11/2/2020 Ocular Manifestations of Systemic Diseases

PUBLISHED APRIL 19, 2010

Ocular Manifestations of Systemic Diseases

Nicholas Beyda, PharmD

Pharmacy Practice Resident

David Cluck, PharmD

Pharmacy Practice Resident

Katia E. Taba, MD, PhD

Department of Ophthalmology

Mark Middlebrooks, PharmD

Director of Pharmacy
Louisiana State University Health Sciences Center–Shreveport
Shreveport, Louisiana

US Pharm. 2010;35(4):HS-2-HS-8.

Many systemic diseases often have an ocular component that manifests secondarily. Patients with ocular
manifestations may rst present in the emergency department with relatively nonspeci c symptoms such
as visual disturbance or eye pain. Unfortunately, many ocular symptoms overlap in terms of the disease
state they may be attributed to. In some cases, however, the information obtained from an ocular

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examination may aid in the differential diagnosis and appropriate management of the underlying disease.
While there are a signi cant number of diseases known to present with ocular involvement, the aim of this
article is to provide a general overview of the commonly encountered ocular manifestations of systemic
disease in clinical practice and to review how they should be approached therapeutically.

Diabetic Retinopathy and Macular Edema

Diabetic retinopathy (DR), one of the leading causes of blindness worldwide among adults aged 20 to 74
years, is the most common microvascular complication of diabetes.1 It has been estimated that nearly all
patients with type 1 diabetes and 60% of those with type 2 diabetes will develop some form of retinopathy
within 20 years of disease onset regardless of their level of diabetic control.2 In patients with type 1
diabetes, retinopathy typically does not develop until 3 to 5 years after disease onset. In contrast,
retinopathy may be the presenting manifestation of type 2 diabetes. Some studies estimate that 20% to 30%
of patients with type 2 diabetes have evident retinopathy at the time of diagnosis.2

Retinopathy can precede nephropathy, making the early detection of ocular manifestations of diabetes
essential. DR can be nonproliferative DR (NPDR) or proliferative (PDR), which is more advanced. DR is graded
according to severity (mild, moderate, or severe). When observed during simple fundoscopic examination,
mild NPDR is generally characterized by microaneurysms and small hemorrhages.1,3 In moderate-to-severe
NPDR, increased vascular permeability, hard exudates, venous bleeding, and intraretinal microvascular
anomalies are noted; these are caused by retinal ischemia. Macular edema is the principal mechanism of
vision loss in DR, and it may be present in both NPDR and PDR (TABLE 1 and FIGURE 1). Macular edema is
often treated with laser photocoagulation.4,5 (See FIGURE 1.)

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PDR is characterized by neovascularization (new vessel formation), which is a response to continued retinal
ischemia.5 Neovascularization can cause vision loss due to vitreous hemorrhages and tractional retinal
detachment, which can be treated by nonincisional surgery (laser photocoagulation) or incisional surgery
(vitrectomy).4,5 There are two types of laser photocoagulation: focal and panretinal. Focal photocoagulation,
which is used to treat macular edema, has been shown to reduce the risk of moderate vision loss by 50% to
70%.6 Panretinal photocoagulation, used to treat PDR, works by creating thousands of laser burns in areas
of the retina away from the macula, causing abnormal vessels to shrink and thereby preventing them from
hemorrhaging. This surgery can reduce the risk of moderate and severe vision loss by 50% in patients with
PDR.6

For patients already diagnosed with diabetes, follow-up with annual retinal screenings and prompt treatment
are key components of patient care (see TABLES 1 and 2 for screening and follow-up recommendations).7,8
Adequate blood sugar control is paramount for preventing and controlling the progression of DR.

