Ocular Sarcoidosis

by Panagiota Stavrou, F.R.C.S.

Sarcoidosis Sarcoidosis is a multisystem granulomatous disease which was first described by Jonathan Hutchinson in 1 ! . "ts clinical manifestations and course can be variable in different ethnic grou#s. $he organs affected more often are the lungs, s%in and eyes. $he fre&uency of ocular involvement ranges from '() to *+). $he characteristics of ocular involvement are ,1when #resent, is seen generally early in the course of the disease ,'- may co.e/ist with asym#tomatic systemic disease and ,0- can #recede systemic involvement by several years. 1ost #atients #resent between the ages of '+ to 2+ years3 however, children and the elderly can be affected. Cases of familial sarcoidosis, including mono4ygotic twins, and husband.wife #airs have also been re#orted. 5iagnosis relies on demonstration of non caseating granuloma by tissue bio#sy. "n cases of sus#ected sarcoidosis where no affected tissue amenable to bio#sy is identifiable, su##ortive evidence of the diagnosis can be obtained through non.invasive investigations including measurement of serum angiotensin converting en4yme ,6C7- and lyso4yme, chest /.ray, chest com#uteri4ed tomogra#hy ,C.$-, gallium scintillogra#hy, #ulmonary function tests, bronchoalveolar lavage, and measurement of serum and urinary calcium. 8cular manifestations 6nterior segment Con9unctival involvement has been re#orted in (.:).!+) of #atients with ocular sarcoidosis ,Figure 1-. Sarcoidosis granulomas are described as solitary, yellow ;millet.seed; nodules. 6nterior uveitis occurs in ''). !+) of #atients with ocular sarcoidosis, and is usually granulomatous and chronic. "ris nodules have been re#orted in u# to 1'.*) of #atients with sarcoidosis associated uveitis. 7/acerbations of granulomatous uveitis are often associated with an a##earance of fresh iris or fundus nodules. Posterior synechiae, cataract and glaucoma are common com#lications. Corneal band %erato#athy develo#s in a few #atientsand is usually associated with hy#ercalcemia.

Figure 1. Con9unctival nodules in a #atient with sarcoidosis. Posterior segment $he most common manifestations at the #osterior segment are vitritis, intermediate uveitis, #anuveitis, #osterior uveitis, retinal vasculitis and o#tic nerve involvement. 8ther manifestations include choroidal nodules and e/udative

retinal detachment. Clinical and<or angiogra#hic cystoid macular edema ,C17- has been re#orted in 1:).!') of #atients. 8verall, #atients with chronic #osterior uveitis and #anuveitis have significantly more com#lications than do #atients with anterior uveitis. ;Candle wa/ dri##ings; and ;#unched.out; lesions can be seen in #atients with uveitis secondary to sarcoidosis ,Figure 2-.

Figure 2. Punched.out choroidoretinal lesions in a #atient with sarcoidosis. Severe retinal vasculitis and ischemic retino#athy with neovasculari4ation, re&uiring scatter #hotocoagulation has been described in some #atients. 8ther less fre&uent com#lications include #eri#a#illary and subfoveal choroidal neovasculari4ation, #osterior scleritis with annular ciliochoroidal detachment causing angle closure glaucoma, and central retinal vein occlusion leading to a #ainful blind eye from neovascular glaucoma. 8rbit 6lthough sarcoid granulomas have been described in most areas inside the orbit, the lacrimal gland a##ears to be the organ most commonly affected. $he fre&uency of lacrimal gland involvement varies from !) to (:). $he nasolacrimal drainage system can also become involved in #atients with sarcoidosis. $he #atients usually #resent with e#i#hora and nasal stuffiness. 7/traocular muscle involvement can occur and #resents with di#lo#ia or #ainful e/ternal o#hthalmo#legia. Sarcoidosis in childhood 7arly onset or #re.school sarcoidosis seen in children is relatively rare. $he classic triad of sym#toms consists of s%in, eye and 9oint lesions3 #ulmonary involvement is rare, at least initially. "t can be easily misdiagnosed as 9uvenile rheumatoid arthritis, as the latter also #resents with sym#toms from the 9oints and eyes. 7/traocular involvement $he lung is the most fre&uently affected organ in #atients with sarcoidosis. Histologically the lesions are distributed #rimarily along the lym#hatics around bronchi and blood vessels, although alveolar lesions are also seen. $he relative fre&uency of granulomas in the bronchial submucosa accounts for the high diagnostic yield of bronchosco#ic bio#sies. =ym#h nodes are involved in almost all cases, es#ecially the hilar and mediastinal ones. $he ma9ority of #atients are asym#tomatic, while others may com#lain about cough or shortness of breath. $he s#leen is enlarged in only 1 ) of cases, although microsco#ical evidence of sarcoid granulomas in s#leen is #resent in three.&uarters of the cases. $he liver is affected less often than is the s#leen, but a finding of elevated liver en4ymes in a sarcoidosis sus#ect may #rom#t #ercutaneous liver bio#sy in the search for histo#athologic

