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Graves' disease

Graves-Basedow disease is a form of thyroiditis, an autoimmune disorder that stimulates the thyroid gland, being the most common cause of hyperthyroidism (overactivity of the thyroid). Also known in the English-speaking world simply as Graves' disease, it occurs most frequently in women (8:1 compared to men) of middle age. Symptoms include fatigue, weight loss and rapid heart beat. Because similar antibodies to those stimulating the thyroid also affect the eye, eye symptoms are also commonly reported. Treatment is with medication that reduces the production of thyroid hormone (thyroxin), surgery thyroidectomy or with radioactive iodine if refractory. more...

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Christina Rossetti famously suffered from this disease in later life.

Signs and symptoms

Graves-Basedow disease is a disorder characterized by a triad of hyperthyroidism, goitre, and exophthalmos (bulging eyeballs).

Due to the many physiological actions of thyroid hormone, many symptoms and signs are linked to Graves' disease:

  • Cardiac: cardiac arrhythmias (especially atrial fibrillation), tachycardia (increased heart rate), collapsing pulse and widened pulse pressure (difference between systolic and diastolic BP) and congestive cardiac failure with peripheral edema, ascites, anasarca.
  • Endocrine: weight loss in the presence of increased appetite, intolerance to heat, elevated basal metabolic rate
  • Dermatological: profuse sweating, thyroid acropachy (clubbing) of the fingernails, onycholysis (fingernail destruction), palmar erythema, pretibial myxedema (3 to 5% of Graves' patients, not to be confused with the myxedema of hypothyroidism)
  • Neurological: tremor (especially noticeable on extending the arms), apprehension, weakness, headache, proximal myopathy (difficulty rising from a chair or squatting position) and hyperactive deep tendon reflexes
  • Gastrointestinal: diarrhea (common), vomiting (rare)
  • Ophthalmological: thyroid eye disease (TED) characteristic of Graves disease include lid retraction (Dalrymple sign) above the superior corneoscleral limbus, lid lag (von Graefe's sign), proptosis or forward displacement of the globes, periorbital swelling and chemosis.

Extremely manifested disease that can sometimes be life-threatening is called the thyroid storm.


On the basis of the signs and symptoms, thyroid hormone (thyroxine or T4, triiodothyronine or T3) and thyroid-stimulating hormone (TSH) are determined in the medical laboratory. Free T4 and Free T3 is markedly elevated, while TSH is suppressed due to negative feedback. An elevated protein-bound iodine level may be detected. A large goiter is sometimes seen on X-rays.

Thyroid-stimulating antibodies may be detected serologically.


Most features are due to the production of autoantibodies that bind to the TSH receptor, which is present on the follicular cells of the thyroid (the cells that produce thryoid hormone). These antibodies activate the cells in the same fashion as TSH itself, leading to an elevated production of thyroid hormone.

The infiltrative opthalmopathy (thyroid eye disease) that is frequently encountered has been explained by the expression of the TSH receptor on retroorbital tissue.

The exact cause of antibody production is not known. Viral infection may trigger antibodies against its epitopes, which cross-react with the human TSH receptor. There appears to be a genetic predisposition for Graves' disease, suggesting that some people are more prone than others to develop TSH receptor activating antibodies due to a genetic cause. HLA DR (especially DR3) appears to play a significant role.


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Ocular manifestations of autoimmune disease - Cover Article
From American Family Physician, 9/15/02 by Sayjal J. Patel

Patients with autoimmune diseases are frequently encountered by family physicians. It is important to understand not only the systemic effects of these diseases but also their ocular manifestations (Table 1). Most ocular complications involve the cornea but may also include the conjunctiva, uvea, sclera, retina, and surrounding structures (Figure 1). The majority of these diseases will ultimately need to be referred to an ophthalmologist.

