What the General Physician Should Know About Diseases of the Uveal Tract

What the General Physician Should I(now About Diseases of the Uveal Tract IRVING H. LEOPOLD, M.D., D.Se. (MED.), F.A.C.S.*

THE uveal tract consists of the iris, ciliary body and choroid. These vascular structures of the eye are responsible for maintaining its structure and nutritive balance. The movement of portions of the iris controlled by a delicately balanced innervation of the sphincter and dilator of the pupil guarantees a rather uniform illumination of the retina, and by cutting off marginal rays contributes toward the sharpening of the retinal image. The ciliary body through its musculature and attachments to the lens capsule contributes to the adjustment of the lens for distant and near objects. It thus aids in the mechanism of accommodation and in producing sharp images on the retina. The chemical and physical composition of the vitreous and of the aqueous humor is dependent on the epithelium, stroma and capillaries of the ciliary body and the iris. These structures help to regulate the intraocular pressure. The ehoroid nourishes the outer layers of the retina, and changes in the amount of blood which circulates through it will alter the intra ocular pressure. Pathologic changes in the iris, ciliary body and choroid have important and varied effeets on the eye as a whole. These tissues can be affected by congenital anomalies, by infiammations, and by tumor growths as well as by injuries (Plate II). DETECTION OF INFLAMMATIONS OF TIlE UVEAL TRACT

The iris, eiliary body and choroid may all be involved in the same inFrom the Department of Ophthalmology, Graduate School of Medicine, Univenity of Pennsylvania, and Wills Eye Hospital, Philadelphia.

* Professor of Ophthalmology, Graduate School of Medicine, University of Pennsylvania, Chief of Ophthalmology, Graduate and St. J oseph's Hospitals and Albert Einstein Medical Center: Attending Surgeon and Director of Research, Wills Eye Hospital. 1679

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A, Coloboma of iris. B, Melanoma of iris. C, Essential atrophy of iris, early stage.

D, Essential atrophy of iris, late stage. Both C and D demonstrate the loss of tissue. E, Ciliary body tumor seen when pupil is widely dilated. F, Eye with uveitis, showing mutton fat deposits on back of cornea.

flammatory process. This is called a diffuse uveitis. When the iris is inflamed, the ciliary body usually shares in the process. There may be occasions when the inflammatory reaction is confined more or less to one of these structures, in which case it would then be known as iritis, cyclitis or choroiditis. It is difficult to distinguish between iritis and iridocyclitis, which together are known as anterior uveitis. If the pain is quite severe, and the injection of the eye extends from the perilimbar area to involve the deep vessels at the scleral tissue, the condition is more likely to be an iridocyclitis than an iritis. With iritis the patient usually has pain, visual blurring, photophobia

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and tearing. He may describe the pain as being located solely in the eye or in the brow, or in the head. It is often described as a throbbing pain. The vessels around the limbus are injected to produce the so-called ciliary flush. This is brought about by dilatation of the ciliary vessels about the limbus and often has a slight violet hue in addition to the evidence of injection. The injection will be confined to this area unless there is a deeper involvement, as of the ciliary body, in which case the episcleral vessels may be injected; or if there is an associated conjunctivitis, as after a chemical burn, in which case the conjunctival vessels are also injected. The pupil is small due to congestion of the iris vessels and iris tissues. As a result of the pouring forth of exudate by the engorged iris vessels, the border of the iris may become adherent to the lens capsule. These points of adherence are known as synechiae. When one attempts to dilate a pupil which has strong synechiae, the pupil may dilate irregularly. The engorgement of the vessels and the increase in their permeability lead to an outpouring of protein cellular material into the aqueous humor; this leads to clouding of the aqueous humor. This can best be visualized with a slit lamp. A beam of light passing through the normal aqueous humor cannot be visualized but when there are particles floating in the aqueous humor, as during iritis, the floating particles can readily be seen in the beam. These are called aqueous floaters, and when the beam itself can be seen through the slit lamp magnification, it is known as an aqueous flare. Some of the plasma-like material and cells in the aqueous humor associated with the increased permeability of the iris vessels may produce deposits on the posterior surface of the cornea. These are known as keratitic precipitates. Sometimes the cells may accumulate in the anterior chamber and form a deposition of purulent-appearing material which is known as an hypopyon. This hypopyon, consisting chiefly of pus cells and debris, is usually sterile when attempts are made to culture it. Usually the pressure in the eye is low during the acute stages of iritis or iridocyclitis. Later, due to blockage of the outflow channels by cells and debris, or by development of synechiae in the angle, called anterior synechia, a rise in pressure or secondary glaucoma may result. The pain associated with iritis or iridocyclitis is usually severe and constant, while in inflammations of the choroid alone it is usually minimal or absent. DIFFERENTIAL DIAGNOSIS