confirmation of the sus#ected diagnosis. Renal insufficiency has been re#orted in #atients with histologically #roven sarcoidosis of the %idneys and has been attributed to hy#ercalcemia and interstitial granulomatous ne#hritis. >.ray abnormalities of the bones can be identified in about one.fifth of #atients. $he radiologically visible lesions are usually seen in the #halangeal bones of the hands and feet, creating small circumscribed areas of bone resor#tion within the marrow cavity. S%in lesions are found in :).0!) of the #atients. $hey may be s#ecific, showing histologically non caseating granulomas, or non.s#ecific, e.g. erythema nodosum. $he s#ecific s%in lesions include lu#us #ernio, infiltrated #la&ues, maculo#a#ular eru#tions, subcutaneous nodules and infiltration of old scars ,Figures 0 ? 2-.

Figure 3 ? 2. S%in manifestations in #atients with sarcoidosis. Histology $he hallmar% of sarcoidosis is a non necroti4ing granuloma. $he center of the granuloma consists of histiocytes, e#ithelioid cells, and multinucleated giant cells which are surrounded by lym#hocytes, #lasma cells, and fibroblasts ,Figure 5-. @ross necrosis is not a feature of sarcoidosis, and suggests alternative diagnoses ,e.g. tuberculosis,

fungal infection, vasculitis, etc-. $he e#ithelioid cells are transformed bone marrow monocytes and have mar%ed secretory activity which includes over 2+ different cyto%ines and other mediators. 6mong the en4ymes and other chemicals secreted by granulomas are 6C7, lyso4yme, glucuroonidase, collagenase, and calcitriol.

Figure 5. @ranulomas consisting of histiocytes, e#ithelioid cells, and multinucleated giant cells. Aveim test "n 1:21, Aveim re#orted the use of a sus#ension derived from the s#leen of a #atient with sarcoidosis that, when in9ected intracutaneously into #atients with bio#sy #roven sarcoidosis, yielded a cutaneous #a#ule containing non caseating e#ithelioid granulomas. Four to si/ wee%s following subcutaneous in9ection of the Aveim reagent, the ty#ical lesion #resents as a red or brownish raised #a#ule ranging from a few millimeters u# to 1.* centimeters in diameter. Histo#athologic analysis of the bio#sied lesion reveals a granuloma com#osed of e#ithelioid cells, occasional =anghans cells and scattered lym#hocytes at its center with a surrounding cuff of mononuclear cells, #rimarily lym#hocytes. Cutaneous anergy "n 1:1(, Boec% first described cutaneous anergy to tuberculin in #atients with sarcoidosis. "t was later on reali4ed that this #henomenon was not limited to tuberculin alone, but that anergy to a variety of other s%in tests.antigens such was also ty#ical. "n 1::2, Aataria and Holter #ro#osed a mechanism for the cutaneous anergy seen in sarcoidosis. 6t sites of granulomatous inflammation, there is a #redominance of hel#er $ lym#hocytes, which #roliferate and secrete large amounts of lym#ho%ines, including interleu%in ,"=-.', monocyte chemotactic factor ,1CF- and migration inhibition factor ,1"F-. $hese lym#ho%ines induce and am#lify the immune res#onse by enhancing $.lym#hocyte #roliferation as well as recruiting and retaining monocytes from the circulation. $he lym#ho%ines and mono%ines #roduced at sites of granulomatous inflammation have their highest concentration locally. Cevertheless, the #rotein molecules diffuse into blood, establishing a concentration gradient between the granulomatous inflammatory site and the remote site of the delayed ty#e hy#ersensitivity ,5$H- s%in test. 6s a result, the traffic of $.hel#er lym#hocytes and monocytes is #referentially directed towards site of granuloma formation. $hat leads to a #re#onderance of su##ressor cells in the #eri#heral blood and com#etitively de#letes the $.hel#er cells and monocytes available to sites of 5$H. 7tiology and #athogenesis $he #rocesses involved in the #athogenesis of sarcoidosis in the lungs include accumulation of C52D lym#hocytes at the affected site. $he cyto%ines and factors secreted by these cells account for the influ/ of monocytes, alveolitis,

