OPHTHALMOLOGIC EFFECTS OF BOWEL DISEASE

GASTROINTESTINAL DISORDERS AND SYSTEMIC DISEASE, PART I

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OPHTHALMOLOGIC EFFECTS OF BOWEL DISEASE Mamdouh L. Nakla, MD, and Karen F. Heffler, MD

Ocular findings in diseases affecting primarily the digestive tract are relatively rare. Yet it is important for the physician to recognize these relationships, appropriately uncover symptoms related to the eye disease, and have the patient evaluated by an ophthalmologist if indicated. In addition, ocular inflammation may be the first indication of bowel disease, such as uveitis in Crohn’s disease. This article clearly describes these associations between ocular disease and gastrointestinal disease and their cause, signs, symptoms, prognosis, and treatment. EYE FINDINGS ASSOCIATED WITH INFLAMMATORY BOWEL DISEASE

Inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, are disorders in which chronic inflammation involves the gastrointestinal tract. Ulcerative colitis is characterized by inflammation and ulceration of the large bowel. Crohn’s disease is a granulomatous disease that can affect any portion of the gastrointestinal tract with fullthickness inflammation. Ocular complications associated with inflammatory bowel disease are relatively infrequent, involving fewer than 10% of patients with Crohn‘s disease and even fewer patients with

From the Department of Ophthalmology, Allegheny University of the Health SciencesHahnemann University Hospital, Philadelphia, Pennsylvania

GASTROENTEROLOGY CLINICS OF NORTH AMERICA VOLUME 27 NUMBER 3 SEPTEMBER 1998

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ulcerative colitis.32Ocular involvement includes uveitis, corneal disease, and scleritis.

Cause

The specific cause of the uveitis, scleritis, and corneal disease related to inflammatory bowel disease is not well understood, but autoimmuThe ability to nity likely has an important role in the respond to a specific immune stimulant in humans is genetically controlled. For example, the strength of an immune reaction against an allograft (tissue taken from another of the same species, other than an identical twin) is determined in large part by antigens on the cell surface membranes. These antigens are products of genes in the human leukocyte antigen (HLA) region on chromosome 6 in humans. Some HLA types have been associated with a greater risk of uveitis, such as HLAB27 in whites associated with uveitis and ankylosing spondylitis. It is not clear why there is an association between certain diseases and HLA types. Various theories have been proposed, including antigens that mimic or alter the HLA specific antigen to allow the host tissue to be attacked or allow increased probability of disease.42Hypersensitivity reactions, including cytotoxic antibody (type 11), immune complexes (type 111), and delayed-type hypersensitivity (type IV), have all been implicated in ocular inflammatory disease. In addition, a dysregulation of T cells, specifically suppressor cells, likely plays a major role in this type of ocular inflammati~n.~~

Uveitis \

Uveitis is an inflammatory condition of the eye that most commonly affects the anterior structures, specifically the iris. This inflammation causes a cellular reaction in the anterior chamber called iritis. When the posterior structures are involved, white blood cells accumulate in the vitreous (vitritis). Other posterior involvement includes inflammatory infiltrates of the retina or choroid or vascular sheathing.14Both ulcerative colitis and Crohn's disease have been associated with inflammatory reactions in the eye, including both anterior and posterior ~ v e i t i s . ~ ~ Symptoms

Individuals with uveitis usually have symptoms consisting of ocular pain, photophobia, and redness. Uveitis may be associated with tearing or blurred vision. Individuals often prefer to stay in a dark room or cover their eyes when confronted with bright light.

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Signs

Although perilimbal injection and pupillary miosis are nonspecific signs of uveitis, the diagnosis requires a slit lamp evaluation. On high magnification, cells can be seen floating in the anterior chamber, usually accompanied by flare (proteinaceous material that allows the usually optically clear aqueous to be visible). The cell and flare are graded by the ophthalmologist to indicate the degree of inflammation. Keratic precipitates are clusters of cells that deposit on the corneal endothelium, including macrophages, lymphocytes, and plasma cells pred0minant1y.l~ Abnormalities of the iris, including nodules and adhesions to the lens (posterior synechiae), may develop with severe or chronic inflammation. The intraocular pressure may be low in uveitis secondary to inflammation of the ciliary body leading to reduced secretion of aqueous15 or because of release of prostaglandins.8Alternatively the intraocular pressure may be elevated because of blockage of the trabecular meshwork by cellular debris,5l because of secondary angle closure, or because of the pressure-elevating effects of topical steroids. Other ocular complications of uveitis include cataract, band keratopathy (calcium deposition in the cornea), vitreous cells or precipitates, fluid in the macula (cystoid macular edema), epiretinal membranes, retinal neovascularization, and retinal vasculitis.4* The prognosis is usually good, provided that the systemic disease is controlled and the patient is compliant with the ocular treatment and follow-up. Diagnosis

