Thyroid-Associated Orbitopathy

Author: Edsel Ing, MD, FRCSC; Chief Editor: Hampton Roy Sr, MD

hyroid!asso"iated or#itopathy $ A%&, fre'uently termed (ra)es ophthalmopathy, is part of an autoimmune pro"ess that "an affe"t the or#ital and perior#ital tissue, the thyroid gland, and, rarely, the preti#ial s*in or digits $thyroid a"ropa"hy&+,-, ., /0 Although the use of the term thyroid ophthalmopathy is per)asi)e, the disease pro"ess is a"tually an or#itopathy in 1hi"h the or#ital and perio"ular soft tissues are primarily affe"ted 1ith se"ondary effe"ts on the eye+ See the images #elo1+

2ong!standing thyroid ophthalmopathy 1ith typi"al features of lid retra"tion $upper and lo1er& and s"leral sho1 1ith proptosis+ his patient3s "hief "omplaint 1as #ino"ular )erti"al diplopia+ A small right hypotropia 1as o#ser)ed on alternate

"o)er testing+ hyroid a"ropa"hy imitates the appearan"e of "lu##ing and is an un"ommon finding in patients 1ith thyroid ophthalmopathy+ his patient re'uired #ilateral or#ital de"ompression and stra#ismus surgery+ hyroid!asso"iated or#itopathy may pre"ede, "oin"ide, or follo1 the systemi" "ompli"ations of dysthyroidism+ he o"ular manifestations of thyroid!asso"iated or#itopathy in"lude eyelid retra"tion, proptosis, "hemosis, perior#ital edema, and altered o"ular motility 1ith signifi"ant fun"tional, so"ial, and "osmeti" "onse'uen"es+ %f those patients affe"ted, .45 indi"ate the o"ular mor#idity of this "ondition is more trou#lesome than the systemi" "ompli"ations of dysthyroidism+ he annual in"iden"e rate of thyroid!asso"iated or#itopathy has #een estimated at -6 "ases per -44,444 1omen and .+7 "ases per -44,444 men in one rural Minnesota "ommunity+,80 here appears to #e a female preponderan"e in 1hi"h 1omen are affe"ted .+9!6 times more fre'uently than men; ho1e)er, se)ere "ases o""ur more often in men than in 1omen+ In addition, most patients are aged /4!94 years, 1ith se)ere "ases appearing to #e more fre'uent in those older than 94 years+

Although most "ases of thyroid!asso"iated or#itopathy do not result in )isual loss, this "ondition "an "ause )ision!threatening e:posure *eratopathy, trou#lesome diplopia, and "ompressi)e opti" neuropathy+ herefore, although the prognosis is generally fa)ora#le for patients 1ith this "ondition, and most patients do not re'uire surgi"al inter)ention,,9, 60 all "lini"ians should #e a#le to re"ogni;e thyroid!asso"iated or#itopathy+ See also the follo1ing:

(ra)es Disease Hyperthyroidism %r#ital De"ompression for (ra)es Disease <ediatri" (ra)es Disease <ediatri" Hyperthyroidism

Etiology
he thyroid gland itself does not "ause thyroid!asso"iated or#itopathy $ A%&, and regulation of thyroid fun"tion does not a#ort this "ondition+ Rather, the thyroid gland, eye mus"les, and preti#ial s*in are espe"ially su#=e"t to the autoimmune atta"*+ Ho1e)er, restoration of the euthyroid state $1ith antithyroid drugs and thyro:ine& may impro)e the eye status to some e:tent+

Thyroid state and irradiation

Many patients 1ith thyroid!asso"iated or#itopathy are hyperthyroid, #ut euthyroidism $.45&, Hashimoto thyroiditis, thyroid "ar"inoma, and ne"* irradiation are also asso"iated 1ith thyroid!asso"iated or#itopathy+ E)en if the patient is euthyroid, thyroid!asso"iated or#itopathy may progress+ In patients 1ho are hyperthyroid, the eye signs of thyroid! asso"iated or#itopathy usually de)elop 1ithin -> months of dysthyroidism; )ery often, they de)elop "on"urrently+

Radioactive iodine
Although some1hat "ontro)ersial, se)eral pu#li"ations ha)e suggested that thyroid a#lation 1ith orally ingested radioa"ti)e iodine!-/- $RAI& $-/- I& may e:a"er#ate thyroid!asso"iated or#itopathy "ompared 1ith antithyroid drugs or surgi"al a#lation+ Ho1e)er, se)eral studies ha)e not sho1n that radioiodine is a signifi"ant ris* for initiation or progression of mild thyroid!asso"iated or#itopathy+,?, >0
-/-

I is #elie)ed to "ause a release of thyroid antigens+ In a study #y @artalena, appro:imately -95 of patients treated 1ith only radioa"ti)e iodine de)eloped or had 1orsening of thyroid! asso"iated or#itopathy+,70 Ho1e)er, some authors feel the threshold for diagnosis of thyroid! asso"iated or#itopathy 1as lo1 $eg, o"ular irritation&+ In "ontrast, none of the patients treated 1ith #oth radioa"ti)e iodine and prednisone had progression of thyroid!asso"iated or#itopathy, and t1o thirds sho1ed impro)ement+,70 %nly /5 of patients treated 1ith methima;ole sho1ed 1orsening of thyroid!asso"iated or#itopathy+

Diseases associated with thyroid-associated orbitopathy

Autoimmune diseases su"h as myasthenia gra)is, Addison disease, )itiligo, and perni"ious anemia ha)e #een des"ri#ed 1ith thyroid!asso"iated or#itopathy+ In one study, >5 of patients 1ith this "ondition had positi)e a"etyl"holine re"eptor anti#odies,-40 ; ho1e)er, at 8+9!year follo1!up )isits, none of the patients 1ith positi)e serology 1as identified "lini"ally to ha)e myasthenia gra)is+ Yersinia enterocolitica infe"tion has #een also asso"iated 1ith thyroid!asso"iated or#itopathy+