and non caseating granuloma formation in the lung and for the resulting #rogressive fibrosis, all characteristic features of #ulmonary sarcoidosis. Sarcoidosis is characteri4ed by ;com#artmentali4ation; of the $ cells, such that the relative #ro#ortion of C52D $ cells in blood is reduced ,e.g. C52<C5 E+. -, while the reverse relation is observed in affected tissue ,e.g. C52<C5 E1. in lung-. $he C52D cells in the involved organs are ;activated; and thus are releasing "=.' and other mediators, while the C52D cells in other sites, such as blood, are &uiescent. "n 1::', Holter et al demonstrated a Aveim.li%e granulomagenic activity in nonviable autologous B6= cells ,C6BCrecovered soon after sym#tomatic onset or rela#se of sarcoidosis but not in #atients with chronic stable sarcoidosis.$he same grou# of investigators demonstrated a Aveim.li%e granolomagenic activity of #eri#heral blood monocytes, the #rogenitors of the alveolar macro#hage. $hese findings suggest that the circulating monocyte is already #rimed with the granulomagenic factor before differentiation into alveolar macro#hage. 6 monocyte source of the factor e/#lains the multisystem distribution of granulomas in sarcoidosis. Chest radiology Sulavi% et al suggested the following roentgen staging of sarcoidosisF +E normal chest radiogra#h3 1E bilateral symmetrical hilar lym#hadeno#athy ,BSH=- only3 'E BSH= with bilateral, symmetrical lung infiltration , Figure 6-3 0E bilateral symmetrical lung infiltration only3 2aE BSH= with bilateral symmetrical lung infiltration indicative of #ulmonary fibrosis ,BS"F-3 2bE BS"F only.

Figure 6. Bilateral symmetrical hilar lym#hadeno#athy and lung infiltration. @allium ,(!@6- scan $he combined abnormal bilateral symmetrical (!@6 u#ta%e of the lacrimal and #arotid glands ,with or without submandibular gland (!@6 u#ta%e- is called the ;#anda; #attern ,Figure !-. $he #resence and #attern of (!@6 u#ta%e in both ,1- the #arahilar and infrahilar broncho#ulmonary lym#h nodes and ,'- the right #aratracheal ,a4ygous- mediastinal lym#h nodes is called the ;lambda; image after its resemblance with the @ree% letter l. Pulmonary u#ta%e of (!@6 is sensitive but not s#ecific in the diagnosis of #ulmonary sarcoidosis as it can occur in a wide variety of other inflammatory and neo#lastic diseases.6bnormal (!@6 u#ta%e in salivary and lacrimal glands may also occur in S9GgrenHs syndrome, tuberculosis and after radiation thera#y.