Rheumatoid Arthritis

Approximately 25 percent of patients with rheumatoid arthritis (RA) will have ocular manifestations. These may include keratoconjunctivitis sicca, scleritis, episcleritis, keratitis, peripheral corneal ulceration, and less common entities such as choroiditis, retinal vasculitis, episcleral nodules, retinal detachments, and macular edema. (1,2)

Keratoconjunctivitis sicca, or dry eye syndrome, is the most common ocular manifestation of RA and has a reported prevalence of 15 to 25 percent. (1,2) Symptoms are historically more prominent during the latter part of the day because of the evaporation of the tear film (Table 2). A simple and easy-to-perform test assessing the function of the lacrimal glands is the Schirmer's test (Figure 2). It is performed by first drying the tear film, then inserting a Schirmer strip into the lower conjunctival cul-de-sac toward the temporal aspect of the lower lid. No anesthetic should be used. After five minutes, if the strip measures less than 10 mm of wetting, the lacrimal glands are not functioning correctly. If a slit lamp is available, corneal examination may reveal punctate erosive keratopathy or filaments. (3,4)

The primary goal in managing dry eye is to replenish or preserve the tear film. Patients should be educated about simple measures such as using sunglasses and room humidifiers, and avoiding dry environments before turning to tear substitutes. Natural or artificial tear substitutes can help alleviate more severe symptoms, but most contain preservatives that can be toxic to the cornea. (5) In severe cases, occlusion of the lacrimal drainage puncta or tarsorrhaphy will be necessary.

Scleritis (Figure 3) or episcleritis (Figure 4) in patients with RA occurs at a prevalence rate of 4 to 10 percent. (1) RA is the most common cause of scleritis, accounting for approximately 18 to 33 percent of cases. (1,2,6) Scleritis and episcleritis are distinguished on the basis of anatomy and appearance (1,2,7) (Table 2). Symptoms may be similar, but the pain in scleritis is more evident and severe. Tenderness to palpation of the globe can help differentiate the two. After asking the patient to look down with eyelids closed, the physician gently presses the globe. Patients with scleritis have tenderness on palpation, while those with episcleritis do not.

Topical phenylephrine 2.5 percent (Neo-Synephrine) can help the physician distinguish dilated vessels caused by scleritis from those caused by episcleritis. The instillation of one to two drops in the affected eye will cause the engorged vessels caused by episcleritis to blanch while those caused by scleritis remain dilated. Patients should be warned that phenylephrine will cause blurred vision and dilation of the pupil for approximately three hours. This test should not be done in patients with a history of glaucoma.

Among the variations of scleritis, necrotizing scleritis with inflammation is the most destructive. In addition to the ocular findings in non-necrotizing scleritis, avascular areas of the sclera or necrosis may be seen, surrounded by scleral edema (Figure 5). Complications include scleral thinning, staphyloma, or perforation. (1,7) Necrotizing scleritis without inflammation is a sign of long-standing RA and can lead to scleromalacia perforans (Figure 6).

Between the two forms of episcleritis, simple episcleritis is more common in patients with RA. The presence of subconjunctival nodules that are mobile over the sclera differentiates nodular episcleritis from simple episcleritis. (1,7) Both forms of episcleritis can be confused with severe conjunctivitis because of the bright-red appearance of the eye and should be differentiated with the help of a thorough history and physical examination.

The importance of correctly diagnosing and distinguishing between scleritis and episcleritis is based on the potential ocular and systemic complications associated with scleritis. Studies have shown that patients with RA-associated scleritis have more widespread systemic disease and a higher mortality rate than those without scleritis. (6-8) The initial treatment of scleritis and episcleritis should be focused on relieving discomfort and stopping progression of the disease. Initial therapy includes oral indomethacin (Indocin) or other nonsteroidal anti-inflammatory drugs (NSAIDs). Patients who do not respond to these medications should be referred to an ophthalmologist for possible treatment with topical steroids or systemic immunosuppressive medications.

Corneal disease in patients with RA can be an isolated complication, but it is most commonly associated with keratoconjunctivitis sicca or a form of anterior scleritis. The spectrum of disease may include keratitis, sclerosing keratitis, and peripheral or paracentral ulcerative keratitis (1,2,6,7) (Table 2). The drying effects of keratoconjunctivitis sicca lead to devitalized epithelial cells and punctate epithelial erosions. Keratitis associated with scleritis may be acute or sclerosing. Acute keratitis has been identified in 30 to 70 percent of patients with scleritis or episcleritis-associated RA. (1,6) It is marked by an inflammatory cell infiltrate that may result in corneal scarring, ulceration, or melting. (1,6)