Smoking
hyroid!asso"iated or#itopathy is asso"iated strongly 1ith smo*ing,--, -.0 ; the more se)ere the eye disease, the stronger the asso"iation+ In one study, smo*ers of European ethni"ity had a .+8 times in"reased ris* for this "ondition "ompared 1ith their Asian "ounterparts+ A"ti)e smo*ers re'uire more stra#ismus surgery than nonsmo*ers, independent of or#ital de"ompression surgery+,-/0

Pathophysiology
In simplest terms, the underlying pathophysiology of thyroid!asso"iated or#itopathy is thought to #e an anti#ody!mediated rea"tion against the thyroid!stimulating hormone $ SH& re"eptor 1ith or#ital fi#ro#last modulation of !"ell lympho"ytes+ !"ell lympho"ytes are #elie)ed to rea"t against thyroid folli"ular "ells 1ith shared antigeni" epitopes in the retroor#ital spa"e+ An a"ti)e phase of inflammation is initially present+

Lymphocytic in iltration! ibroblast reaction! and increased orbital vol"me

2ympho"yti" infiltration of the or#ital tissue "auses a release of "yto*ines $eg, tumor ne"rosis fa"tor , AF0, interleu*in - ,I2!-0& from CD8B "ells stimulating the or#ital fi#ro#lasts to produ"e mu"opolysa""harides, 1hi"h, #y hyperosmoti" shift, "ause tissue edema in the e:trao"ular mus"les+ Fi#ro#lasts are #elie)ed to #e the target and effe"tor "ells in thyroid!asso"iated or#itopathy+ Fi#ro#lasts are e:tremely sensiti)e to stimulation #y "yto*ines and other solu#le proteins and immunoglo#ulins that are released in the "ourse of an immune rea"tion+ he "yto*ines a"ti)ate pre)iously 'uies"ent fi#ro#lasts to se"rete hyaluroni" a"id, a gly"osaminogly"an+ Dou#ling the hyaluroni" a"id "ontent in the or#ital tissue "auses a 9!fold in"rease in the tissue osmoti" load+ In addition, preadipo"yte fi#ro#lasts are influen"ed to transform into adipo"ytes, espe"ially in young patients+ he or#it "an #e des"ri#ed as a pear!shaped #o: 1ith an anterior opening; the stal* of the pear represents the opti" ner)e+ In thyroid!asso"iated or#itopathy, the in"rease in or#ital )olume from the e:trao"ular mus"les and fat "auses for1ard protrusion $proptosis or e:ophthalmos& and, o""asionally, opti" ner)e "ompression at the narro1 posterior ape: of the or#it+ he edema results in tissue damage and fi#rosis, 1ith restri"tion in e:trao"ular motility and lagophthalmos+

Csually 1ithin -!. years of the onset of or#ital in)ol)ement, the inflammation settles to a more 'uies"ent, fi#roti" phase predominated #y s"arring of the or#ital tissues+

Potential pathoimm"nology
hyroid!asso"iated or#itopathy may #e part of a more generali;ed disorder of "onne"ti)e tissue and striated mus"le+,-80 A more e:tensi)e dis"ussion on the pathoimmunology of thyroid!asso"iated or#itopathy is #eyond the s"ope of this arti"le+ Ho1e)er, some of the resear"h in this field is outlined #elo1+ he insulinli*e gro1th fa"tor - re"eptor $I(F!-R& is an autoantigen that may #e important in thyroid!asso"iated or#itopathy, #e"ause of its a#errant e:pression #y thyroid!asso"iated or#itopathy fi#ro#lasts, the promotion of !"ell re"ruitment, and the presen"e of "ir"ulating a"ti)ating autoanti#odies+ helper . "yto*ines $I2!8 and I2!-/& may indu"e the e:pression of -9!lipo:ygenase!-, 1ith upregulation in the produ"tion of -9!hydro:yei"osatetraenoi" a"id $-9!HE E&, "ausing tissue a"ti)ation and remodeling+ Cy"loo:ygenase . $C%D!.& is e:pressed at higher le)els in the or#ital fi#roadipose tissues of thyroid!asso"iated or#itopathy+,-90 here is a positi)e "orrelation 1ith in"reasing se)erity of or#ital disease, suggesting a possi#le relationship 1ith C%D!. e:pression and or#ital inflammation in thyroid!asso"iated or#itopathy+ Eariants in the IL-23R gene are strongly asso"iated 1ith (ra)es ophthalmopathy $or thyroid! asso"iated or#itopathy&+ hese )ariants may predispose to this "ondition #y "hanging the e:pression andFor the fun"tion of IL-23R, there#y promoting a proinflammatory signaling "as"ade+

#linical Eval"ation
hyroid!asso"iated or#itopathy $ A%& usually has a self!limited "ourse o)er - or more years+ Sta#le disease "an o""asionally rea"ti)ate, #ut this is un"ommon+ Signs and symptoms may )ary and depend on the stage that the patient is e:perien"ing+ Initially, an a"ute or su#a"ute stage of a"ti)e inflammation o""urs+ 2ater, the patient progresses to a more 'uies"ent stage, 1hi"h is "hara"teri;ed #y fi#rosis+,-90

Symptoms
<atients may "omplain of the follo1ing o"ular symptoms:

Dry eyes <uffy eyelids Angry!loo*ing eyes @ulging eyes Diplopia Eisual loss

Field loss Dys"hromatopsia <hotopsia on upga;e %"ular pressure or pain

Hyperthyroidism symptoms in"lude the follo1ing:

a"hy"ardiaFpalpitations Aer)ousness Diaphoresis Heat intoleran"e S*eletal mus"le 1ea*ness remor Geight loss Hair loss Irrita#ility (oiter

Hypothyroidism symptoms in"lude the follo1ing:

@rady"ardia Dro1siness <oor mentation Mus"le "ramps Geight gain Dry s*in Hus*y )oi"e Depression Cold intoleran"e

Aumerous eponymous signs are asso"iated 1ith thyroid!asso"iated or#itopathy, in"luding the follo1ing:

Eigourou: sign $eyelid fullness& Stell1ag sign $in"omplete and infre'uent #lin*ing& (ro)e sign $resistan"e to pulling do1n the retra"ted upper lid&

Hoffroy sign $a#sent "reases in the forehead on superior ga;e& MI#ius sign $poor "on)ergen"e& @allet sign $restri"tion of one or more e:trao"ular mus"les&

Proptosis and pse"doptosis

hyroid!asso"iated or#itopathy is the most "ommon "ause of unilateral and #ilateral proptosis in adults+ <roptosis or e:ophthalmos o""urs, #e"ause the or#ital "ontents are "onfined 1ithin the #ony or#it, and de"ompression "an only o""ur anteriorly+ Cnilateral proptosis of thyroid! asso"iated or#itopathy usually refle"ts asymmetri" mus"le in)ol)ement+ Retropulsion $digital palpation of the glo#es through "losed eyelids& is a useful test; it is de"reased in patients 1ith se)ere thyroid!asso"iated or#itopathy+ Earious e:ophthalmometers "an #e used to measure or#ital protrusion+ <seudoptosis and true ptosis may #e seen in patients 1ith thyroid!asso"iated or#itopathy+ <seudoptosis may #e o#ser)ed if "ontralateral lid retra"tion is present+ <tosis may o""ur 1ith thyroid!asso"iated or#itopathy if le)ator dehis"en"e is present+ <atients 1ith thyroid! asso"iated or#itopathy may ha)e "on"urrent myasthenia gra)is, 1hi"h may lead to ptosis+ 2a"rimal gland enlargement is not un"ommon+

Lid retraction! lid lag! and glabellar "rrows

Aormally, the upper lid is lo"ated -!-+9 mm #elo1 the superior lim#us, and the lo1er lid is lo"ated at the inferior lim#us+ Cpper lid retra"tion $Dalrymple sign&, often 1ith temporal flare and s"leral sho1, is the most "ommon o"ular sign of thyroid!asso"iated or#itopathy+ his sign is an important differentiating feature to note in all patients 1ith proptosis+ Me"hanisms for upper lid retra"tion in"lude proptosis, sympatheti" dri)e of the Muller mus"le, upga;e restri"tion, fi#rosis of the le)ator mus"le, and "ontralateral ptosis $myasthenia&+ 2id retra"tion may o""ur in #oth the upper and lo1er lids #e"ause of a sympatheti"ally inner)ated tarsal mus"le in #oth lids+ Cpga;e restri"tion, le)ator fi#rosis, and )ery se)ere proptosis are other possi#le "auses of lid retra"tion+ If eyelid retra"tion is a#sent, then thyroid!asso"iated or#itopathy may #e diagnosed only if: $-& proptosis, opti" ner)e in)ol)ement, or restri"ti)e e:trao"ular myopathy is asso"iated 1ith thyroid dysfun"tion or a#normal regulation, and $.& no other "onfounding ophthalmi" features are apparent+ 2id lag on do1nga;e $)on (raefe sign& is another important feature of thyroid!asso"iated or#itopathy+ Ghile slo1ly mo)ing the fi:ation o#=e"t from up1ard to do1n1ard, the e:aminer should o#ser)e if the eyelid lags #ehind the glo#e on do1nga;e+

%ther lid signs in"lude lid edema and gla#ellar furro1s+ A statisti"ally signifi"ant asso"iation of deep gla#ellar rhytids 1ith thyroid ophthalmopathy has #een des"ri#ed+ his is presuma#ly "aused #y hypertrophy of #ro1 depressor mus"les "ompensating for lid retra"tion+

#orneal and con$"nctival indings

Anterior segment signs in thyroid!asso"iated or#itopathy in"lude superfi"ial pun"tate *eratitis, superior lim#i" *erato"on=un"ti)itis, "on=un"ti)al in=e"tion usually o)er the re"tus mus"le insertions, and "on=un"ti)al "hemosis+ Gith se)ere proptosis, "orneal e:posure 1ith fran* "orneal ul"eration may o""ur+ Superior lim#i" *erato"on=un"ti)itis is a "hroni", often re"urrent "ondition of o"ular irritation, 1hi"h some attri#ute to me"hani"al trauma transmitted from the upper eyelid to the superior #ul#ar and tarsal "on=un"ti)a+ Superior lim#i" *erato"on=un"ti)itis has #een a purported prognosti" mar*er for se)ere thyroid!asso"iated or#itopathy+ he "orneal light refle:es should #e e:amined "losely, #e"ause asymmetri" proptosis and lid retra"tion may mas* the true relati)e positions of the glo#es+

Orbital m"scle involvement

Stra#ismus is "ommon, and it often presents as hypotropia or esotropia, #e"ause the inferior re"tus mus"le and the medial re"tus mus"le are the most "ommonly in)ol)ed e:trao"ular mus"les in thyroid!asso"iated or#itopathy+ he restri"ti)e myopathy sometimes "an #e "onfirmed 1ith for"ed du"tions or ele)ated intrao"ular pressure 1ith eye mo)ement $eg, upga;e in hypotropi" patients& if a diagnosis of thyroid!asso"iated or#itopathy is not re)ealing+ Inferior re"tus mus"le restri"tion may mimi" dou#le ele)ator palsy+ Although esotropia is a more "ommon finding 1ith thyroid!asso"iated or#itopathy, "on)ergen"e insuffi"ien"y has #een des"ri#ed+ In patients 1ith thyroid!asso"iated or#itopathy and e:otropia, the possi#ility of "on"urrent myasthenia gra)is should #e "onsidered+

Pse"do nerve palsies and nerve compression

<seudo!fourth ner)e palsies ha)e #een des"ri#ed 1ith thyroid!asso"iated or#itopathy+ Compressi)e opti" neuropathy may present 1ith #lurry )ision, )isual loss, dys"hromatopsia, or field loss+ <atients 1ith opti" ner)e "ompression may not ha)e mar*ed proptosis or ha)e seemingly mild proptosis, #ut they usually sho1 mar*edly de"reased retropulsion $tight or#its&+ In addition, most "ases of "ompressi)e thyroid opti" neuropathy o""ur 1ithout )isi#le opti" ner)e edema+ For this reason, do"umenting )isual a"uity, "olor )ision, and the presen"e or a#sen"e of a relati)e afferent pupillary defe"t is important during ea"h )isit+