Making a diagnosis of inflammatory bowel-related uveitis requires a diagnosis of Crohn’s disease or ulcerative colitis and exclusion of other causes of uveitis. The differential diagnosis of uveitis includes many entities, including syphilis, tuberculosis, Lyme disease, ankylosing spondylitis, sarcoidosis, trauma, viral infection, Reiter’s syndrome, juvenile rheumatoid arthritis, Behcet’s syndrome, Vogt-Koyanagi-Harada syndrome, systemic lupus erythematosus as well as other infectious causes including toxocariasis, toxoplasmosis, and histoplasmosis.49An excellent history and review of systems is essential to guide the evaluation for most likely causes. Workup should exclude the most common treatable causes, such as tuberculosis and syphilis with testing including chest xray, purified protein derivative, Venereal Disease Research Laboratory (VDRL) and fluorescent treponemal antibody absorption (FTA-ABS). Other testing is done dependent on clinical presentation, systemic symptoms, likelihood of disease (sarcoidosishas a much higher prevalence in African-Americans than in whites), and clinical suspicion. Treatment

Frequently, ocular inflammation is a reflection of the degree of activity of the systemic disease.2O Therefore besides treating the ocular

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disease locally, it is prudent to make sure that the bowel disease is optimally treated and under control. Treatment of uveitis includes topical steroids to decrease the inflammatory reaction and cycloplegics to increase comfort and decrease the likelihood of adhesions between the iris and lens. The least amount of steroid that is necessary is used with the goal to reduce the dose gradually as tolerated until it can be discontinued. Topical steroid use has complications of cataract, increased intraocular pressure, and decreased resistance to corneal infection and recurrence of corneal herpes simplex. When topical steroids are insufficient to control the ocular inflammation, systemic steroids or immunosuppressive agents are required."

Corneal Disease Crohn's disease and ulcerative keratitis are rarely associated with corneal disease. The reported findings include marginal corneal infiltrations, which may be necrotizing or lead to corneal melt.56 Symptoms

Corneal disease usually causes pain, irritation, and foreign body sensation, sometimes associated with decreased vision. Signs

The corneal findings have some similarities to those found in systemic lupus erythematosus and rheumatoid arthritis, although usually not as severe as the latter. White opacities develop in the peripheral and midperipheral cornea. These areas stain with fluorescein and can thin or perforate. In addition, nonstaining opacities have been seen in the superficial corneal s t r ~ m a . ~ ~ Prognosis and Treatment

The prognosis depends to a great degree on controlling the systemic disease. Topical steroids, although sometimes helpful, should be used cautiously because they can contribute to more rapid corneal thinning and perforation. Oral steroids and immunosuppressive therapy are the preferred treatments. Other treatments that can be beneficial include resection of the adjacent conjunctiva in an effort to decrease collagenase activity. Cyanoacrylate tissue adhesive can be applied to the cornea to slow the ulceration or seal the cornea in case of perforation. A lamellar (partial thickness) or penetrating (full thickness) corneal transplant is sometimes necessary in cases of advanced corneal disease?

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Episcleritis and Scleritis

Episcleritis is inflammation of the superficial layer under the conjunctiva. It usually is self-limited and is much less likely to be associated with systemic disease than scleritis. Scleritis is a severe ocular disease that must be treated aggressively to prevent significant visual loss. Scleritis may be diffuse, sectoral, or nodular or involve the posterior structures. Symptoms

Episcleritis usually causes one to feel mild ocular irritation or may cause only redness without significant discomfort. Scleritis usually causes severe boring pain, sometimes described as feeling like a toothache in the eye. Scleritis may cause blurred vision or sensitivity to light as a result of posterior involvement or associated uveitis. Signs