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Several randomized, controlled clinical trials found that the combination of tight glycemic and blood-
pressure control with laser photocoagulation therapy signi cantly prevents the progression of DR.7,9-11 The
Diabetes Control and Complications Trial, which examined the effects of tight glycemic control on the
incidence of DR, nephropathy, and neuropathy in type 1 diabetic patients, concluded that intensive glycemic
control was associated with a 76% mean reduction in risk of retinopathy in patients with no retinopathy at
baseline and with a 54% mean reduction in those with minimal-to-moderate NPDR at 36 months.10 The UK
Prospective Diabetes Study (UKPDS) con rmed the protective effects of tight glycemic control in type 2
diabetic patients, nding a 25% reduction in microvascular complications in the intensive-therapy group.11
The UKPDS also found that every percentage-point decrease in glycosylated hemoglobin was associated
with a 35% reduction in the risk of microvascular complications.11

Hypertension
Hypertension, which occurs in approximately 50 million people in the United States, remains a signi cant
cause of morbidity and a leading cause of cardiovascular mortality.12,13 Hypertension affects the eye in a
multitude of ways, including vascular injury and increased risk of embolic events (e.g., central retinal vein
and branch retinal artery occlusion).

The ocular manifestations of hypertension are commonly classi ed as acute changes or chronic changes
associated with long-term systemic hypertension.13 The perpetual increased pressure in the vasculature
initiates a cascade of events resulting in a change in the physiology of the eye. This sequence of events,
often collectively referred to as hypertensive retinopathy, is the most common manifestation.14 The
differences in the composition of the vasculature and in anatomical location result in a different physiologic
response to increased blood pressure. In the acute phase, hypertension predominantly affects the terminal
arterioles; in chronic hypertension, the observed circulatory changes primarily involve the main retinal
arterioles. Early manifestations include retinal hemorrhage, capillary obliteration, and macular edema
attributable to hypertensive choroidopathy. Long-standing hypertension can result in the development of
compensatory shunt vessels and arteriovenous nicking (impeded circulation in the retina).13

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Hypertension also acts indirectly as a risk factor for other ocular diseases. These include retinal vein
occlusion, retinal emboli, macroaneurysm, and optic neuropathy.

Hypertensive retinopathy is considered a reliable prognostic indicator of systemic disease. Perhaps the
strongest correlation is between hypertensive retinopathy and risk of stroke. A study revealed that
hypertensive retinopathy increased stroke risk two- to fourfold when patients with this condition were
compared with patients who had no retinopathy.15 Studies also suggest that hypertensive retinopathy can
be used to predict incident congestive heart failure, left ventricular hypertrophy, and renal impairment.13

The bene ts of a fundoscopic examination are its ability to predict underlying systemic disease (typically
cardiovascular in nature) and its ability to assess the need for initiating or modifying antihypertensive
therapy. As with DR, disease-state control is of utmost importance in preventing and controlling progression
of the ocular manifestations of hypertension. Blood pressure control, achieved through systemic
pharmacotherapy and lifestyle modi cations, is guided by the patient’s primary care provider.13

HIV/AIDS
Approximately 33 million people are infected with HIV worldwide.16 Opportunistic infections typically
coincide with the patient’s CD4 count; thus, they often present when the CD4 count is ≤200 cells/mm3 or
when the patient is unaware of HIV infection.16 Therefore, CD4 count remains the greatest predictor of
ocular manifestations in HIV patients. It is not uncommon for an HIV patient to experience an ocular
complication at some point in his or her lifetime. HIV infection places patients at risk for both infectious and
noninfectious complications. The ocular manifestations of opportunistic infections are categorized based
on anatomical origin (orbital/adnexal manifestations [external] versus anterior/posterior segment
manifestations [internal]) or nonspeci c systemic infection.

A myriad of infections are associated with the adnexa of the eye, including herpes zoster ophthalmicus
(attributable to reactivation of varicella-zoster virus [VZV] infection in the rst division of the fth cranial
nerve) and conjunctival microvascular disease, which affects up to 75% to 80% of patients.16 The most

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common manifestation is molluscum contagiosum, a viral infection of the skin. Lastly, up to 20% of patients
who develop Kaposi’s sarcoma have ocular manifestations, usually with adnexal involvement.16

As many as 20% of patients may experience damage to the accessory and major lacrimal glands, resulting
in keratoconjunctivitis sicca (dry eye).16 It should be noted that dry eye is a relatively nonspeci c symptom
and can have a number of causes, of which HIV is thought to be paramount. Anterior segment
manifestations are often attributable to an infectious process, including infectious keratitis (bacterial,
fungal, or protozoal in nature) and iridocyclitis (associated with cytomegalovirus [CMV] or VZV). Up to 50%
of patients experience anterior uveitis, which may be caused by a number of different pathogens, including
Treponema, VZV, and herpes simplex virus.16

Thirty percent to 50% of patients with decreased CD4 counts experience posterior segment manifestations,
with the most common abnormalities being attributable to CMV and retinal microvasculopathy.16 CMV is the
most common intraocular infection in AIDS patients. Ocular syphilis should be included in any differential
diagnosis, as it mimics several diseases. Ocular syphilis in HIV-infected patients may present earlier and in
an accelerated form.