%ncreased intraoc"lar press"re

(lau"oma may result from de"reased epis"leral )enous outflo1+ @e"ause of restri"ti)e myopathy, intrao"ular pressure may rise more than > mm Hg on upga;e+ Choroidal folds may also #e seen 1ith thyroid ophthalmopathy+

#"taneo"s indings
<reti#ial dermopathy and thyroid a"ropa"hy $1hi"h mimi"s the appearan"e of "lu##ing& are less "ommonly en"ountered dramati", "utaneous signs of dysthyroidism+ See the images #elo1+

hyroid a"ropa"hy imitates the appearan"e of "lu##ing and is an un"ommon finding in patients 1ith thyroid ophthalmopathy+ his patient re'uired #ilateral

or#ital de"ompression and stra#ismus surgery+ thyroid a"ropa"hy+

<reti#ial my:edema and

TAO #lassi ication

Aumerous "lassifi"ation systems for thyroid!asso"iated or#itopathy $ A%& e:ist, #ut they all ha)e short"omings+

Types % and %%
he simplest "lassifi"ation for thyroid!asso"iated or#itopathy is type I and type II; these . types are not mutually e:"lusi)e+ ype I is "hara"teri;ed #y minimal inflammation and restri"ti)e myopathy+ ype II is "hara"teri;ed #y signifi"ant or#ital inflammation and restri"ti)e myopathy+

&OSPE#S

he Gerner A%S<ECS "lassifi"ation system $and its modifi"ations& is one of the most "ommonly *no1n systems and is used in many endo"rine studies+ A%S<ECS uses a mnemoni" to des"ri#e the presen"e or a#sen"e of signs or symptoms $A%& and grade and "lassify the se)erity and ran* order of )arious "lini"al features $S<ECS& $s oft!tissue in)ol)ement, p roptosis, e :trao"ular mus"le in)ol)ement, c orneal in)ol)ement, and s ight loss&+ Cnfortunately, the A%S<ECS "lassifi"ation has some 1ea*nesses that may limit its prognosti" )alue+ <atients may fall into more than - parti"ular "lass, and they may not progress in an orderly fashion from "lass - to "lass 6+ In addition, patients 1ith )isual loss from "ompressi)e opti" neuropathy may not sho1 mar*ed proptosis or other signs of se)ere disease+

Diagnostic #onsiderations
%r#ital and preseptal "ellulitis are in"luded in the differential diagnosis 1hen e)aluating a patient 1ith suspe"ted thyroid!asso"iated ophthalmopathy $ A%&+ In or#ital "ellulitis, the onset of proptosis is often 'ui"*er, and the patient has other e)iden"e of infe"tion $eg, fe)er, leu*o"ytosis&+ %n neuroimaging, the paranasal sinuses often are opa"ified+ In patients 1ith "arotid "a)ernous fistula, the patient may ha)e a "ranial #ruit, and the dilated epis"leral )essels e:tend to the lim#us+ %r#ital inflammatory syndrome $or#ital pseudotumor& is often more painful than thyroid! asso"iated ophthalmopathy and progresses faster; the tendons are in)ol)ed in or#ital myositis+ %r#ital pseudotumor is asso"iated more often 1ith ptosis than lid retra"tion+ Isolated enlargement of the lateral re"tus mus"le is more li*ely to represent a pro"ess su"h as or#ital inflammatory syndrome rather than thyroid!asso"iated ophthalmopathy+ %ther "auses of thi"*ened mus"les in"lude sar"oidosis, metastases, lymphoma, amyloid, and a"romegaly+ %r#ital ultrasound "an 'ui"*ly "onfirm if the patient has thi"*ened mus"les or an enlarged superior ophthalmi" )ein+ Dorsal mid#rain syndrome $<arinaud syndrome& is a "ondition in 1hi"h patients may present 1ith lid retra"tion and upga;e pro#lems+ In "ontrast to thyroid!asso"iated ophthalmopathy, in <arinaud syndrome, the glo#es ele)ate on the doll3s head maneu)er and the eye tends not to #e in=e"ted or proptoti"+ he oral hypogly"emi" pioglita;one has #een suggested to "ause adipo"yte proliferation in patients 1ith thyroid!asso"iated ophthalmopathy+ Cntil definiti)e studies are performed, alternati)es to the thia;olidinediones might #e "onsidered in patients 1ith thyroid!asso"iated ophthalmopathy+ he serum le)el of hyaluronan is not a sensiti)e indi"ator of its presen"e 1ithin the e:trao"ular mus"les+

Thyroid Disease St"dies

In s"reening for thyroid disease, the "om#ination of free 8 $thyro:ine& and SH $thyroid! stimulating hormone& or serum SH $thyrotropin& are highly sensiti)e and spe"ifi"+ Ho1e)er, #e"ause of "ost, some authors re"ommend initially only using the SH to s"reen for thyroid disease+ Serum SH $thyrotropin& is useful to esta#lish a diagnosis of hyperthyroidism or hypothyroidism+ Csually, the SH is lo1 in hyperthyroidism and high in hypothyroidism+

TS' receptor assays

he nomen"lature for the )arious SH re"eptor assays is "onfusing and in"onsistent+ Assays that measure the #inding of SH to a solu#ili;ed re"eptor are often referred to as RA# $thyroid re"eptor anti#ody&, @II $ SH!#inding inhi#itor immunoglo#ulin&, and 2A S $long! a"ting thyroid stimulator& assays+ Assays that measure the a#ility of immunoglo#ulin ( $Ig(& to #ind to the SH re"eptor on "ells and to stimulate adenylate "y"lase produ"tion ha)e generally #een referred to as the SI $thyroid!stimulating immunoglo#ulin& assays+ SIs may sho1 more signifi"ant asso"iation 1ith the "lini"al features of A% than @II and may #e regarded as fun"tional #iomar*ers for A%+,-60 %ther #lood tests that may #e useful in"lude "al"ulated free 8 $thyro:ine& inde:, thyroid! stimulating immunoglo#ulin, antithyroid anti#odies, and serum / $triiodothyronine&+ he introdu"tion of dire"t assays for SH, free 8, and free / has superseded the usefulness of total 8 and / resin upta*e testing+

