beleŠke iz istorije autoimunske...

7BELEŠKE IZ ISTORIJE AUTOIMUNSKE ORBITOPATIJE

Božo Trbojević

BELEŠKE IZ ISTORIJE AUTOIMUNSKE ORBITOPATIJE

Sažetak: Razvoj znanja o izgledu, prirodi, poreklu i ishodu bolesti očne duplje i oka u bolestima štitaste žlezde bio je veoma spor, sa mnogo nedoumica, kontroverzi i stranputica. Zanimljivo je da prvi pouzdani opisi ove udruženosti potiču od pravnika a ne od lekara. Kasniji dopri-nos arapskih lekara i mislilaca znatno je unapredio medicinsku misao i praksu. Zapadna medicina je baštinila otkrića istočnih naroda ugrađujući evropski smisao za racionalno; rezultat je bolje razumevanje prirode procesa, bolje poznavanje uzroka i razvoja poremećaja ali su terapijske mogućnosti i dalje zaostajale. Tek poslednjih decenija prošlog veka do-lazi do primetnog napretka u defi nitivnom određenju prirode promena u orbitopatiji, postaje jasno da je po sredi imunski posredovan proces i time se donekle tire put boljoj i uspešnijoj terapiji. Uprkos tome, auto-imunska orbitopatija ostaje još uvek jedno od stanja u endokrinologiji koje se najteže kontroliše i leči.

Struma (od latinskog izraza za otok žlezda na vratu) ili goiter (guttur: latinski naziv za grlo) poznata je od antičkih vremena. Reference o bolesti mogu se naći u kineskim i grčkim tekstovima ali kombinacija izbočenih očiju, strume i znakova odgovarajućih hipertiroidizmu izgleda novijeg datuma – prvo u legalnim rimskim tekstovima iz 2–3. veka i u vizantijskom tekstu iz 6. veka naše ere. Još na prelazu drugog u treći vek, rimski pravnik i bliski savetnik imperatora Septimija Severa, Do-mitius Ulpianus, uneo je zakonsku odredbu da rob koji ima gušu i izbočene oči ima manju radnu sposobnost (Si quis natura gutturosus sit aut oculos eminentes habeat, sanus videtur). Ulpianus zaključuje da prodavac roba nije odgovoran zbog smanjenih radnih sposobnosti osobe sa takvim znacima.

Kao kod Ulpianusa i, verovatno, u nekoj vezi sa njegovim pravničkim nasleđem, u vizantijskom pravnom tekstu iz 6, veka čiji je latinski naziv Digesta Corpus Juris Civilis Justiniani, na kome se zasniva kasniji grčki tekst Vasilica stoji: ‘quis natura gutturosus sit aut oculos eminentes habeat’. Pošto se radi isključivo o pravnim a ne

8 MEDICINSKI GLASNIK / str. 7-17

medicinskim dokumentima nije jasno da li je pravnik prepoznao vezu između ova dva medicinska znaka. Poznato je da se fi zionomija rimske populacije u to vreme odli-kovala prominentnim očnim jabučicama i zbog toga se misli da Ulpianus nije svesno prepoznavao povezanost strume i izbočenih očiju, ali su i druga tumačenja moguća.

Prvi medicinski rukopis, u kome se promene na očima i struma povezuju, pripi-suje se monahu Meletiusu, zvanom iatrosofi sta, koji je živeo u 8. veku naše ere. Da se ovi opisi odnose na egzoftalmus i bolest za koju danas znamo da je bolest štitaste žlezde a ne neku drugu bolest, upućuje opis o izuzetnoj razdraženosti ovih osoba i izrazitoj promeni ponašanja. Meletius navodi:„...oči imaju naklonost da otiču i da izlaze napolje ... zbog čega je osoba veoma uznemirena i zastrašena”. Ovakav opis nesumnjivo pokazuje da su vizantijski lekari poznavali bolest štitaste žlezde i da zaslužuju svoje mesto u istoriji tiroidologije.

Tekst arapskog autora Zayn al-Din Sayyed Isma‘il ibn Husayn Gorgani, poznatog i kao Sayyid Ismail Al- Jurjani, „Blago šaha Kvarazma” (Zakhireye Khwarazmshahi ), objavljen je oko 1110. godine. Al-Jurjani je bio doktor i fi lozof i u svojoj enciklope-dijskoj knjizi navodi, kako se verovalo, prvi opis koji povezuje otečen, zadebljali vrat i promene na očima za koje je mislio da su jedinstvena celina blisko povezanih pore-mećaja. Međutim, Al-Jurjani je bio veliki poštovalac Avicene, koji je živeo približno jedan vek ranije i bio je pod velikim uticajem njegovog čuvenog teksta, Al-Qanoon ili Zakoni medicine, posebno treće knjige. Ova istorija je značajna jer podvlači do-minantnu ulogu koju je islamska medicina imala u srednjem veku prenoseći nasleđe ranije, helenističke, rimske i dalekoistočne medicine, dodajući ovim znanjima svoja sopstvena otkrića. Iznenađujuće je kada se proučavaju raniji persijski medicinski tekstovi, pisani više od jednog veka pre nego što je Al-Jurjani dao svoj opis, da je Avicena već opisao povezanost orbitopatije i zadebljalog vrata. Iako Al-Jurjanijeva medicinska enciklopedija zaista predstavlja veliko područje učenja i zaista ugrađuje ideje koje se ne mogu naći ranije, ni u Aviceninom Kanonu, ipak se mora reći da se on u velikoj meri zasniva na otkrićima koja je dao Avicena.

Ibn Sina ili Abu Ali al-Husayn ibn Abd Allah ibn Sina, na zapadu poznat kao Avicena, verovatno je najpoznatiji lekar islamske civilizacije. Bio je i veoma plo-dan pisac, sastavio je skoro 270 različitih traktata od kojih je najveći broj iz oblasti medicine. U svom remek delu Al-Qanoon, koje sadrži više od milion reči, Avicena opisuje potpune studije fi ziologije, patologije, higijene u koje ugrađuje i najvažnije izvore stare helenske i kineske medicine. Njegove knjige predstavljaju prave uzore svog vremena. Između ostalog, Al-Qanoon ili Zakon opisuje i otok prednje strane vrata (strumu) u osoba koje su imale pojačan apetit i koje nisu mogle da se zasite uprkos velikim količinama hrane koju su unosile (Al-Qanoon, Knjiga III, glava 6). U dve glave svog Kanona opisao je i vezu između otoka vrata i izbočenja očiju (Kanon, Knjiga III, deo treći, drugi članak, glava 15 i Knjiga III, deo treći, glava 4). U glavi o egzoftalmusu opisuje diferencijalnu dijagnozu proptoze. Zapazio je da


egzoftalmus može da nastane zbog pritiska iz pozadine orbite, beleži otok rožnjače, hemozu, povećanje mase orbitalne masti i slabost, zamorljivost očnih mišića u kli-ničkom ispoljavanju egzoftalmusa. Opisao je okularne karakteristike kada je uzrok egzoftalmusa zamor ekstraokularnih mišića (Kanon, knjiga III, deo treći, članak 2, glava 15). Njegova dela su prevedena u drugoj polovini 12. veka u Toledu, preveo ih je Gerhard iz Kremone. Kasnije, u 16. veku, Andrea Alpago u Veneciji ponovo prevodi njegova dela na latinski jezik. Od tada, kroz mnoge vekove, Avicenine knjige predstavljaju jedan od najvažnijih medicinskih udžbenika u Zapadnoj Evropi. U stvari, sve do sredine 17. veka medicinski kurikulum evropskih univerziteta zasnivao se na Aviceninim tekstovima. Verovatno je da su najpoznatiji mediteranski univerziteti, kao u Kordobi i Salernu, koristili Avicenine tekstove i pre nego što su prevedeni na latinski jezik pošto su u ovim školama helenska, rimska, arapska i hebrejska iskustva bila jedinstveni delovi kurikuluma. Širokim interesovanjem i znanjima iz različitih oblasti nauke, ali i umetnosti, Avicena je zapravo prototip renesansnog čoveka skoro tri veka pre pojave Medičija i njihovog kruga.