Lastly, systemic infections such as cryptococcal meningitis or toxoplasmosis can have ophthalmic
involvement. These types of infections, despite the eye not being the source of the infection, often result in
nonspeci c symptoms such as visual- eld loss.17

Treatment is largely speci c to the causative pathogen. Most manifestations of ocular disorders attributable
to a viral infection respond to the appropriate antiviral (e.g., acyclovir, cidofovir, ganciclovir, valganciclovir).18
These patients are often managed by a physician specializing in infectious disease. Therapy is usually
selected based on a global assessment of the patient that includes immune status and renal function. While
a number of antivirals are available, use of these agents is not without systemic consequence, with the
kidneys being most at risk for drug-induced harm. Herpesviruses usually are treated with acyclovir or the
valine ester valacyclovir. Other agents, such as cidofovir, foscarnet, and ganciclovir, are typically reserved for
cases of CMV retinitis or refractory herpes infections.18

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Rheumatoid Arthritis
It is estimated that approximately 25% of patients with rheumatoid arthritis (RA) present with ocular
manifestations.19 The most common external manifestation is keratoconjunctivitis sicca, which can be
diagnosed using Schirmer’s test. The test evaluates the functionality of the lacrimal gland by measuring the
amount of tear production through the placement of a Schirmer strip into the lower conjunctival cul-de-sac.

Episcleritis (super cial in ammation of the sclera) and scleritis (deeper in ammation of the sclera) are
common ocular manifestations of RA, occurring in up to 25% and 10% of RA patients, respectively.19 Corneal
disease is commonly associated with dry eye or with a form of anterior scleritis; it can include the presence
of keratitis, sclerosing keratitis, and ulcerative keratitis. A combination of steroids, immunosuppressive
therapy, and surgery often is necessary to prevent perforation of the cornea and permanent vision loss.
Scleritis and episcleritis are distinguished based on anatomy and appearance. While the symptoms may be
similar, pain is typically more severe in patients with scleritis. Application of phenylephrine 10% will help
distinguish scleritis from episcleritis: Engorged vessels in episcleritis will blanch, while those in scleritis will
not.19 In RA, episcleritis is more common than scleritis; however, scleritis tends to be a more destructive
process, with necrotizing scleritis with in ammation being one presentation. It is important to differentiate
scleritis from episcleritis, as studies have documented a higher mortality rate and wider spread of systemic
disease in RA patients with scleritis.19

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic, autoimmune, multisystem disease that affects the eyes in
up to a third of patients. Ocular manifestations can be potentially sight-threatening and may be the
presenting symptom of the disease. Ocular manifestations of SLE include external/anterior segment
complications (usually associated with pain and redness) and posterior segment complications.

Common external eye complications in SLE include keratoconjunctivitis and discoid lupus erythematosus.
Keratoconjunctivitis is the most common symptom associated with SLE, occurring in up to 30% of
patients.19,20 Symptoms, clinical assessment, and treatment of dry eye are similar to those described in
patients with RA (TABLE 3).19 Cyclosporine 0.05% is a commonly prescribed and effective treatment for dry
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eye syndrome. Eyelid disease presents with a discoid lupus-type rash over the eyelids that consists of
raised, scaly lesions that respond well to systemic steroids and antimalarials such as hydroxychloroquine
and chloroquine.

Posterior segment complications consist mainly of retinal disease. Retinopathy is present in 10% of patients
with SLE, with signs correlating to the severity of systemic in ammation; it may indicate inadequate control
of SLE.20 Some forms of retinopathy in SLE are similar to hypertensive retinopathy and DR, making
management and monitoring di cult when these diseases occur simultaneously. Aggressive, severe
retinopathy, in extreme cases, may lead to exudative retinal detachment, and treatment with systemic
immunosuppression is necessary to control the disease.