Episcleritis presents with acute redness of one or both eyes because of engorgement of the vessels in the episcleral plexus. The vessels are superficial and can be moved with a cotton-tip applicator. Episcleritis injection blanches significantly with topical application of phenylephrine. The affected area can be diffuse, sectoral, or nodular. An eye with scleritis has injection of the deeper scleral vessels, in addition to conjunctival and episcleral injection. The scleral vessels do not blanch with phenylephrine application and are not moved with a cotton-tip applicator. In natural light, the inflamed area appears violet in color. Scleritis can involve the anterior sclera diffusely or be nodular or necrotizing. Additionally, it can involve the posterior aspect of the eye with resulting exudative retinal detachment, optic disc swelling, or proptosis.66 Treatment

Episcleritis can be treated with cool compresses, topical vasoconstrictors, and sometimes topical steroids. Scleritis requires systemic treatment, which may include corticosteroids, nonsteroidal anti-inflammatory drugs, or immunosuppressive medications. Recurrences are common, but with control of the underlying disease process, the prognosis is usually good.67 WHIPPLE’S DISEASE

Whipple’s disease (intestinal lipodystrophy) is a rare disorder, most commonly affecting white men, characterized by intestinal malabsorption, arthritis, and the finding of macrophages containing periodic acid-

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Schiff-positive cytoplasmic granules on intestinal mucosal biopsy. Constitutional symptoms of malaise and fever, in combination with abdominal pain, diarrhea, and weight loss, are usual findings. The joints most commonly affected are the ankles and knees. Central nervous system involvement has been do~umented.’~ Eye Findings

Ocular involvement in Whipple’s disease includes anterior uveitis, vitreal inflammation (vitritis), retinal involvement? 29 papilledema and supranuclear ophthalmoplegia, and myoclonic ocular and facial jerks.l8,30,48 Cause

Chronic infection in the intestines has been implicated in Whipple’s disease. The direct effect of infection or the indirect effect of immune processes could be contributing factors to the ocular disease. Microorganisms have been notedm and most recently identified50as Tropheryrna whippelii (Whipple’s bacillus) in ocular tissue. In addition, there is a strong association between the presence of HLA-B27, uveitis, and the progression of spondyloarthropathy to ankylosing ~pondylitis.~~ There may be a genetic predisposition to develop either the disease or some of the more severe extra-articular manifestations of Whipple’s disease. Treatment

Broad-spectrum antibiotics have been traditionally used empirically in the treatment of Whipple’s disease, most commonly tetracycline, erythromycin, ampicillin, penicillin, or chloramphenicol. A report suggests the use of trimethoprim-sulfamethoxazoleas the agent of choice in the treatment of Whipple’s disease because it minimizes the central nervous system involvement and relapses.16In patients with intraocular involvement, antibiotics that achieve effective concentrations in tissue beyond the blood-ocular barrier should be used. Because of the possibility of recurrence, even after apparently successful treatment, it is imperative to evaluate periodically the systemic and ocular condition of these patients.% Early signs of intraocular involvement should be regarded as a possible recurrence of the disease, and antibiotic therapy should be reinstituted. BEHCET’S DISEASE

Behset’s disease is a clinical syndrome first described in 1937 as a triad of recurrent oral and genital ulceration associated with ocular

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inflammation.” There is an association with the HLA-Bw51 antige11.4~ The prevalence of the disease is much higher in the Mediteranean Basin and in the Far East, especially in Japan, where one study estimated an incidence of 1 in 10,000.2 There have been several proposed diagnostic criteria for Behqet’s disease,%,43, 58 the most recent of which is the International Study Group criteria.= The syndrome consists of recurrent aphthous stomatitis, genital aphthous ulceration, ocular disease, gastrointestinal disease, eye lesions, arthropathy, cutaneous vasculitis, and neuroencephalitis.22,43 The most common clinical feature of Behqet’s disease is recurrent oral ulceration. The International Study Group diagnostic criteria require that the patient have oral ulceration as well as two other criteria, including recurrent genital ulceration, eye lesions, skin lesions, or positive pathergy test, to make a diagnosis of Behqet’s disease.22The oral ulcers are small and shallow but painful and can also be found on the lips, gums, tongue, and palate. Hemorrhagic ulcerative lesions may also occur in the stomach, intestine, and anal region.25Patients with gastrointestinal symptoms need to be carefully evaluated to rule out other diseases, such as peptic ulceration, Crohn’s disease, and ulcerative colitis. The eye manifestations include anterior and posterior uveitis as well as retinal vasculitis and are described in more detail subsequently. Skin lesions can include erythema nodosum and maculopapular and pustular lesions as well as acneiform lesions in postadolescent adults.=,25 Pathergy consists of the formation of a pustule 24 to 48 hours after a pin prick that breaks the skin9,10,25,38 and has been reported to be as high as 40% in Behqet’s disease? Neurologic involvement carries an associated increased risk of mortality and can include confusional states, brain stem syndromes with cranial nerve palsies, and meningoencephalitis.26,M, 69 Nondeforming arthritis, primarily of large joints, affects 50% to 60% of patients.”, 25, 71

