Ocular Manifestations of Systemic Disease

The eye can provide clues in many systemic disease processes. Optometrists may be the first to identify systemic disease.

By Carlo J. Pelino, O.D., and Joseph J. Pizzimenti, O.D.

Release Date: April 2011
Expiration Date: April 30 2014

Goal Statement:

As primary care practitioners on the front line of health care, optometrists are increasingly helping patients get the assistance and treatment they need, not only for their ocular health but also for their systemic health. This course explains how to identify ocular manifestations of systemic diseases, and how treatment is rendered both for the eye and the body.

Faculty/Editorial Board:

Carlo J. Pelino, O.D., and Joseph J. Pizzimenti, O.D.

Credit Statement:

COPE approval for 2 hours of CE credit is pending for this course. Check with your local state licensing board to see if this counts toward your CE requirement for relicensure.

Joint-Sponsorship Statement:

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

Disclosure Statement:

Drs. Pelino and Pizzimenti have no relationships to disclose.

We see sick patients all the time. But it’s not just their eyes that are sick. As primary care practitioners on the front line of health care, optometrists are increasingly helping patients get the assistance and treatment they need. In some cases, we can be the first ones to suggest the diagnosis not just of ophthalmic disease but systemic diseases.

You know how this applies for systemic conditions, such as diabetes, in which the eye is a “prime player.” But what about other conditions—such as cardiovascular disease, breast cancer or sarcoidosis—in which ocular involvement might not be the foremost consideration?


Although the death rate from cardiovascular disease (CVD) has declined over the years, mortality data show that CVD accounted for more than one-third of all U.S. deaths in 2007.1 Coronary heart disease caused one of every six deaths in the U.S. in 2007. Each year, an estimated 785,000 Americans will have a new coronary attack, and about 470,000 will have a recurrent attack. Approximately every 25 seconds, an American will have a coronary event, and approximately every minute, someone will die of one.1

In other words, every American (not only every health care professional) should be concerned about heart disease. So, when you suspect cardiovascular disease, question the patient further. (See “Cardiovascular Review of Systems.”) Most often, vascular disease affects blood flow through arteries and/or veins by blocking or weakening the vessel, or by damaging the valves that are found in veins. As a result of decreased or blocked blood flow, organs and other body structures may be damaged by vascular disease.2,3

Cardiovascular Review of Systems

  • Leg pain in calf or thigh
  • Chest pain (sharp, crushing or heaviness)
  • Heart racing (palpitations)
  • Fainting spells
  • Sudden shortness of breath at night or
    lying down
  • Swelling of legs (edema)
  • Depression
  • Stress
  • Smoking or drinking alcohol
  • Diet high in salt, saturated fats
  • Lack of exercise
  • Family history of heart problems
  • Visual changes


Atherosclerosis is the most frequent cause of morbidity from vascular disease. The highest incidence occurs in Finland, Great Britain, Canada and the United States.2,4 Atherosclerosis is defined as a fibrous plaque (atheroma) within the intima of an artery. Atheromas are frequently found in the coronary arteries (heart), the larger branches of the carotid arteries, the circle of Willis (brain), the large arteries of the lower extremities, and the renal and mesenteric arteries.2,4

The incidence of atherosclerosis increases with age. Other risk factors for the formation of atheromas are gender (more common in men in all age groups, but the incidence increases in postmenopausal women), hypercholesterolemia (especially high LDL levels), hypertension, diabetes mellitus, cigarette smoking, obesity, “type A” personality, physical inactivity and the use of oral contraceptive drugs.2,4

Atheromatous plaques have a central core consisting of cholesterol and cholesterol esters, lipid-laden macrophages, calcium and necrotic cellular debris.2,4

Ulceration, hemorrhage into the plaque or calcification of the plaque may occur. Systemic obstructive disease ensues if a thrombus develops at the site of the plaque or embolization occurs.5

A thrombus is a solid mass of platelets and/or fibrin (and other components of blood) that forms locally in a vessel.2,4,5 An embolus moves through the bloodstream until it lodges in a narrowed vessel and blocks circulation. Cardiogenic emboli are a recognized etiology of ischemic stroke and retinal vascular occlusive disease. The mitral and aortic valves are the most common sources of cardiac emboli. Amaurosis fugax (transient monocular vision loss) and cerebral transient ischemic attacks may also occur from cardiogenic emboli.2,4,5 Fibro-platelet and cholesterol emboli originating from the carotid arteries may also cause amaurosis fugax, transient ischemic attack or stroke.


