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SURVEY OF OPHTHALMOLOGY VOLUME 30. NUMBER 4 * JANUARY-FEBRUARY 1986

REVIEW

Pediatric Ocular Sarcoidosis DARREN L. HOOVER, M.D., JEMSHED A. KHAN, M.D., JOSEPH GIANGIACOMO, M.D.

Department of Ophthalmology, University of Missouri School of Medicine, Columbia, Missouri

Abstract. Sarcoidosis is an uncommon cause ofchildhood uveitis. However, the ophthalmologist familiar with the clinical features of childhood sarcoidosis can play a key role in the diagnosis and treatment of this disorder. Two subsets of pediatric sarcoidosis are identified. The 8-15 year age group has almost universal lung involvement, with the eye, skin, liver, and spleen involved in 30-40% of cases. Children 5 years of age and under are characterized by the triad of uveitis, arthropathy, and skin rash. The epidemiology, clinical features, diagnostic evaluation, and ocular management of pediatric sarcoidosis are reviewed. The clinical and laboratory findings that distinguish sarcoidosis from other causes ofchildhood uveitis are discussed. (Surv Ophthal- mol 30:2 15-228, 1986)

childhood uveitis ?? conjunctival biopsy ??

pediatric sarcoidosis

Key words. angiotensin-converting enzyme ?? antinuclear antibodies ??

juvenile rheumatoid arthritis .

Sarcoidosis is a chronic systemic granulomatous disease of uncertain etiology whose manifestations are protean and clinical course variable. The disease usually presents in adults between 20 and 40 years of age.35,4’,75,77 Although the disease is relatively rare in children, several hundred cases in children 15 years of age and under have been documented.37 The ocular features of pediatric sarcoidosis have only infrequently been described in the ophthalmology literature.‘*,**

We became interested in ocular involvement in pediatric sarcoidosis through a patient of our own, a 5-year-old female who presented with painless peri- orbital swelling which had appeared several months after onset of joint stiffness and swelling. In this review, features of our patient, who will be reported in detail elsewhere,54 are integrated with those presented in published reports of 25 other patients with sarcoidosis aged 5 years and under.

A. AGE

I. Epidemiology

Pediatric sarcoidosis can be divided into two subsets on the basis of age at the time of onset of disease and the frequency of organ system involvement. Among children, most cases of sarcoidosis begin between the ages of 8 and 15 years.37,42,48,63,g6 This group is characterized by almost universal lung involvement and involvement of the eye, skin, liver, and spleen in 30 to 40% of cases.42,48,g6 Joint disease is rare.42,48,96;101 In contrast, those cases of sarcoidosis beginning at age five years and under are distin- guished by the triad of uveitis, arthropathy, and skin rash.37,74 Pulmonary disease is present in only one-third of these patients. These two distinct subsets of pediatric sarcoidosis are related by their multisystemic nature and characteristic biopsy finding of noncaseating epithelioid cell granulomas.

215

216 Surv Ophthalmol 30(4) January-February 1986

TABLE 1

HOOVER ET AL

Features of 26 Children With Sarcoidosis Aped 5 years and Under

Report Sex Race Age of Uve- Arthri- Complications Other Ocular Onset itis tis Rash of Uveitis Features

Burman & Mayer (1936)’ Newns & Hardwick (1939)73 Posner ( 1942)83

Castellanos & Galan ( 1946)t4

Lightwood ( 1951)61

Beier ( 1964) 3

Schweizer & Kanaar (1967)g3 Toomey & Bautista (1970) lo4

North et al (1970)74 North et al (1970)74

North et al ( 1970)74

North et al (1970)74

North et al (1970) 74

North et al ( 1970)74

Gluck et al (1972)” Morrison ( 1976)7’ Appleyard ( 1976) ’ Waldman (1977) lo6 Harris ( 1978)33 Cohen et al (1981)”

Henkind ( 1982)35

Hetherington ( 1982)36

Rosenberg et al ( 1983)87

Thomas et al (1983) lo3 Gupta & Chatterjee ( 1983)3’

Khan ( 1985)54

F M F

M

F

M

M F

F M

M

F

M

F

F M F F F F

M

F

F

F M

F

W W W

5 Yr 1.75 yr 9 mo

W 3 Yr

NR 3 Y’

W

W W

W NR

B

2.5 yr

1.5 yr 3.5 yr

9 mo 7 mo

3 Yr

NR 2 Yr

NR 9 mo

NR 4 mo

W W

NR W B W

1.5 yr 4 yr

11 mo 18 mo 2.5 yr 3 mo

B

W

3 yr

3 mo

W

W Indian

W

1.5 yr

4.5 yr 5 yr

1.5 yr

- - -

+

+

-

+ +

+ +

+

+

+

+

+ + + + + +

+

+

+

- -

+

+ + -

+

-

-

+

+

+

NR

+

_ - + _ + -

+ posterior synechiae

+ posterior synechiae

+ -

+ - + posterior synechiae

band keratopathy + posterior synechiae + band keratopathy

_ -

+ band keratopathy “blindness”

+

+

cataracts glaucoma band keratopathy cataracts posterior synechiae band keratopathy cataracts posterior synechiae

-

posterior synechiae posterior synechiae posterior synechiae band keratopathy

NR NR

+ synechiae

+ _

_ - + -

- - _

exophthalmos esophoria

retinal edema macular exudate photophobia

-

- conjunctival cysts episcleritis photophobia “scleral lesions”

_

photophobia iris nodules coirjunctival nodules

-

_

-

iris nodules - - _

optic disc edema focal choroiditis conjunctival nodules photophobia posterior uveitis

focal choroiditis optic neuritis phlyctenular keratoconjuncti- vitis photophobia conjunctival cysts

_ -

optic disc edema focal choroiditis orbital infiltration

F = female; M = male; W = Caucasian; B = Black; NR = not reported.

