Ocular Ischemic Syndrome

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Contents

Introduction

Ocular ischemic syndrome (OIS) is a rare, but vision-threatening, condition usually associated with severe carotid artery occlusive disease. Principal symptoms include visual loss, light-induced transient visual loss, and ischemic ocular pain. [1][2][3] Carotid artery disease represents a major cause of morbidity and mortality and both stenosis and occlusion of the common (CCA) or internal (ICA) carotid arteries may cause ipsilateral ocular signs and symptoms that in turn could herald a cerebral infarction. [4] Ocular signs and symptoms may be the first manifestations of carotid artery disease [5] with the most hallmark ocular symptom, being ipsilateral transient visual loss which occurs in 30-40% of the patients. In addition to occlusion of retinal vessels by emboli, chronic and progressive hypoperfusion of the eye may also lead to global ocular ischemia. [6]

Epidemiology and Pathogenesis

Ocular ischemic syndrome occurs at a mean age of 65 years, is rare before 50, has no racial predilection and men are affected twice as often as women [7][8][9] likely due to the higher incidence of atherosclerotic disease in males. Bilateral involvement may occur in up to 22% of cases. [10][11][12] The degree of stenosis, the presence or absence of collateral vessels, chronicity of the carotid artery disease, its bilaterality, and associated systemic vascular diseases are implicated in the pathogenesis of the OIS. [13]
The incidence of OIS has been estimated at 7.5 cases per million persons per year [14] however this is probably an underestimation as OIS may be misdiagnosed as other ocular vascular diseases such as retinal vein occlusions and diabetic retinopathy.
Approximately 30% of patients with a symptomatic carotid occlusion manifest retinal vascular changes that are usually asymptomatic, and 1.5% of them per year progress to symptomatic OIS. [15] Of patients with ICA occulision undergoing surgical anastomosis between the superficial temporal artery and the middle cerebral artery, 18% presented with OIS. [16] OIS has been reported in 4% of their patients with carotid occlusive disease.[17]
OIS develops especially in patients with poor collateral circulation between the ICA and external carotid artery (ECA) systems or between the two ICAs. Patients with a healthy collateral circulation may not develop OIS even with total occlusion of the ICA, whereas in those with poor collaterals an ICA stenosis <50% may be sufficient to develop OIS. Patterns of occlusion vary from less than 50% stenosis to complete occlusion of at least one CCA or one ICA, often accompanied by occlusion or stenosis of the opposite carotid arterial system. [18]
Patients who develop OIS show decreased blood flow in the retrobulbar vessels and reversal of blood flow in the ophthalmic artery (OA). [19] The OA may behave as a steal artery shunting blood flow away.[20]   

Blood flow in the ophthalmic artery and its branches (A) in a normal individual; (B) in a patient with internal carotid artery occlusion and collateral circulation via the circle of Willis (forward ophthalmic artery flow); and (C) in a patient with internal carotid artery occlusion and collateral circulation via the ophthalmic artery (reversed flow). Reproduced with permission from Costa et al.[21]
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Arterial Blood Supply

 Image:Eyeblood.jpg

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Diagnosis and Ancillary Tests

Flourescein Angiogram

Fluorescein angiography can help to establish the diagnosis of OIS. [22][23]The choroid normally fills completely within 5 seconds after the first appearance of the dye in the choroidal arteries. Patchy or delayed choroidal filling is seen in a majority of eyes with OIS with the filling delayed for >1 minute in some cases. Prolonged choroidal filling time, although not sensitive, is the most specific angiographic sign of OIS. The most sensitive angiographic sign is prolonged retinal arteriovenous time that is present in up to 95% of eyes with OIS. Arterial, and early and late venous circulation times are also prolonged in eyes with OIS. However, delayed retinal circulation time is also observed in eyes with CRAO or CRVO and is not as specific as a prolonged choroidal filling. Staining of the retinal vessels is also commonly seen and has been suggested to be due to endothelial cell damage with rupture of the inner blood-retina barrier due to chronic ischemia. This staining often may imitate the angiographic appearance of frosted branch angiitis seen in inflammatory conditions. Overall, a prolonged arteriovenous transit time is seen in 95% of cases, retinal vascular staining in 85% and delayed choroidal filling in 60%.
About 15% of eyes with OIS show macular edema at the late phase of the fluorescein angiography. [24] Leakage from microaneurysms or from telangiectasia and ischemic damage to the vascular endothelium of small vessels account for the increased permeability with extravasation and accumulation of the dye resulting in increased retinal thickness. Intraretinal fluid accumulation is usually mild to moderate, does not have a cystoid pattern and is often associated with hyperfluorescence of the optic disk attributed to leakage from blood vessels. Retinal capillary non-perfusion can also be seen in some eyes.