Atherosclerosis may lead to ischemic heart disease and myocardial infarction (the most common cause of death in the United States). Other complications include stroke, ischemic bowel disease, peripheral vascular occlusive disease and renal arterial ischemia with secondary hypertension. Weakening of the blood vessel wall may also lead to aneurysm formation.2,4,6

Inflammation may also cause vascular disease. In general, inflammation of blood vessels is referred to as vasculitis. Inflammation may cause narrowing and/or blockage of vessels. Trauma or injury that involves a blood vessel may lead to inflammation or infection. This, in turn, may damage the vessel and lead to its narrowing and/or blockage.2,7

Ocular Manifestations of Cardiovascular Disease

Ocular ischemic syndrome (OIS) is a vision-threatening condition in which hypoperfusion leads to acute and chronic defects in ocular and orbital tissues. OIS can occur before cerebrovascular and cardiovascular complications, so optometrists may be the first provider to encounter these patients.

Ocular ischemic syndrome encompasses a spectrum of clinical findings that result from chronic ocular and orbital hypoperfusion. Venous dilation in association with mid-peripheral dot-and-blot hemorrhages, superficial flame-shaped hemorrhages and microaneurysms in patients with carotid artery obstruction had been termed venous stasis retinopathy, but is now referred to as hypoperfusion retinopathy.8

Ischemic oculopathy describes ischemic changes related to carotid artery occlusive disease not limited to the posterior segment, but also in the anterior segment. Both posterior and anterior segment involvement is referred to as OIS.9

Who Gets OIS?

OIS occurs at a mean age of 65 and is rare before age 50. Men are affected twice as often as women due to a higher incidence of atherosclerotic disease in men.10 No racial predilection exists. Bilateral involvement may occur in up to 22% of cases. The incidence of OIS is estimated at 7.5 cases per million people each year.11 The five-year mortality rate in patients with OIS is about 40%. The leading cause of death is cardiac disease, followed by stroke and cancer.10-12

Up to 29% of patients with a symptomatic carotid artery occlusion manifest retinal vascular changes that are usually asymptomatic, and 1.5% of them per year progress to symptomatic OIS.12

The most common etiology of OIS is severe unilateral or bilateral atherosclerotic disease of the internal carotid artery or marked stenosis at the bifurcation of the common carotid artery. Decreased vascular perfusion may result in tissue hypoxia and increased ocular ischemia, leading to neovascularization.13 Other causes of OIS include giant cell arteritis, carotid artery dissection, neurofibromatosis type I, scleroderma and radiation therapy.

Diagnosing OIS

OIS is probably under-reported because it may be misdiagnosed or even masked by other ocular vascular diseases, such as retinal vein occlusions and diabetic retinopathy. The most common symptoms are amaurosis fugax, gradual or sudden visual loss, and ocular, periocular or facial pain. About 20% of diabetes patients with unilateral retinopathy or marked asymmetry of retinopathy have significant carotid artery stenosis. The stenosis may be contralateral or ipsilateral to the eye with the more severe diabetic retinopathy.14 Also, consider OIS in elderly patients with asymmetric anterior uveitis, intraocular pressure or cataract. (See “Major Clinical Features of OIS.)


In addition to a comprehensive ophthalmic workup, perform arm pulses and carotid auscultation. In patients with suspected giant cell arteritis, ESR and CRP levels must also be evaluated. Duplex carotid ultrasonography is the most commonly used non-invasive test to detect carotid occlusive disease.