PEDIATRIC OCULAR SARCOIDOSIS 217

TABLE 1

(Continued)

Diagnostic Biopsy Site

Svnovium Skin Other ANA

_

_ + +

_ +

c

_ +

+ lymph node, lung, liver, spleen, kidney, bone marrow

+ + lung, muscle, lymph node, bone marrow

+ + muscle, liver, spleen

- +

_ + _ -

+ liver, spleen - Kveim test

+ + + kidney

+ - conjunctiva - + salivary gland

+ parotid gland lymph nodes, Kveim test

+ + conjunctiva, liver, muscle lymph nodes

+

A-

+ + liver + + + liver + + Kveim test + + lymph node

+ conjunctiva

+ conjunctiva + liver + conjunctiva

+

_

- +

+ liver + lymph node - liver

The highest incidence rates of sarcoidosis have been noted in young adults, North American blacks, residents of the South Atlantic and South Central states, and residents of rural areas.6 Gordis’ review3’ of the literature on sarcoidosis in children indicated a low incidence in individuals less than 16 years of age, with a rapid increase in the later teen years, peaking at ages 20 to 29 years. In the United States, the incidence then gradually tapers to a low rate after 70 years of age. 1g,47 Siltzbach and Greenbergg6 reported that in both Japan and Hungary the preva- lence rate of sarcoidosis in children up to the age of 15 years appears to approach that of adults. They attributed this finding to the mass radiographic sur- veys in these two countries.g6 Several studies support this claim. 51,62 For example, Kendig and Niitu” have reported that only 3 of 45 Japanese pediatric patients with sarcoidosis were symptomatic at the time of diagnosis, and their symptoms were related to their coexisting ocular inflammation. All 45 patients demonstrated pulmonary disease on chest x-ray.

B. RACE

The Black population in the United States has the highest rate of sarcoidosis in the world, followed by Norway, Sweden, and Ireland.6 The risk of sarcoidosis is ten times higher in Black adults than in Caucasians in the United States. Statistics compiled from the three largest series of children in the Unit- ed States aged 8-15 years showed a Black-to-Cauca- sian ratio of 3 : 1. Overall, this aggregate of 76 patients from the eastern United States included 55 blacks (72%), 19 Caucasians (25%), and 2 Ameri- can Indians.42,48,g6 In our review of 26 cases of sarcoidosis in children aged five years and younger, the disease afflicted 17 Caucasians and three Blacks (Table 1). The racial identity was not reported in 6 cases.

C. GENDER

There is evidence that adult females are at 2-3 times greater risk for the development of sarcoidosis than males.‘j Males and females were equally affected among children 8-15 years of age.42,48,g6 Among children aged five years and younger, 16 females and 10 males were affected (Table 1).

D. GEOGRAPHIC FACTORS

The rates of adult sarcoidosis in the United States are much higher in the rural areas of the Middle Atlantic and South Central states than in other re- gions.6 The three largest single institution series of children in the 8-15-year age group are from New York, North Carolina, and Virginia.42,48zg6 The incidence of the disease among children five years of age

218 Surv Ophthalmol 30(4) January-February 1986 HOOVER ET AL

and younger is too low to suggest geographic risk factors. The predominance of sarcoidosis in the rural Southeastern United States and Middle Atlantic states suggests an environmental, occupational, or infectious disease factor in the etiology of the disease. Nevertheless, no specific etiologic agent or definite causal association has yet been identified.6

E. FAMILIAL ASSOCIATIONS

The clustering of sarcoidosis in families has been reported. Kendig and associates reported three cases in siblings under 15 years of age.52 Schweizer and Kanaar reported sarcoidosis in a 2-year-old boy and his brother.g3

The British Thoracic and Tuberculosis Associ- ation surveyed its members for families in which more than one member was affected by sarcoidosis.’ Sixty-two instances of familial associations were identified, and included five twin pairs (4 monozy- gotic, 1 dizygotic), 28 sibling pairs, 22 parent-child pairs, and 7 husband-wife relationships. The most significant finding was the preponderance of like- sex over unlike-sex pairs among both siblings and parent-child associations. The rarity of spousal involvement makes a genetic cause of aggregation more likely than an environmental cause. Headings and coworkers studied the familial distribution of sarcoidosis in a black adult population in Washing- ton, D.C. and found substantial support for a multi- genie mode of inheritance.34

Fig. 1. Yellow multifocal chorioretinal granulomas with optic disc edema and posterior vitritis in a 5-year-old child with sarcoidosis.

