Ischemia of the Eye and Brain

The greater your understanding of both basic brain anatomy and vascular supply, the better you can care for your patients with occlusive/ischemic-related eye pathologies.

By Michael N. Block, O.D.

Goal Statement:

This article examines ischemic changes on the cellular, tissue and functional levels, with particular emphasis on both acute and chronic ophthalmic manifestations. Additionally, it reviews the nature of transient ischemic attacks, including relevant cerebral and ocular blood supply.

Faculty/Editorial Board:

Michael N. Block, O.D.

Credit Statement:

This course is COPE approved for 2 hours of CE credit. COPE ID: 25245-SD. Please check your state licensing board to see if this approval counts towards your CE requirement for relicensure.

Joint-Sponsorship Statement:

This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.

Disclosure Statement:

Dr. Block has no relationships to disclose.

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Stroke is the third leading cause of death in the United States.¹ There are 700,000 cases of stroke reported each year; 500,000 are initial attacks and the remaining 200,000 are recurrent attacks.¹ Approximately 88% of strokes are ischemic in nature and may have significant ocular consequences, such as central retinal artery occlusion and visual field loss.¹ Therefore, optometrists should become familiar with the process of ischemic stroke and be able to recognize its associated risk factors, signs and symptoms.

This article examines ischemic changes on the cellular, tissue and functional levels, with particular emphasis on both acute and chronic ophthalmic manifestations. Additionally, it reviews the nature of transient ischemic attacks, including relevant cerebral and ocular blood supply, and discusses symptoms that are correlated to the locations of tissue infarction and occlusion.

History of Ischemic Stroke

Transient cerebral ischemic attacks (TCIAs) have been recognized for more than 2,000 years. Hippocrates described this symptom complex as “apoplexy,” the ancient Greek word for stroke.² Since then, postmortem examination of the brain and its vascular supply has improved our understanding of this syndrome tremendously.

In 1677, Francois Bayle first suggested that apoplexy was caused by atherosclerosis of cerebral arterioles. In 1842, Jean Cruveilhier proposed that apoplexy might be caused by cardiac embolism.³ Drawing upon both individuals’ work, various researchers established an association between carotid disease and a combination of monocular blindness and contralateral paralyses in the late 19th century.³

In 1905, it was suggested that the source of the neurological symptoms was embolic in nature, originating from an occluded carotid artery.³ However, during the next 40 years, experts came to believe that the major mechanism of cerebral ischemic attacks was not embolic. Instead, a hemodynamic theory was proposed, which suggested that these attacks were caused by systemic hypotension and vasospasm.³ Finally, in 1959, the concept of an embolic etiology was reintroduced when C.M. Fisher, M.D., observed a retinal embolus in a patient suffering from transient monocular blindness.³

Today, both the embolic and hemodynamic theories are reported in the literature in connection with cerebral ischemic attacks.

The term “transient ischemic attack” (TIA) was first seen in medical publications in 1965.³ The most recent definition of TIA is “a brief episode of neurological dysfunction caused by a focal disturbance of the brain or retinal ischemia that typically lasts less than an hour, and without evidence of infarction.”⁴ It is a clinical syndrome characterized by an acute loss of focal cerebral or monocular function (transient monocular vision loss [TMVL]) due to insufficient cerebral or ocular blood supply resulting from thrombotic, embolic or occlusive events.

By convention, symptoms that persist less than 24 hours are designated TIAs. However, most transient cerebral ischemic attacks (TCIAs) resolve in less than 30 to 60 minutes, and most TIAs of the eye (TMVL/amaurosis fugax) resolve in five to 10 minutes.⁴ Prolonged cerebral ischemia usually leads to infarction and can result in permanent neurological deficits.

“Minor ischemic stroke” and “reversible ischemic attack” have been used to describe ischemic symptoms that persist for more than 24 hours.⁴ Although TIAs and reversible ischemic attacks differ by severity and durations, they are similar in their underlying disease process. Likewise, TIA and ischemic stroke are qualitatively part of the same spectrum. Anything that causes a TIA may, if more prolonged or severe, cause an ischemic stroke.

Pathophysiology

Occlusion of an intracranial artery will cause reduced blood flow to the area of the brain that it normally would supply. The degree of blood flow reduction and resultant tissue damage from ischemia depends on the individual patient’s collateral circulation.

