitis in the medium sized arteries with h!u (SLE, PAN, GCA, scleroderma) cocyte infiltration and fibrinoid necrosis. The Radiation retinopathy ESR is raised, autoantibodies are present in Human immunodeficiency virus Abnormal erythrocytes Haemoglobinopathies low titres and immunoglobulin levels are Unusual emboli Fat usually high. However none of these tests are Talc specific for PAN. Recently antineutrophil cytoplasmic antibodies (ANCA) have been cally and the diagnosis is supported by the ESR found in the sera of many patients with two dis and confirmed by the temporal artery biopsy. eases related to PAN, namely Wegener's The presence of cotton wool spots in these granulomatosis and microscopic polyarteritis patients means that the retinal circulation as nodosa.14 The latter is solely a renal disease well as the posterior ciliary circulation is and this test may therefore be useful in the involved in the disease progress and that investigation of the cause of an isolated cotton immediate treatment with systemic steroids is wool spot, particularly when associated with imperative to prevent further visual loss. hypertension or other ophthalmological fea The other systemic vasculitides associated tures such as scleritis or proptosis are also with cotton wool spots are systemic lupus presen!. erythematosus (SLE),10 polyarteritis nodosa In the majority of cases cotton wool spots are (PAN) and rarely scleroderma. The clinical due to abnormalities of the vascular endothe manifestations of these diseases are different: lium and this is secondary to an easily identified SLE commonly affects females particularly disease process such as diabetes mellitus West Indians, who present with rashes, mal (Table II). The question arises whether a local aise, arthritis and renal problems, whereas specific immune reaction against endothelial PAN afflicts middle aged men who develop cells can occur in isolation: antiendothelial cell asthma, hypertension, myalgia and neuro pathy. The simple investigations to support the antibodies have been demonstrated in the sera diagnosis of a systemic vasculitis remain the of patients with inflammatory vasculitis15 but ESR and antinuclear antibodies: the latter are their importance in the pathogenesis of the cot present in 90% of the sera of patients with ton wool spot or other retinal vascular disease SLE. Further classificationof these antibodies is not known. reveals that patients with SLE have antibodies The human immunodeficiency virus (HIV) against double stranded DNA whereas is known to infect endothelial cells directly16 patients with scleroderma and mixed connec and cotton wool spots are the most frequent tive tissue disease more frequently have anti manifestation of AIDS to be seen in the fun bodies against RNA. An important subgroup dUS.17 Interestingly, cotton wool spots are not of patients with SLE have recently been identi Table III Investigation of the isolated cottonwool spot fied who have phospholipid dependent clot Cause Investigation ting problems with autoantibodies against

phospholipids. The three common types of 1. Systemic vasculitis ESR these antibodies are 'reagin' in biological false Antinuclear antibodies positive syphilis serology, lupus anticoagulant pius SLE Anti DNA antibodies and anticardiolipin antibodies. Patients with PAN Immunoglobulins Eosinophil count these antibodies and SLE, suffer recurrent GCA Temporal artery biopsy arterial and venous thrombosis, spontaneous C reactive protein abortion, and retinal vascular occlusion.11 2. AIDS HIV antibody Moreover, there is a further important group 3. 