II. Ocular Manifestations A. UVEITIS

Anterior uveitis is the most common ocular mani- festation of sarcoidosis in both the younger and older pediatric age groups. In the 8--15-year age group, anterior uveitis has been found in 21 to 48% of patients. 42,48,g6 The three largest series in this age group described anterior uveitis in 24 of 76 cases (32%). 42,4*,96 Loss of visual acuity or eye pain was described as a presenting symptom in 15 of the 76 cases (20%). Two cases presented with “blindness” at the initial examination and five cases ultimately developed “blindness.” The causes of “blindness” were not delineated and the rates of complications like glaucoma, cataracts, band keratopathy, and posterior synechiae were not discussed. Anterior uveitis and its sequelae were among the most serious consequences of untreated or inadequately treated pediatric sarcoidosis in this age group.42,48,50,g6 Cases of severe granulomatous anterior and posteri- or uveitis in this 8-15-year age group have been reported.28,46

rior and posterior uveitis were described in 5 of the 20 cases. Pain and photophobia were infrequent complaints in these patients whose average age was about two years at the onset of the disease. Compli- cations arising from untreated or inadequately treated uveitis included synechiae, band keratopathy, cataracts, and glaucoma; these affected 14 of the 20 cases. There is no consistency of examination technique among these reports and, in fact, many of these patients may not have had complete ophthalmic examinations.

Two types of adult sarcoid anterior uveitis have been de6ned.4’,75 Chronic granulomatous iridocyclitis is the more common and is characterized by mutton fat keratic precipitates and iris nodules. Chronic iritis has an insidious onset, often leads to secondary glaucoma and cataract formation, and responds poorly to steroids. Acute iridocyclitis, by contrast, is less common and characterized by fine keratic precipitates and ciliary injection without iris nodules. It has an abrupt symptomatic onset and responds well to topical corticosteroids. Detailed descriptions of pediatric sarcoid anterior uveitis have been published only infrequently. Chronic granulomatous iridocyclitis with mutton fat keratic precipitates and iris nodules,28,46 and acute iridocyclitis with fine keratic precipitates and no serious sequelae54 have both been found.

In our review series of 26 cases of pediatric sarcoi- Multifocal chorioretinal granulomas with or dosis in children 5 years of age and under, anterior without optic disc edema and vitritis have been uveitis was present in 20 cases (Table 1). Both ante- documented in both the younger’8,36,54 and older28,46

PEDIATRIC OCULAR SARCOIDOSIS

pediatric age groups (Fig. 1). Obenauf and coworkers described chorioretinal nodules in 11 of 202 adult patients with ophthalmic sarcoidosis, and vitreous cells in six of 202 cases.75 Retinal periphlebitis is frequently found in adult patients, but to our knowledge has not been described in children.4’a75 The posterior segment manifestations of adult sarcoidosis have recently been reviewed.13

B. EYELID INVOLVEMENT

Relatively little attention has been given to eyelid involvement in sarcoidosis.35 Kendig and associates noted characteristic “millet seed” nodules on the eyelids of two siblings 12 and 13 years of age with sarcoidosis.j2 These skin nodules disappeared after a course of systemic prednisone.

C. CONJUNCTIVAL INVOLVEMENT

Conjunctival nodules and cysts have been reported in pediatric sarcoidosis,‘8,74~87,‘04 and a biopsy specimen of these lesions or clinically uninvolved conjunctiva has often been diagnostic.‘8,35s36,74 Lit- erature concerning conjunctival involvement in adult sarcoidosis is discussed elsewhere (Section 1V.A.).

D. SCLERAL AND EPISCLERAL INVOLVEMENT

Scleritis and episcleritis are unusual manifestations of ocular sarcoidosis in both children74 and adults.26

E. LACRIMAL GLAND INVOLVEMENT

Obenauf and coworkers noted swelling of the lacrimal gland in 32 of 532 (6%) adults with sarcoidosis.15 Weinreb has also shown that adult patients with presumptive sarcoidosis and positive gallium scans of the lacrimal gland have a high yield of positive transconjunctival gland biopsies.“’ To our knowledge, lacrimal gland involvement has not been appreciated in children under 15 years of age. It is often asymptomatic and may require a biopsy or gallium scan to prove its existence.35

F. ORBITAL INVOLVEMENT

Orbital infiltration causing proptosis, a rare finding in adults, 75 has been demonstrated by comput- erized axial tomography in one pediatric patient (Fig. 2) .54

In summary, many of the ocular findings in adult patients with sarcoidosis have been described in pediatric sarcoidosis. The rate of ocular involvement in the 8-15-year age group is similar to that described for adults (Table 2). Ocular involvement was found in over 75% of patients five years’of age and under in our review series, and in 18 of 20 patients reported since 1967. Patients in both sub-

Fig. 2. Left orbital infiltration and proptosis in a 5-year-

old child with sarcoidosis.

sets of pediatric sarcoidosis were often asymptomatic in the presence of advanced ocular disease.

III. Systemic Clinical Manifestations The most common presenting complaints from

three series of children aged 8-15 years included constitutional symptoms (38%) and respiratory symptoms (28%). 42,48,g6 Other common presenta- tions included weight loss (30%), fever (24%), eye pain or visual changes (20%), and lymph node en- largement (17%). In contrast, the initial symptom in children aged five years and under is usually arthritis or a rash. Eye pain and photophobia are uncommon despite the frequent incidence of uveitis in this age group (Table 1). Unexplained episodic fevers occurred in 12 of the 26 younger chil- &.en~3,14,18,31,33,36,49,54,61,74,83,87

Multiple organ system involvement is the rule in

TABLE 2

Organ System Involvement in Pediatric and Adult Sarcoidosis

As Age O-5 8-15

yearst years* Adults: -~ No. % No. % No. %

Uveitis 20 77 24 32 202 38 Arthritis 1973 11 **

Rash 21 81 23 30 122 23 Lung 9 35 74 97 505 95 Peripheral lymphadenopathy 11 42 54 71 149 28 Hepatomegaly 13 50 31 41 117 22 Splenomegaly 12 46 26 34 69 13

Wee Table 1 (26 gatients). *From Siltzbach,g Jasper,42 Kendig (76 patients). IFrom 0benauf75 (532 patients). **38 of 532 patients (7.2%) were reported to have “mus-

culoskeletal involvement.”