Potom nastupa duga pauza u opisima i istraživanjima bolesti oka i pojave strume, zadebljanja vrata.

Caleb Hillier Parry (1755–1822) je proveo najveći deo života kao lekar opšte prakse u Batu, Engleska. U spisima, koji su nađeni posle njegove smrti, u poglavlju posvećenom bolestima srca, opisuje i pet pacijenata sa strumom i nesumnjivim hiper-tiroidizmom pod naslovom: ‘‘Enlargement of the Thyroid Gland in Connection with Enlargement or Palpitation of the Heart’’. Jedna od njih je Mrs. Grace B, 37 godina, koju je Parry prvi put video avgusta 1786. Patila je od palpitacija i nepravilnog pulsa koji je dostizao 156 udara. Njena tiroidna žlezda je bila ogromna, dostižući ivicu donje vilice... „oči su bile izbočene, izlazile su iz prostora očnih duplji i imale su izgled neprekidne uplašenosti, nije podnosila uznemirenje i napor, posebno mišićni, kako sam retko do sada video’’. Pacijentkinja je lečena puštanjem krvi i preparatima srebra ali je razvila masivni otok sa noćnom ortopneom. Parry nije bio upućen u dalji tok bolesti ali pretpostavlja da je pacijentkinja ubrzo ‘‘paid her debt to nature’’. Ovaj kratki opis se uobičajeno smatrao prvim opisom oftalmopatije u tiroidnoj bolesti, što, kako smo videli, nije tačno.

Hronološki, sledeći opis egzoftalmusa, zajedno sa oboljenjem štitaste žlezde, saopšten je anonimno 1816. u Medico-Chirurgical Journal and Review. Kako Legg citira „Mlada žena, 22 godine, imala je palpitacije, zadebljanje sa svake strane vrata veliko kao guščje jaje. Oči su bile prominentne kao da hoće da iskoče iz očnih duplji. Bila je veoma nervozna, vitka i izrazito pletorična. Porto vino i kora drveta nisu po-magali. Stavljena je na režim striktnog antifl ogističkog sistema; puštana je krv, pila je samo vodu, nije smela da jede životinjsko meso, nije dobijala kalomel ili digitalis. Posle oko sedam meseci sreo sam je na ulici, bila je vrlo dobro.’’ Legg je opisao još nekoliko slučajeva tiroidne oftalmopatije koje je objavio između 1820–1828.


Robert Graves (1796–1853) je između 1834–1835. na Univerzitetskoj bolnici u Dablinu održao nekoliko predavanja. U jednom je opisao tri osobe sa strumom i palpitacijama. Četvrta pacijentkinja bila je „gospođa oko 20 godina, sa simptomima koji su izgledali kao histerija’’. Razvila je tahikardiju, otok štitne žlezde i uznemire-nost; „Očne jabučice bile su primetno uvećane tako da očni kapci nisu mogli da ih pokriju tokom spavanja ili kada je pokušavala da zatvori oči. Kada su joj oči otvorene beonjače su se videle u širini nekoliko linija oko rožnjače.’’

Od 1822, Carl Adolph von Basedow (1799–1854) obavljao je lekarsku praksu u malom gradu Merzeburgu, između Lajpciga i Halea, u Nemačkoj. Video je tri pacijenta sa strumom u toku nekoliko godina. Prve dve (Madame G i Madame F) pojavile su se sa simptomima fl oridnog hipertiroidizma i egzoftalmusom. U toku bolesti, za obe se mislilo da su poludele i u stvari madam F je bila primljena u azil za umobolne. Jedna od žena imala je promene za koje danas znamo da su pretibijalni miksedem ili dermopatija.

Treći bolesnik, Herr M, 50-godina star muškarac počev od 1832. počeo je da se žali na slabost i pojavu proliva. Žalio se na „toplotu od krvi”, izrazito preznojavanje i prekordijalne opresije. Lice je bilo bledo i otečeno a oči su prominirale izvan očnih duplji; štitasta žlezda je bila uvećana; bolesnik je gubio u težini uprkos dobrom apetitu i dalje je imao učestale tečne stolice. Tok bolesti je bio težak. Posle pojave keratitisa razvija se purulentna infekcija oba oka. Bazedov je preporučio široku inciziju obe očne jabučice da bi se evakuisao gnoj ali je bolesnik odbio ovo rešenje. Izgubio je vid na oba oka i Bazedov zapisuje „nesrećni bolesnik je trpeo nepodnošljive bolove”. Pojavljuju se teški srčani simptomi sa tahikardijom i respiratornim teškoćama zbog velike strume. Pacijent je iznenada umro 1843. godine.

U 1877, Yeo prvi opisuje dve osobe sa jednostranim egzoftalmusom. Razlog za ovaj fenomen ostao je enigmatičan i danas, kao što je bio i pre 130 godina. U pogledu ovog opisa, treba napomenuti da su dva Italijana, Flajani i Testa, publikovali slična zapažanja 1802. i 1810. Njihove studije, nažalost, danas nisu dostupne.

Patološka anatomija

Bazedov je obavio prvu autopsiju pacijenta sa tiroidnom oftalmopatijom, u stvari obdukovao je svog pacijenta, Herr M. Nalaz nije posebno karakterističan pošto su obe očne jabučice bile fi brozne i svedene ispod polovine svoje normalne veličine. Našao je velike količine žutog masnog tkiva u orbitama. Jean-Martin Charcot (1825–1893) je sa-brao svoje rezultate postmortalnih studija orbita bolesnika sa egzoftalmusom i potvrđuje da jabučica izgleda normalno ali da se izvanredno velika masa masti nakuplja u očnim dupljama. Armand Trousseau (1801–1867) citira danski članak u kome se opisuje orbi-talno tkivo u tiroidnoj oftalmopatiji. Kada se traži, može se naći velika količina masnih naslaga u orbitama. Trousseau je mogao da potvrdi ovaj nalaz i u svojih pacijenata.


R Foster Moore je 1920. obavio postmortalnu disekciju orbita u bolesnika koji su umrli sa oboljenjem štitaste žlezde i očiju. On je sažeo osnovnu hipotezu tog doba o uzrocima egzoftalmusa: „(1) iritacija simpatikusnog nervnog sistema koji izaziva grče-nje glatkih mišića u orbiti; (2) zagušenje orbite krvlju; i (3) povećanje mase orbitalne masti.” Moore podvlači da, pošto se egzoftalmus ne povlači posle smrti verovatno nije posledica simpatikusne hiperaktivnosti ili nagomilavanja krvi. „U tom slučaju orbite su sigurno pune zbog hipercirkulacije u njima i ništa drugo nenormalno se neće naći; proptoza je nesumnjivo posledica viška masti. . . Meni izgleda neodbranjivo da porast orbitalne masti predstavlja uobičajeni uzrok egzoftalmusa u Graves, ovoj bolesti i da danas nema zadovoljavajućeg dokaza bilo kog drugog uzroka.’’

U toku 1933, Howard Christian Naffziger (1884–1961) objavljuje pregled mno-gih studija orbitalnih struktura u egzoftalmusu-neke pokušavaju da objasne promene proširenim varikoznim venama ili dilatiranim arterijama orbita ili miozitisom ekstra-okularnih mišića. Naffziger podvlači da u njegovom materijalu upadljivo dominira zadebljanje ekstraokularnih mišića. Rundle i Pochin sprovode studiju osobina različitih tkiva u orbiti u egzoftalmusu. Zaključuju da je povećana količina masti u orbitalnom tkivu u najvećoj meri odgovorna za povećanje mase sadržaja orbita.