Iritis must be differentiated from conjunctivitis. Conjunctivitis produces a superficial type of injection of a pink or light red color. The vessels are quite tortuous. Most of the congestion is near the periphery of the bulbar conjunctiva and becomes less marked as the limbus is approached. The injected conjunctival vessels are often movable and

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can be blanched with 1 :1000 epinephrine. The pericorneal injection associated with iritis cannot be blanched. The vessels have a violet flush rather than a light red color. One would not find an aqueous beam or floaters in conjunctivitis by slit lamp examination, nor any posterior corneal precipitates. The visual acuity is usually not affected in conjunctivitis, whereas it may be involved in acute iritis. The pupil is small in iritis and is not altered in conjunctivitis. Acute iritis or iridocyclitis must be differentiated from acute glaucoma. Both may give rise to marked pain; the eyeball may be quite tender in both, and there is deep ciliary injection. The pupil is usually semidilated in acute glaucoma, small in iritis. The tension is quite high, the cornea is steamy in glaucoma; the tension may be low in the acute phases of iritis. Occasionally when secondary glaucoma occurs, the tension will rise in iridocyclitis. The essential differentiating signs are the size of the pupil, the intraocular pressure, and the clarity of the cornea. CLASSIFICATION OF UVEITIS

The most popular classification of uveitis is that expounded by W oods. 1 He divided uveitis into granulomatous and nongranulomatous varieties. The granulomatous type was thought to be due to systemic diseases such as tuberculosis, syphilis, brucellosis, toxoplasmosis, sarcoid, or virus infection. The nongranulomatous variety was attributed to bacterial allergy arising from some septic focus or foci. Woods has stated that the nongranulomatous type may commence by invasion of the eye by organisms of low virulence or small numbers. They. are destroyed but cause local hypersensitivity of ocular tissues to bacterial protein or soluble bacterial products. The hypersensitivity is thought to be of either the anaphylactic or bacterial type. Reinfection causes a hypersensitivity reaction which is of short duration and characteristic clinical appearance. The granulomatous form is due to organisms which reach the eye, remain viable, proliferate and, because of their toxicity, cause local lesions. A hypersensitive type of reaction may result from the local proliferation of organisms, the violence of which will depend on the degree of local resistance or immunity to the bacteria. There has been a tendency to give less weight to syphilis and tuberculosis in recent years as a cause of uveitis,! and to place emphasis on toxoplasmosis as the cause of this disease.2, 3, 4 Viral diseases have received considerable attention in the last few years as a cause of granulomatous uveitis. 4 The focal infection and bacterial allergy theory has been abandoned by many ophthalmologists but it still retains a strong fascination for others. This concept, however, remains to be proved. The basic causes of uveitis are in most instances not found, so that routine surveys on uveitis patients have fallen into disrepute in many

