Eye (2013) 27, 688–697 & 2013 Macmillan Publishers Limited All rights reserved 0950-222X/13 www.nature.com/eye 1 2 1 2 REVIEW A review of central DD Varma , S Cugati , AW Lee and CS Chen retinal artery occlusion: clinical presentation and management Abstract Central retinal artery occlusion (CRAO) is an that in turn place an individual at risk of future ophthalmic emergency and the ocular ana- cerebral stroke and ischaemic heart disease. logue of cerebral stroke. Best evidence reflects Although analogous to a cerebral stroke, there that over three-quarters of patients suffer is currently no guideline-endorsed evidence for profound acute visual loss with a visual acuity treatment. Current options for therapy include of 20/400 or worse. This results in a reduced the so-called ‘standard’ therapies, such as functional capacity and quality of life. There is sublingual isosorbide dinitrate, systemic also an increased risk of subsequent cerebral pentoxifylline or inhalation of a carbogen, stroke and ischaemic heart disease. There are hyperbaric oxygen, ocular massage, globe no current guideline-endorsed therapies, compression, intravenous acetazolamide and although the use of tissue plasminogen acti- mannitol, anterior chamber paracentesis, and vator (tPA) has been investigated in two methylprednisolone. None of these therapies randomized controlled trials. This review will has been shown to be better than placebo.5 describe the pathophysiology, epidemiology, There has been recent interest in the use of and clinical features of CRAO, and discuss tissue plasminogen activator (tPA) with two current and future treatments, including the recent randomized controlled trials on the 1Flinders Comprehensive use of tPA in further clinical trials. treatment of acute CRAO.6,7 Stroke Centre, Flinders Eye (2013) 27, 688–697; doi:10.1038/eye.2013.25; The aim of this review article is to provide a Medical Centre and Flinders published online 8 March 2013 comprehensive overview of the epidemiology, University, Adelaide, South risk factors, and clinical presentation of CRAO, Australia, Australia Keywords: central retinal artery occlusion; but more importantly to review the evidence for 2Department of management; thrombolysis treatment. Ophthalmology, Flinders Medical Centre and Flinders University, Adelaide, South Australia, Australia Introduction Materials and methods Central retinal artery occlusion (CRAO) was Correspondence: first described by von Graefes in 1859.1 It is For this review, we searched PubMed, The CS Chen, Department of Ophthalmology, Flinders analogous to an acute stroke of the eye and is an Cochrane Database, and The ACP Journal Club Medical Centre and Flinders ophthalmic emergency. The incidence is for the highest level of ‘best evidence’ from 1990 University, Flinder Drive, estimated to be 1 in 100 000 people and accounts to 2012, including early release publications. Bedford Park, Adelaide, for 1 in 10 000 ophthalmological outpatient Search terms included: ‘central retinal artery South Australia 5042, visits.2 A prospective study of 260 eyes with occlusion’, ‘retinal artery occlusion’, in Australia Tel: +61 8 8244252; CRAO showed that people suffer profound conjunction with ‘thrombolysis’, ‘treatment’, Fax: +61 8 82770899. monocular visual loss, with 80% of patients and ‘therapeutics’. In PubMed, the ‘search E-mail: Celia.Chen@health. having a visual acuity (VA) of 20/400 or worse.3 builder’ tool was used for the topic ‘retinal sa.gov.au This reduction in vision increases the fall risk artery occlusion’, and subsearch categories and thus results in increased dependency, and added to this via search builder were: Received: 2 August 2012 in worst-case scenarios leads to institutional ‘classification’, ‘complications’, ‘diagnosis’, Accepted in revised form: 4 22 January 2013 care. CRAO signifies end-organ ischaemia and ‘drug therapy’, ‘epidemiology’, ‘aetiology’, Published online: 8 March often the underlying atherosclerotic disease. It is ‘mortality’, ‘pathology’, ‘physiopathology’, 2013 the same underlying atherosclerotic risk factors and ‘therapy’. A review of central retinal artery occlusion DD Varma et al 689 The abstracts were reviewed by two authors (AWL and CSC) and full articles were subsequently looked at, based on the priority of relevant content. Full articles and references were obtained and references checked for additional material where appropriate. Anatomy and pathophysiology The central retinal artery (CRA) is a branch of the ophthalmic artery (OA), which is the first branch of the internal carotid artery.8 The CRA supplies blood to the surface layer of the optic disc. From here it divides into two main branches (superior and inferior); these then further divide into temporal and nasal branches, which supply blood to the four quadrants of the retina.9 Figure 1 Figure showing the narrowest part of the central The outer retina is supplied by the choriocapillaris retinal artery (common site for embolus), where it pierces the of the choroid that branches off the ciliary artery. dural sheath of the optic nerve (arrowhead) and