Fig. 3. Noncaseating epithelioid granuloma with giant cells from a synovial biopsy in a 5-year-old child with sarcoidosis. ( X 40).

both subsets of pediatric sarcoidosis, and is summa- rized in Table 2. Among children aged 8-15 years, lung involvement is almost universal (97%) and generalized lymphadenopathy is seen in a majority of patients (7 1%). Hepatomegaly, splenomegaly, skin lesions, and uveitis are also found in 30-40% of these children. Joint disease is rare.42,48,g6

Among children aged five years and under, the triad of uveitis, arthritis, and skin rash was the most frequently associated physical finding. The full triad was seen in 14 of 26 patients, and at least two of the three features were seen in 20 of 26 patients (Table 1). Hepatomegaly, splenomegaly, lymphadenopathy, and pulmonary disease were seen less often (Table 2).

Sarcoid arthritis in young children is usually characterized by boggy, nontender effusions of the knees and wrists and synovial thickening. Juvenile rheumatoid arthritis is frequently associated with severe limitation of joint motion, whereas there is very little limitation of motion in childhood sarcoid arthritis.74 Thirteen of the nineteen patients with sarcoid arthritis in our review series had synovial

biopsies performed (Table 1). Ten of the thirteen biopsies showed the characteristic noncaseating granulomata with epithelioid cells (Fig. 3). Arthral- gias but not arthritis were noted in two additional patients.3x31

Cutaneous manifestations can be divided into those that are specific and those that are nonspecific 53 Specific lesions (i.e., those that on biopsy reveal noncaseating granulomas) were found in 14 of 26 children aged five years and under. Nonspecific lesions refer to cutaneous changes that on biopsy fail to reveal granuloma formation, but which are associated with sarcoidosis. Erythema nodosum is the principal example of a nonspecific cutaneous lesion.

Erythema nodosum usually presents as subcuta- neous, erythematous, tender nodules most com- monly in the anterior tibia1 area. It was present clinically in 5 of 26 patients aged five years and younger,3,1~,3~,54J03 and biopsy-proven in two of the five cases.18,36 These lesions tend to involute sponta- neously. The histology reveals septal panniculitis in which the infiltrate consists predominantly of neu- trophils early, and lymphocytes and histiocytes lat-


er.j3 Erythema nodosum is not associated with juvenile rheumatoid arthritis and the other common pediatric arthridities associated with uveitis.21 Its presence in adults with sarcoidosis and uveitis suggests a good prognosis; 72 due to limited data a similar conclusion cannot be made in children.

In pediatric sarcoidosis, involvement of almost every organ system has been described. Parotid gland infiltration is unusual but may present as a facial nerve palsy. 31,74 Cardiac involvement may be detected as a conduction defect on the electrocardio- gram. 42,48,61 Central nervous system disease has also been described, causing seizures and diabetes insi- pidus. 42,48,68,74,83 Renal sarcoidosis is rare in children.6’>*3,104

IV. Diagnostic Testing The laboratory diagnosis of ophthalmic sarcoido-

sis has recently been reviewed by Weinreb and Tessler.“’ Diagnostic testing in the pediatric age group is considered here.

A. BIOPSY

An enlarged lymph node is probably the most appropriate site to biopsy in the older pediatric patient. The three largest series in the 8-15 year age group reported 57 positive peripheral lymph node biopsies in 76 patients. 42,48,g6 Peripheral lymph node biopsies were often positive in younger children too (Table 1).

The skin may be the most appropriate site to biopsy in children aged five years and under. A skin rash was reported in 2 1 of 26 patients in our review series (Table 1). Skin biopsies were reported in 15 cases, and 14 showed characteristic noncaseating granulomas. A skin rash was found in only about one-third of patients aged 8-15 years (Table 2) .42,48,g6

Blind conjunctival biopsies yield diagnostic results in 1 O-28% of cases of suspected adult sarcoidosis.451”2 The yield approaches 75% when typical nodules are present. 67 Cases of positive conjunctival biopsies in children have been reported.18.35,36,74 Most authorities recommend conjunctival biopsies in all cases of suspected sarcoidosis because they are performed easily and virtually without risk.25~45~67~1’2

Less accessible sites such as the lung, liver, and synovium should be biopsied if involvement is clinically suspected and biopsy specimens elsewhere are nondiagnostic. Ziehl-Nielsen’s acid fast stain and Grocott’s methenamine silver stain should always be performed to rule out the presence of mycobac- teria and other microorganisms.