Major Clinical Features of OIS

Anterior Segment

  • Semi-dilated pupil or sluggish reaction
    to light
  • Afferent pupillary defect
  • Synechia
  • Ectropion uveae
  • Neovascularization of the iris or angle
  • Anterior uveitis (usually mild)
  • Asymmetric cataract

Posterior Segment

  • Dilated (non-tortuous) retinal veins
  • Narrow arteries
  • Hemorrhages in mid-periphery
  • Microaneurysms
  • Disc edema
  • Cotton-wool infarct
  • New vessels on the disk (NVD)
  • New vessels elsewhere (NVE)
  • Emboli


Treatment of OIS

Ocular treatment is directed toward controlling anterior segment inflammation, minimizing retinal ischemia, and preventing or treating neovascular glaucoma. Initial topical therapy may include steroids and cycloplegic agents to reduce inflammation and stabilize the blood-aqueous barrier.

Panretinal photocoagulation causes regression of iris neovascularization in 36% of the treated eyes with OIS.10 If neovascular glaucoma develops, incisional surgery or cycloablation are often needed.

Systemic Treatment

Given the high rate of vascular death, these patients must be referred to a neurologist or to the patient’s primary care physician for full medical assessment and management. Therapeutic options include antiplatelet agents, pharmacotherapy of hypertension, diabetes, dyslipidemia or coronary artery disease, as well as cessation of smoking and weight reduction. Evidence suggests that aspirin 325mg p.o. q.d. be used as a first-line agent in OIS patients with atherosclerosis.15

The American Academy of Neurology and the American Heart Association/American Stroke Association recommend carotid endarterectomy (CEA) for symptomatic stenosis of 50% to 99% if the perioperative risk of stroke or death is less than 6%.16 In asymptomatic patients, CEA is recommended for a stenosis of 60% to 99% if the perioperative risk of stroke or death is less than 3%.16 CEA is most beneficial for the treatment of OIS if performed early, before neovascular glaucoma develops.


How is breast cancer related to the eye? By metastasis.

Malignant neoplasms are capable of spreading by invasion and metastasis. Metastasis may occur in several ways. It can result from spread into body cavities, which involves direct “seeding” of serous membranes. Another route of metastasis is by lymphogenous spread, in which cells travel through the lymphatic system to nearby or distant nodes. Metastasis may also occur by hematogenous spread, in which cells travel through the bloodstream.

Breast cancer is defined as a neoplasia that forms in tissues of the breast, usually the ducts and lobules (milk-producing glands). Malignant cancers of the breast arise through a series of molecular alterations at the cellular level, resulting in the uncontrolled outgrowth and spread of epithelial cells.

Breast cancer is the leading cause of cancer death among women worldwide. (Male breast cancer, though rare, can occur.) The American Cancer Society estimated nearly 1.4 million new cases of invasive breast cancer worldwide in 2008.17 In the United States, an estimated 207,090 women were diagnosed with breast cancer and 39,840 women died of it in 2010.17

Breast Cancer Risk Factors

img3Epidemiological studies have identified several factors that increase the chance of a woman developing breast cancer. Risk factors are identified based on their effect on the level and duration of exposure to endogenous estrogen.

  • Age. The median age of diagnosis for breast cancer is about 61.18 The chance of getting breast cancer increases with advancing age.
  • Personal health history. Having cancer in one breast increases the risk of cancer in the other breast.18
  • Family health history. Risk is increased if a first-degree relative has breast cancer. The risk is even higher if the family member had breast cancer before age 50.18
  • Genetic factors. Mutations in certain genes, such as BRCA1 or BRCA2, substantially increase the risk. Women who inherit a mutation in the BRCA1 or BRCA2 gene have an estimated 50% to 80% lifetime risk of developing breast cancer.18
  • Radiation therapy to the chest. Women who have had radiation therapy to the chest (including the breasts) before age 30 are at an increased risk.18
  • Reproductive and menstrual history. Women who never had children are at an increased risk. The older a woman is when she has her first child, the greater the chance of breast cancer. Women who had their first menstrual period before age 12 are at an increased risk. Those who went through menopause after age 55 are at an increased risk of breast cancer.
  • Race. In the U.S., breast cancer is diagnosed more often in white women than in other races.18
  • Breast density. Women whose mammogram shows a larger than normal area of dense tissue (compared to others in their age group) are at increased risk of breast cancer.18
  • Hormone replacement therapy (HRT). Postmenopausal women on HRT are at greater risk for breast cancer incidence and mortality.18
  • Excess weight. The chance of getting breast cancer after menopause is higher in women who are overweight, or obese.18
  • Alcohol. Studies suggest that the more alcohol a woman drinks, the greater her risk of breast cancer.18