Uzrok

U veku koji je sledio objavljeno je mnogo publikacija Graves-a i Basedow o zajedničkoj pojavi strume, srčanih simptoma i proptoze. Autori su pokušavali da objasne ovu neobičnu udruženost simptoma. Cooper u jednom od najranijih revijal-nih prikaza o udruženosti strume i oftalmopatije podvlači da je dvoje od pet bole-snika pogrešno dijagnostikovano kao hidroftalmija (verovatno je značenje glaukom) i najveći deo teškoća je poticao od lečenja živom kome su bolesnici podvrgnuti. Cooper nije pokušavao da utvrdi tok bolesti ali je insistirao da predstavi svoj način lečenja: „ako ima znakova anemije, čuje se šum nad sudovima vrata, ako postoje palpitacije i, pored toga, uvećanje štitaste žlezde ima dovoljno razloga da se misli da su promene oka sekundarne: ovo mišljenje je još sigurnije ako se bolesnik ne žali na bol i nelagodnost u očima ili poremećaj oštrine vida. Najuspešniji lekovi su gvožđe, aloja, mirta sa sedativima, potapanje tela u hladnu slanu vodu posle čega se primenjuju frikcije i, ako ima znakova histerije, frikcija duž kičme stimulacijskim linimentima.’’

Iako je lako podsmevati se teorijama i idejama koje su važile više od 100 godina ranije u uslovima sasvim različitim od današnjih, neki od stavova su čak i u to vreme izgledali isuviše revolucionarni i skoro nerazumni. Tako, Jones 1860. piše: „Osnova bolesti je slabost, posebno nervnog sistema koji, uticajem na različite vazomotorne nerve, izaziva različite simptome. Tako efuzija iza očnih jabučica izaziva proptozu; hiperemija i pojačana aktivnost celularnih elemenata štitaste žlezde izazivaju strumu;


pareza vagusa izaziva palpitacije i povraćanje. Povoljan efekat tonikuma značajno podržava ovakvo stanovište.” Mnogi autori su ukazivali na srčane i neurološke pore-mećaje kao verovatne uzroke (ne posledicu) bolesti. Zapažanje da je „egzoftalmusna struma” neurološka bolest pojavljuje se 1861. godine. Poznati francuski lekari, kao Trousseau i Charcot, podržavaju ovo gledište. Tako Pierre Marie (1853–1940) piše članak o karakteristikama tremora koji su, po mišljenju Marie a prevideli mnogi prethodni istraživači.

U 1890. Mackenzie objavljuje dva klinička članka o Graves–Basedow-ljevoj bolesti, i zaključuje: Tako, gospodo, to je ono što hoću da vam predložim kao poreklo i razvoj ove veoma neobične bolesti. Verovatno je da poremećaj funkcije tiroidnog tela, čiji je značaj u vezi sa ishranom i transmisijom nervnih sila dokazan, ima veliki značaj u nastanku mnogih sekundarnih simptoma kojima sam poklonio pažnju, ali realna bolest je rasprostranjeni poremećaj emocionalnog nervnog sistema.’’ Paul Julius Moebius (1853–1907) u kratkom ali uticajnom članku odbija prethodno mišljenje da je Basedow-ljeva bolest oboljenje krvi, srčana bolest ili neurološka bolest. Potvrdio je da je u vreme kada je sam razmišljao o prirodi Basedow-ljeve bolesti mislio da je ona neki oblik histerije. Zapazio je da su simptomi miksedema na neki način sasvim suprotni simptomima hipertiroidizma i pretpostavlja da je Basedow ljeva bolest poremećaj tiroidne žlezde. Odbacio je argumente popularne u to vreme da je štitasta žlezda rudimentarni organ ili da je njena uloga da reguliše moždani krvotok. Nije se bavio objašnjenjem egzoftalmusa.

U 1893. George Redmayne Murray (1865–1939) – koji je aprila 1891. prvi dao tiroidni ekstrakt pacijentu sa hipotiroidizmom – objavljuje rad u kome zapaža da su „neki od simptoma egzoftalmusne strume posledica hiperaktivnosti tiroidne žlezde”. Smatra da „smanjenje sekretorne aktivnosti popravlja stanje bolesnika”. Citirao je izveštaj da je hirurško uklanjanje žlezde dovelo do potpunog izlečenja. Posebno je istakao da uzrok egzoftalmusa ne mora da se u potpunosti pripiše hipersekreciji štitaste žlezde. U nekih bolesnika, lečenih od hipertiroidizma, posle operacije egzoftalmus ostaje nepromenjen ili se čak pogoršava. Pored toga, davanje tiroidnog ekstrakta ne izaziva egzoftalmus.

Hirsch objavljuje reviju o egzoftalmusu u kojoj iznosi mišljenje koje je jednu generaciju kasnije potpuno odbačeno. On pravi razliku između „malignog egzoftal-musa” i „egzoftalmusa sa difuznom toksičnom strumom”: „Maligni egzoftalmus je klinička celina različita od egzoftalmusa, kako se vidi u tirotoksikozi. Ova stanja mogu imati sličnost u etiologiji; različita klinička slika i razlike u postupku ukazuju da je neophodno da kliničar bude upoznat sa dijagnoznim kriterijumima za bolest i da hirurg poznaje osnovni proces na kome se zasniva lečenje.”

Iako mnogi bolesnici sa proptozom imaju hipertiroidizam, mali broj bude eutiroidan ili je čak hipotiroidan. Razlozi za kliničke varijacije u ispoljavanju nisu poznati. Mehanički ili spoljašnji faktori mogli bi da imaju ulogu – na primer pušenje


ili lečenje radiojodom. U 1946. Iason je nabrojao više od 25 pretpostavljenih uzroka egzoftalmusa. Neki su bili pomalo čudni (ruptura jugularnih sudova zbog sisanja snega ili ispijanja ledene vode ili adrenalna insufi cijencija).

Studije u periodu oko II svetskog rata otkrile su da hipofi za larvi i amfi bija luči tirotrofnu supstancu i kasnije je to potvrđeno u sisara. Spekulisalo se da taj hormon može da ima ulogu u nastanku egzoftalmusne strume. Ipak, 1953. godine Werner u pažljivo urađenoj studiji zaključuje da tirotropin nije uključen u patogenezu Graves-ove bolesti. Bez obzira, hipofi zektomija se i dalje obavljala u lečenju egzoftalmusa deceniju kasnije.

Operacije na simpatikusnom sistemu

Abadie je 1899. obavio sekciju cervikalnog simpatikusnog stabla u boles-nika sa teškim bilateralnim egzoftalmusom. On je tvrdio da je operacija postigla izvanredan uspeh i izlečenje. Nije imao sumnju da je procedura vredan postupak u lečenju egzoftalmusa. U toku naredne jedne do dve godine nekoliko drugih, naročito francuskih, autora (Jaboulay, Jonnesco, Poncet, Reclus, Faure) preuzima proceduru koja je često izvođena dvadesetih godina prošlog veka pošto se još uvek verovalo da je egzoftalmusna struma neurološka bolest. Cannon sa saradnicima insistira da je moguće izazvati hipertiroidizam u mačke stimulacijom simpati-kusnih nerava. Eksperimenti za proveru ovog postulata sprovedeni su 1939. ali neuspešno, i radovima Brain-a stavljena je tačka na spekulacije da je egzoftalmus neurološka bolest.