While the brain demonstrates a very high metabolic demand, it is unable to store large amounts of glucose and oxygen. The supply of glucose needed for energy must be delivered by a continuous blood flow. Lack of available glucose leads to inadequate adenosine-5’-triphosphate (ATP) levels, energy depletion and loss of homeostasis, and it ultimately results in cellular accumulation of calcium ions and reduced pH levels.⁵ Additionally, mitochondrial metabolism is reduced because of oxygen depletion.

When these processes occur, brain tissue rapidly becomes ischemic. Depending on the severity of cerebral blood flow reduction, tissue death can occur in as little as four to 10 minutes.⁵ The tissue immediately surrounding the actual infarct is called the “ischemic penumbra,” and cellular death will eventually occur if blood flow is not restored.

After the patient is medically stabilized, the goal is to save this tissue from irreversible infarct. If timely reperfusion does take place, the patient’s symptoms will only be temporary or transient.

Patterns of Blood Flow

There is a dual blood supply to the brain that allows for both anterior and posterior circulation. The two main arterial systems that supply cerebral blood are the carotid (anterior) and the vertebrobasilar (posterior). Both systems are joined at the base of the brain.

At the neck, the carotid arteries bifurcate into the external carotid (ECA) and internal carotid (ICA), and this is often the site of atheromatous disease. After emerging from the cavernous sinus, the ICA branches to form the ophthalmic artery (OA), which in turn gives rise to the central retinal artery. There are two internal carotid arteries that provide blood and its nutrients to the ipsilateral cerebral hemisphere. The ECA supplies the face, scalp, skull and meninges, while the ICA supplies the brain itself. Once the ICA penetrates the skull, there is terminal branching to form the anterior cerebral (ACA) and middle cerebral arteries (MCA).

The vertebral arteries, which supply the lower brainstem and cerebellum, join to form the basilar artery; the basilar artery supplies the upper brainstem and cerebellum. The basilar artery’s terminal branch is the posterior cerebral artery (PCA), and it supplies the occipital lobe and visual cortex.⁷

At the base of the skull is the Circle of Willis, which connects the anterior and posterior circulatory systems (figure 1). The anterior communicating artery connects the two ACAs. This provides the potential for one carotid artery to supply both right and left hemispheres, although complete redistribution does not always occur. The posterior communicating arteries connect the carotid and basilar circulation, which completes the circle.

Similar to one carotid artery’s potential to supply both the right and left hemispheres, the carotid can also feed the terminal basilar vasculature, shunting blood flow from the anterior to the posterior circulation. A posterior-to-anterior shunt can also occur when the basilar artery supplies the carotid circulation. This means the cerebral vascular architecture is somewhat redundant. So, while abrupt occlusion of an artery will almost always be symptomatic, gradual occlusion may cause no symptoms.

Embolic travel to the carotid terminal branches, particularly the MCA, is most often responsible for stroke. Although thrombotic carotid disease is usually implicated, cardiogenic embolism is the cause of 20% of TIAs and stroke.^6,7 Atrial fibrillation, valvular disease and aortic arch syndrome are usually the cardiac sources. Checking the pulse may help identify many cases of atrial fibrillation. Like carotid-based emboli, cardiac emboli enter the carotid circulation and frequently obstruct the MCA. The ACA and OA can also be affected, but to a lesser degree.⁶ Atherosclerosis is often the underlying arterial disease process that produces occlusion.

Locating the Site of TIA3
Symptom	Arterial Territory
	Carotid	Vertebrobasilar	Either
Monocular visual loss Dysphasia	X X
Diplopia# Vertigo# Bilateral simultaneous acuity loss Bilateral simultaneous weakness Bilateral simultaneous sensory loss Crossed sensory/motor loss		X X X X X X
Unilateral weakness* Unilateral sensory loss* Dysarthria# Homonymous hemianopsia Ataxia# Dysphagia#			X X X X X X
# Only when combined with one other symptom. * Usually regarded as carotid.