Sclerosing keratitis is a chronic process marked by an area of opacified and vascularized cornea that progresses toward the visual axis. This area of opacification may be more evident with fluorescein staining. Peripheral and paracentral ulcerative keratitis can occur in association with, or in the absence of, scleritis and are marked by corneal thinning in the juxtalimbal cornea (peripheral) or the central (paracentral) cornea (1,2) (Figure 7). Without treatment, perforation (Figure 8) and visual loss may occur. Care must be taken when prescribing steroids to prevent further thinning of the cornea. It is important that the patient receive a thorough ocular examination with frequent slit lamp follow-up evaluations. Typically, topical steroids, immunosuppressive therapy, surgical intervention, or a combination of the above will be required to preserve vision. Surgical options include ulcer debridement, conjunctival resection, corneal graft, application of tissue adhesives, sclerectomy, and scleral patch grafting. (1,2,8)

Other, less common ocular manifestations of RA include choroiditis, retinal vasculitis, episcleral nodules, exudative or serous retinal detachments, and macular edema. (1,2,6) A high index of suspicion can preserve vision and prevent further ocular complications.

Juvenile Rheumatoid Arthritis

Juvenile rheumatoid arthritis accounts for approximately 80 percent of cases of uveitis in children. (1,2,9) Delay in diagnosis can lead to cataracts, glaucoma, and blindness. Although uveitis can be found in all forms of juvenile RA, it is most commonly found in the pauciarticular subtype. Most patients will be symptom-free or have blurred vision (Table 2). On examination, the patient may have decreased visual acuity, band keratopathy, synechiae (Figure 9), cataracts, or elevated ocular pressure. Diagnosis or suspicion of juvenile RA should prompt a referral to a pediatric ophthalmologist. Recommendations for ocular screening examinations are based on the risk of developing uveitis (Table 3). (10) Therapy involves close monitoring by an ophthalmologist, with the use of cycloplegic agents, steroids, NSAIDs, or immunosuppressive agents. (1,2)

Sjogren's Syndrome

The primary ocular manifestation of Sjogren's syndrome is keratoconjunctivitis sicca. The signs and symptoms are similar to those of keratoconjunctivitis sicca associated with RA. In addition to the treatment noted above, 5 mg of oral pilocarpine (Salagen) four times daily may improve the symptoms of dry eyes and dry mouth. (11,12) [Reference 11, Evidence level A, randomized controlled trial ] Patients should be cautioned that the side effects of diaphoresis and poor night vision may occur.


Among the seronegative spondyloarthropathies, uveitis in ankylosing spondylitis is the most common ocular manifestation. It occurs in approximately 25 percent of patients with ankylosing spondylitis, in up to 37 percent of patients with Reiter's syndrome, in approximately 20 percent of patients with psoriatic arthritis, and in up to 9 percent of patients with enteropathic arthritis (arthritis associated with Crohn's disease or ulcerative colitis). (2,13-15) Ocular symptoms can be unilateral or bilateral, and pain is caused by ciliary spasm in response to anterior chamber inflammation. As noted earlier, patients suspected of having uveitis should be referred to an ophthalmologist. Complications include glaucoma, cataracts, or blindness.

Systemic Lupus Erythematosus

Ocular disease occurs in 20 percent of patients with systemic lupus erythematosus (SLE). In some cases, ocular disease may indicate reactivation of SLE that was thought to be in remission. (16) External ocular manifestations include keratoconjunctivitis sicca, conjunctivitis, uveitis, episcleritis, scleritis, keratitis, and a discoid lupus rash over the eyelids that is often confused with blepharitis. (16,17) Neuro-ophthalmic involvement in SLE is primarily caused by microinfarction, hemorrhage, or vasculitis in various locations of the eye and along the visual pathway. Typical complications include optic neuritis, ischemic optic neuropathy, hemianopia, amaurosis, internuclear ophthalmoplegia, pupillary abnormalities, oculomotor abnormalities, pseudotumor cerebri, and visual hallucinations. (16)

Retinal disease primarily occurs in patients with active SLE and may include cotton-wool spots (Figure 10), retinal hemorrhages, retinal vasculitis, or proliferative retinopathy. Treatment of ocular disease is based on specific pathology and underlying disease. (16) Keratoconjunctivitis sicca is thought to be the most common manifestation and can be treated as noted above.