Ocular Findings

Ocular manifestations are present in approximately 70% of those with Behqet’s disease,12,23 with uveitis being the most common eye 39 The uveitis usually involves both anterior and posterior fk1ding.3~~ segments. The iritis is most commonly nongranulomatous with fine deposits on the corneal endothelium, although large mutton-fat keratic precipitates have been described.12In early reports, hypopyon, a layered accumulation of white blood cells in the anterior chamber, was a frequent fi11ding.3~ More recent studies suggest that with earlier diagnosis and aggressive treatment, hypopyon is now found in fewer than 10% of Behqet’s patients.12,39 Posterior segment involvement is more common than anterior and includes retinal vasculitis, retinal hemorrhages, macular edema, focal areas of retinal necrosis, ischemic optic neuropathy, and ~itritis.~~

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Treatment

Behqet’s disease is a chronic recurrent disorder that tends to recur over a 2- to 4-year period and may result in blindness if the ischemic optic neuropathy and retinopathy are not adequately treated. Treatment includes the use of oral corticosteroids, chlorambucil, or other immunosuppressive drugs. Colchicine has been found useful in both Japan and the United States. Studies suggest the efficacy of cyclosporine in Behqet’s disease.62 LIVER DISEASE Liver Failure

There are few complications of liver failure secondary to hepatic disease that affect the eye. Jaundice is one of the hallmarks of liver failure and is often detected by a yellow discoloration of the skin, conjunctiva, and body fluids. Jaundice occurs because bilirubin cannot be excreted into the bile, so its blood level rises, and the bilirubin pigment accumulates in tissue. Vitamin A deficiency may occur in patients with acute or chronic liver disease. In acute hepatitis, low plasma levels of vitamin A are apparently due to failure of the release of vitamin A from the liver into the plasma. In chronic liver disease with cirrhosis, vitamin A deficiency is caused by malabsorption of fat, impaired hepatic storage of retinyl esters, and decreased synthesis or hepatic release of retinol-binding protein.53 Ocular Findings

Bilirubin accumulates particularly in the vascularized conjunctiva and subconjunctival connective tissue (Tenon’s) overlying the white sclera, so that the normal white sclera appearance is altered by discoloration of the conjunctiva, and scleral icterus results.70Icterus is usually noticeable when the serum bilirubin level exceeds 2.5 mg/dL. Reduction of plasma vitamin A secondary to hepatic disease causes night blindness and xerophthalmia (xerosis of the cornea and conjunctiva). Vitamin A serves as a precursor to the photosensitive visual pigment that participates in the initiation of neural impulses from the photoreceptors. In addition, vitamin A is also necessary for maintenance of the conjunctival mucosa, particularly goblet cells, and corneal stroma.21 Night blindness is the earliest and most common manifestation of vitamin A deficiency. This condition can be confirmed by electroretinography and dark adaptation Xerophthalmia associated with vitamin A deficiency is caused by loss of the mucus-secreting conjunctival goblet cells with keratinization of the conjunctiva. Early changes are

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a superficial punctate keratopathy and Bitot’s spots (triangular patches of gray, foamy material near the limbus). There may be progression to corneal ulceration and p e r f ~ r a t i o n . ~ ~ Patients with advanced hepatic cirrhosis may exhibit eyelid retraction and eyelid lag on downgaze (Graefe’s sign).61These signs, which are also seen in Graves’ disease, are thought to be due to increased circulating levels of sympathetic amines in plasma. Prognosis and Treatment