Prolonged Retinal and Choroidal Circulation in Ocular Ischemic Syndrome in Internal Carotid Artery Occlusion at 19, 24 and 49 seconds (left, middle and right). Reproduced with permission from Open Journal of Ophthalmology 

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Indocyanine Green Angiography

Indocyanine green (ICG) angiography allows for better evaluation of the choroidal vascular abnormalities. [25] The arm-to-choroid circulation time (time from the injection of the dye to the first appearance of the dye in the choroidal arteries, usually ~10 seconds), and the intra-choroidal circulation time (time from the first appearence of the dye in the choroidal arteries to complete dye filling in the choroidal veins, usually ~5–6 seconds) are both prolonged. Choroidal hypoperfusion results in occlusions of the choriocapillaries with areas of vascular filling defects in the posterior pole or the mid-periphery. Delayed filling or occlusion of the choriocapillaris in the peripheral watershed zones can also be observed.

Figure: Indocyanine green angiography in ocular ischemic syndrome. A: Choroidal hypofluorescence corresponding to the main posterior watershed zone between the medial and lateral posterior ciliary arteries. B: Filling of the choroidal watreshed zone is delayed, with some part of it remaining hypofluorescent 10 seconds later. Reproduced with permission from Mendrinos et al. 2010 [26]
Image:Icg.jpg

Electroretinography

The b-wave of the electroretinograph (ERG) corresponds to activity of Müller and/or bipolar cells and reflects the functional status of the inner retinal layer, whereas the a-wave corresponds to activity of photoreceptors. In CRAO, where there is ischemia of the inner retina, the amplitude of the b-wave is decreased. In contrast, in eyes with OIS where both the retinal and the choroidal circulation are compromised, there is ischemia of the inner and outer retina that results in decreased amplitude of both a and b waves. [27] Reduction in the amplitude of the oscillatory potential of the b-wave has been demonstrated in eyes with carotid artery stenosis even if the fluorescein angiography is normal. Carotid artery surgery increases ocular blood flow leading to improved retinal function and has been suggested to increase a and b wave amplitudes. [28]

Reduced Scotopic and Photopic ERG in Ocular Ischemic Syndrome (obtained with permission from Online Journal of Ophthalmology)

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Visual-evoked potentials

Visual-evoked potentials (VEP) after exposure to intense light stimulation (photostress) show an increase in latency and a decrease in amplitude. Photostress induces transient VEP changes consisting of an increase in response latency and a decrease in amplitude. The time it takes the VEP to recover to the baseline status (ie. recovery time after photostress) ranges in normal subjects between 68 and 78 seconds. This recovery time after photostress is prolonged in patients with severe carotid artery stenosis and improves following endarterectomy surgery. The VEP may elicit visual dysfunction prior to the appearance of ophthalmological and may be a useful investigation.

Ophthalmodynamometry

Ophthalmodynamometry is used to estimate the pressure in the ophthalmic artery (OA) at the site of origin of the central retinal artery (CRA). Measurements are performed by increasing IOP by gradually applying pressure to the globe and observing the arteries on the optic disc until they begin to pulsate. [29][30] The pressure required to produce artery pulsations on the optic dsic reflects the OA diastolic pressure, whereas the force required to cause cessation of arterial pulsations reflects the OA systolic pressure. In OIS, the CRA perfusion pressure is low and for this reason the pressure necessary for the pulsations to appear is reduced. Diastolic readings are decreased in OIS, and may improve or return to normal after carotid artery surgery. They are considered to be more reliable than systolic readings.