Thyroid pero(idase st"dies

hyroid pero:idase anti#odies and anti#odies to thyroglo#ulin may #e useful 1hen trying to asso"iate eye findings 1ith a thyroid a#normality, su"h as euthyroid (ra)es disease+ he thyroid pero:idase test is also "alled the antimi"rosomal anti#ody test and the antithyroid mi"rosomal anti#ody test+ he antithyroglo#ulin test is also "alled the antithyroid anti#ody test+ he serum le)el of hyaluronan is not a sensiti)e indi"ator of its presen"e 1ithin the e:trao"ular mus"les+

#T Scanning and )R%

If the diagnosis of thyroid!asso"iated or#itopathy $ A%& "an #e esta#lished "lini"ally, then it is not ne"essary to routinely order a "omputed tomography $C & s"an or a magneti" resonan"e image $MRI&+ Ho1e)er, if these studies are re'uired, o#tain a:ial and "oronal )ie1s+,-?0 MRI is more sensiti)e for sho1ing opti" ner)e "ompression, 1hereas C s"anning is performed #efore #ony de"ompression, #e"ause it sho1s #etter #ony ar"hite"ture+ Aeuroimaging usually re)eals thi"* mus"les 1ith tendon sparing+ he inferior re"tus mus"le and the medial re"tus mus"le are usually in)ol)ed+ @ilateral mus"le enlargement is the norm; unilateral "ases usually represent asymmetri" in)ol)ement rather than normality of the less in)ol)ed side+

Isolated re"tus mus"le in)ol)ement may o""ur in up to 65 of patients; in this su#group of patients, the superior re"tus mus"le may #e the most fre'uently in)ol)ed mus"le+ Isolated lateral re"tus mus"le enlargement 1ithout other e)iden"e of mus"le enlargement is un"ommon in thyroid!asso"iated or#itopathy and suggests another disease pro"ess $eg, or#ital myositis&+ Aeuroimaging may also sho1 a dilated superior ophthalmi" )ein+ In addition, api"al "ro1ding of the opti" ner)e is 1ell )isuali;ed $see the image #elo1&+ %""asionally, the proptosis of thyroid!asso"iated or#itopathy results in straightening of the opti" ner)e+

A:ial "omputed tomography $C & s"an in a patient 1ith "ongesti)e thyroid or#itopathy+ he re"ti mus"les are thi"*ened 1ith api"al "ompression+ he tendons are spared+ %n C s"ans, or#ital fat density is higher in A% patients, and it is negati)ely "orrelated to fat )olume #ut positi)ely "orrelated to mus"le )olume and mus"le density+,->0

'istologic *eat"res
Findings on histologi" e:amination of thyroid!asso"iated or#itopathy in"lude the follo1ing:

Fi#rosis 1ith degenerati)e "hanges in the eye mus"les 2ympho"yti" "ell infiltration Enlargement of fi#ro#lasts A""umulation of mu"opolysa""harides Interstitial edema In"reased "ollagen produ"tion

O"tpatient )anagement
Most patients 1ith thyroid!asso"iated or#itopathy $ A%& "an #e o#ser)ed; the follo1!up inter)al depends on disease a"ti)ity+ Monitor for )isual loss from "orneal e:posure and opti" neuropathy and for stra#ismus de)elopment+ he author does not re"ommend the use of eye e:er"ises for patients 1ith se)ere restri"ti)e stra#ismus; doing so may ele)ate intrao"ular pressure+

Eisual field and "olor )ision testing may help in early dete"tion of )isual loss+ In patients 1ith diplopia, prisms may #e #enefi"ial to those 1ith small!angle and relati)ely "omitant de)iations+ If a patient has dry eye symptoms, "onsider ha)ing them use artifi"ial tears during the day, lu#ri"ating ointment at night, and pun"tal plugs+ ape o""lusion of one lens or segment of the glasses may #e helpful+ If this does not 1or*, try an o""luder or )aulted eye pat"h $1ith "are not to tou"h the "ornea or "ompress the or#it&+

Patient ed"cation
Inform patients that thyroid!asso"iated or#itopathy usually runs a self!limited #ut prolonged "ourse o)er - or more years+ <atients should also reali;e that no immediate "ure is a)aila#le+ ,-70 In addition, en"ourage patients to stop smo*ing to de"rease the ris* of "ongesti)e or#itopathy+ Sleeping 1ith the head of the #ed ele)ated may de"rease morning lid edema+ For patient edu"ation information, see Endo"rine System Center as 1ell as hyroid <ro#lems+

Steroids
Systemi" steroids are usually reser)ed for patients 1ith se)ere inflammation or "ompressi)e opti" neuropathy in thyroid!asso"iated or#itopathy $ A%&+ he "onsensus statement of the European (roup on (ra)es3 or#itopathy $EC(%(%& suggests intra)enous glu"o"orti"oids for patients 1ith ad)an"ed thyroid!asso"iated or#itopathy+,/0 Ao "ases of li)er failure 1ere seen in patients re"ei)ing less than > g of methylprednisolone+ Steroids may de"rease the produ"tion of mu"opolysa""harides #y the fi#ro#lasts+ <ulse intra)enous steroids $eg, methylprednisolone - g e)ery other day for /!6 "y"les& "an #e "onsidered #ut may only marginally impro)e long!term disease out"ome+ hus, if ne"essary, high!dose steroids and higher intra)enous doses are gi)en for "ompressi)e opti" neuropathy+ If no response o""urs after 8> hours, steroids pro#a#ly 1ill not 1or*; at this point, the patient should ha)e surgi"al de"ompression and maintain steroids+ Ad=un"ti)e "y"losporine, o"treotide, and intra)enous immunoglo#ulin $IEIg& are less "ommon modalities of medi"al treatment for opti" ner)e "ompression+ If a good steroid response o""urs, or#ital radiation may #e "onsidered+ In se)ere "ases of thyroid!asso"iated or#itopathy, "om#ined steroids, radiation, and surgery may #e re'uired+ In patients 1ith 1orsening A% despite or#ital de"ompression, intranasal steroids "an #e used+