B. KVEIM TEST

In children, the Kveim test may be useful because of its noninvasive nature. The Kveim test attempts

to elicit a specific skin reaction by the intracutane- ous injection of emulsified sarcoid tissue into patients with suspected sarcoidosis. Siltzbach and Greenberg reported a positive reaction in 16 of 18 patients in the 9-15 year age range.g6 Kendig and Niitu reported a positive reaction in four of four Japanese patients aged 8-15 years.5’ In our review series of children aged five years or less, the Kveim test was performed on three patients3,74,106 and two positive reactions were elicited.74,‘06 The Kveim test is now done infrequently because the testing agent is not commercially available and must be obtained from the spleen of a patient with active sarcoidosis.82

C. RADIOLOGIC STUDIES

Radiographic evidence of bilateral hilar adenopathy, with or without parenchymal involvement, is the hallmark of the disease in older children.42~48~68~g6 The association of paratracheal adenopathy with hilar adenopathy is more frequent in children (88%) than in adults (31-37%) .68 Parenchymal lesions may be classified as (1) miliary size densities, (2) micronodular lesions, (3) large confluent mass lesions that may progress to cavitation, (4) intersti- tial fibrosis, or (5) “alveolar sarcoid” resembling pulmonary edema. 3g Parenchymal disease without hilar adenopathy is uncommon in children.68

Hetherington found that abnormal hand bone roentgenograms were unusual in older children, but were common in up to 50% of children less than four years of age. 37 Typical findings included lacy osteopenia and punched out lesions. Merten and coworkers6* studied a total of 26 patients (average age 13 years) with sarcoidosis and found no lytic lesions in the hands or feet in 10 patients for whom radiographs of the hands and feet were obtained. Skeletal sarcoidosis in this series was limited to axial involvement: thoracic spondylitis in one case, and cervical-thoracic-lumbar spondylitis associated with focal lytic destruction in the sternum and ribs in another. Jasper and Denny obtained hand x-rays in 21 of 25 patients aged 8-15 years and all were norma1.42 North and associates studied five patients under four years of age and found only slight joint osteoporosis in three patients and normal joint findings by x-ray in two others.‘* Radiologic evidence of erosive bone disease was felt to be less common in early childhood sarcoid arthritis than in juvenile rheumatoid arthritis.

D. SERUM ANGIOTENSIN CONVERTING ENZYME (ACE)

Epithelioid cells derived from macrophages are the most likely source of increased serum ACE activity in sarcoidosis.g7 Consequently, the serum ACE level appears to reflect the total body mass of


ACE-producing granulomas and, hence, disease activity.

Serum ACE values are elevated in 60-90% of adult patients with sarcoidosis and they correlate well with disease activity. “* About 80% of children aged 8-15 years with sarcoidosis also have an elevated serum ACE level at the time of initial diagnosis, and correlation with pulmonary disease activity has been seen.85 Only two children aged live years and under have been reported as having elevated serum ACE levels in our review series,87,‘03 and one of these patients had severe pulmonary disease.‘03 Two other children aged five years and under had normal serum ACE levels despite the presence of anterior and posterior uveitis;35a54 one of these patients was receiving topical corticosteroids when the serum ACE values were obtained.54

Serum ACE values are unusually high in normal children compared to normal adults and remain high until 18 years of age. 85 Mean serum ACE activity in 164 normal children from 0 to 15 years of age was 46.7 5 11.93 nM/min/cc; 32 normal adults over 18 years of age had a mean value of 32.1 + 8.53 nhllminlcc in the same study. Therefore, serum ACE activity in children with suspected sarcoidosis must be compared to normal age-matched values.

Elevated serum ACE measurements in adult patients with granulomatous uveitis support a presumptive diagnosis of sarcoidosis.86~‘0~“’ The diagnostic value of elevated serum ACE activity in pediatric patients with uveitis remains unproven. Increased serum ACE activity is nonspecific and has also been reported to occur in primary biliary cirrhosis,“’ Gaucher’s disease,58 leprosy,5g histoplasmosis 88 histiocytic medullary reticulosis,84 hyper- thyro;dism,“” and diabetes mellitus.60 These disease entities, with the rare exception of diabetes mellitus, are not associated with childhood uveitis.

Systemic glucocorticosteroids significantly lower serum ACE levels in both adults** and children85 with active pulmonary sarcoidosis. Weinreb and Kimura”’ studied adult patients with granulomatous uveitis and no evidence of systemic sarcoidosis. Patients treated with topical steroids had lower mean serum ACE activity than untreated controls, but there was significant overlap in the range of serum ACE measurements in these two groups.

E. SERUM ANTINUCLEAR ANTIBODIES

Serum antinuclear antibodies were sought in 14 of the 26 patients aged five years and under in our review series (Table 1). They were present in only one of these 14 patients. 87 Nine patients with the triad of sarcoid arthritis, uveitis, and absent antinuclear antibodies were identified; only one patient had arthritis, uveitis, and antinuclear antibodies

present (Table 1). This laboratory test may help differentiate childhood sarcoid arthritis from juvenile rheumatoid arthritis, in which over 80% of patients with uveitis have antinuclear antibodies.g0

F. SERUM AND URINE CALCIUM

Elevated serum and urine calcium levels in sarcoidosis are due to increased sensitivity to vitamin D or increased activity of 1, 25 dihydroxy vitamin D, which in turn increases absorption of calcium from the intestine. Hypercalcemia and hypercalcuria occur in lO-17% of adult cases.57

Among children aged 9 to 15 years, Siltzbach and Greenberg found serum calcium levels above 11.5 mg% in three of 13 patients.g6 Jasper and Denny found serum calcium levels above 11 mg% in 13 of 25 cases,42 and Kendig found identical calcium elevations in 5 of 30 cases.48 Overall, hypercalcemia was identified in 2 1 of 68 cases in these three series of children aged 8-l 5 years. Urine calcium levels were not reported.

