Diagnosis and Treatment of Uveitis in Association with Sarcoidosis

DIAGNOSIS AND TREATMENT OF UVEITIS IN ASSOCIATION WITH SARCOIDOSIS

BY G. Victor Simpson, M.D.

SARCOIDOSIS MAY BE DEFINED as a chronic disease of unknown etiology. It may initially appear in the lymphatic system, for example, the mediastinal and other glands. Later it may become a widespread systemic disorder with the appearance of erythema nodosum. Involve- ment of the lacrimal and parotid glands, generalized skin and bone involvement, and serious manifestations in the lungs and eyes may develop at any time. Sarcoidosis is characterized pathologically by a reaction which develops into a granuloma or tubercle. These lesions have many epi- thelioid and giant cells, with the giant cells containing refractile, or apparently calcified, bodies. There is almost never any caseation and the lesions heal by hyalinization without shrinkage which is not the characteristic of healing in tuberculosis.1 A review of the literature indicates that this disorder had more trouble reaching its present status than most diseases. In 1869 Carl William Boeck, a Norwegian dermatologist, described an unusual skin lesion. In the same year Jonathan Hutchison, the celebrated English physician, independently reported a skin disease which he named "Mortimer's Malady." Twenty years later Besnier dignified the disease by renaming it "lupus pernio." Carl William Boeck had no further connection with the disease but in 1899 Caesar Boeck, nephew of the first Boeck, reported histologic studies of the skin and gland lesions. He was rewarded by having the disease named after him. Whereas all previous studies had described only the skin lesions, several separate descriptions of sarcoid reactions in various parts of the body were published in the next few years. Schaumann recognized the systemic nature of the disease and suggested that it be named "benign lymphogranulomatosis" to distinguish it from Hodgkin's disease, which in 1917 was called "malignant lymphogranulomatosis" and was usually a fatal disease. Schaumann studied the histologic changes in the skin and lymph gland lesions and pointed out the presence of TR. AM. OPHTH. Soc., vol. 66, 1968 118 G. Victor Simpson the refractile bodies which he thought were pathognomonic of the disease. It is now apparent that Carl William Boeck, Hutchison, Caesar Boeck, Schaumann, Heerfordt, Jungling, Kienock, and others were describing a late stage in the progress of sarcoidosis. The quiet and asymptomatic early period had been overlooked until the practice of large-scale radiography revealed lesions of the mediastinal glands and infiltrations of lung tissue which were identified as sarcoid. Complete credit cannot be given to routine roentgenographic studies. In the search for causes of ill-defined symptoms, such as cough, shortness of breath, and loss of weight, or to determine an etiology for uveitis, roentgenographic studies of the chest were to lead to the finding of paratracheal and hilar gland adenopathy, typical of granulomatous disease. Sarcoidosis is therefore a much more common disease than was previously thought. Under present management it need not be considered to be always a chronic debilitating disorder. The number of cases of sarcoidosis in New York City has been established by radiographic surveys to be about 30 per 100,000 of population. Siltzbach estimates that for every case of late symptomatic sarcoidosis there are at least four cases which will be uncovered by wider use of chest radiography. Surveys of sarcoidosis in Sweden show a frequency of 64 cases per 100,000 of population but there is reason to believe its occurrence may be higher.2 Special areas in the United States have a higher rate, particularly the southeastern states, New England, and the northern mid-west states. Series of cases have been reported from Boston, New York, Philadelphia, and Baltimore. An incidence of 11 cases per 100,000 has been reported by the Veterans Administration. Statistics on age will vary somewhat unless the age for the onset of the disease is specifically used in the record. The onset is most frequent between twenty and forty years of age but the disease has been known to occur early in life and in old age. In the United States the disease is ten to fifteen times more frequent in the Negro than in the Caucasian population and, curiously, African Negroes are much less susceptible. The disease occurs with equal frequency in Caucasian males and females but Negro females are affected with approximately twice the frequency of Negro males. Eye involvement is more common in Negro females than in Negro males.

EnOLOGY Until the cause of sarcoidosis has been further clarified, its relationship to tuberculosis must be considered. There are serious differences Uveitis in Association with Sarcoidosis 119 between the two diseases that a casual observer would find difficult to reconcile, but some students of the disease are persuaded that some- how tuberculosis is responsible for sarcoidosis. Scadding3 believes there is strong evidence that in some cases sarcoidosis is related to tubercu- lous infection. It has also been suggested that sarcoidosis is related to the collagen or the reticuloendothelial diseases. Certainly, on the basis of the tissue reaction, the diseases are not alike. In the group rather loosely included under the heading of auto-immune diseases, the characteristic reaction is fibrinoid degeneration or fibrinoid necrosis.4 In sarcoidosis, wherever the involvement, the reaction is a non-caseating granuloma.5 The im- munological and blood chemistry responses within the host in each disease are in some respects alike, which does suggest a common etiology. Cummings and Hudgins suggested in 1958 that there was a relationship between sarcoidosis and pine pollen. Cummings6 reported at the Third International Conference on Sarcoidosis in 1963 that, although it had been proved that pine pollen had antigenic properties, the relationship of these antigenic qualities to the etiology or pathogenesis of sarcoidosis remains in doubt. There is a relationship between the incidence of sarcoidosis in the southeastern United States and pine forests but reports from other parts of the world have failed to confirm a cor- relation between the incidence of patients with sarcoidosis and pine forests.