Xerophthalmia may lead to significant visual loss in 50% of patients if no treatment is provided. Vitamin A therapy may reverse corneal keratinization, Bitot’s spots, and ulceration, and if replacement is given at an early stage, it may cause reversal of night blindne~s.5~. 52 Wilson’s Disease

Wilson’s disease is an autosomal recessive disease in which excessive amounts of copper are deposited in the liver, basal ganglia, cerebral cortex, and corneas. The estimated prevalence of the disease is 1 in 30,000. Intestinal absorption of dietary copper is normal in patients with Wilson’s disease, but their biliary excretion of copper is defective. There is a low serum level of ceruloplasmin, which carries copper in a bound state in plasma. The low ceruloplasmin levels lead to copper overload in the liver and extrahepatic tissues.l7 Ocular Findings

Copper is deposited into the peripheral cornea at the level of Descemet’s membrane, in a golden brown, brownish green, greenish yellow, or deep reddish ring starting at the limbus and extending 1 to 3 mm. The earliest site of visible deposition is in an arc in the superior peripheral cornea from the 10 o’clock to the 2 o’clock position and then in the inferior peripheral cornea from 5 o’clock to 7 o’clock. Later the two segments join to form a complete ring (Kayser-Fleischer ring). Visual acuity is not affected by the corneal change.6 Cataracts resembling sunflowers (central pigmented lens opacities with tapering extensions) may also occur in Wilson’s disease and are apparently due to deposition of copper in the anterior and posterior lens c a p s ~ l eOther .~ ocular findings include nystagmus, saccadic and pursuit gaze abnormalities, and defects of convergence and Treatment

The Kayser-Fleischer ring has apparently disappeared after liver tran~plantation~~ as well as after therapy with the copper-chelating agent penicillamine.60

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Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is a chronic, progressive liver disease manifested by cholestasis of unknown origin. Pathologic features include intrahepatic bile duct obstruction, periportal hepatitis, and eventual cirrhosis. Ocular Findings

Sjogren’s syndrome has been associated with PBC. It is defined by keratoconjunctivitis sicca and xerostomia with or without the association of connective tissue disease, chronic hepatitis, or PBC.’ Sicca complex, which is the combination of keratoconjunctivitis sicca and xerostomia, is found in 70% to 100% of PBC patients. Treatment

The severe dry eye that results from Sjogren’s syndrome requires frequent artificial tears placement every hour. These are usually preservative-free. If there is still no relief, punctal plugs are usually employed, first placed in the inferior punctum then if necessary superiorly. This is usually done in addition to the artificial tears placement.

ADENOMATOUS POLYPOSIS SYNDROMES

Adenomatous polyps arise from benign neoplastic epithelium. Adenomatous polyposis syndromes include familial adenomatous polyposis, Gardner ’s syndrome, Muir-Torre syndrome, and Turcot’s syndrome. Familial adenomatous polyposis is characterized by the progresdive development of 100 to 1000 adenomatous polyps in the colon. Persons who inherit the gene for familial adenomatous polyposis inevitably develop colon cancer in their 30s and 40s, unless colectomy is performed. Gardner’s syndrome is an autosomal dominant disorder that consists of the combination of more than 100 colonic adenomatous polyps, benign soft tissue and bony tumors, dental abnormalities, and desmoid tumors. The genetic defect responsible for familial adenomatous polyposis and Gardner’s syndrome has been mapped to the long arm of chromosome 5.%Muir-Torre syndrome is an autosomal dominant disorder associated with colonic adenomas and colon cancer not genetically linked to familial adenomatous polyposis. Other manifestations include sebacious adenomas and carcinomas, basal cell and squamous carcinomas, and multiple keratoacanthomas.40Turcot’s syndrome is a rare disorder characterized by adenomatous colonic polyps and neuroepithelia central nervous system tumors.ffi