Orbitalna hirurgija

Egzoftalmus može biti agonalna bolest ne samo zbog ekstremnog naruživa-nja bolesnika već i zbog bola i ugrožavanja vida, kako je prvi opisao još Basedow. Zbog toga nije iznenađenje da su medicinske zajednice insistirale na prepoznavanju bolesti u ranom stadijumu i traganju za postupcima u lečenju. Još 1867. v Graefe je preporučio lokalnu hirurgiju za vraćanje očnih jabučica i simptomatsko poboljšanje. Oktobra 1910. Julius Dollinger u Budimpešti obavlja prvu veliku operaciju sa ek-splicitnim ciljem da ublaži egzoftalmus u Graves–Basedow-ljevoj bolesti. Bolesnik nije imao klinički primetnu tiroidnu hiperfunkciju ali je imao tešku proptozu desnog oka sa keratitisom. Uprkos velikim dozama morfi na trpeo je velike bolove. Uklonjen je spoljašnji zid orbite sa brzim, izrazitim ali kratkim poboljšanjem. Ovaj pristup se zasnivao na tehnici koju je razvio Rudolf Ulrich Kroenlein (1847–1910) – jedan od vodećih hirurga u drugoj polovini 19. veka.


Moglo bi se očekivati da je 100 godina posle Dollinger-ove operacije postignuta saglasnost u pogledu orbitalne hirurgije. Oskar Hirsch (1877–1965) je 1930–20. godina posle pionirskog rada na pituitarnoj hirurgiji – opisao uklanjanje poda orbite. Naffziger, takođe pionir pituitarne hirurgije, uvodi uklanjanje krova orbita. Dollinger-ov članak je izgleda bio nepoznat ili zaboravljen u Sjedinjenim Državama jer je nekoliko studija 1936–1940. opisalo uklanjanje lateralnog zida orbite kao novu proceduru.

Opisano je i priređeno mnogo drugih hirurških procedura na koštanim granicama orbita, neke opisuju resekciju tri od četiri strane; u stvari, jedva da je neka kost orbite ostala pošteđena.

Dekompresija mekih tkiva izgleda logična alternativa u svetlu ranog saznanja da je akumulacija masti značajna pojava u tiroidnoj orbitopatiji. U stvari, rane publikacije su saopštile zadovoljavajući ishod posle uklanjanja delova orbitne masti čupanjem forcepsom koliko je bilo moguće. Hirsch je primenio isti princip u kombinaciji sa uklanjanjem donjeg sprata orbite. Ovaj princip se još uvek primenjuje, kako saopšta-va Adenis sa saradnicima. Razvijene su i različite tehnike za doterivanje zahvaćenih spoljašnjih mišića oka i očnih kapaka.

Nedavno, 2009, Leong i sar. zapažaju da „postoji mirijada tehnika u praksi za dekompresiju orbita ali nijedna ne postiže trajno dobar ishod sa malo komplikacija’’. Oni su našli u literaturi na engleskom jeziku 56 članaka o ovom problemu objavlje-nih od 1990. do 2006. U njima je bilo moguće identifi kovati 15 različitih hirurških tehnika.

Radioterapija

U bolesnika sa Graves-Basedow-ljevom bolešću korišćeni su različiti modaliteti radijacione terapije. Prvo su američki hirurzi 1902. preporučili spoljašnje zračenje vrata. Od 1904. nekoliko izveštaja je objavljeno i u Evropi. U nekim zemljama zračenje postaje najčešće korišćena terapija u lečenju strume i hipertiroidizma. Na početku II svetskog rata u Sjedinjenim Državama pokrenuta su ispitivanja lečenja Graves-Ba-sedow-ljeve bolesti i drugih hipertiroidnih stanja radioaktivnim jodom (Hamilton i Lawrence; Hertz i Roberts). Ishod prvih studija je objavljen 1946. godine; korišćena je mešavina izotopa I130 i I131 u odnosu 90:10. Rezultati veće serije objavljeni su kasnije. U većine je terapija radiojodom izlečila hipertiroidizam za nekoliko meseci od primene. U većine se zatim razvija hipotiroidizam, dok je mali broj rezistentan na primenu radiojoda. Pored toga, radiojod dovodi do porasta tiroreceptorskih antitela u serumu, što bi moglo da bude praćeno pogoršanjem bolesti orbite. Lečenje hiperti-roidizma radiojodom još uvek je praćeno nedoumicama i postupak se koristi mnogo više u Sjedinjenim Državama nego u Evropi.

Drugi vid zračne terapije opisan je 1929. godine (Mandeville): radioterapija orbita. Ishod je opisan samo u malog broja bolesnika i rezultati su bili konfl iktni. Prvi


veći izveštaj dugotrajnog praćenja i ishoda orbitne radioterapije saopšten je skoro 30 godina kasnije, čemu ubrzo sledi i slepa studija poređenja terapije kortikosteroidima i radioterapije.

Konzervativna terapija

Veliki napredak je postignut kada je 1943. Astwood saopštio da je isprobao 106 hemijskih supstanci i našao da derivati tiouree inhibišu tiroidnu funkciju. Ubrzo je tiourea široko primenjivana u lečenju hipertiroidizma.

Izgleda da postoji izvestan odnos između lečenja hipertiroidizma i toka egzoftal-musa. Često ali ne obavezno se očne promene ublažavaju paralelno sa remisijom autoimunskog hipertiroidizma. Postalo je jasno da su neophodni specifi čni terapijski koraci u nekim slučajevima egzoftalmusa. Sa nalazom da je egzoftalmusna struma autoimunska bolest zaključeno je da bi lečenje kortikosteroidima moglo da bude od koristi. Dva od prvih testiranja lečenja steroidima bila su zasnovana na pogrešnoj pretpostavci da TSH ili neki drugi faktor koji izaziva pojavu egzoftalmusa učestvuju u patogenezi i da steroidi deluju tako što inhibišu sekreciju tih faktora iz hipofi ze. The Medical Research Council Committee je 1955. sproveo ispitivanje kortizonom ili kortikotropinom (ACTH). Rezultati su bili razočaravajući – na prvom mestu zbog toga što su primenjene vrlo male doze kortizona. Sistemsko davanje kortikosteroida se pokazalo efi kasnim ali su bile potrebne velike doze steroida, činjenica koja je i danas veliki problem. Kasnije su se pojavili radovi koji dokazuju da je intravenska primena steroida praćena boljim odnosom povoljnih prema nepovoljnim efektima.

Garber izveštava o uticaju metilprednizolona u umerenim dozama datim u supkonjunktivalni prostor. Zaključuje da je postupak bezopasan i efi kasan. Kasnija istraživanja ovog postupka nalaze da nije tako efi kasan ali je još uvek u upotrebi. Wiersinga i saradnici prvi objavljuju rezultate kontrolisane studije efekata steroida prema ciklosporinu u lečenju Graves-Basedow-ljeve orbitopatije. Saopštavaju se i drugi modaliteti lečenja: primena somatostatina, nesteroidnih imunosupresiva, cito-statika, monoklonskih antitela...

Amsterdamska deklaracija

„The pathogenesis of Graves’ orbitopathy is still poorly understood. Through research into the normal and abnormal situations, approached by different disciplines, might elucidate the problems and enable better management to prevent this disfi guring disease.”

Ovo stanovište izgleda tačno kao što je bilo i pre više stotina godina. Neki pa-cijenti imaju izvanredno dobar ishod dok drugi trpe zbog dugotrajne teške bolesti.


Pacijenti sa dobrim ishodom nisu dobili neki potpuno nov i različit način lečenja. Razlike u uspehu lečenja i toku bolesti su više ispoljavanje neujednačenosti u ocena-ma i mogućnostima medicinskog i hirurškog lečenja, koje se veoma malo promenilo proteklih decenija. Slična zapažanja su vodila kliničare, pacijente i političare da formulišu deklaraciju Sv. Vinsenta (St. Vincent declaration) za obolele od dijabetesa. Deklaracija Sv. Vinsenta je ispala preterano ambiciozna u predviđenim vremenskim okvirima za postizanje ciljeva ali je bez sumnje uspešna. Dovela je dijabetes u vrh agendi zdravstvenih ustanova, zdravstvenih ekonomista i kliničara. Ona je postavila uslove potrebne da se poboljša nega dijabetesnih bolesnika ne kroz nove egzotične postupke već izgradnjom infrastrukture neophodne da zdravstvena nega dosegne do svih kojima je potrebna.