PURPOSE OF THIS STUDY This is a report of the study of the charts of 39 cases of anterior granulomatous uveitis to determine whether or not there were findings in the history, age, sex, race, onset, and the clinical picture of the eyes which could arouse a strong suspicion of sarcoidosis which might be confirmed by a reasonable study before resorting to hospitalization and surgery. The study led to a critical examination of the results of the investigation, which had been done to determine an etiology, so the further purpose of this paper is to report on the studies that were most useful in supporting the presence of the suspected systemic disease. During the past few months a small amount of Siltzbach-Kveim antigen became available for skin testing.7 The antigen has been used in the recommended manner on 14 patients to support the etiological diagnosis. A summary of the most effective immediate treatment for sarcoid uveitis and its complications will be given. It was evident from an examination of these charts that a program of supervision and therapy 120 G. Vt'ctor Simpson was necessary for the patient until the resolution of the systemic disease. It also became apparent that there are inevitable obstacles in the way of perfect management of this disease.

SELECTION OF CASES In selecting 39 well-defined cases of anterior granulomatous uveitis, 334 charts were reviewed. It is admitted that in the selection of the charts we had the advantage of knowing the duration of the attack. In general, non-granulomatous anterior uveitis is self-limited whereas granulomatous uveitis may continue its activity indefinitely under the power generated by the systemic disease. Importance, however, was not placed unduly on the duration of the attack but rather upon the clinical appearance of the eye, especially its appearance before treatment. It is important, in any event, to record what types of uveitis were rejected. (1) The largest group rejected was considered to be non-granulomatous. These were traumatic, allergic, associated with spondylitis, associated with Reiter's disease, associated with Bechet's recurrent disease, cases of sympathetic uveitis, or cases considered phacogenic in origin. (2) All cases that manifested a well-defined chorioretinitis, whether a primary attack or a recurrence, were rejected. (3) A minority of cases that were considered to be heterochromic cyclitis, diffuse uveitis such as in Vogt-Koyanagi-Harada disease, and juvenile chronic non-heterochromic cyclitis with or without joint symptoms were rejected. (4) A few charts were rejected because the information was incom- plete, the skin tests were not read at the proper time, or the patient refused prolonged treatment. This left 39 charts that seemed to contain adequate information for this study.

PERTINENT INFORMATION ON THE CHARTS HISTORY As emphasized by Hogan, Kimura, Hughes, and others, time spent with a detailed history of the patient's life and the eye disease will be rewarding. The most useful information that can be obtained is that the patient has the disease. Seven of our patients were under treatment for sarcoidosis, but the majority neither knew of the disease nor had any family contact with it. Special attention during history taking, if Uveitis in Association with Sarcoidosis 121 sarcoidosis is suspected, must be given to the onset and duration of the disease in each eye separately. If one eye is blind it is worthwhile to obtain as accurate a description of the illness as possible. It is most important to question if any local or systemic treatment has already been provided for either eye because of the effect even inadequate treatment has on the development of the classical clinical picture. Part of the history should include questioning on tuberculosis, histoplasmosis, brucellosis, beryllium contact, silicosis, leprosy, and moniliasis. Three of our patients gave a history that the entire illness began with a sore throat and an attack of suspected mumps. It is quite probable that it was an involvement of the parotid gland by sarcoid. The history should include careful inquiry concerning any joint trouble. Non- granulomatous uveitis is more often related to joint problems but in early sarcoid, arthralgia is frequently a complaint. The majority of our patients felt that the eye trouble came on with no other systemic symptoms. This is important because it is a warning to ophthalmologists that the eyes can become involved in sarcoidosis during the asymptomatic stage of the disease.

AGE Six of the 7 patients who knew they had the disease were under thirty-two years of age. The seventh patient was forty-eight years old when the eyes became involved but had had the disease for some years. Of our group of patients in whom a diagnosis of sarcoidosis seemed fairly reasonable, 23 were under forty years of age and the remaining 9 were under fifty-two. In this total series, the onset of the disease occurred in 76 per cent before the end of the third decade. This compares suitably with Mayock's analysis of 145 patients with a review of 9 of the larger series in the literature.8