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clinics simply because of the frequent absence of associated systemic disease or evidence of an etiologic factor. Nevertheless, an occasional cause is determined by such survey, and they should be pursued even though they are costly to the patient and disappointing to the physician. Although one must state that in most cases the cause is not found, there are definite cases of uveitis which have been proved due to tuberculosis, sarcoid, syphilis, leprosy and toxoplalSmosis. 5 Uveitis may be the result of sympathetic ophthalmia, i.e., when one eye is injured and the second eye becomes inflamed because of the initial injury to the other eye. Various joint diseases may be associated with eye lesions, such as the acute arthritides seen in rheumatic fever, gonorrheal arthritis, Reiter's disease and gout, and the chronic arthritides including rh~umatoid arthritis, Still's disease and Marie-Strumpell disease. 6 Acute rheumatic fever and gonorrheal arthritis are accompanied by iritis in 4 to 5 per cent of the cases; Reiter's disease, nonspecific urethritis, is associated with iritis in approximately 10 per cent of cases. Uveitis may occur in 2 per cent of patients with gout, and in approximately the same percentage of patients with rheumatoid arthritis. Still's disease may produce uveitis in 20 per cent of the subjects so affected, and Marie-Strumpell's disease may produce an even higher incidence. Behcet's disease is an entity characterized by recurrent iritis, hypopyon, aphthous ulcers of the buccal cavity and genitalia, nodular skin erythema, arthralgias, and thrombophlebitis in the fundus and extremity. The etiology is unknown. There is some evidence that the streptococcus may play a role in the etiology of uveitis as obtained from skin-testing to the various antigenic streptoccocal derivatives and by analysis of the streptococcal antihyaluronidase and antistreptolysin titers in the blood stream of patients with uveitis. This evidence, however, is not clear-cut.7, 8, 9, 10 It should be pointed out that although the granulomatous and nongranulomatous classification of uveitis has been widely adopted in ophthalmology, the evidence that granulomatous lesions are necessarily infective and nongranulomatous reactions are allergic in origin has not been proved to everyone's satisfaction,u With a full realization of the lack of information and knowledge concerning the basic causes of uveitis, it is still necessary to have a working classification for the physician who must care for these patients. For this purpose cases may be grossly divided into those of exogenous and those of endogenous origin. The former includes those infections which come from outside the eye and produce a direct infection in the eye either by bacteria, fungi or viruses. This can be the result of a penetrating injury with inoculation of organisms, or due to the spread of infection from adjacent tissues such as the sclera, cornea or retina. The endogenous types include sympathetic ophthalmia, endophthal-

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mitis phakoanaphylactica, the various metastatic purulent infectiom; of the eye which arise from direct infection by blood-borne bacteria, and the cases of nonpurulent uveitis. The latter group makes up the great bulk of the cases seen, and these may be divided clinically into the granulomatous and the nongranulomatous types. Sympathetic ophthalmia is a bilateral inflammation of the entire uveal tract caused by a perforating wound that has involved the uveal tissue in one eye. The damaged eye is known as the exciting eye, and the originally uninjured eye is known as the sympathizing eye. The incidence of sympathetic ophthalmia appears to be decreasing. This may be due to earlier removal of potentially exciting eyes, since removal of an eye prior to the onset of sympathetic ophthalmia prevents its development, or possibly to the use of steroid therapy. Endophthalmitis phakoanaphylactica is a type of uveitis which is thought to be due to sensitivity to lens protein. It is most frequently seen after a lens in one eye has been injured, releasing lens material to the aqueous hum or, so that antibodies can be formed in the uveal tissues. Subsequent operation or injury to the lells on the other side may produce uveitis by reason of lens protein sensitivity. Lens protein is organ-specific, not just species-specific, so that a subject can become sensitized to his own lens protein. THERAPY OF UVEITIS

One should attempt to eliminate responsible organisms from the system, lower the allergic response of the eye by desensitization of the tissues, and use measures to increase the immunologic response of the patient. In addition, local therapy to prevent complications is important. Local Therapy

It is essential in iritis and iridocyclitis to dilate the pupil. This is best done by the instillation of 1 or 2 per cent atropine sulfate every hour for two or three hours and then once, twice or three times daily, depending on the amount required to maintain the pupil in the dilated state. If synechiae are present, reinforcement of the cycloplegie effect of atropine may be obtained by the use of 10 per cent Neo-Synephrine. Frequent instillations of the Neo-Synephrine must be avoided in patients with eardiovascular difficulties. Local heat in the form of compresses or diathermy may give relief of discomfort. Synechiae which fail to respond to cycloplegic instillation plus the use of adrenergic drugs in the form of drops or ointment, may respond to subconjunctival injection or iontophoresis applications with these agents. These are best carried out by an ophthalmologist. Local antibiotics or antiviral agents rarely have any value in the treatment of iritis or iridocyclitis. Local steroids are of definite help and will be discussed later.