Ophthalmic Symptoms

• Anterior/carotid. A hallmark of TIA of the eye is amaurosis fugax, which manifests as severe monocular vision loss or blindness that occurs abruptly and resolves in less than five minutes. Occasionally, there is reported vision loss perceived as a curtain descending across the visual field. The patho-physiological correlation to amaurosis is a transient embolic occlusion of the central retinal or OA.⁶ Most frequently, the source is ipsilateral carotid atheroma (anterior), although retinal emboli may also originate from the heart. Amaurosis/TMVL may coexist with other symptoms, such as contralateral hemiparesis and hemisensory deficit. However, it is unlikely that a patient would present to the office with amaurosis because of the short duration of the TIA. Observing a TIA embolus that passes through the retinal circulation is rare.⁶

• Posterior/vertebrobasilar. Bilateral symptoms, which occur less frequently, are attributed to occlusion of the vertebrobasilar system. This is because the basilar artery is the single source of blood supply to both posterior hemispheres through its terminal posterior cerebral arteries.⁸ Bilateral transient vision loss, often described as “looking through a fog,” is suggestive of vertebrobasilar (posterior) insufficiency, especially when coexisting with diplopia and vertigo (see “Locating the Site of TIA,” left). Diplopia, in this context, may be due to third, fourth or sixth nerve involvement; internu-clear ophthalmoplegia or skew deviation.⁸ While complete third nerve palsy presents as exotropia and hypotropia (with restricted adduction and supraduction) combined with unilateral ptosis and mydriasis, incomplete third nerve involvement is common. There are many presentations of brainstem stroke, and several of those involve oculo-motor paresis with contralateral symptoms. However, because there are far more anterior circulation TIAs, posterior symptoms are less common.³

Unlike stroke, homonymous hemianopsia is rarely reported by TIA patients. This is likely because of the difficulty many patients may have in perceiving visual field loss in the presence of more severe symptoms. Additionally, patients need to cover each eye in order to distinguish this symptom from monocular vision loss. Due to chiasmal crossing of only the nasal optic nerve fibers, the hemianopsia is contralateral. This visual field defect is indicative of a disorder in the optic tract, optic radiations or cortex, and is usually a result of posterior cerebral artery involvement (figure 2). Rarely, the ischemic source is the middle cerebral artery.³

Motor Symptoms

Patients who have experienced cerebral TIAs most commonly describe motor symptoms. In the Oxford Community Stroke Project, 5.4% of TIA patients reported weakness (usually one-sided), although heaviness and clumsiness were also documented.³ Dysphagia (difficulty swallowing), while common in stroke, is rare in TIA. This may be because patients spend a small percentage of their day eating, causing this symptom to go unnoticed. Limb shaking has been reported, but is as rare as dysphagia.

Forty percent of subjects reported disturbances in speech.³ Within this category, dysarthria (articulation difficulties) is most common, while dysphasia (difficulty understanding and formulating sentences) occurred in only 18% of the study’s patients. The combination of dysphasia and monocular vision loss is strongly associated with carotid disease/anterior circulatory ischemia.³

Sensory Symptoms Sensory

Symptoms often include numbness and tingling. Similar to motor symptoms, sensory loss is usually unilateral, and may affect the face, arm or leg. Clinically, patients frequently report a combination of motor, sensory and visual symptoms. Headaches, which occur in 16% of TIA cases, are non-throbbing and usually present on the same side as the cerebral ischemia.³ When headaches coexist with amaurosis fugax, they usually present above the affected eye. The cause of the headaches is still debated.

Inflammatory Vascular Disease

Giant cell arteritis (GCA), a vasculitis seen mainly in elderly white females, is a non-atherosclerotic cause of arterial disease that affects large- and medium-sized arteries. Its effect on the posterior ciliary arteries leads to arteritic ischemic optic neuropathy, which frequently produces chalky-white edematous disc, unlike the hyperemic disc edema seen in non-arteritic ischemic optic neuropathy.⁹ Cotton-wool spots and retinal ischemia may also be present.

Vision loss is generally severe (no light perception [NLP] to count fingers [CF]). It initially manifests uni-laterally, then frequently progresses to bilateral loss in a matter of days or weeks. Patients often present with headaches, fever, scalp tenderness and recent weight loss due to jaw claudication and pain.