SEX AND RACE In this series 100 per cent of the patients were Negro; 25 per cent were male and 75 per cent were female. This study makes no attempt to determine the number of patients with generalized sarcoidosis whose eyes will be involved, but James states that about one-quarter of all patients with sarcoidosis will have ocular lesions, predominantly uveitis. Sarcoidosis is 10 to 15 times more common in the Negro, but it does occur in Caucasians and they, too, may have uveitis. ONSET AND CLINICAL PICTURE The onset of uveitis in sarcoidosis may be sudden and painful but it does not compare with the abruptness, pain, redness, and photophobia 122 G. Victor Simpson of acute anterior non-granulomatous uveitis. Well over 75 per cent of the cases in this series began with mild subjective symptoms, little or no redness or photophobia, and many times blurring of vision was the main complaint. One of the changes that produced more pain, additional loss of vision, and forced medical attention was the onset of secondary glaucoma. It is probable that the wide difference in the clinical picture as described by various authors is a result of the duration of the disease without treatment. Sarcoid uveitis was frequently seen in our clinic as a bilateral disease and in one eye the picture of granulomatous uveitis with Koeppe and Busacca nodules had been developing for three to four weeks, but only when the second eye became involved did the patient seek treatment. Granulomatous uveitis could not have been diagnosed at that time in the second eye. It cannot be too strongly emphasized that the duration of the untreated disease makes a great difference in the clinical picture. Although the subjective differences between non-granulomatous and granulomatous anterior uveitis may be quite marked, the slit-lamp differences are controversial. In granulomatous disease the precipitates are larger, not so white, and more likely to be described as mutton fat. There are more and larger cells in the anterior chamber but somewhat less protein in the aqueous. If the disease is due to sarcoidosis and has had time to develop, Koeppe and Busacca nodules will be seen on the iris. Not all of our patients with anterior sarcoid uveitis had Koeppe and Busacca nodules, but when these nodules were present systemic sarcoidosis was either confirmed or strongly suspected. In two of our patients who had Koeppe and Busacca nodules, sarcoid was present and in addition the patients had positive serological tests for syphilis. Treatment for both diseases was given. In another patient, nodules were reported in one eye on one occasion but sarcoidosis could never be establislhed. In this series the disease was bilateral in 31 patients, unilateral in 6, and in 2 patients one eye was already blind. The following findings should arouse a suspicion of sarcoidosis: (1) Anterior uveitis in a Negro, especially female, with an onset between twenty and forty years of age makes sarcoidosis a possible diagnosis. (2) Disease is likely to be bilateral, but not necessarily at its beginning. The onset will frequently be gradual with mild, if any, symptoms of redness, pain, and photophobia. Blurring of vision will always be present. (3) Slit-lamp findings usually permit the changes to be classified as granulomatous and if Koeppe and Busacca nodules are seen, the Uveitis in Association with Sarcoidosis 123 probability of sarcoidosis is very strong. Occasionally a large granulomatous nodule will be seen in the lower iris angle.

INVESTIGATION OF PATIENTS In spite of a tendency to minimize the importance of physical examinations, blood tests, and roentgenograms, our clinic feels that considerable assistance will be obtained by a thorough study of the patient. It is sufficient to itemize the tests that have been made a routine part of the study of patients suspected to have sarcoidosis and to discuss the tests that are most valuable in supporting a diagnosis of systemic sarcoidosis. 1. Chest roentgenogram 2. Serum protein electrophoresis 3. Biopsies 4. Kveim test 5. Radiograph of hands and long bones 6. Blood calcium 7. Skin tuberculin tests 8. Sickle-cell preparation, hemoglobin electrophoresis, complete blood count, fasting blood sugar, sedimentation rate, serology, and urinalysis. The roentgenogram of the chest, the electrophoretic study of serum proteins, and the biopsies are the three most important tests. The ophthalmologist should have some understanding of the lym- phatics of the mediastinum and lungs.9 The lymph glands of the thorax may be divided into two groups: (1) parietal and (2) visceral. The only glands in the parietal group with which sarcoid may be con- cerned are the posterior mediastinal. These glands lie behind the peri- cardium in relation to the esophagus and aorta. The visceral glands consist of the superior mediastinal and the para-tracheobronchial groups. The superior mediastinal glands lie in front of and on each side of the trachea, behind- the aortic arch, which places this group high in the thorax. The azygos node is a part of this group. The para-tracheobronchial group consists of glands in front of and on each side of the trachea, glands which lie between the two main bronchi, and hilar glands which lie between the divisions of each bronchus and within the substance of the lung at the hilum. The involvement of the paratracheal and hilar nodes in sarcoid is not comparable to their involvement in pulmonary disease such as carcinoma, where the primary is in the bronchus or lung and the regional glands are involved secondarily. CZU C X, tn

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,{o . 130 G. Victor Simpson In sarcoid the posterior mediastinal, paratracheal, and hilar glands are primarily involved and the adenopathy is the initial lesion. All forms of sarcoidosis are thought to begin with asymptomatic intrathoracic lymphadenopathy. The involvement of the lung parenchyma is somewhat more obscure. Whether there might be early interstitial lung changes that are not detectable on the roentgenogram remains un- answered, but initially the roentgenographic findings seem characteristically limited to the glands. In 31 of 39 (80 per cent) of our patients the chest roentgenograms revealed some abnormality. Even this rather high incidence of thoracic involvement is less than that found by Mayock,8 who reported that 92 per cent of his patients had an abnormal chest roentgenogram at some time during the period of observation. James1o studied 123 patients with ocular sarcoidosis and found that 91 (74 per cent) had intrathoracic involvement. The earliest roentgenographic change in our group of patients was described as a fullness in the hilar regions. The reports ranged from a right superior mediastinal mass, unilateral or bilateral paratracheal adenopathy, unilateral or bilateral hilar adenopathy, occasionally an enlargement of the azygos node, which is pathognomonic of sarcoid, to extensive involvement of all these areas. Some reports indicated bilateral calcified nodular densities near the hilar areas which are the residual of healed granulomatous disease. Such a report would require the exclusion of all other systemic granulomatous diseases. The differential diagnosis will exclude silicosis, tuberculosis, histoplasmosis, and eosinophilic granuloma from sarcoid. The parenchymal changes which were found at times with or without paratracheal or hilar adenopathy were described as a fine granular appearance in the lungs, scattered irregular nodules and masses throughout the lungs, or diffuse linear and nodular densities. Frequently the report would indicate that the changes were definitely sarcoidosis and at other times would refer to granulomatous pneumonitis and indicate that the differential diagnosis included sarcoidosis. Regression of the adenopathy and parenchymal mottling frequently occurred while the patient was under observation, but on two occasions recurrence of hilar adenopathy took place coincident with a return of the uveitis. In spite of the thoracic disease in this group of patients, there were few if any constitutional symptoms and no pulmonary symptoms such as cough or sputum, although some of the patients admitted having shortness of breath. It is quite evident, therefore, that had the Uveitis in Association with Sarcoidosis 131 chest roentgenogram not been a part of the routine study, few, if any, symptoms suggested a chest examination.