'Nil obvious' Blood pressure Blood glucose of patients who do not have an autoimmune Smoking habits disease such as SLE but nevertheless THE INVESTIGATION OF PATIENTS WITH RETINAL VASCULAR OCCLUSION 467 seen in any asymptomatic HIV carriers but sion. Malignant disease, paraproteinaemia, only patients with AIDS or AIDS related nephrotic syndrome, tuberculosis and Beh complex. High fibrinogen levels and raised <;et's syndrome are all examples of this. Beh circulating immune complexes are thought to <;et's disease is of particular importance to the contribute to their pathogenesis in this situ ophthalmologist as severe inflammatory eye ation.18 The HIV antibody test should not be disease is an integral part of the symptom undertaken lightly by the ophthalmologist as complex, and this diagnosis must always be the result has far reaching consequences for considered in any patient who presents with a the patient. If HIV infection is suspected the pan uveitis in association with branch retinal patient should be referred to a special clinic vein occlusion. Similarly, hypersensitivity (eg, genitourinary medicine, haemophiliac, reaction to tuberculous antigen can produce a drug addiction) for advice and counselling florid pan unveitis and the picture of central before the test is requested. retinal vein occlusion. Recently, great interest has been directed Retinal Vein Occlusion towards the natural anticoagulants, which Retinal vein occlusion commonly occurs in either prevent coagulation or precipitate fibri elderly patients and is another feature of nolysis, and the possibility that deficiency of generalised arteriosclerosis. A similar history these natural anticoagulants may cause an and examination is required as from patients increased tendency to clot (thrombophilia). with retinal artery occlusion. However, Antithrombin III, heparin CoFactor II, plate slightly different points should be empha let Factor III, protein C and protein S all act sised. Specific ophthalmological features on the coagulation pathway whereas fibrino associated with central retinal vein occlusion lysis is mediated by Factor XII, prekallikrein, are open angle glaucoma and elevated intra urokinase and tissue plasminogen activator. ocular pressurel9 whereas hypermetropia is The most common deficiencies recognised are more prevalent in branch retinal vein those of antithrombin III, protein C and pro occlusion. 20 tein S and assays are readily available in most The two important contributory factors are routine laboratories. Homozygous Protein C vessel wall disease and increased blood vis deficiency and protein S deficiency are associ cosity. The investigations are summarised in ated with recurrent thromboses.22,23 However the association between heterozygous Protein Table IV. Hypertension and hyperlipidaemia are the most prevalent underlying medical Table IV Investigation of retinal vein occlusion conditions and an association with regular Cause Test alcohol intake has also been suggested.20 Increase in blood viscosity is an important 1. Vascular disease consideration in the pathogenesis of retinal Hypertension Blood pressure vein occlusion although it is probable that this Urinalysis Renal function must be combined with vessel wall disease to Hyperlipidaemia Cholesterol produce actual occlusive phenomena. The Triglycerides cells in the blood have a greater influence on Lipoprotein profile viscosity than plasma, and the red cells exert Smoking Diabetes mellitus Urinalysis the greatest effect because of their large Blood glucose number than either leucocytes or platelets. Systemic vasculitis ANA The haemoglobin and packed cell volume Anti DNA antibodies reflect the number of red cells whereas a 2. Increased viscosity Full blood count raised ESR suggests a raised plasma viscosity. ESR Fibrinogen Interestingly, Appiah and Trempe found an Packed cell volume association between elevated ESR of unspeci Platelet function tests fied cauSe and central retinal vein occlusion.20 Plasma protein Some systemic diseases are associated with Protein C Protein S an increased viscosity and therefore risk of Antithrombin III thrombosis which includes retinal vein occlu- 468 E. M. GRAHAM