Sličnost između zbrinjavanja dijabetesnih bolesnika i osoba sa Graves-ovom orbitopatijom inspirisala je pojavu Amsterdamske deklaracije. Ovaj dokument podvlači da bolesnici sa Graves-ovom orbitopatijom mogu i treba da dobiju bolju negu i postupak. Ona veliku pažnju poklanja poboljšanju kvaliteta života pacijenata, prevenciji i bržoj nezi i lečenju, prvenstveno u centrima sa najvišim standardima u lečenju orbitopatije.

Oktobra 2009. na Desetom internacionalnom simpozijumu o Graves-ovoj orbi-topatiji potpisana je Amsterdamska deklaracija.

Opšti ciljevi Deklaracije su:– Smanjenje morbiditeta vezanog za Graves-ovu orbitopatiju i poboljšanje ose-

ćanja pacijenata i kvaliteta života;– Sprečavanje pojave Graves-ove orbitopatije u bolesnika sa velikim rizikom.

Petogodišnji ciljevi su:– Povećanje opreza za ovu bolest kod zdravstvenih profesionalaca i menadžera– Ustanovljenje puteva usmeravanja i pružanja pomoći;– Podrška postojećim centrima u postupku sa ovim stanjem;– Stvaranje novih specijalizovanih centara tamo gde ne postoje;– Ustanovljenje kontrole i mehanizama praćenja kvaliteta osiguranja i pružanja

pomoći obolelima od Graves-ove orbitopatije;– Implementacija mera za smanjenje incidence i morbiditeta od ove bolesti: – prepolovljavanjem vremena od pojave do dijagnoze,– prepolovljavanjem vremena od dijagnoze do upućivanja u specijalizovani

centar. Odgovarajući postupak sa tiroidnom disfunkcijom, uključujući i radiojod;– energične mere protiv pušenja u bolesnika sa rizikom za pojavu Graves-ove

orbitopatije– Poboljšanje postojeće istraživačke mreže i razvoj internacionalnog zajedničkog

istraživanja.


Tiroidni eponimi

Nije neobično za bolest poznatu vekovima ali kojoj ne znamo tačnu etiologiju i optimalno lečenje da ne postoji i saglasnost o njenom nazivu. Izgleda da nema razloga za neslaganje sa činjenicom da je Parry prvi, iako kratko, opisao osnovne simptome egzoftalmusne strume. Zbog toga je izgledalo opravdano kada je Sir William Osler držao da „ako treba dati ime nekog lekara za ovu bolest, nesumnjivo to treba da bude ime izuzetnog lekara iz Bata”. Basedow je jedan od lekara koji je prvi dao potpuni opis kliničkih simptoma egzoftalmusa u egzoftalmusnoj strumi. Prvobitno je izgledalo da će bolest biti imenovana po Basedow u i sa tim se saglasio i Charcot. Od 1862. o problemu je više puta diskutovano na sastancima Francuske medicinske akademije. Odlučeno je da je najčešće upotrebljavan naziv „egzoftalmusna struma” pogrešan jer ni egzoftalmus niti struma nisu uvek prisutni u pacijenta. Trousseau, doajen francuske medicine, je podržao da eponim bude Graves-ovo ime i da se bolest zove Graves-ova bolest („il nous faudrait substituer au nom de Basedow celui de Graves . . . serait dit maladie de Graves’’) i time je stvorio put da se ovaj naziv prihvati u najvećem delu medicinske zajednice. U zemljama nemačkog govornog područja i delu evropskog kontinenta formalno se još uvek koristi naziv Basedow-ljeva bolest. Svakako da danas ne bi bio uspešan pokušaj da se bolest nazove Parry-jevim imenom ali izgleda da bi naziv Graves-Basedow-ljeva bolest bio sasvim dobra alternativa.

Kroz vreme, korišćeni su različiti nazivi za egzoftalmusnu komponentu bolesti i neki su još u upotrebi. Najnoviji izraz „orbitopatija” bi možda bolje zvučao kao Graves-Basedow-ljeva orbitopatija umesto tiroidna ili „thyroid associated’’, pošto neki bolesnici sa promenama na orbitama nemaju ili imaju samo blage tiroidne poremećaje. Graves-Basedow orbitopatija, ne oftalmopatija, bila bi dobra oznaka pošto su promene u celoj orbiti a ne samo u jabučicama.


Božo Trbojević

NOTES FROM THE HISTORY OF AUTOIMMUNE ORBITOPATHY

Summary: The development of knowledge about the appearance, nature, origins and outcomes of the orbit and eye disorders in thyroid gland di-seases has been very slow with a number of dilemmas, controversies and side tracks. It is interesting that the fi rst reliable descriptions of this unity come from a lawyer and not from a doctor. Later contributions of Arab doctors and philosophers greatly improved medical theory and practice. Western medicine adopted discoveries of eastern nations adding European rationality to them; the result was a better understanding of the nature of the process and better knowledge of the causes of the disorder and its development, but treatment options were still falling behind theory. Not until the last few decades of the twentieth century was there a notice-able progress in the defi nite identifi cation of the nature of the changes in orbitopathy, which made it clear that it was an autoimmune process and which led to a better and more successful treatment. Despite all this, autoimmune orbitopathy is still one of the conditions in endocrinology which is most diffi cult to control and cure.

Struma (from a Latin expression for swelling in neck glands) or goiter (guttur: Latin word for the throat) has been known since ancient times. References about the disease can be found in Chinese and Greek texts but the combination of bulging eyes, goiter and symptoms of Hyperthyroidism seems to be of more recent origin – it fi rst appeared in legal Roman texts from 2nd and 3rd centuries and in a Byzantine text from 6th century A.D. At the turn of the 3rd century, the Roman jurist and legal adviser to Em-peror Septimius Severus, Domitius Ulpianus, introduced a legal regulation according to which a slave with goiter had a reduced working ability (Si quis natura gutturosus sit aut oculos eminentes habeat, sanus videtur). Ulpianus concluded that a salesman was not responsible for the reduced working ability of a person with these symptoms.

Just like in Ulpianus’ documents, probably related to his legal heritage, a By-zantine legal text from 6th century whose Latin name is Digesta Corpus Juris Civilis Justiniani, and on which the later Greek text Vasilica is based, states: ‘quis natura

19NOTES FROM THE HISTORY OF AUTOIMMUNE ORBITOPATHY

gutturosus sit aut oculos eminentes habeat’. Since they are mainly legal and not medical documents, it is not clear whether the jurist recognized the connection between these two medical symptoms. It is well-known that the physiognomy of Roman population at the time was characterized by prominent eyeballs and that is why it is believed that Ulianus did not notice the connection between goiter and prominent eyes, although other theories are also possible.

The fi rst medical manuscript in which changes in the eyes and struma are connected is attributed to monk Meletius, alias iatrosophist, who lived in 8th century A.D. We now know that these descriptions refer to exophtalmos and the disease which is today known as a thyroid gland disorder, and not some other, on the basis of the description of exceptional irritation of these people and a remarkable change in behavior. Meletius says: “... eyes have a tendency to swell and protrude … because of which a person is very upset and frightened”. This description undoubtedly proves that Byzantine doctors knew about the thyroid gland disorder and that they deserve a place in the history of thyroidology.