SERUM PROTEIN ELECTROPHORESIS For many years the analysis of the serum protein consisted of a breakdown into albumin and globulin fractions and the result was spoken of as the albumin-globulin ratio (A/G ratio). With an increase in knowledge of serum proteins and the development of electrophoretic equipment and methods, the globulin fraction, particularly, has undergone more minute separation. We now have alpha-i, alpha-2, beta and gamma globulin fractions, along with globulin X which denotes a fraction behaving abnormally, usually in the gamma position.1' The analysis is spoken of as the electrophoretic pattern of serum proteins and has become a most valuable laboratory determination. The principle involved in electrophoresis is simple. Individual protein fractions have different electrical charges and when placed in an electrical field migrate at different speeds and therefore assume different positions. The method by which the best separation of the serum protein fractions can be achieved has improved, and at present the acetate paper technic is the standard procedure. The electrophoretic separation of normal serum determines albumin to be approximately 60 per cent of the total protein (3.4-4.1 gm per 100 ml); alpha-i globulin, 4 per cent (0.2-0.7 gm per 100 ml); alpha-2 globulin, 8 per cent (0.6-0.7 gm per 100 ml); beta globulin, 12 per cent (0.7-0.74 gm per ml); and gamma globulin 16 per cent (0.9-1.1 gm per ml). Percentages obtained in this manner, together with a chemically determined total protein value, are used to calculate the absolute values in grams per 100 ml. The test will have more clinical usefulness if the fraction values as expressed in grams per 100 ml are used for comparison rather than percentages. There are only a few diseases in which the electrophoretic pattern is pathognomonic. Perhaps the best example is the pattern found in multiple myeloma. There is a larger number of diseases, including sarcoidosis, in which the pattern is characteristically altered and should be highly suggestive of the diagnosis. There was significant alteration in the serum electrophoresis pattern in 26 of our patients and the alteration was found in a very high percentage of patients with positive chest findings. The several points in the typical pattern of sarcoidosis may be sum- marized as follows: (1) over-all moderate increase in the protein content of the serum (over 8 gm per 100 ml), (2) moderate decrease 132 G. Victor Simpson in albumin value (below 3.4 gm per 100 ml), and (3) step-like increases above normal in globulin values beginning with alpha-i and including gamma globulin.

BIOPSIES The clinical findings of bilateral paratracheal or bilateral hilar lymphadenopathy and a characteristic alteration in the serum electrophoresis is fairly good evidence that the patient has sarcoidosis, but it is helpful to obtain a biopsy compatible with the clinical diagnosis. Of the 7 patients in this study who knew they had the disease when they were first seen in the eye clinic 5 had already had a positive biopsy. Four of these had a positive scalene-node biopsy and one had both positive skin and liver biopsies. The other 2 patients had refused any type of biopsy, but the clinical diagnosis was firmly established and the uveitis was typically granulomatous. Only 4 of the remaining 32 patients were subjected to a biopsy and, in each, a scalene node showed granulomas consistent with a diagnosis of sarcoid. A higher percentage of our patients should have had a biopsy, but other support- ive evidence was strong. These 32 cases were asymptomatic. The eyes were involved early in the disease and we relied upon the clinical appearance of the eyes, the chest roentgenogram, and the serum electrophoretic pattern for a diagnosis. These patients had no conjunctival follicles, skin or scar lesions, and no peripheral glands could be palpated, so a biopsy would have meant hospitalization and a surgical procedure. Lofgren and Snellman'2 in a paper at the Third International Conference on Sarcoidosis in 1963 call attention to the increase in the findings of palpable peripheral glands with experience and they suggest that physician and surgeon together chek the patient. A scalene-node biopsy is not without some danger, and must be performed carefully to avoid pneumothorax. The areas Lofgren and Snellman suggested for biopsy are: (1) Conjunctival follicles (2) Sarcoid skin lesions (3) Post-traumatic cutaneous scars on elbows, knees, or post- operative scar areas (In the absence of recent redness and swell- ing of scar areas it is unlikely that a biopsy from those areas would show sarcoid histology.) (4) Scalene node or other palpable peripheral lymph nodes (epi- trochlear, axillary, or inguinal) (Scalene nodes can be felt only in advanced cases, so the procedure is usually carried out in the Uveitis in Association with Sarcoidosis 133 absence of palpable lymph adenopathy. The fatty tissue removed contains lymph glands.) (5) Polyps in nose, nasopharyngeal mucosa, or tonsil (6) Bronchial mucosa (7) Mediastinal glands (Carlen's mediastinoscopy).