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Specific Therapy

Where a diagnosis can be made of tuberculosis, leptospirosis, gonorrhea or toxoplasmosis, specific therapy may be administered. The dosage must be adequate to allow penetration into the diseased ocular tissues; however, since these are vascular tissues, usually massive systemic doses are not required. Diabetic iridocyclitis may respond to specific measures for the control of the diabetes, but in the late stages where one sees rubeosis iridis diabetica (that is, numerous dilated vessels on the iris), therapy is directed at controlling the discomfort and is no longer specific. Where there is definite proof of an allergy due to the streptococcus or some other allergen, removal of the antigen, or desensitization if the antigen cannot be entirely removed, is in order. Desensitizing doses must be below those which will produee an ocular flare-up. Tubercular protein desensitization, popular for many years, has been discarded by most ophthalmologists today but still has strong devotees. 7. 12 Desensitization theoretically increases the resistance of the patient against the disease. Steroid Therapy

Approximately eight years ago, cortisone was found to have an antiinflammatory effect on iritis and iridocyclitis when instilled as drops, ointment or injected subconjunctivally into the eye. This agent, used locally, was found to be as beneficial as intramuscular or intravenous ACTH for reducing the inflammation of anterior uveitis. Systemic administration was helpful in the more severe cases of iridocyclitis and posterior uveitis which had failed to respond to local therapy with these steroids. Since these observations, it has been shown that many of the derivatives of cortisone and related compounds such as hydrocortisone, free alcohol and acetate, hydrocortisone l' butyl acetate, 9-alpha-fluorohydrocortisone, prednisone and prednisolone all have definite antiphlogistic activity when applied locally to the eye. These agents have no specific effeet against the cause of the uveitis. They simply control the inflammatory action until the natural resistance of the host overcomes the basic cause or specific therapy can be introduced. If the basic cause is not removed when the steroid therapy is stopped, the disease process recurs. Uveitis which responds only to systemic therapy with cortisone and hydrocortisone does so with prednisolone and prednisone in smaller dosage. Intravenous ACTH is occasionally effective where eortisone fails. Prednisolone rarely is effective where hydrocortisone fails by systemic routes of administration. Steroids have been particularly helpful, according to most inve5tigators, in the uveitis associated with sarcoid, sympathetic ophthalmia, endophthalmitis phakoanaphylaetica, in postoperative iridocyclitis, posttraumatic iridocyclitis, in the iridocyclitis accompanying acute rheuma-

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toid disease but not with the chronic variety. The steroids have not been helpful in the uveitis associated with Vogt-Koyanogi's syndrome, heterochromic iridocyclitis, and there have been warnings against its use in tuberculous uveitis. Woods 13 and others14 , 15. 16 have presented evidence that the tuberculous type of uveitis may flare with great violence with the cessation of steroid therapy. Contraindications to Steroid Therapy

Contraindications to systemic steroid therapy include hypertension, peptic ulcer, tuberculosis, diabetes, heart disease and coincident infectious diseases unresponsive to antibiotic therapy. It is also essential to realize that there are ocular contraindications. Herpes simplex keratitis may be aggravated by the use of local or systemic steroids. Blood as well as cortical material in the anterior chamber may be delayed in their absorption by the anti-inflammatory properties of local or systemically administered steroids. If an ocular infection is present and specific antibiotic therapy or chemotherapeutic agents are not or cannot be employed and the natural resistance of the host is unable to overcome the infecting agent, the use of steroids may eventually aggravate and increase the severity of the lesion. It is necessary that the same precautions be taken with prolonged steroid therapy for ocular disease as for diseases elsewhere in the body. Frequent urinalyses, checks on blood pressure, weight measurements, and administration of potassium and close observation for the development of acne, moon facies, supraclavicular fat, etc., must be routine. Any sign of exacerbation of the ocular inflammation should be a warning for the discontinuance of steroid therapy. When withdrawing the drug, it should reduced slowly. If cortisone, prednisolone or hydrocortisone has been be employed systemically, it may be well to taper with ACTH before concluding this form of treatment. Concentrations and Dosages