Among children aged five years and under, hypercalcemia was identified in five of 26 patients.‘,‘4,6’,74,g3 Three additional patients had elevated urine calcium excretion despite normal serum calcium levels.‘813’,36

G. HYPERGAMMAGLOBULINEMIA

Hypergammaglobulinemia has been noted in 2&25% of adults, primarily among Blacks.57 Siltz- bath and Greenberg reported total serum globulin levels above 3.5 gm/lOO cc in 10 of 16 patients;g6 Kendig reported identical elevations in 22 of 30 patients aged 8-15 years. 48 The incidence of this laboratory finding in younger children is difficult to de- termine due to infrequent reporting.

H. MISCELLANEOUS

Other laboratory anomalies reported with frequency in pediatric sarcoidosis include eosinophilia, leukopenia, elevated erythrocyte sedimentation rate, and elevated serum alkaline phosphatase.37,48

V. Differential Diagnosis Sarcoidosis is an uncommon recognized cause of

uveitis in childhood. Perkins reported four cases of sarcoid uveitis out of 150 cases of uveitis in persons under the age of 16 years.8’ Two patients had only chronic anterior uveitis and two had chronic anteri- or uveitis and papillitis. More recently, Kanski and Shun-Shin44 reported only three cases of sarcoid anterior uveitis among 340 patients under 15 years of age with anterior uveitis and a specific systemic disease.

Juvenile rheumatoid arthritis (JRA) is by far the most common systemic disorder associated with


TABLE 3

Summary ofFindings in Juvenile Rheumatoid Arthritis (JRA) and Uveitis Versus Childhood Sarcoid Arthritis (CSA) and Uveitis

JRA with uveitis# CSA with uveitis*

1. Uveitis

2. Articular involvement

3. Skin lesions

4. Orbital infiltration

Anterior uveitis present in lo-20% of patients with JRA Often clinically silent Posterior segment inflammation rare

Characteristically nongranulomatous ANA present in 79 to 88% ACE values unknown Pauciarticular in 80 to 90% of cases Usually minimal joint swelling Marked pain and limited motion are characteristic Radiographic erosive bone disease common Giant cells and granulomas on joint biopsy uncommon Good response to salicylates Rash in 7 of 32 cases with pauciarticular arthritis II

Erythema nodosum not reported

Not reported

Anterior uveitis present in 16 of 19 cases (84%) with arthritis Often clinically silent Posterior segment inflammation in 3 of 16 cases with anterior uveitis and arthritis Granulomatous or nongranulomatous ANA absent in 9 of 10 cases ACE values may be elevated Usually polyarticular Usually marked joint swelling Minimal pain and limitation of motion are characteristic Radiographic erosive bone disease in about one-half of cases with arthritis Noncaseating granulomas in 10 of 13 joint biopsies Poor response to salicylates Rash in 14 of 16 patients with both arthritis and uveitis 5 years of age and under Erythema nodosum in 5 of 26 cases aged 5 years and under Reported in 1 case54

*Data derived from cases listed in Table 1 #See section V. A for further discussion.

anterior uveitis in childhood, accounting for over 80% of patients in the review by Kanski and Shun- Shin.44 Chylack and coworkers followed 210 patients with JRA closely for 14 years and detected iridocyclitis in 36 cases (1 7.2%).17 Other disorders causing childhood iridocyclitis include juvenile ankylosing spondylitis, juvenile psoriatic arthritis, Reiter’s disease, Behcet’s disease, and Vogt-Koyan- agi-Harada syndrome. 44 Sarcoidosis in children aged five years and under may resemble JRA because a rash, arthritis, and uveitis may be seen in both clinical entities. However, distinguishing features should be sought (Table 3). The diagnosis of sarcoidosis should be entertained when the arthritis is polyarticular, when the uveitis is granulomatous, when both anterior and posterior uveitis are present, when antinuclear antibodies are absent, and when the serum angiotensin-converting enzyme level is elevated.

A. JUVENILE RHEUMATOID ARTHRITIS

In recent years, rheumatologists have identified three subgroups of JRA based on clinical findings and serologic studies: systemic onset (Still’s disease), polyarticular, and pauciarticular.7,‘2,89 By definition, polyarticular disease involves five or

more joints, and pauciarticular disease involves fewer than five joints.

About 20% of all JRA patients present with an acute systemic illness whose manifestations include a high fever, evanescent rash, hepatosplenomegaly, lymphadenopathy, polyserositis, myocarditis, peri- carditis, pneumonitis, and pleuritis. Severe arthritis develops in 25%. 12,8g Calabro followed 20 children for 15 years with this presentation and detected chronic iridocyclitis in only one case.” Systemic onset JRA accounts for only l-6% of patients with JRA and uveitis.‘7x44

About 40% of children with JRA develop sym- metric polyarticular disease, in which joints are swollen, tender, and restricted in motion. Except for a low-grade fever, weight loss, and mild hepatosplenomegaly, systemic manifestations are by definition absent.‘2,8g Calabro followed 48 children for 15 years with polyarticular JRA and detected iridocyclitis in only one case.12 Polyarticular JRA accounts for about 9-14% of patients with JRA and uveitis.‘7a44

About 40% of children with JRA have pauciarticular arthritis.‘2,8g Iridocyclitis is the most serious complication in this subgroup which accounts for 78-90% of patients with JRA and uveitis.17s44 Large


joints such as the knees, ankles, and elbows are most often involved. Calabro found a low grade fever present in 16 of 32 patients, while rash (7), lymphadenopathy (6)) splenomegaly (7)) and hepatomegaly (4) were found less frequently over a 15-year period.” The frequency of iridocyclitis in pauciarticular JRA ranges from 22 to 34%.‘*,” Of these patients 72-80% are female.‘2~8g The mean age at onset was 7.3 years in one study. There were two onset peaks, one between ages 1 and 3 years, another from 11 to 13 years.‘*