THE KVEIM TEST Like other systemic granulomatous diseases, sarcoidosis may be present in the host a sufficient length of time to stimulate antibodies before the eye becomes involved. As ophthalmologists we are very much aware that the eye seems fated to share a late part in systemic diseases. We are therefore well acquainted with the need of skin testing, and though at times we may be confused and disappointed by the results, the over-all assistance that is provided is very much worthwhile. Assuming that a safe antigen becomes available that will detect systemic sarcoidosis, the test should become a part of the search for the cause in all uveitis patients. It is reassuring to be toldl that even the patient with asymptomatic sarcoidosis will respond witl a positive Kveim test. The Kveim test did not arouse much interest until Louis E. Siltzbach M.D., clinical professor of medicine at Mount Sinai School of Mledi- cine, and Dr. Merrill W. Chase of the Rockefeller Institute were suic- cessful in preparing a Kveim suspension from human sarcoid spleen.'3 This suspension was recommended by the Second International Con- ference on Sarcoidosis in 1960 to be a standard for calibration of specificity and sensitivity of suspensions, throughout the world. It is recommended that 0.15 ml of the antigen be injected intracutaneously into the forearm or thigh. Careful attention to many details will make the test more useful and it is suggested that anyone using the test for the first time consult Dr. Siltzbach's writings.7"14 The immediate reaction to the suspension is mild; it is of no importance and will disappear within a few days. The resulting small papule is excised four to six weeks after the injection, and tlle biopsy material is fixed, stained, and sectioned. A positive test is the finding of granulomas similar to those seen in sarcoid. The Kveim test is the only specific means of diagnosing sarcoidosis. The Siltzbach-Kveim antigen skin test was performed on 14 patients with uveitis; 7 patients had a negative test and 7 had a positive test. In 5 patients with negative tests there were no other confirming signs of sarcoidosis. In 2 patients with negative tests, however, a skin or 134 G. Victor Simpso-n scalene-node biopsy had previously been positive for sarcoid. One of these patients unquestionably had sarcoidosis which had been completely inactive for five years. The other patient was still on a maintenance dose of oral steroids after six years of treatment. In all 7 patients with a positive Kveim test, other supporting findings of sarcoidosis were present.

ROENTGENOGRAMS OF HANDS AND LONG BONES The bones of the fingers and the long bones of the body are involved very late in sarcoidosis. It is almost certain that the diagnosis will be well established by this time. Roentgenograms of this type have been discontinued in our clinic.

BLOOD CALCIUM The normal blood calcium varies from 9 to 11.5 mg/100 ml. An elevation of the blood calcium level has been found in association with sarcoidosis and has been thought to be a supporting laboratory test. A blood calcium was ordered for all of our patients and in not a single instance was an abnormal finding recorded. It is probable that the majority of the patients had had the disease for too short a time for the calcium to be altered. If this experience can be considered a fair trial the test is useless to support a diagnosis of sarcoidosis. The test has been discontinued in our studies.

SKIN TUBERCULIN TEST The best reported skin tuberculin testing to come to our attention is that by Schlaegel.15 To prove an anergy to tuberculin, which has been considered an important aid in establishing a diagnosis of sarcoidosis, a program such as that carried out by Schlaegel should be a part of the routine study. All of our patients were tested with first- and occasionally second-strength purified protein derivative, but the results could not be interpreted in a uniform manner because the readings were made by various observers and frequently the patients did not return at forty-eight hours as requested. It is usually accepted that the skin test reaction to purified protein derivative is depressed in sarcoidosis. Studies at the present time would not correspond to those made a few years ago, because fewer patients react to tuberculin now. For testing to be of any value in support of a diagnosis of sarcoidosis the reaction of the patient to tuberculin protein prior to the onset of sarcoidosis would have to be known. Whether the depressed reaction to tuberculin is part of a generalized lack of skin sensitivity is not clear. No importance was Uveitis in Association with Sarcoidosis 135 placed, in our group of patients, upon the skin reactivity to tuberculin in establishing a diagnosis of sarcoidosis.

NON-SPECIFIC STUDY Sickle-cell studies and hemoglobin electrophoresis should be performed on every Negro patient. There is no connection between sickling or abnormal hemoglobin and uveitis, but the retinal abnormalities that go along with sickling and abnormal hemoglobin are asymptomatic and quite bizarre. These abnormalities will confuse the clinical picture and may result in mismanagement of the basic disease. Complete blood count, fasting blood sugar, sedimentation rate, serology, and urinalysis should always be done in every major illness, and sarcoidosis is no exception. The results of this additional investigation provide valuable information, although they play no part in confirming the disease. The only frequently abnormal finding in this series of patients was a moderate leukopenia.