Cortisone acetate and hydrocortisone acetate may be obtained in 0.5 to 2.5 per cent concentrations for ophthalmic use. Prednisolone, prednisone and 9-alpha-fluorohydrocortisone are presently marketed in 0.5 per cent concentrations. These agents are also available combined with antibiotics, but the local use of antibiotics in the therapy of uveitis is not necessary or advisable. Prolonged use of steroids locally may lead to the development of fungi as well as bacteria in the cul-de-sac. Steroids may be injected sUbconjunctivally in a dosage of approximately 1 to 5 mg. of the preparations available for intramuscular administration. Systemically, ACTH may be given in a dosage of 10 to 20 mg. in 500 cc. of 5 per cent glucose over an 8-hour period by slow intravenous drip, or may be administered by intramuscular injection of 20 mg. four times daily, or by comparable gel preparations which allow slower absorption,

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over a longer period of time, from a single depot, reducing the necessity for frequent intramuscular injections. Oral cortisone and hydrocortisone may be given in doses as high as 300 mg. the first day in divided doses, reducing the amount to 100 mg. or less for maintenance. The amount administered will depend on the severity of the inflammation and the response to the selected dosage schedule. Prednisone and prednisolone may be given in a dosage of 40 to 80 mg. initially, reducing it gradually to the minimum amount which will produce the desired anti-inflammatory effect. Drop instillations may be instilled every half hour, hour, or three or four hours, as the particular diseased eye may require. Ointment preparations may be substituted at night. Other agents which have some anti-inflammatory effect include salicylates, phenylbutazone and go1:i salts when administered systemically. REFERENCES 1. Woods, A. C.: The Influence of Hypersensitivity on Endogenous Uveal Disease. Am. J. Ophth. 30: 257, 1947. 2. Woods, A. C., Jacobs, L., Wood, R. M. and Cook, M. K.: A Study of the Role of Toxoplasmosis in Adult Chorioretinitis. Am. J. Ophth. 37: 163, 1954. 3 Alvaro, M. E.: Steroids in Ocular Disease. Ophthalmologica (Basil) 127: 85,1954. 4. Sorsby, A.: Systemic Ophthalmology. London, Butterworth, 1951, p. 118. 5. Hogan, M.: Ocular Toxoplasmosis. A.M.A. Arch. Ophth. 56: 333, 1956. 6. Godtfredsen, E.: Pathogenesis of Concurrent Eye and Joint Disease. Brit. J. Ophth. 33: 261, 1949. 7. Woods, A. C.: The Use of Specific Streptococcic Vaccine in Nongranulomatous Uveitis. Arch. Ophth. 51: 129, 1953. 8. Leopold, I. H. and Dickinson, T. G.: Antihyaluronidase and Antistreptolysin Titers in Uveitis. Tr. Am. Acad. Ophth. & Laryng. 58: 201, 1954. 9. Smith, C. and Ashton, N.: Studies on the Etiological Problem of Uveitis. Brit. J. Ophth. 39: 545, 1955. 10. Hallett, J. and Leopold, J. H.: Streptococcal Antihyaluronidase in Uveitis. A.M.A. Arch. Ophth. 55: 313, 1956. 11. Ashton, N.: Allergic Factors in the Etiology of Uveitis. Acta 17th Councilium Ophthalmologicum, Vol. n. University of Toronto Press, 1955, p. 1214. 12. Bennett, G.: Uveitis~A Clinical and Statistical Study. Brit. J. Ophth. 39: 727, 1955. 13. Woods, A. C.: Present Status of ACTH and Cortisone in Clinical Ophthalmology. Am. J. Ophth. 34: 945, 1951. 14. Hogan, M., Thygeson, P. and Kimura, S.: Uses and Abuses of Adrenal Steroids and Corticotropin. Tr. Am. Ophth. Soc. 52: 145, 1954. 15. Leopold, 1. H., Purnell, J. E., Cannon, E. J., Steinmetz, C. G. and McDonald, P. R: Local and Systemic Cortisone in Ocular Disease. Am. J. Ophth. 34: 361, 1951. 16. McDonald, P. R, Leopold, 1. H., Vogel, A. W. and Mulberger, R D.: Hydrocortisone in Ophthalmology; Clinical and Experimental Studies. A.M.A. Arch. Ophth. 49: 400, 1953. 1930 Chestnut Street Philadelphia 3, Pennsylvania