Imaging Methods for the Evaluation of Carotid Occlusive Disease

Carotid Duplex Ultrasound

Duplex carotid ultrasonography is the most commonly used non-invasive test and combines B-mode ultrasound and Doppler ultrasound, providing both anatomical imaging of the vessel and flow velocity information. The parameters used to classify severity of stenosis include peak systolic velocity (PSV), end-diastolic velocity, and the ICA/CCA PSV ratio. Compared to conventional intra-arterial digital substraction angiography (DSA) for detection of high-grade symptomatic carotid artery stenosis, duplex ultrasound has a sensitivity of 89% and a specificity of 84%. For detecting occlusion, duplex ultrasound has a sensitivity of 96% and a specificity of 100%.

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Peak Systolic Velocity (cm/sec)     ICA Stenosis (% diameter)
125 – 225                                           50 – 70
225 – 350                                           70 – 90
>350                                                   >90

Color Doppler Imaging of Retrobulbar Vessels

Color Doppler imaging of retrobulbar vessels is a useful adjunct to conventional duplex ultrasound for carotid artery examination. Distal to a hemodynamic significant stenosis, the blood pressure is decreased and the Doppler effect is dampened, causing diminished blood flow velocity. Therefore, studying the flow profile in the OA, the CRA and the short posterior ciliary arteries (SPCA) may provide hemodynamic information about the carotid and retrobulbar circulations such as velocities and pulsatility indices (an indicator of vascular resistance) of the orbital arteries. These parameters are significantly reduced in patients with significant carotid artery stenoses as compared to a normal, age-matched population with no carotid disease. Doppler imaging of retrobulbar vessels also allows studying the flow direction in the OA Reversed OA flow pattern is a highly specific indicator of ipsilateral high-grade ICA stenosis or occlusion.
Figure: Color Doppler imaging of a normal ophthalmic artery, displaying a pulsatile, positive waveform with a dicrotic notch during systole (left) and a negative, pulsatile waveform in reversed ophthalmic artery flow with a higher end diastolic velocity suggesting the existence of a shunt. Reproduced with permission from Costa et al.[31] Image:Doppler.jpg

Magnetic Resonance Angiography and Computed Tomographic Angiography

New non-invasive or minimally invasive methods, and combinations of them, are increasingly used as the second-line investigation tool after duplex ultrasound for carotid stenosis. Magnetic resonance angiography (MRA) and computed tomographic angiography (CTA) have gradually replaced DSA.
A review of carotid MRA performance data found that for the diagnosis of 70–99% carotid stenosis, MRA had a pooled sensitivity of 95% and a pooled specificity of 90% which are superior to a conventional DSA. [32] For detection of complete occlusions, MRA yielded a sensitivity of 98% and a specificity of 100% which is similar to duplex ultrasound. Limitations of MRA include claustrophobia, pacemakers and metallic stents or implantable defibrillators, and obesity.
Potential advantage of MRA and CTA over conventional angiography is their ability to allow better carotid plaque characterization and identification of a plaque as well as to evaluate for cerebrovascular accident simultaneously. [33] The combined use of MRA, CTA, and doppler ultrasound improves diagnostic accuracy for high-grade symptomatic carotid stenoses and minimizes the need for invasive carotid arteriography. Disadvantages of CTA are the necessity of administrating a nephrotoxic iodinated contrast agent and ionizing radiation and/or artifacts related to heavily or circumferentially calcified arterial walls.

Figure: 3D- reconstructed magnetic resonance angiography in carotid artery disease. A: High-grade stenosis of the left internal carotid artery origin (arrow) in a 58-year-old diabetic woman. B: Severe bilateral stenosis at the origin of the internal carotid arteries (arrows) in a 48-year-old woman. Reproduced with permission from Mendrinos et al. [34]

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Carotid Arteriography

Conventional intra-arterial digital substraction angiography has been considered as the gold standard for imaging the cerebrovascular system Nevertheless, it is not ideal for screening and follow-up both because of the risks of disabling cerebral infarction, systemic complications and high cost. In patients with arteriosclerosis, a 4% risk of transient ischemic attack or minor cerebral infarction, a 1% risk of major cerebral infarction, and a <1% risk of mortality have been reported. [35] In patients with OIS, who have poor collateral circulation and severe carotid artery disease, arteriography-related risks may be even higher.