The iris and ciliary body are the principal tissues involved in the eye disease of JRA, both clinically and histologically. ‘7,65 The intraocular inflammation is typically nongranulomatous, with fine- to medi- um-sized keratic precipitates, cells and flare in the anterior chamber, and a small to moderate number of cells in the anterior vitreous. Posterior segment inflammation has been reported infrequently and only in conjunction with antecedent anterior segment inflammation. Chylack reported one patient with “unilateral papillitis” and one with “severe cystoid maculopathy” among 36 cases of iridocyclitis with definite JRA. I6 Three other reports have identified posterior segment involvement in JRA, including inflammatory cells in the vitreous,55 a central retinal scar,‘05 and a single choroidal focus of inflammation.24

Schaller and associates described positive tests for antinuclear antibodies in the serum of 51 of 58 patients (88%) with chronic iridocyclitis and JRA.qO Kanski and Shun-Shin reported antinuclear antibodies present in 198 of 250 patients with JRA and uveitis (79%).44 Only about 30% of patients with JRA but without iridocyclitis have antinuclear antibodies present. q” The presence of serum antinuclear antibodies is useful in identifying patients with JRA at risk for chronic iridocyclitis.

Arthritis precedes the onset of uveitis in the vast majority of cases of JRA.” With a greater emphasis on regular slit-lamp biomicroscopy and the early treatment of uveitis, the rates of secondary cataract formation and glaucoma may be lowered in JRA.

Cooper and coworkers studied the histopatholo- gical parameters of JRA joint biopsies.*O The most common features among 23 accessions included synovial hypertrophy and hyperplasia, fibrocyte hy- percellularity, and focal aggregations of lymphocytes and histiocytes. Synovial giant cells were found in only two of the 23 accessions. This con- trasts with sarcoid arthritis where 10 of 13 joint biopsies in children showed giant cell granulomas (Table 1).

B. JUVENILE ANKYLOSING SPONDYLITIS

Ankylosing spondylitis typically affects the sacro-

iliac and spinal joints, although involvement of peripheral joints in the lower limbs may precede the spinal disease. ” Acute iridocyclitis occurs in 5-10% of patients with juvenile ankylosing spondylitis. In Kanski and Shun-Shin’s series of 340 patients, juvenile ankylosing spondylitis accounted for 14% of childhood anterior uveitis associated with a systemic disorder.44 In contrast to juvenile rheumatoid arthritis and childhood sarcoid arthritis, males are affected in about 90% of cases.44,8q Patients are typically negative for serum rheumatoid factor and ANA, and positive for the HLA B-27 histocompati- bility antigen.

C. JUVENILE PSORIATIC ARTHRITIS

Psoriatic arthritis is characterized by the coexis- tence of psoriasis and arthritis.8g Joint changes precede or follow the skin disease with about equal frequency. Four of 43 patients reported by Lambert and coworkers developed anterior uveitis.56 Two of these four patients had significant titers of antinuclear antibodies which were present in only four of the other 39 patients. The presence of serum antinuclear antibodies was felt to be a risk factor for uveitis. Juvenile psoriatic arthritis accounted for 9 of 340 patients with childhood anterior uveitis and a systemic disease in Kanski and Shun-Shin’s series.44 Seven of the nine patients were female, seven of nine had bilateral disease, and three cases underwent cataract surgery.

D. REITER’S DISEASE

This classic syndrome consisting of arthritis, ure- thritis, and conjunctivitis has rarely been reported in children.” Symptoms typically develop over the course of two weeks, and an antecedent history of diarrhea is common. Chronic anterior uveitis is a rare complication.44~7q~gg

E. BEHGET’S DISEASE

Behcet’s disease is a rare cause of childhood uveitis. This necrotizing vasculitis is characterized by arthritis, genital ulcerations, recurrent aphthous stomatitis, and recurrent hypopyon iritis.76 Kanski and Shun-Shin reported two pediatric cases: one patient had a single episode of acute iridocyclitis and another had severe bilateral chronic anterior uveitis and retinal ischemia.44

F. VOGT-KOYANAGI-HARADA SYNDROME

Vogt-Koyanagi-Harada syndrome is a rare cause of childhood uveitis. Perkins reported one case out of 150 patients with uveitis under the age of 16 years. 81 Kanski and Shun-Shin reported one case out of 340 patients under 15 years of age with anteri- or uveitis and a systemic disorder.44 Clinical mani-


festations include bilateral chronic iridocyclitis, posterior uveitis including exudative retinal detachment, tinnitus, neck stiffness, central nervous system and cranial nerve lesions, alopecia, poliosis, and vitiligo. loo Orientals, American Blacks, Hispan- ics, and American Indians are at greater risk for acquiring this disease.

VI. Management The efficacy of medical and surgical management

of the ocular complications of pediatric sarcoidosis has not been comprehensively studied. The frequency of secondary glaucoma and cataracts is also unknown due to infrequent reporting *of pediatric sarcoidosis in the ophthalmic literature.i8J8 The following discussion provides general guidelines for the ophthalmic management of this disorder.

