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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
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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
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9BELEŠKE IZ ISTORIJE AUTOIMUNSKE ORBITOPATIJE
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.
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10 MEDICINSKI GLASNIK / str. 7-17
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.
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11BELEŠKE IZ ISTORIJE AUTOIMUNSKE ORBITOPATIJE
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;
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12 MEDICINSKI GLASNIK / str. 7-17
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
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13BELEŠKE IZ ISTORIJE AUTOIMUNSKE ORBITOPATIJE
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.
-
14 MEDICINSKI GLASNIK / str. 7-17
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
-
15BELEŠKE IZ ISTORIJE AUTOIMUNSKE ORBITOPATIJE
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.
-
16 MEDICINSKI GLASNIK / str. 7-17
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.
-
17BELEŠKE IZ ISTORIJE AUTOIMUNSKE ORBITOPATIJE
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.
-
18 MEDICINSKI GLASNIK / str. 18-29
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
-
20 MEDICINSKI GLASNIK / str. 18-29
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.
-
21NOTES FROM THE HISTORY OF AUTOIMMUNE ORBITOPATHY
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.
-
22 MEDICINSKI GLASNIK / str. 18-29
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
-
23NOTES FROM THE HISTORY OF AUTOIMMUNE ORBITOPATHY
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
-
24 MEDICINSKI GLASNIK / str. 18-29
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
-
25NOTES FROM THE HISTORY OF AUTOIMMUNE ORBITOPATHY
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.
-
26 MEDICINSKI GLASNIK / str. 18-29
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
-
27NOTES FROM THE HISTORY OF AUTOIMMUNE ORBITOPATHY
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.
-
28 MEDICINSKI GLASNIK / str. 18-29
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
-
29NOTES FROM THE HISTORY OF AUTOIMMUNE ORBITOPATHY
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.
01s prelom4201e prelom42