Duplex ultrasound should be chosen as the first-line investigation of patients suspected of having carotid stenosis. If surgically significant stenosis is identified or in equivocal cases, further imaging with either MRA or CTA should be performed. Only if results are contradictory or inconclusive, should DSA be performed. [36]

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Internal Carotid Artery Occlusion in Ocular Ischemic Syndrome (reproduced with permission from Open Journal of Ophthalmology)
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Symptoms

Visual Loss

Decrease in visual acuity is found in almost all the patients with the vision loss occurring suddenly over a period of seconds to minutes or upon awakening to over a period of days. In a series of 43 patients, at initial presentation, 35% of eyes had a VA of 20/20 to 20/40 and in 35% had vision of counting fingers or worse. [37] Similarly, in 52 patients studied by Sivalingam et al, 43% of the affected eyes had an initial VA of 20/20 to 20/50, and 37% had vision of counting fingers or worse. [38] Mizener et al reported initial VA of 20/40 or better in 15% of their cases, whereas 65% had VA of 20/400 or less. [39]
Visual fields on presentation can vary greatly from normal, to a central scotoma, to nasal defects, centrocaecal defects and the presence only of a central or temporal island.[40]
A history of transient visual loss is present in approximately 10–15% of patients with OIS. This is most frequently caused by transient embolization of the CRA or its branches, but vasospasm may also play a role. In these cases, a dark or black shade spreads across the visual field that lasts for a few seconds to minutes. Less commonly, severe carotid artery disease causes transient visual loss as a result of choroidal hypoperfusion. Conditions that either increase retinal metabolic demands or decrease perfusion pressure can precipitate transient visual loss and reflect the inability of a borderline ocular circulation to maintain stable the ocular blood flow. This has been reported following exposure to bright light, postural change, or after eating a meal. Visual loss resulting from hypoperfusion of the choroid often lasts several minutes to hours and may be associated with positive visual phenomena.

Pain

Pain may be present in up to 40% of the eyes with OIS. 13,16Pain may be the result of increased IOP or may be ischemic in origin. Ischemic pain begins gradually over hours to days and is described as a dull, constant ache in the affected eye, over the orbit, upper face, and temple, and may worsen when the patient is upright. Lying down relieves or lessens pain. The description ocular angina may be used to describe this discomfort. Ischemic pain may be confused with that from secondary glaucoma, but pain in eyes with OIS would not be explained by a slight IOP elevation. Pain from both increased IOP and ischemia may be present in the same patient. In older patients, giant cell arteritis should be excluded. The signs are summarized in Table 1. [41]


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Table 1. Ophthalmic signs in Ocular Ischemic Syndrome

Anterior Segment Posterior Segment Orbital
Conjunctival and Episcleral Injection Narrowed retinal arteries Orbital pain
Corneal edema and descemets folds Dilated retinal veins Anterior and posterior segment ischemia with intraocular inflammation and hypotony
Corneo-scleral melting Retinal hemorrhages Ophthalmoplegia
Corneal hypoesthesia Microaneusyms Ptosis
Spontaneous hyphema Macular capillary telangectasia
Iris atrophy Retinal arteriovenous communications
Fixed semi-dilated pupil or sluggish reaction to light with relative afferent pupil defect Cotton-wool spots
Anterior and posteriro synechiae Cherry-red spot
Uveal ectropion Neovascularization of disc
Rubeosis iridis Neovascularization elsewhere
Neovascular glaucoma Choroidal neovascular membrane
Iridocyclitis (cell, flare, keratic precipitates) Vitreous hemorrhage
Asymmetric Cataract Cholesterol Emboli, Spontaneous retinal arterial pulsations, anterior ischemic optic retinopathy, wedge shaped areas of chorio-retinal atrophy