TREATMENT The best, but not the only, form of treatment for ocular sarcoidosis is the use of corticosteroids and almost without exception the response is dramatic. There are two reasons for this response; (1) the anti- inflammatory action of the agent, and (2) the immuno-suppressive effect of the steroid upon an antigen-antibody reaction.1618 Corticosteroids may be given topically for ocular sarcoidosis, in the form of drops, ointment, or subconjunctival injections which are designed to act over a prolonged period. They may also be given systemically in the form of tablets or parenteral preparations by intramuscular or intravenous methods. The absorption of oral steroids is good, so the parenteral means is rarely necessary. There are almost no contraindications to intensive use of topical steroids over a long enough period of time to bring sarcoid uveitis under good control. The possibility of a rise in the intraocular pressure is offset by the hypotonia of the uveitis. It has been our practice to administer oral as well as topical steroids in sarcoid uveitis. The systemic disease from which the patient is suffering is responsible for the uveitis and it is hoped that some of the power of the disease will be suppressed by oral steroids. The ocular involvement in sarcoidosis usually requires energetic steroid treatment. If a routine roentgenogram of the chest reveals asymptomatic sarcoid adenopathy, even if erythema nodosum has been or is present, the best treatment is observation. The reason for withholding oral steroid therapy is the dis- 136 G. Victor Simpson erythema nodosum has been or is present, the best treatment is observation. The reason for withholding oral steroid therapy is the dis- covery that spontaneous regression of the paratracheal and hilar adenopathy and the parenchymal lesions was followed by fewer recurrences than wlhen oral steroids had been given during the course of the illness and had to be discontinued. The management of sarcoid uveitis, lhowever, requires sufficient steroid to control the eye disease, but, if possible, not enough to add to the patient's systemic difficulties. The contraindications to giving oral steroids such as diabetes, peptic ulcer, tuberculosis, and mental depression should be scrupulously observed. Sarcoid uveitis is difficult to cure completely. Frequently a low-grade flare and cells in the aqueous may follow the acute attack or the patient may halve repeated recurrences when treatment is withdrawn. This plhase of the disease requires the most careful management. The ideal is to find a maintenance regimen of topical and oral steroid therapy that will completely control the disease until complete regression occurs. This requires seeing the patient fairly frequently and mak- ing minor adjustments of dosage. Prolonged treatment with steroids raises problems with which an ophtlhalmologist should be familiar. The patient should be on a low salt diet and extra potassium should be provided by orange juice and bananas. Gastric upset can be avoided by regular use of antacids (Gelusil, Maalox, or Amphojel). Prolonged streoid therapy produces adrenal suppression which may be controlled to some extent by giving the total forty-eight-hour dosage at one time on alternate days. Further control of adrenal suppression is obtained by a monthly intramuscular injection of 40-80 units of ACTH.

ALTERNATE THERAPY If for good reason the use of steroids is discontinued, a substitute therapy must be employed. Chloroquine may be given in doses of 250 mg daily. Good results have been reported by Siltzbach in cutaneous sarcoid.1Y Butazolidin or Tandearil in 100-mg doses one to four times daily may be given for their anti-inflammatory action. These drugs are very valuable and are in no way related to steroids. Frequent blood studies are necessary to avoid side effects. Chloroquine and Butazolidin should never be given at the same time.

SARCOID AND PREGNANCY The peak age of onset for sarcoidosis is the third decade which is Uveitis in Association with Sarcoidosis 137 the child-bearing period. Siltzbach20 reported 22 patients who had generalized active sarcoid disease during pregnancy. He considered that 6 of the patients had improved, 14 showed no substantial change, and 2 had deteriorated. So it would seem that pregnancy has a rela- tively favorable effect upon sarcoid. It is possible that the helpful influence was due to the increase in the mother's own corticosteroids, which are known to be elevated during pregnancy. However, the im- provement evident during pregnancy was lost during the postpartum period. Relapses were common, and the conclusion was that if the disease was active, pregnancy was not going to be permanently helpful to a sarcoid patient. Experience with sarcoid uveitis and pregnancy in this series has made us feel that a pregnancy was likely to be damaging to the eye. Two of our patients who were doing fairly well became pregnant and each of them developed a blind eye. This should not be blamed entirely upon the pregnancy since the added transportation and economic problems to clinic patients increased the burden of the disease. Visits to the clinic were curtailed, regularity of medication was forgot- ten, if not entirely abandoned, and the eye disease was bound to suffer. Whether this occurred during the pregnancy or the postpartum period was not entirely known, but it seemed fairly evident that a pregnancy was not the most helpful treatment for sarcoid uveitis. A most important point that has been determined quite accurately is that steroids administered to the mother in adequate oral or topical dosage to control the disease in no way injures the pregnant mother or the baby.22 It is suggested, however, that when the pregnancy terminates, the mother should receive extra oral steroids and the pediatrician should be alerted that the mother has been receiving steroids so that he might properly give the newborn baby steroid medication in decreasing doses until it may be permanently discontinued.

PROGNOSIS The ophthalmologist must consider the systemic as well as the eye disease in regard to a prognosis. The eye disease will do exceedingly well if the patient is seen soon after his eye becomes involved and nothing interferes with the ideal management. The drugs are available with which to treat (and most probably cure) the eye disease and its complications, if unexpected and uncontrollable situations do not arise in the patient's life. Economic difficulties, family problems, inability to get off from work to attend the clinic, pregnancy, et cetera, will influence the outcome of the eye disease. 138 G. Victor Simpson The systemic disease may require management by the medical department or the chest clinic. The milder clinical forms of the disease with lymphadenopathy and perhaps diffuse mottling of the lung parenchyma will last two years or less.21 Regression of the systemic disease occurred in many of our patients without significant impairment of any organ. It is probable that patients with more disseminated sarcoidosis will heal with some scarring. It is in the most chronic forms of systemic sarcoidosis that substantial organ impairment leads to permanent disability or worse.