showing the site of an thrombus in the central retinal artery behind the lamina Both of these must be functioning to maintain retinal cribrosa (star). Abbreviations: PCA, posterior ciliary artery; function, as both CRA and ciliary artery originate CRA, central retinal artery; ON, optic nerve; dura, duramater; from the OA. Pia, piamater (reproduced from)65. One important variation to this is the presence of a cilioretinal artery. A study on 1000 consecutive patients, using fundus fluorescein angiography (FFA), found a cilioretinal artery to be present in 49.5% of patients.10 Once the CRA is occluded, the ability of the retina to When present, it supplies the papillomacular bundle, recover depends on whether the offending embolus or which contains the maximum amount of photoreceptors thrombus is dislodged, and more importantly by the 15,16 essential for central vision. In these patients, the macula retinal ischaemic tolerance time. Conclusions from may still be perfused in acute CRAO. This means it is electrophysiological, histopathological, and possible for good vision to be maintained. However, this morphometric studies showed that in old atherosclerotic does not always occur. A detailed study of 260 eyes with hypertensive rhesus monkeys, no detectable damage was CRAO showed the presence of cilioretinal artery in 35 done with CRAO of 97 min. However, between 105 and eyes. Of these, 60% had an initial VA of 6/30 or worse.3 240 min there was a variable degree of partial retinal 16 Such poor results are due to the variability in size of the recovery seen on visual-evoked potential. A large cilioretinal artery and the area it supplies. Therefore, degree of interindividual variability in regard to the CRAO infarcts will deprive retinal blood supply, relationship between the length of CRAO and the extent reducing the thickness of the inner retinal layers. of retinal damage was found. At 240 min, complete or However, a cilioretinal artery, if present, will maintain almost total optic nerve atrophy and nerve fibre damage the thickness of the retina to variable extents, depending resulting in massive irreversible retinal damage was 16 on how much of the retina it supplies.3 found in all eyes. This suggests that the time window The exact location where CRAO occurs is debated. for intervention is finite and inversely proportional to the Anatomical studies show that the narrowest part of the degree of recovery. The exact retinal tolerance time when CRA lumen is where it pierces the dural sheath of the irreversible damage occurs is not yet known, but would 16 optic nerve and not the lamina cribrosa, and that this was appear to be no longer than 4 h. the most common location where CRAO occured11 (Figure 1). Embolism is the most common cause of Types of CRAO CRAO, the major source of this being carotid artery 3 disease, usually due to atherosclerotic plaques. Carotid CRAO can be divided into four different subclasses: stenosis and the heart are other important sources of emboli.9 In all, 74% of these emboli are shown to be made (1) Non-arteritic permanent CRAO (Figure 2). of cholesterol, 10.5% were calcific material, and 15.5% (2) Non-arteritic transient CRAO. were fibrin.12 It is equally probable that an occlusive (3) Non-arteritic CRAO with cilioretinal sparing thrombus13 at the level immediately posterior to the (Figure 3). lamina cribrosa also causes CRAO.14 (4) Arteritic CRAO (Figure 4). Eye A review of central retinal artery occlusion DD Varma et al 690 (1) Non-arteritic permanent CRAO Risk factors for non-arteritic CRAO include: arterial hypertension, diabetes mellitus, carotid artery disease, The majority of CRAOs are caused by platelet fibrin coronary artery disease, transient ischaemic attacks thrombi and emboli as a result of atherosclerotic disease (TIAs) or cerebral vascular accidents, and smoking and account for over two-third of all CRAO cases.17–19 tobacco. These have been found to be significantly more common in patients with CRAO than in the general population. A recent aged-matched cohort study, including 249 patients (289 eyes) with CRAO, confirms these associations with the addition of renal disease.20 Other risk factors are a family history of any type of vascular disease. In younger patients (under 50 years), proatherogenic states, such as hyperhomocystenemia, factor V Leiden, protein C and S and anti-thrombin deficiencies, anti-phospholipid antibodies or prothrombin gene mutations, sickle cell disease, and migraine due to vasospasm and paraneoplastic syndromes may all contribute to non-arteritic CRAO.17 Ocular risk factors can include raised intraocular pressure, optic nerve head drusen, and a preretinal Figure 2 Colour fundus photograph of the right eye showing arterial loops. These result in reduced perfusion pressure 21,22 acute CRAO with cherry-red spot and cattle trucking of the across the optic nerve head. arterioles. (2) Non-arteritic transient CRAO Non-arteritic transient CRAO (transient monocular blindness) accounts for 15–17% of CRAOs and has the best visual prognosis.3,23 This is analogous to a TIA affecting the eye.