Potential )edical Therapies

he antio:idant selenium $.44 m"g daily& 1as sho1n in one study to help patients 1ith mild (ra)es or#itopathy+,.40 Anti!CD.4 $ritu:ima#& therapy,.-0 to deplete @!"ell lympho"ytes, and anti!tumor ne"rosis fa"tor $anti! AF& drugs, su"h as etaner"ept, infli:ima#, and da"li;uma#, ha)e #een used in patients 1ith thyroid!asso"iated or#itopathy $ A%&, #ut more studies are re'uired to determine their ris*!#enefit ratio+ <otential side effe"ts of ritu:ima# in"lude

infusion rea"tions and, rarely, in"reased ris* of infe"tion and progressi)e multifo"al leu*oen"ephalopathy+ %"treotide, pento:ifylline, ni"otinamide, plasmapheresis, and intra)enous immunoglo#ulin are not mainstream medi"al treatments of thyroid!asso"iated or#itopathy+ %"treotide, a potent syntheti" somatostatin analogue, has a #enefi"ial effe"t in this "ondition, espe"ially in patients 1ith a positi)e %"treoS"an!--- $indium!--- ,--- In0 pentetreotide&+ 2anreotide is a longer!a"ting somatostatin analogue, 1hi"h is administered only on"e e)ery . 1ee*s; this agent may pro)ide some #enefit+ <ento:ifylline and ni"otinamide may #e useful; #oth agents are #elie)ed to inhi#it "yto*ine!indu"ed gly"osaminogly"an synthesis #y the retroor#ital fi#ro#lasts+ he role of plasmapheresis and intra)enous immunoglo#ulin $IEIg& is not 1ell delineated+ %ne randomi;ed trial of IEIg $- g IgF*g #ody 1eight J . "onse"uti)e d e)ery / 1*& )ersus oral prednisolone $for .4 1*, 1ith initial dose of -44 mgFd& sho1ed #oth treatments to #e e'ually effe"ti)e in patients 1ith a"ti)e thyroid!asso"iated or#itopathy+,..0 Fe1er ad)erse effe"ts 1ere o#ser)ed in the IEIg treatment group+

Orbital Radiation
%r#ital irradiation is sometimes is pres"ri#ed for moderate to se)ere inflammatory symptoms, diplopia, and )isual loss in patients 1ith thyroid!asso"iated or#itopathy $ A%&+ he radiation $-944!.444 "(y fra"tionated o)er -4 d& is usually administered )ia lateral fields 1ith posterior angulation+ Radiation is #elie)ed to damage or#ital fi#ro#lasts or perhaps lympho"ytes+ he radiation re'uires se)eral 1ee*s to ta*e effe"t, and it may transiently "ause in"reased inflammation+ hus, most patients are maintained on steroids during the first fe1 1ee*s of treatment+ In addition, #etter response to radiation is o#ser)ed in patients 1ith a"ti)e inflammation 1ho are treated 1ithin ? months of the onset of thyroid!asso"iated or#itopathy+ Radiation may #e more effe"ti)e if "om#ined 1ith steroid treatment+ Studies that suggest that radiotherapy is ineffe"ti)e in thyroid!asso"iated or#itopathy must #e s"rutini;ed to ensure that the radiation 1as administered to appropriate "andidates at the appropriate time+ For e:ample, the (orman et al study used serum thyroid!stimulating immunoglo#ulin , SI0 as a surrogate of a"ti)e eye disease+,./0 Although the #lood test is an indi"ator of immunologi" a"ti)ity, it may not refle"t the "lini"al progression of thyroid! asso"iated or#itopathy+ Furthermore, the patients in that study 1ere enrolled at a median of -+/ y after the onset of eye symptoms, suggesting that many of the patients in the study 1ould not ha)e progressi)e eye symptoms or signs indi"ati)e of an ongoing or#ital pro"ess+,./0 Although impro)ement of motility distur#an"es "an o""ur 1ith radiotherapy, radiation is limited 1hen used in isolation to treat diplopia+

Potential adverse e ects and contraindications

Catara"t, radiation retinopathy, and radiation opti" neuropathy are possi#le ris*s+ hese effe"ts are not "ommon if treatment is appropriately fra"tionated and the eyes are shielded+

Mar'ue; et al found -.5 of their study patients de)eloped "atara"ts after irradiation $median follo1!up, -- y&+,.80 Ga*el*amp et al also #elie)ed that or#ital irradiation for thyroid!asso"iated or#itopathy is a safe treatment modality, e:"ept possi#ly for patients 1ith dia#etes mellitus+,.90 Radiation may #e a relati)e "ontraindi"ation for patients 1ith dia#etes mellitus #e"ause of the ris* of 1orsening retinopathy+

Prevention o %-+,+-Associated TAO

o pre)ent progression of thyroid!asso"iated or#itopathy $ A%& from radioa"ti)e iodine, pretreating and post treating the patient 1ith lo1!dose steroids $eg, 4+9 mgF*gFd up to . mo posttreatment& has #een suggested if no "ontraindi"ations for steroids e:ist and this therapy is agreed to #y the patient+ Follo1ing radioa"ti)e iodine, the patient should #e monitored "losely for the de)elopment of hypothyroidism+