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Ocular Manifestations

The most prominent ocular manifestation of familial adenomatous polyposis, Gardner 's syndrome, and Turcot's syndrome is congenital hypertrophy of retinal pigment epithelium (CHRPE). These lesions are bilateral and appear as darkly pigmented oval lesions in the periphery of the retina with smaller ones closer to the optic disc ranging in size from 0.1 to several disc diameters." A study notes that these lesions are different than the classic unilateral CHRPE lesions or congenital grouped pigmentation (bear tracks).57The number of lesions varies from as few as 1 lesion to as many as 30. Bilateral multiple areas of retinal pigment epithelial hypertrophy are rarely seen in patients without Gardner 's Other ocular features seen in Gardner's syndrome include orbital osteomas, epidermoid cysts of the eyelids, and angioid streaks (streaks with a cracked-mud appearance radiating from the optic nerve). Neuroophthalmic manifestations have been noted in Turcot's syndrome, including papilledema, diplopia, nonreactive pupils, corneal hypoesthesia, ptosis, and decreased visual acuity? The ocular manifestations of Muir-Torre syndrome include sebaceous tumors or keratoacanthomas of the skin of the eyelids. Benign sebacious tumors of the ocular adnexa are extremely rare and should raise the possibility of an associated colon or visceral carcinoma.24 Prognosis and Treatment

Characteristic bilateral CHRPE lesions may be an excellent marker by which to identify persons at risk of developing intestinal carcinoma. CHRPE lesions alone are asymptomatic and do not cause visual disturbance. The presence of angioid streaks may cause visual loss from subretinal neovascularization. PSEUDOXANTHOMA ELASTICUM

Pseudoxanthoma elasticum is a systemic disease inherited in an autosomal recessive or dominant fashion in which the primary defect is abnormal production of elastic fibers with secondary calcification. Manifestations of the disease involve the skin, the cardiovascular system, the gastrointestinal syndrome, and the eye. Cutaneous findings, such as skin folds in the axilla and the neck, are helpful in the recognition and diagnosis of this disorder. Abnormalities of the elastic tissue of the vascular system may lead to serious complications from hemorrhage and peripheral vascular disease. Gastrointestinalhemorrhage in pseudoxanthoma elasticum usually occurs early in the course of the disease. A study suggests that pseudoxanthoma elasticum should be considered in

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patients with gastric hemorrhage, especially if no apparent cause is found and yellow plaques are seen in endoscopyN Ocular Manifestations

Angioid streaks are the hallmark of pseudoxanthoma elasticum. Clinically the streaks form an incomplete ring around the optic disc then radiate anteriorly toward the equator of the globe. The color of the streaks varies from reddish brown to dark brown (cracked-mud appearance). Histopathologically, there is fragmentation of the calcified elastic fibers of Bruch‘s membrane at the choroidal-retinal interface.” The retina may also exhibit a peau d’orange appearance. Subretinal hemorrhage may occur from minor trauma in these patients, and if the macula is involved, vision may be affected. These eyes are also predisposed to subretinal neovascular membrane formation, which also may affect vision if the macula is involved. Treatment of Ocular Manifestation

Patients with angioid streaks should be warned about the development of subretinal hemorrhage from minor ocular trauma. Protective eyewear should be worn, especially with contact sports. CONCLUSION

Ocular diseases or complications are associated with a host of gastrointestinal diseases. These include inflammatory bowel disease, Whipple’s disease, Behqet’s disease, liver disease, adenomatous, polyposis syndromes, and pseudoxanthoma elasticum. Recognition of ocular diseases in association with gastrointestinal diseases is important for both diagnostic considerations and early interventions. References 1. Alarcon-Segovia D, Diaz-Jouanen E, Fishbein E Features of Sjogren’s syndrome in primary biliary cirrhosis. Ann Intern Med 7931, 1973 2. Aoki K, Fujioka K, Katsumata H, et al: Epidemiological studies on Behget’s disease in the Hokkaido district [Japanese]. J Clin Ophthalmol 152239-2243, 1971 3. Arffa RC: Immunologic disorders. In: Grayson’s Diseases of the Cornea, ed 3. St. Louis, Mosby-Year Book, 1991, p 474 4. Avila ME’, Jalkh AE, Feldman E, et al: Manifestations of Whipple’s disease in the posterior segment of the eye. Arch Ophthalmol 102:384,1984 5. Behcet’s Disease Research Committee of Tapan: Guide to diagnosis of Behcet’s disease. Jpn J Ophthalmol 18291,1974 6 . Cairns p,Walshe JM: The Kayser-Fleischer ring. Trans Ophthalmol SOCUK 90187,1970