Breast Cancer and the Eye

Intraocular/orbital metastasis is the most common malignancy of the eye, but often goes undiagnosed.20 The frequency of intraocular metastasis in patients dying of cancer is approximately 12%. Breast carcinoma in women and lung carcinoma in men are the most common primary foci.20

The uveal tract, with its rich vascular network, is the site in the globe most often involved in metastatic disease. Less commonly, other ophthalmic structures—including the optic nerve, conjunctiva and lacrimal gland—are the sites of metastatic cancer. The overall survival time (eight to 12 months on average) for these patients is poor.20-22

Review of Systems for Cancer19

Change in bowel or bladder habits.
A sore that does not heal.
Unusual bleeding or discharge.
Thickening of lump in breast or else where.
Indigestion or difficulty swallowing.
Obvious change in wart or mole.
Nagging cough or hoarseness.


Treatment and Management

Management of intraocular/ orbital metastasis may include observation, chemotherapy, photocoagulation, cryosurgery, surgical resection, localized plaque therapy and external beam radiation.20,22 The specific therapy chosen is an individualized process that must take into account the clinical condition of the patient.


The choice of cancer therapy for the primary site depends upon the location and grade of the tumor(s), the stage of the disease, and the general status of the patient. Surgery is considered primary treatment for breast cancer, as many early-stage patients are cured with surgery alone.

Medical treatment may include chemotherapeutic drugs. These agents are divided into the following groups: natural products, angiogenesis inhibitors and biologic therapy (immunotherapy).23,24 Tamoxifen is a selective estrogen receptor modulator (SERM) that binds to and inhibits estrogen receptor signaling in the breast. Remember that tamoxifen treatment might bring about ocular side effects, including maculopathy.

Radiation therapy may be indicated as either a therapeutic or palliative measure. Monoclonal antibody therapy and bone marrow transplant may also be effective.17,19,24

Treatment of choroidal metastasis is not without potential complications and side effects, such as cataract, radiation retinopathy, optic neuropathy, exposure keratopathy, retinal detachment and epiretinal membrane.


Sarcoidosis (also called sarcoid) is a granulomatous condition (i.e., one that is characterized by an organized collection of macrophages). It can affect virtually every body system, especially the respiratory and lymphatic systems.25 Pulmonary symptoms occur in up to one-half of all sarcoidosis patients and most commonly include dyspnea, dry cough and chest tightness or pain.25,26

When sarcoidosis affects the pulmonary system, the lungs are involved in more than 90% of patients.25 Parenchymal infiltration and irreversible pulmonary fibrosis can occur if the disease progresses, eventually leading to respiratory failure. Sarcoidosis also can affect the lymphatic, ocular, nervous, hepatic, renal, endocrine, musculoskeletal and myocardial systems.25,26

In the U.S., sarcoidosis is slightly more predominant in women than in men.25-27 The annual incidence in whites is 10 to 14 cases per 100,000 people. The annual incidence is much higher in blacks, especially women, at 36 to 64 cases per 100,000.27 The condition usually presents between 20 and 29 years of age.25

Mortality from sarcoidosis is about 5% in the U.S., most commonly due to respiratory failure from pulmonary involvement.25-27

Ocular Manifestations of Sarcoidosis

The ocular manifestations of this condition are well documented. About one quarter of patients with systemic sarcoidosis have ocular involvement. Uveitis is the most common of these, affecting 25% percent of sarcoidosis patients.28 Anterior uveitis occurs in 20% to 70% patients, typically as an acute iritis or iridocyclitis.29-31 Physical findings of acute anterior uveitis indicative of sarcoidosis are muttonfat or granulomatous keratic precipitates.32

The posterior segment is affected in about 20% of patients, usually in the form of chorioretinitis. Ocular sarcoidosis can also affect the adnexa and the orbit, typically the lacrimal gland. Much less frequent ocular manifestations include scleritis, glaucoma and cataracts.

