Ocular Ischemic Syndrome

Etiology

The major etiology of the disease is atherosclerosis. The following disease can also predispose to disease. These are dissecting aneurysm of carotid vessels, Takayasu arteritis, giant cell arteritis, aortic arch syndrome, fibrovascular dysplasia, Behcet’s disease, trauma or inflammation that can lead to stenosis of carotid arteries. In addition to these, one should screen for comorbid conditions like hypertension (73%) and diabetes (56%). These patients have an overall higher risk of myocardial infarction and stroke, as compared to the general population.[6]

Epidemiology

OIS is a rare disorder with an estimated occurrence of 7.5 cases/year/million people, though this may be an underestimation due to delayed diagnosis and underdiagnosis.[7] Twice as common as females, with males affected. The mean age at presentation ranges from 50 to 80 years and is 65 years. In approximately 20 percent of cases, the condition is bilateral.[8]

Pathophysiology

Most of the cases of OIS have ipsilateral stenosis of the ICA, which results in the reduction of central retinal artery perfusion pressure by 50%.[7] Ocular perfusion abnormalities are noted when the stenosis in common carotid or internal carotid artery reaches 70%. Half of the cases have 100% obstruction of the carotid artery, and in about 10% of the cases, the obstruction is bilateral and almost complete If a patient has symptomatic occlusion of carotid artery around one third will manifest associated changes in retinal vasculature that may be asymptomatic, with around 1.5% of these developing symptomatic disease per year. The subgroup of cases that undergo surgery for ICA occlusion; anastomosis between the superficial temporal artery and the middle cerebral artery. They have an 18% incidence of OIS due to the severity of occlusion.[8] Rarely obstruction of the ipsilateral ophthalmic artery can also be responsible for the ocular ischemic syndrome, or a chronic central retinal artery obstruction alone can cause the dilated retinal veins and retinal hemorrhages seen in eyes with the ocular ischemic syndrome.[9] The ocular findings may be the initial manifestation of carotid occlusive disease and ophthalmologist may be the first person consulted in as much as 70 % of cases.[10]

The variability of ocular manifestations with stenosis of the carotid artery depends on the health of the collateral circulation that exists in between the ICA and the external carotid artery. The healthy collateral system protects the eye from manifesting OIS even with those having total occlusion, whereas cases with poor collaterals and stenosis <50% may develop OIS.[2]

This finding can be explained by the “Steal Phenomenon” that occurs in the absence of poor collaterals the ophthalmic artery acts as a shunt vessel in the circle of Willis between the ECA and the distal unobstructed part of ICA thus shunting blood flow away. This phenomenon has been supported by the fact that there is retrograde flow noted in Doppler flowmetry in some patients with OIS.[11] In the presence of collaterals, this shunting occurs through collateral vessels, and the ophthalmic artery has an anterograde flow.

The leading cause of mortality in these patients is cardiovascular disease (approximately 66%), which is followed by a stroke. Therefore as soon as the diagnosis of OIS is made, the patient should be systemically evaluated by the cardiologist in conjunction with a vascular surgeon.[10]

History and Physical

Though OIS is associated with many unique symptoms, the most common symptom of the disease is gradual vision loss over weeks or months in 80% of the cases. Less frequently, there can be an abrupt decrease in vision that can be associated with neovascular glaucoma and a cherry-red spot in the retina (12%).[10] The presentation visual acuity ranges from 0.4 to 1.0 Log Mar in 43% of patients to counting fingers or worse in 37%. After one year, the rates are 24% and 58%, respectively. Loss of light perception develops in the late stages of the disease as a result of neovascular glaucoma

The other characteristic of the disease is dull aching ocular or periorbital pain referred to as “ocular angina”(40%), which is due to ocular ischemia or raised intraocular pressure or due to ischemia of ipsilateral meninges. Features of amaurosis fugax are present in 12% of the cases. Prolonged visual recovery on exposure to bright light is another complaint due to macular ischemia and delayed recovery of photoreceptors consequent to the compromised blood supply.[12]

Clinical Features

The anterior segment features are rubeosis iridis(67%) leading to neovascular glaucoma, low-grade inflammation in the anterior chamber ( Flare: 50%, Cells 1+:18%), anterior and posterior synechiae, atrophy of sphincter pupillae (semi-dilated pupil) with sluggish reaction to light, spontaneous hyphema, asymmetric cataract, conjunctival and episcleral injection, and corneal edema with Descemet`s folds (sometimes with bullous keratopathy), rarely scleral melting has been reported.