The text of an Arab author Zayn al-Din Sayyed Isma‘il ibn Husayn Gorgani, also known as Sayyid Ismail Al- Jurjani, “The treasure of Khwarazm Shah” (Zakhireye Khwarazmshahi ) was published around 1110. Al-Jurjani was a doctor and a philo-sopher and in his encyclopedic book he stated, as it was believed, the fi rst description that connected a swollen thickened neck with changes in the eyes, and he thought that they were a unique unity of closely connected disorders. However, al-Jurjani was a devoted follower of Avicenna, who lived almost a century earlier, and he was greatly infl uenced by his famous manuscript, Al-Qanoon or The canon of medicine, particularly by the third book. This history is important because it underlines the do-minant role of Islamic medicine in the Middle Ages transferring the knowledge from the earlier Hellenistic, Roman and Far East medicine and adding its own discoveries to them. When analyzing earlier Persian medical manuscripts, written more than a century before Al-Jurjani made his description, it is surprising to see that Avicenna had already analysed the connection between orbitopathy and a swollen neck. Altho-ugh Al-Jurjani’s medical encyclopedia really offers a wide range of knowledge and incorporates ideas that have not been found before, not even in Avicenna’s Canon, it still has too be said that it is greatly based on Avicenna’s discoveries.

Ibn Sina or Abu Ali al-Husayn ibn Abd Allah ibn Sina, known as Avicenna in the West, is probably the most famous doctor of Islamic civilization. He was also a very fruitful author, he wrote almost 270 different tractats of which the largest number was in the area of medicine. In his masterpiece Al-Qanoon, which contains more than a million words, Avicenna describes complete studies in physiology, pathology, hygiene into which he incorporates the most important sources of Hellenic and Chinese me-dicine. His books are real role models of his time. Among other things, , Al-Qanoon or The Canon describes the swelling in the front part of the neck (goiter) in people


who have had a better appetite and who have not been able to feel full despite the large quantities of food they have eaten (Al-Qanoon, Book III, chapter 6). In the two chapters of his Canon, he describes the connection between the swollen neck and prominent eyes (Canon, Book III, part three, article two, chapter 15 and Book III, part three, chapter 4). In the chapter on exophthalmos, he describes the differential diagnosis of proptosis. He notices that exophtalmos may appear due to the pressure from the back of the orbit, he notifi es the swelling of the cornea, chemosis, increased mass of orbital fat and weakness, fatigue of eye muscles in the clinical presentation of exophthalmos. He describes ocular characteristics when the cause of exophthal-mos is fatigue of extraocular muscles (The Canon, book III, part three, article 2, chapter 15). His works were translated in the second half of 12th century in Toledo by Gerard of Cremona. Later in 16th century, Andrea Alpago in Venice translated his works into Latin again. Since then, through many centuries, Avicenna’s books have represented some of the most signifi cant medical books in Western Europe. In fact, until 17th century, medical curriculum of European universities was based on Avicenna’s manuscripts. It is highly likely that the most famous Mediterranean universities such as Cordoba and Salerno used Avicenna’s texts even before they were translated into Latin since in these schools Hellenic, Roman, Arabic and Hebrew experiences were integrated parts of the curriculum. With his broad interests and knowledge of different areas of science and arts, Avicenna is actually a prototype of a Renaissance man almost three centuries before the appearance of the Medici and their circle.

After this, there is a very long pause in the descriptions and analyses of eye diseases and the appearance of goiter, the swelling in the neck.

Caleb Hillier Parry (1755–1822) spent most of his life working as a general practitioner in Bath, England. In the documents found after his death, in a chapter related to heart diseases, he described fi ve patients with goiter and undoubtedly a case of hyperthyroidism under the title: ‘‘Enlargement of the Thyroid Gland in Connection with Enlargement or Palpitation of the Heart.’’ One of them was Mrs. Grace B, age 37, who Parry saw for the fi rst time in August, 1786. She suffered from palpitations and irregular heatbeat which went up to 156. Her thyroid gland was enormous, reaching the edge of the lower jaw... “her eyes were prominent , leaving the orbits and had the appearance of constant fear, she could not stand anxiety and strain, particularly the one of the muscles, which I had rarely seen before.’’ The patient was treated by drawing blood and with silver concoctions, but she developed a massive swelling with the night orthopnea. Parry was not involved in the disease any longer, but it is assumed that the patient very soon ‘‘paid her debt to nature.’’ This short description was usually considered to be the fi rst description of ophtalmopathy in thyroid gland disorders, which, as we have already seen, was not correct.


Chronologically speaking, the next description of exophthalmos together with the thyroid gland disorder was an anonymous one from 1816 in Medico-Chirurgical Journal and Review. According to Legg ‘‘A young woman, aged 22, had palpitations, swellings on both sides of the neck as big as a goose egg. The eyes were so prominent that they looked as if they were going to fall out of the orbits. She was very nervous, thin and extremely plethoric. She was treated on the basis of a strict antiphlogistic system; her blood was drawn, she drank only water, she was not allowed to eat ani-mal meat, she did not receive calomel and digitalis. About seven months later, I met her in the street, she was very well.’’ Legg described several more cases of thyroid ophtalmopathy, which he published between 1820 and 1828.

Robert Graves (1796–1853) gave several lectures at the University Hospital in Dublin in the period of 1834–1835. In one of them, he described three people with goiter and palpitations. The fourth patient was ‘‘a lady around 20 years of age, with symptoms that resembled hysteria.’’ She had tachycardia, a swollen thyroid gland and suffered from anxiety; ‘‘orbits were noticeably prominent so that the eyelids could not cover them while she was sleeping or trying to close her eyes. When her eyes were open, the whites could be seen in the width of several lines round the cornea.’’

Since 1822, Carl Adolph von Basedow (1799–1854) was a doctor in the small town of Merzeburg between Leipzig and Halle in Germany. He saw three patients with goiter within several years. The fi rst two (Madame G and Madame F) had the symptoms of fl orid hyperthyroidism and exophtalmos. During the illness, they were both considered to be insane and Madame F was sent to an asylum. One of the women had changes which are today known to be pretibial myxedema or dermopathy.

The third patient, Herr M, aged 50, started to complain about weakness and diarr-hea in 1832. He complained about “blood heat”, extreme perspiration and precordial oppression. His face was pale, and the eyes bulged out from the orbits; the thyroid gland was enlarged; the patient was losing weight despite his good appetite and was still having frequent liquid bowel movements. The course of the disease was very diffi cult. After the appearance of keratitis, purulent infection of both eyes appeared too. Basedow recommended him to make a wide incision in both eyeballs in order to eliminate the pus, but the patient rejected it. He lost sight in both eyes and Basedow wrote down that “the unfortunate patient had unbearable pain”. Severe heart disorder symptoms appeared with tachycardia and respiratory diffi culties due to serious goiter. The patient died suddenly in 1843.

In 1877, Yeo was the fi rst to describe two people with one-sided exophthalmos. The reason for this phenomenon is still an enigma just like it was 130 years ago. In reference to this description, it has to be mentioned that two Italians, Flaiani and Testa published similar observations in 1802 and 1810. Their studies, unfortunately, are not available today.


Pathological anatomy

Basedow did the fi rst autopsy of a patient with thyroid ophtamopathy. In fact, he did the autopsy of his patient, Herr M. The fi ndings were not particularly typical since both eyeballs were fi brous and reduced to half their normal size. He found large quantities of yellow fat tissue in the orbits. Jean-Martin Charcot (1825–1893) gathered his fi ndings of postmortal studies of the orbits of patients with exophtalmos and confi rmed that the eyeball looked normal but that an extremely large mass of fat was collected in the orbits. Armand Trousseau (1801–1867) quoted a Danish article in which orbital tissue in thyroid ophtalmopathy was described. When looked for, a large quantity of fat could be found in the orbits. Trousseau was able to confi rm these fi ndings in his patients.

