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Protein C and protein S deficiency associated with retinal, optic nerve, and cerebral ischaemia
  1. Department of Ophthalmology, University of Rochester School of Medicine and Dentistry, Rochester, USA
  1. Dr J Ambati, Retina Service, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA.

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Editor,—Deficiencies in the vitamin K dependent factors protein C and protein S can lead to arterial or venous thrombosis. Branch and central retinal arterial and venous occlusions1-4 have been associated with deficiencies in these plasma proteins, as have amaurosis fugax5 and stroke.6 We report, to the best of our knowledge, the first case of ischaemic optic neuropathy associated with combined protein C and protein S deficiency.


A 47 year old woman with non-insulin dependent diabetes mellitus with documented absence of previous retinopathy presented with blurring of vision and bright flashing lights in her right eye for 2 weeks, associated with vague periocular discomfort and left sided facial and leg numbness. Best corrected visual acuity was 20/30 right eye and 20/25 left eye. The anterior segment examination was unremarkable and the intraocular pressures were 15 mm Hg right eye and 14 mm Hg left eye. A large cotton wool spot was present inferotemporal to the right optic disc (Fig 1). The overlying vitreous was clear. The retinal venules appeared moderately tortuous but undilated. Fluorescein angiography revealed normal arterial filling but markedly delayed arteriovenous filling and late disc hyperfluorescence. When she returned 2 weeks later, this cotton wool spot was smaller, but other cotton wool spots superior to the disc had appeared (Fig 2). The patient underwent carotid Doppler and cerebral angiography studies which revealed near complete occlusion of the right internal carotid artery. Coumadin therapy was instituted and extensive diagnostic evaluation was pursued. She returned 2 weeks later and all the cotton wool spots were resolving.

Figure 1

Initial large cotton wool spot inferotemporal to right optic disc.

Figure 2

Initial cotton wool spot along the inferotemporal vessel resolving 2 weeks later with appearance of new cotton wool spots superiorly.

Three days later she was admitted to the hospital with syncope and left hemiparesis due to an infarct in the territory of the right middle cerebral artery. She also suffered sudden, painless loss of vision to the level of hand movements in the right eye. Fundus examination 6 weeks later revealed a pale optic disc with both generalised and focal narrowing of the retinal arterioles, and an overall reduction in venous calibre and tortuosity (Fig 3). Three months later, at which time the visual acuity remained at hand movements, electroretinography (ERG) was performed to distinguish retinal vascular pathology from optic nerve embarrassment. The right eye exhibited modest reductions in scotopic b-wave amplitudes in response to dim white flash (33%) and to bright white flash (20%) compared with the left eye. Cone b-wave implicit time on 30 Hz flicker testing was only slightly longer in the right eye compared with the left eye (30.5 ms versus 29.5 ms). Oscillatory potential amplitudes were normal in both eyes. These results were interpreted as showing insufficient evidence for ischaemic retinal damage as an explanation for her profound loss of vision. The patient was diagnosed with ischaemic optic neuropathy in the right eye based on clinical findings and the ERG results. Laboratory testing revealed that protein C antigen was 47% and protein S antigen 46% of normal levels. Activated protein C and antithrombin levels were normal, and no lupus anticoagulant activity was detected.

Figure 3

Six weeks after initial presentation. Note pale disc with narrowing of the retinal arterioles and an overall reduction in venous calibre and tortuosity.


This patient, with combined protein C and protein S deficiency, suffered ipsilateral retinal, optic nerve, and cerebral ischaemia within a period of 6 weeks. The rapid changes in the appearance of cotton wool spots over a period of several days, which is not consistent with their natural course in diabetic retinopathy,7 combined with neurological symptoms prompted us to search for systemic causes of ischaemia, including evaluation for hypercoagulable states. We suggest that new cotton wool spots in a patient free of other signs of vascular retinopathy such as microaneurysms or retinal haemorrhages should raise the spectre of a systemic basis for the ischaemia. As the ERG was not compatible with occlusion of the ophthalmic or central retinal arteries, demonstrating only mild retinal ischaemia, we ascribed the sudden visual loss in the face of diffuse disc pallor to optic nerve ischaemia, perhaps from occlusion of multiple ciliary vessels. Ischaemic optic neuropathy has, to our knowledge, not previously been associated with protein C or protein S deficiency, and expands the spectrum of ophthalmic manifestations of the hypercoagulable state.


Supported, in part, by the Heed Ophthalmic Foundation (Dr Ambati) and an unrestricted grant from Research to Prevent Blindness, Inc, New York, NY (University of Rochester), USA.