Posterior segment manifestations are narrowed retinal arteries (90%), dilated and not tortuous retinal veins (90%), retinal hemorrhages (80%), microaneurysms (80%), retinal telangiectasia, cherry-red spot (12%), cholesterol emboli, glaucoma (neovascular glaucoma, normal-tension glaucoma), neovascularization (optic disc 35%, retina 8%), cotton-wool spots (6%), vitreous hemorrhage (4%), spontaneous retinal arteries pulsations (4%), anterior and posterior ischemic optic neuropathy (2%), choroidal neovascular membrane, areas of chorioretinal atrophy.[6]

Evaluation

Fluorescein Angiogram

This is the most important modality in establishing a diagnosis of OIS. The most specific feature of the disease is a delay in choroidal filling with the patchy pattern seen in 60% of cases with more than five seconds from the first appearance of dye until complete choroidal filling. Sometimes even delayed more than 1 minute. The most sensitive parameter is prolonged arteriovenous transit time being more than eleven seconds from the first appearance of retinal arterial dye until complete retinal venous filling. This is seen in 95% of cases though it is least specific. The observation of well-demarcated, leading edge of fluorescein dye within a retinal artery after intravenous injection is a distinctly unusual finding secondary to hypoperfusion.[5]

Late arterial staining is present in 85% of cases that occur due to damage to endothelium due to ischemia. This may imitate frosted branch angiitis on angiography.

Macular edema in the late phases of the angiogram is seen in 17% of cases.[13] Additional signs are retinal capillary non-perfusion, microaneurysms hyperfluorescence, optic nerve head hyperfluorescence.

Indocyanine Green Angiography (ICG)

ICG will better delineate any abnormality in choroidal vessels with prolongation of time in which the dye reaches choroid (normal is around 10 seconds) and in the intrachoroidal circulation time (around 5-6 second). Areas of the vascular filling defect are seen in the posterior pole and mid-periphery. There can also be a delay in filling or occlusion of choriocapillaris in the peripheral watershed area.[14]

Electroretinogram (ERG)

There is a reduction in amplitude of both a and b wave in OIS as there is the affliction of circulation of layers of the inner retina (b wave) and outer retinal layers( a wave). In central retinal artery occlusion, where only the inner layers are affected, there is a decrease in amplitude of b wave only. Some patients also have a reduction of oscillatory potential noted in b wave, which may be an early sign of carotid artery stenosis even when the fluorescein angiography is normal. The changes in ERG are somewhat reversible after carotid artery surgery.[15]

Visual-evoked Potentials (VEP)

VEP after exposure to intense light stimulation (photostress) shows an increase in latency and a decrease in amplitude. The time required for VEP to return to baseline status (i.e., recovery time after photostress) in normal individuals is 68-78sec, and this is prolonged in patients with OIS. VEP changes may appear before ophthalmic features.

Ophthalmodynamometry

This estimated the pressure required to elicit arterial pulsation(Diastolic pressure), whereas the pressure required to cause its cessation is the diastolic pressure. In OIS, there is a reduction in both values, which improves or returns to normal after carotid artery surgery. Positive in unilateral cases. Light, digital pressure is a good substitute in which light, digital pressure on the lids can induce retinal arterial pulsations, if not already present.[16]

Imaging modalities for evaluation of Carotid Occlusive Disease

Color Doppler Imaging of Retrobulbar vessels

Distal to obstruction, there is a dampened doppler effect. Reversed OA flow pattern is a highly specific indicator of ipsilateral high-grade ICA stenosis or occlusion.

Carotid Duplex Ultrasound

This combines B mode ultrasound (anatomical imaging) and Doppler scan ( Flow velocity). It is used to measure the peak systolic velocity(PSV), end-diastolic velocity, and ICA/CCA PSV ratio. For detecting stenosis and occlusion, this modality has a sensitivity of 89% and 96% and specificity of 84% and 100%, respectively. The relation of PSV (cm/sec) to ICA stenosis (% diameter) stenosis is as follows 125 to 225 cm/sec: 50 to 70%, 225 to 350 cm/sec: 70 to 90%, >350 cm/sec: >90%. MRA angiography is similar to Doppler ultrasonography in diagnosing carotid stenosis.[17]

Magnetic Resonance Angiography and Computed Tomographic Angiography

With 70 to 99% carotid stenosis, MRA had a pooled sensitivity of 95% and a pooled specificity of 90%, which are superior to a conventional DSA. For the detection of complete occlusions, MRA yielded a sensitivity of 98% and a specificity of 100%, which is similar to duplex ultrasound.[18]

Carotid Arteriography

Intra-arterial digital subtraction angiography (DSA) was considered as the gold standard for imaging the cerebrovascular system, but this is not used routinely for screening and follow up as it is fraught with complications like cerebral infarction, systemic complications, and high cost. So this modality is reserved only for doubtful cases.