Systemic Associations

Atherosclerosis of the carotid vascular system is the major cause of OIS and may be its initial manifestation. [42][43][44]  Atherosclerotic plaques are usually located at the site of carotid bifurcation or at the proximal segment of the ICA, however an intracranial carotid artery stenosis may also lead to OIS. Generally, ≥ 90% stenosis of the ipsilateral carotid arterial system is present in eyes with OIS and rarely the site of occlusion is the ophthalmic artery or bilateral ECAs. OIS has been reported to be the initial manifestation of carotid occlusive disease in approximately 70% of the patients. Patients with OIS often have systemic vascular diseases that are related to atherosclerosis. These include ischemic heart disease, previous cerebrovascular accident or transient ischemic attack, peripheral vascular disease, systemic arterial hypertension, and diabetes. [45] The prevalence of both systemic arterial hypertension and diabetes is significantly higher among patients with OIS compared to controls. The average stroke rate has been reported to be significantly higher in patients with OIS (4% per year) compared to 0.49% per year in controls. OIS may also appear in patients with giant cell arteritis, aortic arch syndrome, Takayasu and case reports associated with arteritis carotid artery dissection, hyperhomocysteinemia, radiotherapy of the neck with carotid occlusion, thyroid orbitopathy, moya-moya disease and neurofibromatosis, and scleroderma have been described. 

Differential diagnosis

Diabetic retinopathy and Central Retinal Vein Occlusion (CRVO) are the two most likely conditions to be confused with OIS. A basic differentiating feature is the low retinal artery pressure in eyes with OIS. Table 2 lists the clinical and angiographic signs that help to differentiate these three. [46]
The differential diagnosis of OIS should also include the hyperviscosity syndromes. Fundus manifestations caused by serum or blood hyperviscosity include optic disk swelling, retinal capillary microaneurysms, cotton-wool spots, retinal hemorrhages, dilated retinal veins, and retinal venous occlusion. A basic workup should therefore include a complete blood cell count with differential, serum protein electrophoresis, and immunoelectrophoresis.

Table 2. Clinical and Fluorescein Angiography Signs differentiating Ocular Ischemic Syndrome from Central Retinal Vein Occlusion and Diabetic Retinopathy.

Clinical Sign Ocular Ischemic Syndrome Central Retinal Vein Occlusion Diabetic Retinopathy
Retinal Veins Dilated but not tortuous Dilated and tortuous Dilated and beheaded
Age 50's to 80's Variable 50's to 80's
Hemorrhages (location) dot and blot (mid-periphery) and in deeper retinal layers Flame shaped (all quadrants) in nerve fiber layer Dot and blot
(posterior pole and mid-periphery)
Microaneurysms 
(Location)
Common
(mid-periphery)
Uncommon Common
(Posterior pole)
Other Microvascular abnormalities Macular telangectasias, retina AV communications, capillary dropout opto-ciliary shunts, capillary dropouts intraretinal microvascular abnormalities, capillary dropout
Hard exudates No Rare Common
Optic Disc Normal Edema (common) Rarely diabetic papillopathy
Central retinal artery perfusion pressure Decreased Normal Normal
Fluorescein Angiography
A-V transit time Prolonged Prolonged Usually normal
Retinal Vessel Staining Arteries>Veins Veins>Arteries Usually absent
Macular edema Rare Common Common
Choroidal filling Delayed, patchy Normal Usually normal

Management of Ocular Ischemic Syndrome

The management of OIS involves a multidisciplinary approach, including the ophthalmologist, cardiologist, neurologist, vascular surgeon, neurosurgeon, rheumatologist and interventional neuroradiologist. The aim is threefold, firstly to treat the ocular complications and prevent further damage, secondly to investigate and treat the associated vascular risk factors, and thirdly to perform vascular surgery whenever indicated.

Ocular treatment

The ocular treatment is directed toward control of anterior segment inflammation, retinal ischemia, increased IOP and neovascular glaucoma. Topical therapy includes steroids to suppress anterior segment inflammation, and cycloplegics to stabilize the blood–aqueous barrier and limit iris movement in order to decrease the likelihood of a spontaneous hyphema. Medical treatment of increased IOP consists of ocular hypotensive agents that reduce aqueous outflow (topical β-adrenergic blockers, or α-agonists that also increase uveoscleral flow), along with topical and/or oral carbonic anhydrase inhibitors. Prostaglandins, pilocarpine and other anticholinergic agents, should be avoided whenever possible because they increase ocular inflammation. Since pilocarpine acts on the outflow pathway, it is not effective in eyes with angle neovascularization.
When neovascular glaucoma develops, IOP control is usually refractory to medical therapy and surgery (trabeculectomy with antimetabolites or aqueous shunt implants) or diode laser cyclophotocoagulation is often required. In patients with no useful vision and in pain who are thought to have limited potential for visual recovery, cycloablation is a viable option. If the eye remains painful, retrobulbar injection of alcohol or chlorpromazine may provide relief. If these fail to alleviate pain in a blind eye, enucleation or evisceration should be considered. Panretinal photocoagulation may be effective in same patients with ocular neovascularization caused by carotid occlusive disease and may prevent development of neovascular glaucoma. In eyes with poor fundus visualization, 360° transconjunctival cryotherapy or transscleral diode laser retinopexy may be considered.[47][48]
Intravitreal anti vascular endothelial growth factor (bevacizumab and ranibizumab) and triamcinomlone have been used in the treatment of iris neovascularization and cystoid macular edema complicating OIS.