Overview o S"rgical %ntervention

Appro:imately 95 of patients 1ith thyroid!asso"iated or#itopathy $ A%& may re'uire surgi"al inter)ention+ he patient should *no1 that multiple!staged pro"edures may #e re'uired+,.6, .?, .>0 In ele"ti)e "ases, listen "arefully to 1hat the patient desires; the patient3s e:pe"tations may not #e realisti"+ he timing of surgery is important+ Cnless "ompressi)e opti" neuropathy or se)ere "orneal e:posure is present, surgery is generally delayed during the a"ti)e inflammatory phase of thyroid!asso"iated or#itopathy+ Surgery is usually performed during the 'uies"ent "i"atri"ial phase of the disease+ a*ing preoperati)e photographs is ad)ised+ Gith stra#ismus surgery, do"ument prism measurements or fields of single #ino"ular )ision+ Re"ording #aseline!automated perimetry also is useful+ he se'uen"e of surgery is also important+ If the patient has mar*ed proptosis, stra#ismus, and lid deformity, perform surgery in the follo1ing order: -+ %r#ital de"ompression .+ Stra#ismus surgery /+ 2id!lengthening surgery 8+ @lepharoplasty hese pro"edures 1ill #e #riefly re)ie1ed in the follo1ing se"tions+

Orbital Decompression
%r#ital de"ompression may #e performed as the initial treatment of "ompressi)e opti" neuropathy or used if medi"al treatment is ineffe"ti)e+ A "om#ination of medi"al and surgi"al treatment may #e re'uired in "ompressi)e opti" neuropathy+

horoughly e:plain the potential "ompli"ations of or#ital de"ompression $eg, #lindness, hemorrhage, diplopia, perior#ital num#ness, glo#e malposition, sinusitis, lid malposition& to the patient #efore surgery+

Proced"re overview
Follo1ing #ony or#ital de"ompression, open the perior#ita+ 2ittle redu"tion in proptosis o""urs until the perior#ita is slit+ o de"ompress the opti" ner)e, at least . or#ital 1alls are usually de"ompressed $traditionally, the medial 1all and floor of the or#it&+ Medial de"ompression for "ompressi)e neuropathy must #e ta*en posteriorly all the 1ay to the ape: of the opti" "anal+ Surgery "an #e approa"hed from a transor#ital or trans!sinus route+ ransor#ital routes in"lude su#"iliary in"isions, lid "rease in"isions, medial in"isions $"utaneous, trans"arun"ular&, and "oronal in"isions+ rans!sinus routes in"lude transantral approa"hes and endos"opy+ Medial 1all remo)al should not e:tend a#o)e the frontoethmoidal suture+ his a)erts #leeding from the ethmoidal arteries and pre)ents "ere#rospinal fluid $CSF& lea*s+ Ghen the or#ital floor is remo)ed, preser)ation of a strut of #one #et1een the ethmoid and ma:illary #ones may redu"e stra#ismus from inferomedial shift in the glo#e position+ @alan"ed de"ompression of the medial and lateral or#ital 1alls is fre'uently des"ri#ed+ A)oiding de"ompression of the or#ital floor theoreti"ally de"reases the ris* of postoperati)e diplopia and lid retra"tion+ 2ateral 1all de"ompression does little to relie)e api"al "ompression #ut helps to reprodu"e proptosis+ Ealgus repositioning of the or#ital 1all and or#ital rim!onlay, porous!polyethylene grafts are ad=un"ti)e te"hni'ues to redu"e proptosis+ Four!1all de"ompression $1ith de"ompression of the or#ital roof& re'uires a neurosurgi"al approa"h+

Orbital at decompression
%r#ital fat de"ompression 1ithout #ony remo)al has #een des"ri#ed for thyroid!asso"iated or#itopathy $ A%& 1ithout api"al "ompression+ Candidates for or#ital fat de"ompression should sho1 predominant enlargement of the or#ital fat "ompartment, rather than the re"tus mus"les on or#ital imaging+ Cnli*e "osmeti" #lepharoplasty, 1ith or#ital fat de"ompression, fat is also remo)ed posterior to the e'uator of the glo#e+ Inferiorly, the fat is remo)ed through a trans"on=un"ti)al approa"h, 1hi"h may #e fa"ilitated 1ith lateral "anthotomy and "antholysis+ Superiorly, fat remo)al is through a lid "rease in"ision, usually "onfined to the nasal 'uadrant+ A study #y 2iao et al "onfirms that a reasona#le and effe"ti)e redu"tion in proptosis "an #e safely a"hie)ed #y e:tensi)e or#ital fat remo)al alone+,.70 he study did not "orrelate indi)idual "ase results 1ith e:tent of e:trao"ular mus"le hypertrophy "ompared 1ith degree of fat hypertrophy, thus greatly impa"ting results in indi)idual "ases+ he ris* of postoperati)e 1orsened stra#ismus 1as not addressed and li*ely still remains a $theoreti"al&

ris*+ Relying solely on fat de"ompression in "ases of impending or a"tual opti" ner)e "ompression is not ad)isa#le+

Strabism"s S"rgery
Su""essful, early stra#ismus surgery during a"ti)e thyroid ophthalmopathy has #een des"ri#ed, #ut stra#ismus surgery generally is delayed until thyroid!asso"iated or#itopathy $ A%& is ina"ti)e and the prism measurements ha)e #een sta#le for at least 6 months+ <atients should reali;e that the goal of surgery is to minimi;e diplopia in primary and reading positions+ E:pe"ting #ino"ular single )ision in all positions of ga;e may not #e realisti"+ <atients should also reali;e that multiple stra#ismus surgeries and prisms may #e re'uired+ @e"ause of the restri"ti)e myopathy of thyroid!asso"iated or#itopathy, predominantly re"essions, rather than rese"tions, are performed+ Ghene)er feasi#le, ad=usta#le suture surgery is re"ommended+ In patients intolerant of "ons"ious suture ad=ustment, hang!#a"* sutures "an #e ad=usted using the "orneal light refle:es+ In sele"t patients 1ith thyroid! asso"iated or#itopathy, stra#ismus surgery "an #e performed using topi"al anesthesia+ o pre)ent o"ular is"hemi" syndrome, do not operate simultaneously on more than . mus"les per eye+