Treatment / Management

In managing a case of OIS, three factors need to be dealt; firstly, the ocular complications and prevention of its deleterious effects, secondly treating the associated systemic causative factor and associated comorbidities and last any surgical intervention whenever required. Thus this is a multidisciplinary approach.

Ocular Treatment

Increased IOP in OIS is often refractory to medical therapy. Drugs reducing aqueous production can be used like β blockers and α agonists. Drugs with a propensity to cause inflammation should be avoided as prostaglandin analogs, pilocarpine, and anticholinergics. Panretinal photocoagulation should be done prior to surgery if the view is clear; this will lead to regression of iris vascularisation in 36% of cases and control of IOP if angles are still open.[19] Else patient has to undergo trabeculectomy with antimetabolite, shunt procedure, or cyclodestructive procedures in case of the painful blind eye prior to considering radical surgeries as enucleation and evisceration. Retrobulbar injection of alcohol or chlorpromazine has also been tried for pain relief by destroying the ciliary ganglion.(B3)

To treat anterior segment inflammation, topical steroids can be used. Sometimes patients also benefit from intravitreal AntiVEGF, which controls the NVI and macular edema associated with the disease.

Systemic Treatment

Patients with OIS should be thoroughly evaluated by a neurologist and physician and treated for the associated and predisposing comorbidities.

Surgical Management

Surgical treatment will only benefit the patient visually before development if NVI and NVG as these are signs of chronicity and irreversible damage.

Carotid Artery Endarterectomy (CEA)

The only landmark trial evaluating surgery in a patient with carotid stenosis is the North American Symptomatic Carotid Endarterectomy (NASCET) trial. This trial demonstrated the superiority of CEA and aspirin therapy (2-year stroke rate 9%) in preventing stroke compared to aspirin only (2-year stroke rate 26%) in the patient with carotid artery stenosis, either symptomatic or asymptomatic. Thus it was recommended that CEA should be performed in symptomatic cases of carotid artery stenosis (60 to 99%) if the perioperative risk of stroke or death is <6% and in asymptomatic cases if the risk is <3%. The surgery has been proved to increase the blood flow in the ophthalmic artery and prevent or reverse the ischemic changes.[20] The presence of NVI indicates that ischemic changes are chronic, and the patient might not benefit much from surgery visually, but symptomatically will be better. Aspirin is the preferred treatment if the stenosis is <70%.

Carotid Artery Stenting (CAS)

This is done in the patient where CEA can be associated with complications as in the patient with difficult surgery due to previous irradiation, neck surgery, recurrent stenosis, tracheostomy, and stenosis above the level of C2 (Second cervical) vertebral body. High-risk medical comorbidities as recent myocardial infarction, unstable angina, congestive cardiac failure are also an indication for stenting.[21](A1)

Bypass Surgery (Extracranial-Intracranial: EC-IC)

This involves establishing an anastomosis between the superficial temporal artery EC branch and the middle meningeal artery IC branch. Indicated in a case of complete occlusion of ICA or CCA, or when stenosis is difficult to assess as above C2 level. This prevents cerebral ischemia.[21](A1)

Differential Diagnosis

The disease needs to be differentiated from central retinal vein occlusion and diabetic retinopathy.

In central retinal vein occlusion, the veins are dilated and tortuous, and usually have flame shaped superficial hemorrhages in all quadrants, microaneurysms and hard exudates are not as common at the posterior pole, there can be the presence of optico-ciliary shunts at the disc with disc edema. Central retinal artery perfusion pressure is normal, and on fundus fluorescein angiography, there is a delay in arterio-venous transit time with staining of veins in late phase and pooling of dye at macula suggestive of edema.

In patients with diabetic retinopathy, the pathological changes are seen at posterior pole with dilated and beaded vessels, dot and blot, flame-shaped hemorrhages, and microaneurysm with leaking hard exudates. On fluorescein angiography, there is no delay in arterio-venous transit time. There will be leaking microaneurysms and edema, leaking neovascularisation can be noted.

Prognosis

Five-year mortality in patients with OIS is 40%, with myocardial infarction accounting for 67% of cases and cerebrovascular accidents for 19%.[15]

The visual prognosis is also dismal, with about 50% of patients having worse than finger counting vision in a year after diagnosis. Patients with NVG has still worse prognosis with over 80% developing visionless than finger counting in three months. In a study, it was found that the duration of macular ischemia may be a better indicator of visual prognosis as compared to baseline visual acuity.

Complications

Ocular complications are neovascularization of the anterior and posterior segment; neovascular glaucoma is a potential complication that leads to loss of vision, anterior and posterior ischemic optic neuropathy, vitreous hemorrhage, ophthalmoplegia, uveitis, hypotony.