Figure !. Bilateral symmetrical gallium u#ta%e by the lacrimal, #arotid, and submandibular glands ,Panda sign-. 6ngiotensin converting en4yme ,6C76C7 is normally #resent in the vascular endothelium of many organs ,lung, %idney, small intestine, uterus, #rostate, thyroid, testes, adrenals- and in macro#hages. $he latter source accounts for elevated 6C7 levels in #atients with sarcoidosis. $he induction of 6C7 synthesis in e#ithelioid cells and macro#hages is caused by a soluble 6C7. inducing factor ,6"F-. 6C7 is elevated in (+.:+) of #atients with active sarcoidosis. 6 normal serum 6C7 does not e/clude the diagnosis, es#ecially if the disease is in its early stages, locali4ed to a small area ,e.g. the eye-, and therefore with a small e#ithelioid cell ;barden;. False low values are also measured in #atients ta%ing 6C7 inhibitors or in #atients with endothelial abnormalities, such as dee# vein thrombosis, and in #atients who have had chemothera#y or radiation. $reatment with systemic steroids or other immunosu#ressive agents can also affect 6C7 levels with values normali4ing with ade&uate control of intraocular inflammation. 8ther disorders associated with elevated serum 6C7 include @aucherHs disease, le#rosy, chronic #ulmonary disease, rheumatoid arthritis, s#ondylitis, #rimary biliary cirrhosis, tuberculosis, histo#lasmosis, histiocytic medullary fibrosis, hy#erthyroidism and diabetes mellitus. Pulmonary function tests Pulmonary function tests are useful in the initial diagnosis and follow u# of #atients with sarcoidosis. $heir sensitivity in disease with and without roentgen evidence of #arenchymal involvement has been re#orted as !+) and 2+) res#ectively. $he most common abnormalities seen early in the course of the disease are a #ost e/ercise increase in the alveolar.arterial o/ygen gradient and diffusing ca#acity and a reduction in lung com#liance. Bronchoalveolar lavage ,B6=-. $ransbronchial lung bio#sy ,$B=B$he earliest #athologic finding in #atients with sarcoidosis is a mononuclear alveolitis com#osed of increased C5 2D lym#hocytes ,with an increased C52<C5 ratio-, monocyte.macro#hages, and rare B lym#hocytes. $issue for bio#sy from the bronchial mucosa or the ad9acent lung is obtained through a fibreo#tic bronchosco#e. Con caseating granulomas have been re#orted in *2. ) of #atients who underwent $B=B.$he rate of #ositive findings by $B=B is higher in #atients with radiologic evidence of #ulmonary infiltration, and is a##ro/imately (+) among #atients with hilar lym#hadeno#athy whose chest radiogra#hs show normal lung #arenchyme. Hy#ercalcemia Hy#ercalcemia has been re#orted in 1+.1*) of #atients with sarcoidosis and is related to increased serum concentrations of 1,'*.dihydro/y.vitamin 50 ,calcitriol-. Calcitriol is #roduced at sites of active disease by alveolar macro#hages and #ossibly $ lym#hocytes. 7levated serum levels of calcitriol in he#ercalcemic #atients with sarcoidosis lead to increased absor#tion of calcium and #hos#hate from the gastrointestinal tract which leads to hy#ercalcemia and hy#ercalciuria. =yso4yme =yso4yme is an en4yme normally secreted by monocytes and #olymor#honuclear leu%ocytes. Several re#orts have shown that the levels of serum lyso4yme are raised in #atients with sarcoidosis and may be related to disease activity. Raised lyso4yme levels have been re#orted in #arallel to raised serum 6C7 levels. "t is thought that the e#ithelioid cell of the sarcoid granuloma is the source for both lyso4yme and 6C7.