Clinicians should be aware that agents used to treat SLE and RA may cause ophthalmic complications. The
aminoquinolones chloroquine and hydroxychloroquine are antimalarials used to treatment SLE and RA.
Chloroquine, and to a lesser extent hydroxychloroquine, can cause irreversible sight-threatening
maculopathy at higher doses. Patients should undergo routine screening for retinal toxicity when receiving
either of these drugs, as should patients who have been receiving therapy for more than 10 years or who
have renal disease. Doses of chloroquine >3.5 mg/kg/day or doses of hydroxychloroquine >6.5 mg/kg/day
signi cantly increase the risk of renal toxicity and should be monitored closely.21,22

REFERENCES

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1. Abu El-Asrar AM, Al-Mezaine HS, Ola MS. Pathophysiology and management of diabetic retinopathy. Expert Rev Ophthalmol. 2009;4:627-647.
2. Dhanes T, Graham EM. Ocular disorders associated with systemic diseases. In: Riordan-Eva P, Whitcher JP, eds. Vaughan & Asbury’s General
Ophthalmology. 17th ed. New York, NY: McGraw-Hill Medical; 2008: chapter 15.
3. Wipf JE, Paauw DS. Ophthalmologic emergencies in the patient with diabetes. Endocrinol Metab Clin North Am. 2000;29:813-829.
4. Mavrikakis E, Lam W-C, Khan BU. Macular edema, diabetic. http://emedicine.medscape.com/article/1224138-overview. Accessed January 27,
2010.
5. Gunderson CA, Karnath B. Retinal manifestations of diabetes mellitus and hypertension. Hosp Physician. 2003;39:15-18.
6. Mohamed Q, Gillies MC, Wong TY. Management of diabetic retinopathy: a systematic review. JAMA. 2007;298:902-916.
7. Fong DS, Aiello L, Gardner TW, et al. Diabetic retinopathy. Diabetes Care. 2003;26:S99-S102.
8. ONE Network. American Academy of Ophthalmology. Diabetic retinopathy PPP—September 2008.
http://one.aao.org/CE/PracticeGuidelines/PPP_Content.aspx?cid=d0c853d3-219f-487b-a524-326ab3cecd9a.
9. American Diabetes Association. Executive summary: standards of medical care in diabetes—2010. Diabetes Care. 2010;33(suppl 1):S11-S61.
10. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression
of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986.
11. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight
patients with type 2 diabetes (UKPDS 34). Lancet.
12. Dellacroce JT, Vitale A. Hypertension and the eye. Curr Opin Ophthalmol. 2008;19:493-498.
13. Oh KT, Hughes BM, Moinfar N. Hypertension. http://emedicine.medscape.com/article/1201779-overview. Accessed January 27, 2010.
14. Wong T, Mitchell P. The eye in hypertension. Lancet. 2007;369:425-435.
15. Wong TY, Klein R, Couper DJ, et al. Retinal microvascular abnormalities and incident stroke: the Atherosclerosis Risk in Communities Study.
Lancet. 2001;358:1134-1140.
16. AIDS Epidemic Update December 2009. Geneva, Switzerland: UNAIDS/WHO; 2009.
http://data.unaids.org/pub/Report/2009/2009_epidemic_update_en.pdf. Accessed February 20, 2010.
17. Moraes HV. Ocular manifestations of HIV/AIDS. Curr Opin Ophthalmol. 2002;13:397-403.
18. Copeland R, Phillpotts BA. Ocular manifestations of HIV. http://emedicine.medscape.com/article/1216172-overview. Accessed January 27,
2010.
19. Patel SJ, Lundy DC. Ocular manifestations of autoimmune diseases. Am Fam Physician.
20. Sivaraj RR, Durrani OM, Denniston AK, et al. Ocular manifestations of systemic lupus erythematosus. Rheumatology. 2007;46:1757-1762.
21. Chloroquine hydrochloride and chloroquine phosphate. In: McEvoy GK, Miller J, Litvak K, eds. AHFS Drug Information 2004. Bethesda, MD:
American Society of Health System Pharmacists; 2004:822-827.
22. Hydroxychloroquine sulfate. In: McEvoy GK, Miller J, Litvak K, eds. AHFS Drug Information 2004.
Bethesda, MD: American Society of Health System Pharmacists; 2004:827-828.

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