Neurosarcoidosis has been called the “the great mimicker” because those affected with the disease can present with non-specific and variable symptoms that can be seen with many other pathologies. Although uncommon, neuro-ophthalmic sarcoidosis may present early, even before a known diagnosis of systemic sarcoidosis is found. Neuro-ophthalmic sarcoidosis may affect the afferent or efferent visual pathways, along with the presentation of ocular motor, trochlear, abducens and facial nerve palsies.33,34 While many sarcoidosis patients with ocular involvement experience severe pain and photophobia, more than one third have no ocular symptoms.35

Pathways to Diagnosis

The lack of a single diagnostic test, as well as the diverse presentations, make the diagnosis challenging. Patients with sarcoidosis most commonly present in winter and early spring, suggesting an environmental trigger.26,36

For a definitive diagnosis, histologic proof of a noncaseating epithelioid granuloma, clinicoradiologic features and exclusion of similar diseases are necessary.25,37,38 A complete blood count (CBC) with differential and platelets, along with serum calcium and 24-hour urine calcium levels, should be performed if you suspect sarcoidosis.37

Sarcoid granulomas produce both angiotensin-converting enzyme (ACE) and lysozyme. Serum ACE levels are significantly elevated in patients with sarcoidosis. So serum ACE levels should be tested to help monitor both disease activity and treatment response.26,37 However, this test has poor sensitivity because it is found to be elevated in only 40% to 60% of sarcoid patients.39 Serum lysozyme should also be tested because it has been shown to be a more sensitive marker of sarcoidosis activity.

Because 90% of sarcoidosis patients have radiographic involvement, a postero-anterior chest radiograph should be obtained to stage the disease. The four stages:

  • Stage I pulmonary sarcoid: bilateral hilar lymphadenopathy (BHL).
  • Stage II: BHL plus pulmonary infiltrates.
  • Stage III: pulmonary infiltrates without BHL.
  • Stage IV: pulmonary fibrosis.

Pulmonary function testing can be ordered to identify defects in lung diffusing capacity and vital capacity.26,37,38

Biopsy is required for diagnosis in most cases. The skin is the most easily accessible tissue for biopsy, although conjunctival tissue has also been used. A transbronchial lung biopsy is the most accurate method and will show the presence of noncaseating granulomas.25,26,37

Treatment Overview

Most cases of sarcoidosis are not fatal, so the primary goals of treatment are to alleviate symptoms, resolve inflammatory lesions that interfere with organ function, and prevent pulmonary fibrosis. There is no curative treatment.25,26,38-41 Oral corticosteroids for a minimum of 12 months are the mainstay of treatment for pulmonary sarcoid.

Patients with Stage I disease do not require treatment.25,42 Symptomatic patients with Stage II or III disease usually show improved chest radiograph findings during treatment. Patients with Stage IV disease usually respond poorly or not at all to systemic therapy; lung transplantation may be a viable option for these patients.42

Multiple relapses may occur, and patients may require long-term, lowdose corticosteroid therapy.42 Cytotoxic agents and immunomodulators may be used in patients who do not respond to corticosteroids or as steroid-sparing agents. Rheumatrex (methotrexate, STADS Pharmaceuticals) and Imuran (azathioprine, GlaxoSmithKline) are preferred. Antimalarials such as Plaquenil (hydroxychloroquine, Sanofi Aventis) and Aralen (chloroquine, Sanofi Aventis) can also be considered in patients with pulmonary sarcoid.25,38,42,43

Consider referring any patient who presents with evidence of bilateral, granulomatous, recurrent or chronic uveitis for systemic and radiologic testing to rule out sarcoidosis. Optometrists can facilitate early diagnosis and treatment of this disease to enhance the patients quality of life.

Dr. Pizzimenti is an associate professor at Nova Southeastern University College of Optometry. Dr. Pelino is an assistant professor at Pennsylvania College of Optometry at Salus University. Both doctors lecture extensively on oculosystemic disease, and they co-author Review’s “Review of Systems” column.


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