Severe vision loss is preceded by transient vision loss (30% of patients) and diplopia (5% of patients). In these cases, be sure to order erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP); the definitive diagnoses can be made by temporal artery biopsy.^10,11

Acute Optometric Implications Central retinal artery occlusion (CRAO), branch retinal artery occlusion (BRAO) and OA occlusion are the end result of embolic travel into the ophthalmic circulation. The main difference between a TIA of the eye that produces transient monocular vision loss/amaurosis and the severe persistent vision loss characteristic of CRAO is the length of time the embolus is lodged in the ophthalmic circulation. Just as with cerebral TIA and stroke, TIA of the eye and CRAO share the same etiologies; however, the chief difference between the conditions is symptom severity. Spontaneous recanalization usually takes place within 48 to 72 hours; yet, massive, irreversible retinal ischemia is often the result after four hours of occlusion.^11,12 These retinal emboli can be seen in the office about 20% of the time.

On clinical observation, the acute CRAO retina appears pale due to the ischemia. It displays a cherry-red spot because the underlying choroid is supplied by the posterior ciliary arteries. The entire retina, including the macula, is pale when there is occlusion of the OA (a rare occurrence), as both the retina and choroid are deprived of blood. Cotton-wool spots, vascular boxcarring and optic atrophy may also be present (figure 3).¹²

Chronic Optometric Implications

Ocular ischemic syndrome (OIS) is a rare, but severe, form of chronic ischemia that can affect both anterior and posterior segments. OIS is associated with chronic hypoperfusion due to severe carotid stenosis that causes changes in OA blood flow. Research has shown OA reversals in blood flow in some patients and disturbances in flow velocity in others.¹³ Symptoms are varied and include sudden vision loss, gradual vision loss, transient vision loss and orbital pain.¹³ Anterior segment signs include rubeosis irides, anterior chamber inflammation and dilated episcleral veins due to increased collateral blood flow in the context of carotid occlusion.¹⁴

Patients who present with OIS and rubeosis (a late sign) have a poor prognosis; 97% demonstrate CF vision in the first year.¹⁵ Posterior segment involvement includes dilated non-tortuous veins, mid-peripheral hemorrhages, digitally-induced arterial pulsations, attenuated arterioles, macular edema and optic nerve neovascularization.¹⁵ Conditions associated with OIS include diabetes, hypertension, cardiac disease and cerebrovascular disease.¹⁴

The development of neovascular glaucoma is an ominous sign, because intraocular pressure is frequently difficult to control. Prostaglandin analogues and pilocarpine may promote or exacerbate inflammation and should be avoided. Topical therapeutic options include carbonic anhydrase inhibitors, alpha adrenergic agonists, beta blockers and steroids to control inflammation. Trabeculectomy, aqueous tube shunt and cyclo-destruction may be necessary to achieve proper IOP control.¹⁰

Anterior segment signs of OIS may be mistaken for non-granulomatous uveitis, and posterior signs confused with central retinal vein occlusion (CRVO) and asymmetric proliferative diabetic retinopathy (PDR).^10,14,15

While the treatment of the involved eye is clearly of immediate concern, you must also understand the underlying pathology that leads to ischemia. There is significant visual risk to the contralateral eye, as occlusion of one OA is frequently accompanied by stenotic changes in the fellow eye. If not properly treated, OIS patients could develop ischemic damage in the fellow eye and be at high risk for further cardiovascular and cerebrovascular events.¹⁴

Management

The visual prognosis of CRAO is generally poor. Treatment to improve blood flow and vision should be performed as soon as possible. Conservative options include ocular massage, medical IOP reduction to increase retinal perfusion pressure, pharmacologic vasodilation (sublingual, retrobulbar and IV), re-breathing exhaled carbon dioxide, breathing carbogen, hyper-baric oxygenation and paracentesis. A combination of these treatments has reported to be more effective than any individual one.¹⁴

• Local intra-arterial fibrinolysis. Local intra-arterial fibrinolysis (LIF), also referred to as intra-arterial thrombolysis, is a popular invasive treatment for CRAO that involves OA catheterization with fibrolytic agents.