Retinal disease has a high morbidity and should be treated aggressively by an ophthalmologist. (16,17) Ophthalmic screening programs in SLE are controversial. Most physicians agree that patients on antimalarial or steroid regimens should receive a full dilated-eye examination on initiation of therapy then with routine examinations in low-risk patients and yearly for high-risk patients. High risk is defined by medication dosage (>6.5 mg per kg hydroxychloroquine or >3 mg per kg chloroquine), duration of use (more than five years), high body fat level, presence of renal or liver disease, presence of concomitant retinal disease, and age greater than 60 years. (16,18)

Multiple Sclerosis

The ocular manifestations of multiple sclerosis (MS) can be divided into afferent and efferent disorders (19) (Table 1). Optic neuritis is diagnosed in 75 percent of patients with MS and is the presenting symptom in 14 to 25 percent of Cases (19,20) (Table 2). Visual field defects in patients with MS are a result of demyelination along the visual pathway. Bilateral internuclear ophthalmoplegia is almost always caused by a demyelinating disorder. (19) Dysmetria, nystagmus, and cranial nerve palsies, especially involving the sixth and third nerves, may result from lesions of the brain stem and cerebellum.

Nystagmus, which may be the first neurologic finding in patients with MS, is commonly horizontal but may also be rotary or vertical. (19) Patients with suspected ocular involvement should receive magnetic resonance imaging (MRI), a full dilated-eye examination, and treatment with intravenous corticosteroids if the MRI is positive. (20) Periodic follow-up evaluations should be done to monitor the progression of disease.

Giant Cell Arteritis

Up to 50 percent of patients with giant cell arteritis present with ocular symptoms that include pain, diplopia, visual loss, and amaurosis fugax, in addition to headache, jaw claudication, and neck pain. (21,22) It is important to note that ocular involvement is common in the absence of systemic signs and symptoms. (21,22) Patients may have temporal artery tenderness or a decreased temporal artery pulse, but diagnosis is confirmed with biopsy of the artery and elevated titers of erythrocyte sedimentation rate and C-reactive protein. Biopsy will remain positive for up to two weeks after the initiation of corticosteroid therapy. (21) Intravenous corticosteroids should be used in patients with visual symptoms. (21) Immediate therapy can be dramatic in effect and prevent further vasculitic complications, permanent blindness, or death.

Graves' Disease

Exophthalmos (Figure 11) occurs in approximately 50 percent of patients with thyroid disease (23) (Table 2). It is strongly associated with smoking and may also be found in patients who are euthyroid or hypothyroid. (23) If signs of optic nerve compression, such as decreased visual acuity, reduced visual fields, relative afferent pupillary defect, and loss of color vision are present, computed tomography or MRI of the orbit is recommended. (23-25)

Patients with suspected ocular disease should be referred to an ophthalmologist for a full dilated ocular examination. Mild ocular disease can be treated with simple methods such as lubrication drops applied hourly, sleeping with the head elevated, wearing sunglasses during the daytime, and taping eyelids closed at night. Systemic corticosteroid therapy or radiotherapy is reserved for more severe cases, and surgical decompression of the orbit or tarsorrhaphy may be required in patients with sudden visual loss or extensive corneal damage, respectively. (23,25)

Figure 1 redrawn with permission from Bradford CA. Basic ophthalmology for medical students and primary care residents. 7th ed. San Francisco: American Academy of Ophthalmology, 1999, and the photographs in Figures 3 through 8, 10, and 11 are used with permission from Tang RA. Ocular manifestation of systemic disease. San Francisco: American Academy of Ophthalmology, 1996.

The authors indicate that they do not have any conflicts of interest. Sources of funding: none reported.

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Navy Medical Department or the U.S. Navy Service at large.

A list of terms and definitions is available on the Web site at


(1.) Fuerst DJ, Tanzer DJ, Smith RE. Rheumatoid diseases. Int Ophthalmol Clin 1998;38:47-80.

(2.) Harper SL, Foster CS. The ocular manifestations of rheumatoid disease. Int Ophthalmol Clin 1998;38:1-19.

(3.) Whitcher JP Jr, Gritz DC, Daniels TE. The dry eye: a diagnostic dilemma. Int Ophthalmol Clin 1998;38: 23-37.

(4.) Friedlaender MH. Ocular manifestations of Sjogren's syndrome: keratoconjunctivitis sicca. Rheum Dis Clin North Am 1992;18:591-608.

(5.) Geerling G, Daniels JT, Dart JK, Cree IA, Khaw PT. Toxicity of natural tear substitutes in a fully defined culture model of human corneal epithelial cells. Invest Ophthalmol Vis Sci 2001;42:948-56.