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7. Cairns JE, Williams HP, Walshe JM: Sunflower cataract in Wilson’s disease. BMJ 395, 1969 8. Camras CB, Bita LZ, Eakins K E Reduction of intraocular pressure by prostaglandins applied topically to the eyes of conscious rabbits. Inv Ophthalmol Vis Sci 161125,1977 9. Chajek T, Fainaru M: Behcet’s disease: Report of 41 cases and a review of the literature. Medicine (Baltimore) 54:179, 1975 10. Chamberlain M A Behcet’s syndrome in 32 patients in Yorkshire. Ann Rheum Dis 36491, 1977 11. Clarkson JG, Altman R D Angioid streaks. S w Ophthalmol26:235-246, 1982 12. Colvard DM, Robertson DM, ODuffy JD: The ocular manifestations of Behcet’s disease. Arch Ophthalmol951813-1817, 1977 13. Comer G, Brandt L, Abissi, et al: Whipple’s disease: A review. Gastroenterology 78:107-114,1983 14. Ducker JS, Brown GG, Brooks L: Retinal vasculitis in Crohn’s disease. Am J Ophthalmol 103664,1987 15. Duke-Elder S, Perkins E S Diseases of the uveal tract. In Duke-Elder S (ed): System of Ophthalmology. London, Henry Kimpton, 1966 16. Durand DV, Lecomte C, Cathebras P, et al: Whipple disease: Clinical review of 52 cases. The SNFMI Research Group on Whipple Disease. Societe National Francaise de Medecine Interne. Medicine (Baltimore) 76:170-184, 1997 17. Frommer DJ: Defective biliary excretion of copper in Wilson’s disease. Gut 15125129, 1974 18. Gartner J: Whipple’s disease of the central nervous system, associated with ophthalmoplegia externa and severe asteroid hyalitis, a clinicopathologic study. Doc Ophthalmol49:155, 1980 19. Hogan MH, Kimura SJ, Thygeson P: Signs and symptoms of uveitis: 1. Anterior uveitis. Am J Ophthalmol47155, 1959 20. Hopkins DDJ, Horan E, Burton IL, et a1 Ocular disorders in a series of 332 patients with Crohn’s disease. Br J Ophthalmol58:732,1974 21. Hoyt C S Vitamin metabolism and therapy in ophthalmology. Surv Ophthalmol 24177,1979 22. International Study Group for Behcet’s Disease: Criteria for diagnosis of Behcet’s disease. Lancet 335:1078,1990 23, Jabs DA: The rheumatic diseases. In Ryan S (ed): The Retina. St. Louis, CV Mosby, 1989, pp 457-480 24. Jacobiec FA, Zimmerman LE, La Piana F, et a1 Unusual eyelid tumors with sebacious differentiation in the Muir-Torre syndrome. Ophthalmology 95:1543, 1988 25. James DG, Spiteri MA: Behcet’s disease. Ophthalmology 89:1279, 1982 26. Kalbain W, Challis MT: Behcet’s disease: Report of twelve cases with three manifesting as papilledema. Am J Med 49:823, 1970 27. Kaplan HJ, Willig J L Immunology of uveitis. In Tasmin W, Jaeger EA (eds): Duane’s Clinical Ophthalmology. Philadelphia, JB Lippincott, 1990 28. Kinzler KW, Nilbert MC, Su LK, et al: Identification of familial adenomatous polyposis locus genes from chromosome 5q21. Science 253:661, 1991 29. Knox DL, Bayless TM, Yardley JH, et a1 Whipple’s disease presenting with ocular inflammation and minimal intestinal svmutoms. Tohns Houkins Med I 123175,1968 30. Knox DL, Green WR, Troncoso JC, et il: Serebra1 ocular ViThipple’s disease: A 62-year odyssey from death to diagnosis. Neurology 45:617425, 1995 31. Knox DL, Snip RC, Stark WJ: The keratopathy of Crohn’s disease. Am J Ophthalmol 90:862-865, 1980 32. Knox DL, Schachat AP, Mustonen E Primary, secondary, and coincidental ocular complications of Crohn’s disease. Ophthalmology 91:163, 1984 33. Korelitz BI, Coles Rs:Uveitis (iritis) with ulcerative and granulomatous colitis. Gastroenterology 5278, 1976 34. Lebwohl M Images in clinical medicine: Pseudoxanthoma elasticum. N Engl J Med 329:1240,1993 35. Leirisalo-Rep0 M. Enteropathic arthritis, Whipple’s disease, juvenile spondyloarthropathy, uveitis and SAPHO syndrome. Curr Opin Rheumatol 72M-289, 1995

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