C deficiency and thrombosis is not yet proven risk factor of occlusive ocular vascular disease in systemic lupus erythematosus and the 'primary' and it is possible other features are required antiphospholipid syndrome. Ann Rheum Dis for a thrombotic tendency. The relationship 1989,48: 358-61. between Protein C deficiency and retinal vein 12 Levine SR, Crofts JW, Lesser GR, Floberg J, Welch occlusion is not known although one prelimi KMA: Visual symptoms associated with the pres· Ophthalmology nary study suggested an association with ence of a lupus anticoagulant. 1988,95: 686-92. branch retinal vein occlusion but not central 13 Kleiner RC, Najarian LV, Schatten S, Jabs DA, Patz retinal vein occlusion.24 A, Kaplan HJ: Vaso occlusive retinopathy associ· The antiphospholipid antibodies are ated with antiphospholipid antibodies. (Lupus acquired immunoglobulins which encourage anticoagulant retinopathy). Ophthalmology 1989,96: 896-904. thrombosis by interfering with endothelial 14 Savage COS, Wincarls CG, Jones S, Marshall PD, cells and preventing the interaction of natural Lockwood CH: Prospective study of anticoagulants with platelets. There is a sig radio-immunoassay for antibodies against neu· nificant association between patients with trophil cytoplasm in the diagnosis of systemic vas Lancet1987, 1: 1389-93. SLE with anticardiolipin antibodies and ret culitis. 15 Baguley E and Hughes GRV: Antiendothelial cell inal vascular occlusions but not specifically antibodies. (Editorial). J Rheumatol 1989, 16: retinal vein occlusion. 24 Although this tend 716-7. ency was not found in a pilot study of patients 16 Pomerantz RJ, Kuritzkes DR, de la Monte SM, with isolated idiopathic retinal vein occlu Rota TR, Albert D, Bor DH, Feldman EL, Schooley RT, Hirsch MS: Infection of the retina sion25 the test is still worth doing particularly by human immunodeficiency virus type I. NEngl in young patients. J Med 1987, 317: 1643-7. 17 Jabs,DA, Green WR, Fox R, Polk BF, Bartlett JG: References Ocular manifestation of Acquired Immune Defi I Ross Russell RW: The source of retinal emboli. ciency Syndrome. Ophthalmology 1989, 96: Lancet1968. 2: 789-92. 1092-9. 2 Arruga J and Sanders MD: Ophthalmological find "Engstrom RE, Holland GN, Hardy D, Meiselman ings in 70 patients with evidence of retinal embol HJ: Abnormal blood rheologic factors in patients ism. Ophthalmology 1982, 89: 1336-47. with human immunodeficiency virus-associated 3 Caltrider ND, Irvine AR, Kline HJ, Rosenblatt A: conjunctival and retinal microvasculopathy. Retinal emboli in patients with mitral valve pro Invest Ophthalmol VisSci (suppl) 1988, 29: 43. 9 lapse. AmJ Ophthalmol1980, 90: 534-9. 1 Frucht J, Shapiro A, Merin S: Intraocular pressure 4 Tippin J, Corbett JJ, Kerber RE, Schroeder E, in retinal vein occlusion. BrJ Ophthalmol1984, Thompson SH: Amaurosis fugax and ocular 68: 26-8. 0 infarction in adolescents and young adults. Anns 2 Appiah AP and Trempe CL: Differences in Neuro11989, 26: 69-77. contributory factors among hemicentral central 5 Wang FM and Henkind P: Visual system involve and branch retinal vein occlusion. Ophthal· ment in giant cell (temporal) arteritis. Surv Oph· mology 1989,96: 364-6. thalmol1979, 32: 264-71. 21 Dodson PM, Kubicki AJ, Taylor KG, Kritzinger 6 Hupp SL, Kline LB, Corbett JJ: Visual disturbances EE: Medical conditions underlying recurrence of of migraine. Surv Ophthalmol1989, 33: 221-36. retinal vein occlusion. BrJ Ophthalmol1985,69: 7 J ampol LM: Arteriolar occlusive disease of the mac· 493-6. ula. Ophthalmology 1983, 90: 534-9. 22 Seligsohn U, Berger A, Abend M, Rubin L, Attias 8 McLeod D, Marshall J, Kohner EM, Bird AC: The D, Zivelin A, Rapaport SI: Homozygous protein role of axoplasmic transport in the pathogenesis C deficiency manifested by massive venous of retinal cotton wool spots. Br J Ophthalmol thrombosis in the new born. NEngl J Med 1984, 1977, 61: 177-91. 310: 559-62. 9 Mansour AM, Jampol LM, Logani S, Henderly D: 23 Comp PC and Esmon .CT: Recurrent venous Cotton wool spots in Acquired Immunodeficiency thrombo-embolism in patients with partial defi· Syndrome compared with Diabetes Mellitus, ciency of protein S. N EnglJ Med 1984, 311: Systemic Hypertension and Central Retinal Vein 1525-8. Occlusion. Arch Ophthalmol1988, 106: 1074-7. 24 Chung MM, Trese MT, Hong YJ: Protein C levels in 0 1 Lanham JG, Barrie T, Kohner EM, Hughes GRY. retinal vein occlusions. Invest Ophthal Vis Sci SLE retinopathy: evaluation by fluorescein (suppl) 1989,30: 477. angiography. Ann of RheumDis 1982, 41: 473--8. 25 Merry P, Acheson J, Asherson R, Hughes GRV: II Asherson RA, Merry P, Acheson JF, Harris EN, Management of retinal vein thrombosis. BrMedJ Hughes GRV: Antiphospholipid antibodies: a 1988,296: 294.