Proced"re considerations
Surgery of the inferior re"tus mus"le deser)es spe"ial mention+ Inferior re"tus mus"le re"ession may de"rease upper lid retra"tion, #ut it also often results in lo1er lid retra"tion despite disse"tion of the lo1er lid retra"tors+ @e"ause the inferior re"tus mus"le has su#sidiary a"tions $e:"y"lotorsion and addu"tion&, inferior re"tus mus"le re"essions may lead to a "omponent of intorsion and A!pattern stra#ismus+ If )isuali;ation during stra#ismus surgery is diffi"ult, espe"ially for the superior re"tus mus"le, a )erti"al lid split te"hni'ue may #e "onsidered+ @otulinum to:in in=e"tions are used #y some "lini"ians during the a"ute phase of thyroid! asso"iated or#itopathy as a tempori;ing measure until or#ital de"ompression "an #e "ompleted+ Ho1e)er, opti" neuropathy follo1ing a #otulinum to:in in=e"tion for stra#ismus in a patient 1ith thyroid!asso"iated or#itopathy has #een reported+

Lid-Lengthening S"rgery
If restoration of the euthyroid state does not impro)e lid retra"tion, "onsider lid!lengthening surgery+ his surgery de"reases "orneal e:posure and "an #e used to "amouflage mild!to! moderate proptosis+ In patients un1illing to "onsider lid surgery, possi#le alternati)es to upper!lid lengthening in"lude #otulinum to:in in=e"tions to the upper lid and su#"on=un"ti)al triam"inolone+ 2ateral tarsorrhaphies "an de"rease upper and lo1er lid retra"tion, #ut the author does not prefer this method+

Amelioration of .!/ mm of upper lid retra"tion "an #e done 1ith a MKller mus"le e:"ision+ 2ateral le)ator tenotomy is often helpful to de"rease the temporal flare+ If further amounts of lid re"ession are re'uired, le)ator re"ession "an #e "onsidered+ 2o1er lid!lengthening usually re'uires a spa"er material+ (raft materials in"lude human a"ellular dermis, tarsus, and "on=un"ti)a from the upper lid, hard palate, and ear "artilage+ Hori;ontal tightening pro"edures $eg, lateral tarsal strip& in"rease s"leral sho1 in patients 1ith proptosis+ In the hori;ontally tight eyelid, lateral "anthal ad)an"ement is a useful ad=un"t to enhan"e the effe"t of retra"tor re"ession and redu"tion of temporal flare+

-lepharoplasty
@lepharoplasty is the last phase of restorati)e surgery in thyroid!asso"iated or#itopathy $ A%&+ he trans"on=un"ti)al approa"h to lo1er lid #lepharoplasty "an #e used if no e:"ess lo1er lid s*in is present+ Cpper lid #lepharoplasty is performed trans"utaneously 1ith "onser)ati)e s*in e:"ision+ @ro1 fat rese"tion may #e "onsidered+ Da"ryope:y may #e re'uired if la"rimal gland prolapse o""urs+

#ons"ltations
<atients 1ith thyroid!asso"iated or#itopathy $ A%& #enefit from "onsultation and follo1!up "are 1ith an endo"rinologist+ %r#ital de"ompression "an #e performed in "on=un"tion 1ith an otorhinolaryngologist, espe"ially 1hen endos"opi" pro"edures are "ontemplated+ Aeurosurgi"al "onsultation is re'uired 1hen de"ompression of the or#ital roof is performed+

Pregnancy and TAO

he in"iden"e of hyperthyroidism in 1omen 1ho are pregnant has #een reported to #e appro:imately 4+.5+ Information on the management of thyroid!asso"iated or#itopathy $ A%& during pregnan"y is not 1idely a)aila#le+ he author is not a1are of literature that supports "esarean deli)ery o)er )aginal deli)ery in 1omen 1ith this "ondition 1ho are pregnant+ If a pregnant 1oman 1ith thyroid!asso"iated or#itopathy has "ompressi)e opti" neuropathy, steroids "an usually #e administered in "onsultation 1ith the o#stetri"ian and an endo"rinologist+ Ideally, surgery should #e deferred until after deli)ery 1hen possi#le+ Ho1e)er, if emergent or#ital de"ompression is re'uired, nona#dominal surgery may not impose the same ris*s to the fetus as that of a#dominal surgery+

#hildhood TAO

In general, "hildren 1ith thyroid!asso"iated or#itopathy $ A%& tend to ha)e a more #enign disease "ourse, 1ith less ophthalmoplegia, than adults+ In "omparison 1ith adults, surgi"al inter)ention is infre'uently re'uired 1ith "hildren+ Children and their parents should #e "ounseled to a)oid smo*ing+ Se"ondhand smo*e seems to e:a"er#ate autoimmune thyroid disease, and passi)e smo*ing may ha)e a deleterious effe"t on "hildhood thyroid!asso"iated or#itopathy+

Special #onsiderations
he "lini"ian should #e a1are that thyroid!asso"iated or#itopathy $ A%& "an #e asymmetri"+ In addition, opti" ner)e "ompression in thyroid!asso"iated or#itopathy "an o""ur in the a#sen"e of o#)ious proptosis; for this reason, al1ays "he"* for retropulsion+ hyroid!asso"iated or#itopathy should not #e mista*en for a dural arterio)enous malformation or a "arotid "a)ernous fistula $see Diagnosti" Considerations&+ Early diagnosis and appropriate monitoring of thyroid!asso"iated or#itopathy may de"rease "orneal e:posure and "ompressi)e opti" neuropathy+ In patients 1ith thyroid!asso"iated or#itopathy 1ho ha)e proptosis and inferior s"leral sho1, simple hori;ontal tightening of the lo1er lid 1ill result in in"reased glo#e e:posure+ @efore performing #ony or#ital de"ompression, "omputed tomography $C & s"an should #e o#tained, #e"ause these studies delineates #ony anatomy #etter than magneti" resonan"e imaging $MRI&+