(6.) McGavin DD, Williamson J, Forrester JV, Foulds WS, Buchanan WW, Dick WC, et al. Episcleritis and scleritis. A study of their clinical manifestations and association with rheumatoid arthritis. Br J Ophthalmol 1976;60:192-226.

(7.) Watson PG, Hayreh SS. Scleritis and episcleritis. Br J Ophthalmol 1976;60:163-91.

(8.) Messmer EM, Foster CS. Destructive corneal and scleral disease associated with rheumatoid arthritis. Medical and surgical management. Cornea 1995; 14:408-17.

(9.) Waheed NK, Miserocchi E, Foster CS. Ocular concerns in juvenile rheumatoid arthritis. Int Ophthalmol Clin 2001;41:223-34.

(10.) American Academy of Pediatrics. Guidelines for ophthalmic examinations in children with juvenile rheumatoid arthritis. Pediatrics 1993;92:295-6.

(11.) Vivino FB, Al-Hashimi I, Khan Z, LeVeque FG, Salisbury PL 3d, Tran-Johnson TK, et al. Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with Sjogren syndrome: a randomized, placebo-controlled, fixed-dose, multicenter trial. Arch Intern Med 1999;159:174-81.

(12.) Manoussakis MN, Moutsopoulos HM. Sjogren's syndrome. Otolaryngol Clin North Am 1999;32: 843-60.

(13.) Rosenbaum JT. Acute anterior uveitis and spondyloarthropathies. Rheum Dis Clin North Am 1992; 18:143-51.

(14.) Banares A, Hernandez-Garcia C, Fernandez-Gutierrez B, Jover JA. Eye involvement in the spondyloarthropathies. Rheum Dis Clin North Am 1998; 24:771-84.

(15.) Lyons JL, Rosenbaum JT. Uveitis associated with inflammatory bowel disease compared with uveitis associated with spondyloarthropathy. Arch Ophthalmol 1997;115:61-4.

(16.) Nguyen QD, Foster CS. Systemic lupus erythematosus and the eye. Int Ophthalmol Clin 1998; 38:33-60.

(17.) Soo MP, Chow SK, Tan CT, Nadior N, Yeap SS, Hoh HB. The spectrum of ocular involvement in patients with systemic lupus erythematosus without ocular symptoms. Lupus 2000;9:511-4.

(18.) Marmor MF, Carr RE, Easterbrook M, Farjo AA, Mieler WF. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology 2002;109:1377-82.

(19.) Kidd D. Presentations of multiple sclerosis. Practitioner 1999;243:24-6,28-30.

(20.) Davis EA, Rizzo JF. Ocular manifestations of multiple sclerosis. Int Ophthalmol Clin 1998;38:129-39.

(21.) Neff AG, Greifenstein EM. Giant cell arteritis update. Semin Ophthalmol 1999;14:109-12.

(22.) Hayreh SS, Podhajsky PA, Zimmerman B. Ocular manifestations of giant cell arteritis. Am J Ophthalmol 1998;125:509-20.

(23.) Weetman AP. Graves' disease. N Engl J Med 2000; 343:1236-48.

(24.) Adam A, Mishriki YY. The painful, protruding eye. Unilateral euthyroid Graves' ophthalmopathy. Postgrad Med 1999;105:81-4.

(25.) Coday MP, Dallow RL. Managing Graves' orbitopathy. Int Ophthalmol Clin 1998;38:103-15.

SAYJAL J. PATEL, LT, MC, USNR, is an ophthalmology resident at Naval Medical Center, San Diego. He received his medical degree from Jefferson Medical College of Thomas Jefferson University, Philadelphia.

DIANE C. LUNDY, CAPT, MC, USN, is currently serving as Director of the Glaucoma Service at Naval Medical Center, San Diego. She received her medical degree from the Uniformed Services University of the Health Sciences F. Edward Hebert School of Medicine, Bethesda, Md. She completed an ophthalmology residency at Naval Medical Center, San Diego, and a glaucoma fellowship at the Doheny Eye Institute, Los Angeles.

Address correspondence to Lt. Sayjal J. Patel, 34520 Bob Wilson Dr., San Diego, CA 92134-2202 (e-mail: Reprints are not available from the authors.

COPYRIGHT 2002 American Academy of Family Physicians
COPYRIGHT 2002 Gale Group

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