A. UVEITIS

Topical steroids and cycloplegics are the main- stay of treatment of sarcoid uveitis. Most authors used topical steroids routinely and reserved systemic and local injections for the more severe cases.37 Kendig recommends systemic prednisone in all cases of uveitis, beginning with 1 mg/kg body weight daily.48 Complications of longterm systemic steroid therapy in children include death from masked infection, retardation ofgrowth and skeletal maturation, osteoporosis, peptic ulcer disease, my- opathy, psychosis, hypertension, glaucoma, cataract formation, and pseudotumor cerebri.” Due to the frequency of asymptomatic uveitis and the ocular morbidity of uveitis in pediatric sarcoidosis, all such patients should have complete eye examinations every three months as advocated for juvenile rheumatoid arthritis.32

B. SECONDARY GLAUCOMA

Secondary glaucoma is due to infiltration of the trabecular meshwork with inflammatory cells and debris, closure of the anterior chamber angle by peripheral anterior synechiae, or steroids.” Drugs which lower aqueous production such as timolol and carbonic anhydrase inhibitors are the most appropriate therapeutic agents in this setting.g4 Timo- 101 is not approved by the FDA for use in children, but its clinical application and efficacy have been described.5,40,64J’4 Documented side effects include asthmatic attacks, bradycardia, dissociated behav- ior, light-headedness, and tearing. Olson and coworkers reported a premature infant who was treated with timolol and developed apnea, but it is unclear whether the apnea was caused by timolol or was coincidental.” Side effects of carbonic anhydrase inhibitors include transitory paresthesias, transient myopia, malaise, anorexia, weight loss,

fatigue, headache, weakness, failure to thrive in in- fants, gastric distress, diarrhea, renal stones, and hyperuricemia.* Carbonic anhydrase inhibitors ap- pear to be tolerated better in young patients than in older individuals.g5

The prognosis for control of intraocular pressure after filtering procedures is worse in children than in adults,2~10~6g in Blacks than in Caucasians,@.‘jg and in the presence of intraocular inflammation.g8 Conse- quently, standard filtering procedures are at a high risk for failure in patients with pediatric sarcoidosis. Kanski and Shun-Shin performed filtration surgery on 22 eyes of children with anterior uveitis and reported success in only four eyes.44 The criteria for success were not defined, but 11 of the 22 eyes had a final vision of no light perception. Artificial draining implants may improve the outcome of filtration surgery in juvenile glaucoma.70 Postoperative subconjunctival 5-fluorouraci138 and preoperative subconjunctival triamcinolone acetonide*’ are two in- vestigational adjuncts to standard filtration surgery, which may also improve the outcome in eyes with a poor surgical prognosis.

Trabeculodialysis may be an alternative operation in these patients. In this procedure, peripheral anterior synechiae are first retracted, then the trabe- culum is disinserted from the scleral sulcus using a goniotomy knife. Kanski and McAllisteP reported their results in 30 eyes with secondary glaucoma due to chronic anterior uveitis undergoing this procedure. After a mean follow-up period of 23 months, 18 of30 eyes (60%) had intraocular pressures below 21 mm Hg.

C. SECONDARY CATARACT

Cataract surgery should be approached with cau- tion in children with uveitis. Adequate preoperative control of intraocular inflammation is thought to be a major factor in the success of cataract extraction in these patients. 23 Intraocular microsurgical techniques in which the entire lens and a portion of the anterior vitreous are excised are preferred’5J3,44 over the older needling and aspiration technique.g’ The operation may be performed through a limball or pars planaz3 approach. Cystoid macular edema, macular pucker, optic disc edema, glaucoma, inflammatory membranes, secondary posterior capsule opacification, and retinal detachment are the major causes of poor visual acuity following cataract extraction in patients with uveitis.‘5J3 These complications may be less common with modern microsurgical techniques. Secondary membrane formation and posterior capsule opacification are particularly devastating during the amblyogenic years by both reducing the visual acuity and by preventing accu- rate retinoscopy. Aggressive optical correction and


occlusion therapy is required for all aphakic children.80

Addendum Lindsley and Godfrey (Pediatrics Vol. 76, No. 5,

November 1985) have recently described two additional cases of sarcoidosis with the onset under 5 years of age. Both cases were characterized by the triad of uveitis, arthritis, and a skin rash and both were misdiagnosed as juvenile rheumatoid arthritis for many years.

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Outline

I. Epidemiology A. Age B. Race C. Gender D. Geographic factors E. Familial associations

II. Ocular manifestations A. Uveitis B. Eyelid involvement C. Conjunctival involvement D. Scleral and episcleral involvement E. Lacrimal gland involvement F. Orbital involvement

III. Systemic clinical manifestations IV. Diagnostic testing

A. Biopsy B. Kveim test C. Radiologic studies D. Serum angiotensin-converting enzyme E. Serum antinuclear antibodies F. Serum and urine calcium G. Hypergammaglobulinemia

HOOVER ET AL

H. Miscellaneous V. Differential diagnosis

A. Juvenile rheumatoid arthritis B. Juvenile ankylosing spondylitis C. Juvenile psoriatic arthritis D. Reiter’s disease E. Behcet’s disease F. Vogt-Koyanagi-Harada syndrome

VI. Management A. Uveitis B. Secondary glaucoma C. Secondary cataract

Supported in part by a grant from Research to Prevent Blindness, Inc.

Roy Wilson, MS, assisted with the photography in this project. Theresa Stathem and Linda Davis assisted with the preparation of this article.

Requests for reprints should be sent to Joseph Giangiacomo, M.D., Institute of Ophthalmology, University of Missouri-Colum- bia, One Hospital Drive, Columbia, MD 65212.

review - l. v. prasad eye instituteclassroster.lvpei.org/cr/images/archeive/2016/jan/priya...

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