In 1920, R Foster Moore published a postmortal dissection of orbits of patients who died and had thyroid gland and eye disorders. He summarized the main hypothe-sis of the causes of exophthalmos of that time ‘‘: (1) irritation of sympaticus nervous system which causes spasms of smooth muscles in the orbit; (2) congestion of the orbit with blood; and (3) increased mass of orbital fat.’’ Moore pointed out that since exophthalmos did not disappear after death, then it probably was not the consequence of the hyperactivity of sympaticus or blood congestion. “in that case, orbits are defi -nitely full due to the hypercirculation inside of them and there is nothing else that is abnormal and that can be found there; proptosis is undoubtedly the result of excessive fat … As far as I am concerned, it is unacceptable to consider the increase in orbital fat as the main cause of exophthalmos in Graves disease and that today there is no other satisfactory proof for it. ’’

During 1933, Howard Christian Naffziger (1884–1961) published an overview of a large number of studies of orbital structures in exophthalmos – some tried to explain the changes by means of broadened varicose veins or dilated arteries or myositis of extraocular muscles. Naffziger pointed out that thickening of extraocular muscles dominated his material. Rundle and Pochin did a study on the properties of different tissues in the orbit in exophtalmos. They concluded that the increased quantity of fat was mainly responsible for the increase in the mass content of the orbits.

The cause

In the following century, after both Graves and Basedow, a great many studies were published about the connections between goiter, heart symptoms and proptosis. The authors tried to explain this unusual combination of symptoms. In one of his earlier overviews of the connections between goiter and ophtalmopathy, Cooper pointed out that in two out of fi ve patients the diagnosis was wrongly set to be hydrophtalmia (the probable meaning of this is glaucoma) and the largest number of problems derived from


mercury treatment that was used on them. Cooper did not try to establish the course of the disease, but he insisted on presenting the treatment: “if there are signs of anemia, there is a sound in the vessels of the neck, if there are palpitations, in addition to the enlargement of the thyroid gland, there is enough reason to think that the changes in the eye are of secondary nature: this is even more true when the patient complains about pains and uneasiness in the eyes or about the disorder of the eyesight. The most successful medication is iron, aloe, myrta with sedatives, immersing the body into cold salty water after which frictions are used, and, if there are signs of hysteria, a friction was used along the spine with stimulative liniments’’

Although it is easy to mock theories and ideas that were accepted 100 years ago under the circumstances that were completely different from the present ones, even then some of the opinions seemed too revolutionary and almost unreasonable. So, in 1860 Jones wrote:” The basis of the disease is weakness, especially of the nervous system which, by affecting various vasomotor nerves, causes different symptoms. Thus, the effusion of eyeballs causes proptosis; hyperemia and increased activity of cellular elements of the thyroid gland cause goiter; vagus paresis causes palpitati-ons and vomiting. The favourable effect of tonicum greatly supports this opinion.” Many authors pointed at the heart and neurological disorders as the probable causes (not consequences) of the disease. “Exophtalmos goiter” as a neurological disease was mentioned for the fi rst time in 1861. Famous French doctors such as Trousseau and Charcot supported this attitude. So, Pierre Marie (1853– 1940) wrote an article about tremor characteristics, which, in his opinion, many earlier researchers had overlooked.

In 1890, Mackenzie published two clinical articles about Graves - Basedow disease and concluded: “That is, gentlemen, what I want to suggest to you as the origins and development of this unusual disease. It is possible that the disorder in the functioning of the thyroid body, whose importance in terms of nutrition and transmi-ssion of nervous powers has been proved, is highly relevant in the appearance of many secondary symptoms that I have paid attention to, but the real disease is a widespread disorder in the nervous system. ’’ In his short but infl uential article, Paul Julius Mo-ebius (1853–1907) rejected the opinion that Basedow disease was a blood disorder, heart disease or a neuorological disease. He admitted that while he was thinking about the nature of Basedow disease, he thought it to be some kind of hysteria. He noticed that myxadema symptoms were in a way completely different from hyperthyroidism symptoms and he suggested that Basedow disease was a thyroid gland disorder. He rejected the arguments that were popular at the time about the thyroid being a rudi-mentary organ or that its role was to regulate blood circulation in the brain. He did not deal with the explanations of exophthalmos.

In 1893, George Redmayne Murray (1865–1939)— who, in April 1891, was the fi rst to give a thyroid extract to the patient with hyperthyroidism - published a study


in which he stated that “some of the symptoms of exophthalmos goiter are the result of hyperactivity of the thyroid gland”. He claimed that “the reduction in secretory activities improved the patient’s condition.” He quoted the report which said that the surgical removal of the gland led to the complete recovery. He particularly pointed out that the cause of exophtalmos did not necessarily have to be the hypersecretion of the thyroid gland. In some patients treated for hyperthyroidism, after the operation, exophthalmos remained unchanged or even deteriorates. In addition to this, giving thyroid extracts to patients does not cause exophthalmos.

Hirsch published a journal on exophthalmos where he expressed an opinion that was completely rejected a generation later. He made a distinction between “malignant exophthalmos” and “exophtalmos with a diffused toxic goiter”: “Malignant exophtal-mos is a clinical unit different from exophthalmos observed in thyrotoxicosis. These conditions may be similar in ethymology; a different clinical picture and differences in the procedure point at the fact that it is necessary for the diagnostician to be familiar with diagnosing criteria for the disease and for the surgeon to be familiar with the basic process on which the treatment is based.”

Although many patients with proptosis have hyperthyroidism, a small number is euthyroid or even hyperthyroid. The reasons for clinical variations in effusion are not known yet. Mechanical or external factors could be relevant – for example, smoking or radioiodine treatment. In 1946, Iason mentioned more than 25 suggested causes of exophthalmos. Some were somewhat strange (rupture of jugular vessels due to sucking snow or drinking icy water or adrenalin insuffi ciency).

Studies from the period round World War II showed that the thyroid gland of larvae and amphibiae secretes a thyrotropic substance, which was later confi rmed in mammals, too. It was speculated that this hormone might play a role in the appearance of exophthalmos goiter. However, in 1953, Werner concluded in an elaborate study, that thyrotrophine was not included in the pathogenesis of Graves disease. Regardless of this, hypophysectomy continued to be used in the treatment of exophthalmos for another decade.

Operations on the sympaticus system

In 1899, Abadie did the section of the cervical trunk of sympaticus in patients with severe bilateral exophthalmos. He claimed that the operation was extremely successful. He never doubted that the procedure was a valuable method in exophthalmos treatment. In the following years, several other, mainly French authors (Jaboulay, Jonnesco, Poncet, Reclus, Faure) took over the procedure which was still very popular in the 1920s since it was still believed that exophthalmos goiter was a neurological disease. Cannon and his associates insisted that it was possible to cause hyperthyroidism in a cat by stimulating sympaticus nerves. Experiments to prove this hypothesis were


done in 1939 but unsuccessfully, and Brian’s work fi nally put an end to speculations about exophthalmos being a neurological disease.

Orbital surgery

Exophthalmos can be an agonal disease not only because of the extreme defor-mation of the patient but also because of the pain and the risk for the patient’s sight, which was Basedow the fi rst to describe. It was no surprise then that medical commu-nities insisted on identifying the disease in an early phase and searching for treatment procedures. As early as 1867, v Graefe recommended local surgery for putting the eyeballs back and symptomatic improvement. In October 1910, in Budapest, Julius Dollinger did the fi rst huge surgery with the explicit aim to alleviate exophthalmos in Graves–Basedow disease. The patient did not have a clynically noticeable thyroid hyperfunction, but he had a severe proptosis of the right eye with keratitis. Despite large doses of morphine, she went through great pain. The external wall of the orbit was removed and there was a remarkable but brief recovery. This approach was based on the technique developed by Rudolf Ulrich Kroenlein (1847–1910)—one of the leading surgeons in the second half of 19th century.

It might have been expected that 100 years after Dollinger’s operation there would be a concensus in terms of orbital surgery. Oskar Hirsch (1877–1965), after a pioneer work on pituitary surgery, described the removal of the orbital fl oor in 1920-30. Dollinger’s article seemed be unknown or forgotten in the United States until several studies between 1936 and 1940 described the removal of the lateral wall of the orbit as a new procedure.

Many other surgical procedures on the bony edges of the orbit were described and developed, some described the resection of three out of four sides; in fact, there was hardly a bone in the orbit that was spared.