Systemic Medical treatment

OIS patients should be referred to a primary care physician as well as a neurologist for full medical and neurological assessment. It is essential to treat associated systemic diseases. In addition lifestyle modifications, cessation of smoking and weight reduction need to be recommended.

Surgical treatment


Carotid Artery Endarterectomy

The landmark North American Symptomatic Carotid Endarterectomy (NASCET) trial demonstrated the superiority of CEA and aspirin therapy in preventing stroke compared with aspirin therapy alone for both symptomatic and asymptomatic carotid artery stenosis. [49][50] Based on these trials, the American Academy of Neurology and the American Heart Association/American Stroke Association recommend CEA for symptomatic stenosis of 50–99% if the perioperative risk of stroke or death is <6%. [51] In asymptomatic patients, CEA is recommended for a stenosis of 60–99% if the perioperative risk of stroke or death is <3%.
CEA has been shown to be effective in reversing or preventing the progression of chronic ocular ischemia or in increasing ocular blood flow. [52][53] [54] Peak systolic velocity of flow in the ophthalmic artery rises after surgery [55] and any reversal of ophthalmic artery flow is corrected.[56] Carotid artery surgery therefore can reduce ocular ischaemia and improve hypotensive retinopathy as well as reduce the risk of stroke. However it is important to note that the presence of iris neovascularization implies a greater degree of ocular ischemia and damage, making reversal of ischemia and visual recovery unlikely and limiting any beneficial effect of CEA on visual acuity.

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Carotid Artery Stenting

Endovascular carotid artery stenting (CAS) is an treatment alternative in patients who need CEA. CAS has been used for patients who are considered to be at high-risk for complications after CEA including those with anatomic conditions rendering surgery technically difficult, such as previous neck irradiation or radical neck surgery, recurrent stenosis after CEA, contralateral recurrent laryngeal-nerve palsy, tracheostomy, and carotid stenosis above the C2 vetebral body. [57] Medical conditions that increase the risk of surgery, such as unstable angina, recent myocardial infarction, multivessel coronary disease, congestive heart failure, are also indications for CAS. Carotid artery stenting has been shown to improve the ocular blood flow in patients with acute and chronic forms of OIS. [58] 

Image:Stent.jpg


Extracranial–Intracranial (EC-IC) Arterial Bypass Surgery

EC-IC bypass surgery involves the surgical anastomosis of the superficial temporal artery with a branch of the middle cerebral artery. It is indicated when there is complete occlusion of the ICA or the CCA or when ICA stenosis is inaccessible (at or above the C2 vertebral body) to CEA. [59] The aim is to increase cerebral blood flow and prevent the development of cerebral ischemia. CEA usually improves ocular hemodynamic parameters, but stabilization or improvement in vision seems to occur only when performed early before development of iris neovascularization or neovascular glaucoma. Carotid endarterectomy is also beneficial in preventing cerebral infarctions. A multidisciplinary approach is essential when considering surgery in patients with OIS factoring in the patients anatomic considerations and associated co-morbidities.

Prognosis

The overall mortality rate for patients with OIS is 40% at 5 years with the leading cause of death being cardiovascular disease, usually myocardial infarction, (67%) followed by cerebral infarction. (19%) It is therefore essential that physicians adopt appropriate therapeutic options aiming at primary prevention of myocardial and cerebral infarction.

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Original article contributed by: Dilraj Singh Grewal, MD
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