SUMMARY The diagnosis, prognosis, and treatment of sarcoid uveitis has been discussed. The cause of sarcoidosis is still unknown, but the asymptomatic stage of the disease can now be more frequently recognized. The eye can become involved at any time during the illness, but in 80 per cent of the patients in this series the uveitis developed during the silent stage of the sarcoid infection. Examination of the charts of these patients has shown that the uveitis is characterized by a mild to moderate onset and if treatment is delayed Koeppe and Busacca nodules will be seen. Otherwise, the clinical picture, while frequently described as granulomatous, may not appear too different from any other anterior uveitis. If the patient is not aware of the systemic disease, a search must be undertaken. Chest roentgenograms, serum electrophoresis, and biopsies are the important tests. When the diagnosis has been confirmed, topical and oral steroids are the treatment of choice and the disease in the eye is usually brought under control quickly. Complete cure may be difficult to obtain and relapses and recurrences are to be expected. The patient must remain under frequent observation. Chloroquine and Butazolidin should be tried if steroids fail. The prognosis of early sarcoi(1osis with mediastinal adenopathy is good and is not made worse by the development of uveitis. The over- all effect of pregnancy on sarcoidosis and sarcoid uveitis is not good. It is very important to remember that if steroids are indicated they should be continued throughout the pregnancy. The pediatrician should be advised of the steroid medication so that it may be continued in the newborn for a short tapering-off period.

ACKNOWLEDGMENTS The author is grateful to William D. Foote, M.D., chief of the Uveitis in Association with Sarcoidosis 139 ophthalmological section of Washington Hospital Center, Washington, D.C., for permission to refer to many patients seen in the eye clinic. The author is also grateful to Charles W. Sprunt, M.D., eye patholo- gist of Washington Hospital Center, for his kind help in preparing and reading slides of the Kveim test, and also for his instructions regarding the sarcoid reaction. Finally, the author is grateful to the residents of the hospital and the record department for their assistance.

REFERENCES 1. Uehlinger, E., The sarcoid tissue reaction, Acta med. scandinav., 425(Suppl.): 7, 1964. 2. Siltzbach, L., Current thoughts on the epidemiology and etiology of sarcoidosis, Editorial, Am. J. Med., 39:361, 1965. 3. Scadding, J. G., The relationship of sarcoidosis to tuberculosis, Acta med. scandinav., 425( Suppl. ) :266, 1964. 4. Anderson, W. A. D., Pathology Text Book, Fifth Ed., Vol. 1, St. Louis, C. V. Mosby, 1966, p. 374. 5. Anderson, W. A. D., Pathology Text Book, Fifth Ed., Vol. 2, St. Louis, C. V. Mosby, 1966, p. 1030. 6. Cummings, M. M., An evaluation of the possible relationship of pine pollen to sarcoidosis (a critical summary), Acta med. scandinav., 425(Suppl.):48, 1964. 7. Siltzbach, L., The Kveim test in sarcoidosis-a study of 750 patients, J.A.M.A., 178:476, 1961. 8. Mayock, R. L., P. Bertrand, C. E. Morrison, and J. H. Scott, Manifestations of sarcoidosis-analysis of 145 patients, with a review of nine series selected from the literature, Am. J. Med., 35:67, 1963. 9. McGregor, A. L., Synopsis of Surgical Anatomy, Ninth Ed., Baltimore, Williams and Wilkins, 1963. 10. James, D. G., The diagnosis and treatment of ocular sarcoidosis, Acta med. scandinav., 425( Suppl.):203, 1964. 11. Stephenson, J. M. and W. T. Snoddy, Protein electrophoresis-an aid to clinical diagnosis, J. Oklahoma M.A., 53:817, 1960. 12. Lofgren, S. and B. Snellman, Principles and procedures for obtaining biopsies in sarcoidosis, Acta med. scandinav., 425( Suppl.) :225, 1964. 13. Chase, M. W., The preparation and standardization of Kveim testing antigen, Am. Rev. Resp. Dis., 84( Suppl.) :86, 1961. 14. Siltzbach, L. E., An international Kveim test study, Acta med. scandinav., 425( Suppl. ) :178, 1964. 15. Schlaegel, T. F., Jr., Granulomatous uveitis: an etiological survey of 100 cases, Tr. Am. Acad. Ophth., 62:813, 1958. 16. Schwartz, B., Corticosteroids and the Eye, In Intemational Ophthalmology Clinics, Vol. 6, No. 4, Boston, Little, Brown and Co., 1966. 17. Svanberg, N., The therapy of sarcoidosis, Acta med. scandinav., 425(Suppl.): 295, 1964. 18. Israel, H. L., Steroid therapy in sarcoidosis, Acta med. scandinav., 425 (Suppl.) :297, 1964. 19. Siltzbach, L. E., and A. S. Teirstein, Chloroquine therapy in 43 patients with intrathoracic and cutaneous sarcoidosis, Acta med. scandinav., 425 (Suppl.) :302, 1964. 140 G. Victor Simpson 20. Siltzbach, L., In A. F. Gallmacher and J. J. Rovinsky, Sarcoidosis in Medical, Surgical and Gynecological Complications of Pregnancy, Baltimore, Williams and Wilkins, 1960. 21. Douiglas, A. C., The prognosis of early sarcoidosis, Acta med. scandinav., 425( Suppl.):284, 1964. 22. Parks, J. L., Personal conmmunication.