The decompression of soft tissues seemed to be a logical alternative in the light of the early knowledge about fat accumulation being a signifi cant phenomenon in thyroid orbithopathy. In effect, early publications reported of a satisfactory outcome after the removal of pieces of orbital fat by extracting them with forceps as much as possible. Hirsch applied the same principle in combination with the removal of the lower level of the orbit. This principle is still applied according to Adenis and his associates. Different techniques for adjusting the affected external muscles of the eyes and eyelids have also been developed.

Recently, in 2009, Leong and associates noticed that “there was a myriad of techniques in the procedures for the decompression of orbits but none of them achi-eved a long-term outcome with few complications.” In the literature in English, they found 56 articles on this problem, published between 1990 and 2006. It was possible to identify 15 different surgical techniques in them.


Radiotherapy

In patients with Graves Basedow disease, modalities of radiation therapy were used. First, American surgeons recommended external radiation of the neck. Since 1904, several reports were published in Europe, too. In some countries, radiation became the most frequently used method in the treatment of goiter and hyperthyroi-dism. At the beginning of World War II, in the United States of America, there were studies of the treatment of Graves Basedow disease and other hyperthyroid conditions by radioactive iodine (Hamilton and Lawrence; Hertz and Roberts). The results of the fi rst studies were published in 1946; a mixture of isotopes I130 ad I131 in the 90:10 ratio. The results of the larger series were published later. In most patients, the radioiodine therapy cured hyperthyroidism a few months after its application. In most of them, hypothyroidism was developed afterwards, whereas a small number of them were resistant to radioiodine. Additionally, radioiodine causes the growth of thyroceptor antibodies in the serum, which could be followed by the development of the disease of the orbit. The treatment of hyperthyroidism with radioiodine is still connected to dilemmas and the procedure is used much more in the United States than in Europe.

Another type of treatment was described in 1929 (Mandeville): radiotherapy of the orbits. The results are described only in a small number of patients and they were contradictory. The fi rst more elaborate report of the long-term monitoring of orbital radiotherapy was made public almost 30 years later, and it was later followed by a blind study on the comparison between corticosteroid therapy and radiotherapy.

Conservative therapy

A major step forward was made in 1943 when Astwood reported that he had tried 106 chemical substances and found out that tiouree derivatives inhibit the thyroid fun-ction. Very soon, tiouree became widely used in the treatment of hyperthyroidism.

It seems that there is a certain relationship between hyperthyroidism treatment and the development of exophthalmos. Very often but still not necessarily, changes in the eyes are alleviated simultaneously with the remission of autoimmune hyper-thyroidism. It has become clear that specifi c therapeutic steps are necessary in some cases of exophthalmos. With the evidence that exophthalmos goiter is an autoimmune disease, it has been concluded that using corticosteroids might be useful. The fi rst two assessments of steroid treatment were based on the incorrect assumption that TSH or some other factor which caused exophthalmos also took part in the pathogenesis and that steroids worked in such a way as to inhibit the secretion of these factors from the thyroid gland. In 1955, The Medical Research Council Committee did a research on cortison or corticotropine (ACTH). The results were disappointing – fi rst of all


because very small doses of cortisone were used. Systematic application of cortico-steroids proved to be effi cient, but large doses of corticosteroids were needed, which is something that is still a huge problem. Some time later, studies that proved that intravenous application of steroids was followed by a better ratio between favourable and unfavourable effects also appeared.

Garber reported about the infl uence of methylprednisolon in moderate doses injected in subconjunctiveal space. He concluded that the procedure was harmless and effi cient. Later analyses of this procedure proved that it was not so effi cient, but it is still being used. Wiersinga and associates were the fi rst to publish the results of the controlled study of the effects of steroids on cyclosporine in the treatment of Graves Basedow disease. Other modalities of the treatment were also reported: application of somatostatine, non-steroid immunosuppressives, cytostatics, monoc-lonal antibodies …

Amsterdam declaration

‘‘The pathogenesis of Graves’ orbitopathy is still poorly understood. Through research into the normal and abnormal situations, approached by different disciplines, might eluci-date the problems and enable better management to prevent this disfi guring disease.’’

This opinion seems to be correct just like it was several hundred years ago. Some patients recover remarkably well whereas others suffer from a long-lasting and serious disease. Patients with good outcomes do not receive a completely new and different treatment. The differences in the successfulness of treatment and the development of the disease are more visible in the evaluation discrepancies and possibilities for medical and surgical treatment, which have changed very little in the last few decades. Similar ideas induced clinicists, patients and politicians to design St. Vincent declara-tion for people with diabetes. St. Vincent Declaration turned out to be overambitious in the given time limits, but it was undoubtedly successful. It brought diabetes to the top of agendas of health centres, health economists and clinicists. It set the criteria for the improvement of treatment of patients with diabetes not by means of new and exotic procedures but by building infrastructure necessary for health care to reach everybody who needs it.

The similarity between the treatment of patients with diabetes and people with Graves orbithopathy inspired the appearance of Amsterdam Declaration. This docu-ment points out that patients with Graves orbithopathy can and should receive a better treatment and better care. It pays special attention to the improvement of quality of life of the patients, prevention, faster treatment and care, mainly in the centres with the highest standards in orbithopathy treatment.

In October 2009, at the Tenth international symposium on Graves orbithopathy, Amsterdam Declaration was signed.


General objectives of the Declaration are: – reduced morbidity related to Graves orbithopathy and improvement of patients’

feelings and quality of life; – prevention of Graves orbithopathy in high-risk patients; Five-year long objectives are: – increasing precautions against this disease in health professionals and mana-

gers;– establishing ways of directing and giving help; – supporting the existing centres in procedures applied in this condition;– creating new specialized centres in the areas where they do not exist;– establishing control and mechanisms for monitoring insurance quality and

offering help to people with Graves orbithopathy; Implementation measures for the reduction of incidence and morbidity in this

disease: – Making the interval between the appearance and diagnosis half as long; – Making the interval between the diagnosis and sending a patient to a specia-

lized centre half as long;– An adequate procedure with thyroid dysfunction including radioiodine;– Energetic measures against smoking in patients with the risk of developing

Graves orbithopathy;– improving the existing research networks and developing joint international

research.

Thyroid eponyms

It is not uncommon for a disease that has been known for centuries and whose ethyology and optimum treatment we do not know that there is not even an agree-ment on its name. It seems that there are no reasons for disagreement with the fact that Parry was the fi rst who, although briefl y, described the basic symptoms of exophthalmoses goiter. Thus it seemed justifi ed when Sir William Osler said that “if the disease should be given the name of a doctor, then it should be the name of the outstanding doctor from Bath”. Basedow was one of the doctors who were the fi rst to give a complete description of clinical symptoms of exophthalmos in exophthalmos goiter. It fi rst seemed that the disease would be named after Basedow, and Charcot agreed with it. Since 1862, the problem was discussed at the meetings of the French Medical Academy on several occasions. It was decided that the most frequently used term “exophthalmos goiter” was incorrect since neither exophthalmos nor goiter was always observed in patients. Trousseau, the doyen of French medicine, supported the eponym of Graves and naming this disease Graves disease (‘‘il nous faudrait substituer au nom de Basedow celui de Graves... serait dit maladie de Graves’’) and


thus he enabled this name to be accepted by the majority in the medical community. In the German speaking areas and in one part of the European continent, the name Basedow disease is still formally used. Today, the attempt to name the disease after Parry would be unsuccessful, but it seems that the name of Graves Basedow disease would be a very good alternative.

As time went by, different names for exophthalmos component of the disease were used and some of them still are. The newest term “orbithopathy” might sound better as Graves Basedow orbithopathy instead of thyroid or ‘‘thyroid associated’’ since some patients with orbital changes do not have or only have mild thyroid disorders. Graves Basedow orbithopathy, not ophtalmopathy, would be a good name since the changes occur in the whole orbit and not just in the eyeballs.

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