This procedure entails insertion of a catheter at the femoral artery. The catheter is then advanced to the carotid bifurcation where angiography is performed, which is followed by local anticoagulant therapy. A microcatheter is then further advanced to the OA where thrombolysis is started with Actilyse (alteplase, Boehringer Ingelheim). While some visual improvements have been claimed, several studies have been controversial.^10,11,16

When comparing LIF with more conservative treatment options, one study found no statistical difference in either visual improvement or final outcome.¹²

Additionally, 75% of CRAO emboli consist of cholesterol and another 10% are comprised of calcium; fibrolytic agents cannot dissolve these materials.¹² So, the rationale for this treatment is suspect, because only a maximum of 15% of CRAO patients can benefit from LIF.

A recent systematic review of the literature, however, suggested a significant increase in visual acuity in patients who underwent LIF.¹⁷

Unfortunately, many factors made this conclusion problematic, including problems in study design, methodology, scientific rationale, and a lack of pre- and post-LIF fluorescein angiography.¹⁸

Another study challenged reported LIF visual outcomes by dividing patients into four different subgroups based on CRAO type: nonarteritic CRAO, non-arteritic CRAO with cilioretinal sparing, transient non-arteritic CRAO and arteritic CRAO.¹²

The authors noted that each subgroup had a different prognosis for visual outcome. Contrary to results from several previous reports, this study demonstrated some spontaneous improvement in both visual acuity and fields during the first several days after CRAO onset.

The nature of the improvement varied and was dependent on the type of CRAO. Many prior studies of LIF lumped all CRAO patients together and did not compare subjective post-treatment visual acuity improvements with spontaneous visual improvement resulting from the natural history of the disease process.¹² However, due to the infrequent occurrence of retinal arterial occlusions, treatment studies have been limited. Additionally, treatment criteria have been inconsistent. While there are many treatment options available, there is no clear evidence-based protocol for the optimal therapy of CRAO.¹¹

• Carotid endarterectomy. The North American Symptomatic Carotid Endarterectomy Trial (NASCET) examined the benefits of carotid endarterectomy (CE) for the treatment of carotid artery occlusion.¹⁹ NASCET showed that the risk of ipsilateral stroke decreased in patients with stenosed carotids who underwent CE. However, the greatest risk reduction occurred in symptomatic patients (recent TIA or stroke) with a higher degree of stenosis.^19,20

In a different study, color Doppler flow imaging was used to study the effect of CE on OIS. While there were many study limitations, such as size and lack of randomization, CE appeared to be an appropriate treatment for patients with OIS due to reversal of OA blood flow traced to carotid stenosis.¹³

• Carotid angioplasty. Carotid angioplasty with stenting, a relatively new and alternative strategy for improving carotid flow among high risk patients, has also been shown to improve OA blood flow in patients with reversed or altered flow patterns.

When compared to CE studies, success rates were comparable, and complications of stroke and death not significantly different.²¹

The greater your understanding of both basic brain anatomy and vascular supply, the better you can care for your patients with occlusive/ischemic-related eye pathologies. With this knowledge, you can trace many ophthalmologic and neurologic deficits to the offending ischemic circulation––whether anterior/carotid or posterior/basilar.

Also, you will be able to understand the development of acute or chronic ophthalmic syndromes with greater perspective, because signs and symptoms usually do not occur in isolation. Although management strategies for ophthalmic occlusions still remain somewhat limited and controversial, newer, more promising procedures currently await validation.

Dr. Block is affiliated with Visiting Eye Care Service and Grand Central Optical in New York. He currently cares for homebound and nursing home residents in addition to practicing general optometry. Send comments or questions to mblock475@aol.com.

References

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18. Hyreh SS. Intra-arterial thrombolysis for central retinal artery occlusion. Br J Ophthalmol 2008 May;92(5):585-7.
19. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1991 Aug 15;325(7):445-53.
20. Kawaguchi S, Toshisuke S, Iwakashi H, et al. Effect of carotid artery stenting on ocular circulation and chronic ocular ischemic syndrome. Cerebrovasc Dis 2006;22(5-6):402-8.
21. Eskandari MK, Longo GM, Vijungco JD. Does carotid stenting measure up to endarterectomy? A vascular surgeon’s experience. Arch Surg 2004 Jul;139(7):734-8.
22. Beers MH, Porter RS, Jones TV (eds). The Merck Manual of Diagnosis and Therapy, 18 ed. Merck: Whitehouse Station, N.J., 2006: 922. (Figure reprinted with the permission of the authors.)