Con9unctival bio#sy $he #ositive yield of con9unctival bio#sy ranges from 12) to 2+.2 ). $he lower forni/ is the most #referred site and to#ical anaesthesia is sufficient. 6 higher #ositive yield has been re#orted in #atients with follicles, those with ocular abnormality consistent with sarcoidosis, those with #ulmonary infiltrates and those with histologically confirmed non ocular sarcoidosis. Furthermore, e/amination of multi#le sections of each bio#sy is also recommended as granulomas may be #resent in limited numbers which may be missed if the number of sections is not ade&uate. TREATMENT $he treatment of ocular sarcoidosis de#ends on the ty#e of involvement. 1ild anterior uveitis is treated by to#ical steroids and cyclo#legics. Systemic steroids are indicated in anterior uveitis not res#onding to to#ical steroids, and in #atients with #osterior uveitis, neovasculari4ation, or orbital disease with visual sym#toms or o#tic nerve com#romise. Patients who are refractory to steroids may res#ond to the addition of oral non steroidal anti. inflammatory drugs. "f inflammation #ersists, chemothera#y ,a4athio#rine, cyclos#orin, methotre/ate- may be re&uired. Secondary glaucoma not res#onding to medical treatment has been treated by trabeculectomy and cryoablative thera#y.Retinal neovasculari4ation with evidence of ischemia on angiogra#hy res#onds well to #anretinal #hotocoagulation. References 6%ova I6, Foster CSF Cataract surgery in #atients with sarcoidosis.associated uveitis. 8#hthalmology 1+1F2!0, 1::2. Cric% RP, Hoyle C, Smellie HF $he eyes in sarcoidosis. Br J 8#hthalmol 2*F2(1, 1:(1. Hunter 5@, Foster CSF 8cular manifestations of sarcoidosis. "nF 6lbert 51, Ja%obiec F6, eds. Princi#les and Practice of 8#hthalmology. Philadel#hiaF Saunders, 1::2. Jabs 56, Johns CJF 8cular involvement in chronic sarcoidosis. 6m J 8#hthalmol 1+'F':!, 1: (. Aarma 6, Huhti 7, Pou%%ula 6F Course and outcome of ocular sarcoidosis. 6m J 8#hthalmol 1+(F2(!, 1: . Aataria IP, Holter JFF Cutaneous anergy in sarcoidosis. "n James 5@ ,ed-F Sarcoidosis and 8ther @ranulomatous 5isorders ,vol !0, =ung Biology in Health and 5isease-. Cew Ior%, 1ar%el 5e%%er, #. 1 1, 1::2. Aataria IP, Holter JFF "mmunology of sarcoidosis. Clin Chest 1ed 1 F!1:, 1::!. Holter JF, Par% HA, S9oerdsma AJ, et alF Conviable autologous bronchoalveolar lavage cell #re#arations induce intradermal e#ithelioid cell granulomas in sarcoidosis #atients. 6m Rev Res#ir 5is 12*F (2, 1::'. 1aKL J, 1arcoval J, @raells J, et alF Cutaneous involvement in sarcoidosis. Relationshi# to systemic disease. 6rch 5ermatol 100F ', 1::!. Power JJ, Ceves R6, Rodrigue4 6, et alF $he value of combined serum angiotensin.converting en4yme and gallium scan in diagnosing ocular sarcoidosis. 8#hthalmology 1+'F'++!, 1::*. Rothova 6, 6lberts C, @lasius 7, et alF Ris% factors for ocular sarcoidosis. 5oc 8#hthalmol !'F' !, 1: :. Rothova 6, Suttor#.van Schulten 1S6, $reffers JF, et alF Causes and fre&uency of blindness in #atients with intraocular inflammatory disease. Br J 8#hthalmol +F00', 1::(. Sulavi% SB, S#encer RP, Jeed 56, et alF Recognition of distinctive #atterns of gallium.(! distribution in sarcoidosis. J Cucl 1ed 01F1:+:, 1::+. Sulavi% SB, S#encer RP, Palestro CJ, et alF S#ecificity and sensitivity of distinctive chest radiogra#hic and<or (!@a images in the noninvasive diagnosis of sarcoidosis. Chest 1+0F2+0, 1::0.