DISCUSSION DR. SANIUEL J. KNINIRA. Sarcoidosis is a very proteani disease and the eye is said to be involved in 25 to 50 per cent of patients with the systemic disease. Ocular sarcoid uveitis accounts roughly for 40 to 50 per cent of those with ocular sarcoid. Therefore, only a small percentage of the patieits with sarcoidosis have uveitis, aind in maIny cases it is difficult to be sure that sarcoid is a factor. Sarcoidosis is indeed less common in the western states. Our uveitis series is a consultative series, and therefore, we see more serious types of disease; hence, the percentage of sarcoid uveitis should be higher than the quoted 3 to 5 per cent of all uveitis due to sarcoid in this country. The diagnosis of sarcoid uveitis is a very presumptive one at best. WVe do suspect this type of uveitis if the patient is Negro and the uveitis is grainulomatous in type. WVe are more sure of our diagnosis if there is a solid nodule present on the iris along with hilar lymphadenopathy. I must add that there are no pathognomonic signs of ocular sarcoidosis. As Dr. Simpson has pointed ouit, the uveitis often starts subacutely in the younger age group and is often asymptomatic. However, the disease may start acutely with iris nodules aind muitton-fat keratitic precipitates, and these patients do have symptoms of uveitis. Often these patients have erythema nodosum type of skin lesions. The disease becomes chronic and the prognosis poor because of the resuiltant complications: cataracts, posterior synechia, and glauicoma. In about a third of the patients the disease "burns itself out." I agree with Dr. Simpsoni, that chest radiography, serum electrophoresis, anid biopsies are the most importaint tests. We have not used the Kveim test for sarcoidosis because of the difficulty of obtaining and keeping a reliable standardized Kveim antigen. I would like to ask Dr. Simpson three questions: (1) Is it possible to give 0.15 ml of Kveim antigen intracutaneously as it is stated in the paper? (2) Were serological tests for syphilis done in any of these cases, since syphilis is an important differential diagnostic problem? (3) What is the cause of decreased vision in many of these cases? Lastly, I would like to ask Dr. Simpson to comment on the prognosis of this type of uveitis. In our experience, the treatment of this type of uveitis has been most difficult; and the ultimate prognosis is usually poor. DR. DAVID G. COGAN. Dr. Simpson, the blood calcium has not given you Uveitis in Association with Sarcoidosis any clues to the diagnosis in your cases. Elevation of the blood calcium may be infrequent in band keratopathy, but I would like to cite a single case of a patient in whom corneal calcification secondary to blood calcium elevation in sarcoidosis was the presentinig symptom. As a matter of fact, this is the most marked case of corneal calcification that I have seen from hypercalcemia. The patient was a middle-aged Caucasian who complained of blurring of vision. On examination he had an extensive diffuse calcification beneath the epithelium of the corneas. He had no other symptoms. Radiographs of the chest were normal. Not unitil the patieInt was found to have a mild fever and a slightly tender right upper quadranit, did we discover that he had a granuloma in the liver. A biopsy of the liver disclosed typical sarcoid. He was treated with steroids for the next five or more years, anid his corneal calcification largely disappear-ed on1 this regimen. The calcificationi came back, as did the other symptoms of hepatitis, wbhen steroids were reduced. DR. G. VICTOR SYNIPSON. I appreciate Dr. Kimura's and Dr. Cogan's remarks. If I uinderstood Dr. Kimura correctly, he asked whether I had any difficulty injecting 1.5 ml of aintigeni intracutianieously. No, we have not had any difficulty. I do this paiticular test myself because of the scarcity of the antigen. I use a loupe for good visioIn so that I cani tell when the hair follicles are lifted up. I know then that the anitigeni is intracutaneous. In additioni to the specific tests for sarcoid disease, we have a battery of tests. We use the VDRL as a routine test for syphilis, and if it is non-reactive we do not pursue the testing any further. If the test is reactive the FTA test and others are employed. Sarcoid disease is a very serious one in the Negro race and must sturely be responsible for mainy partially or totally blind patienits in the eastern anid southeastern United States. It is not too difficult to establish the etiology in a case of sarcoid uveitis, aind the available drugs will pretty well control the eye disease. However, the complications developing from delayed initial treatment, or failure to conitiniue treatment, are difficult to manage, and considerable impairment of functioni, if not total loss of vision, may result. NVhat this disease needs is an organized attempt to find and eliminate the cause. A project of this sort could be started by a committee from each national eye society. It was a surprise to me that so little has been written in this country about such a serious disease. In the meantime, it is not einough that the patient with sarcoid uveitis be told when to returni to the cliniic. The social worker must be alerted if the patient has missed a visit, and find out why the visit was missed. Many times it is for financial reasons, and a way must be found for the patient to continue visits to the clinic and never to be without necessary treatment. These few remarks have to do with the prognosis, because it is my belief that if these cases are watched, the prognosis will be better.