NEUROreal-j.mtak.hu/2885/4/isz 2014 3-4 e-mag.kicsi.pdf2014. március 30. Ideggyógyászati Szemle/Clinical Neuroscience 2014;67(3–4):73–144. NEUROSCIENCE CLINICAL SZEMLE IDEGGYÓ

2014. március 30.

Ideggyógyászati Szemle/C

linical Neuroscience 2014;67(3–

4):73–144.

NEUROSCIENCECLINICAL

SZEMLEIDEGGYÓGYÁSZATI

3–4. SZÁM • 2014. MÁRCIUS 30.67. ÉVFOLYAM

Selye szimpóziumSomogyi Árpád, Szabó Sándor, Roger Guillemin, Volker Jahnke,Milagros Salas-Prato, Yvette Taché, Lázár György, Gyires Klára, Vécsei László, Horváth Zoltán, Tuka Bernadett, Dunai Magdolna,Palkovits Miklós, Ludmila Filaretova, Makara Gábor, Giulio Gabbiani,Kovács Kálmán, Fabio Rotondo, Horváth Éva, Luis V SyroAz MDS-UPDRS magyar validációja: Miért szükséges újabb Parkinson-pontozóskála?Horváth Krisztina, Aschermann Zsuzsanna, Ács Péter, Bosnyák Edit, Deli Gabriella, Pál Endre, Késmárki Ildikó, Horváth Réka, Takács Katalin,Komoly Sámuel, Bokor Magdolna, Rigó Eszter, Lajtos Júlia, Klivényi Péter, Dibó György, Vécsei László, Takáts Annamária, Tóth Adrián, Imre Piroska, Nagy Ferenc, Herceg Mihály, Hidasi Eszter,Kovács NorbertGyulladásos temporalis leukoencephalopathia együttes megjelenésekét B-sejtes malignomávalGarzuly Ferenc, Hahn Katalin, Iványi László János, Kereskai László,Gábor Valéria, Kovács G. Gábor, Budka Herbert, Kalman Bernadette

Selye symposiumÁrpád Somogyi, Sándor Szabó, Roger Guillemin, Volker Jahnke,Milagros Salas-Prato, Yvette Taché, György Lázár, Klára Gyires, László Vécsei, Zoltán Horváth, Bernadett Tuka, Magdolna Dunai, Miklós Palkovits, Ludmila Filaretova, Gábor Makara, Giulio Gabbiani,Kálmán Kovács, Fabio Rotondo, Éva Horváth, Luis V SyroValidation of the Hungarian MDS-UPDRS: Why do we need a new Parkinson scale?Krisztina Horváth, Zsuzsanna Aschermann, Péter Ács, Edit Bosnyák,Gabriella Deli, Endre Pál, Ildikó Késmárki, Réka Horváth, Katalin Takács,Sámuel Komoly, Magdolna Bokor, Eszter Rigó, Júlia Lajtos, Péter Klivényi, György Dibó, László Vécsei, Annamária Takáts, Adrián Tóth, Piroska Imre, Ferenc Nagy, Mihály Herceg, Eszter Hidasi,Norbert KovácsAssociation of temporal lobe inflammatory leukoencephalopathy withtwo B cell malignanciesFerenc Garzuly, Katalin Hahn, László János Iványi, László Kereskai,Valéria Gábor, Gábor G. Kovács, Herbert Budka, Bernadette Kalman

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Telítô dózis- amikor fontos a gyors terápiás válasz

RÖVIDÍTETT ALKALMAZÁSI ELÔÍRÁS: Vimpat 50 mg filmtabletta, Vimpat 100 mg filmtabletta, Vimpat 150 mg film-tabletta, Vimpat 200 mg filmtabletta, Vimpat 10 mg/ml oldatos infúzió. Minôségi és mennyiségi összetétel. Ható-anyag: 50 mg, 100 mg, 150 mg, 200 mg lakozamid filmtablettánként, illetve 200 mg lakozamid 20 ml-enkéntGyógyszerforma: rózsaszínû, sötétsárga, lazacszínû, illetve kék, ovális filmtabletta. Tiszta, színtelen oldatos infúzió. Terápiásjavallatok: A Vimpat adjuváns terápiaként javasolt epilepsziában szenvedô, felnôtt és serdülô (16-18 éves) betegek – másodlagosgeneralizációval járó vagy anélküli – parciális görcsrohamainak kezelésére. Adagolás és alkalmazás: A lakozamid terápiaelkezdhetô mind szájon át történô, mind intravénás alkalmazással. Az oldatos infúzió alternatív készítmény olyan betegekszámára, akiknél a szájon át történô alkalmazás átmenetileg nem lehetséges.A Vimpat-ot naponta kétszer kell alkalmazni.A javasolt kezdô adag naponta kétszer 50 mg, amelyet egy héttel késôbb naponta kétszer 100 mg-os kezdô terápiás dózisrakell emelni. A válaszreakciótól és a toleranciától függôen a fenntartó dózis minden héten tovább emelhetô naponta kétszer50 mg-mal, a napi 400 mg-os maximális ajánlott adag (naponta kétszer 200 mg) eléréséig. A lakozamid-kezelés elkezdhetôegyetlen 200 mg-os telítô dózissal is, amelyet körülbelül 12 órával késôbb egy naponta kétszer 100 mg-os (200 mg/nap)fenntartó adagolás követ. A telítô dózis ilyen alkalmazása csak bizonyos betegeknél alkalmazható, orvosi felügyelet mellett,folyamatosan ellenôrizve a központi idegrendszeri mellékhatások esetleges emelkedését. Az oralis alkalmazásról az intra-vénásra történô áttérés, vagy fordítva, közvetlenül, titrálás nélkül végezhetô. A napi összdózist, és a naponta kétszeri adagolástfenn kell tartani. A Vimpat bevehetô étkezés közben vagy attól függetlenül. Amennyiben a Vimpat adását meg kell szakítani,ajánlatos ezt fokozatosan végezni. Súlyos vesekárosodásban és végstádiumú vesebetegségben szenvedô betegeknél azajánlott maximális dózis napi 250 mg. Olyan betegek esetében, akiknek hemodialízisre van szükségük, a megosztott napidózis legfeljebb 50%-ának megfelelô kiegészítô adag alkalmazása ajánlott, közvetlenül a hemodialízis befejezését követôen.A végstádiumú vesebetegségben szenvedôk kezelését óvatosan kell végezni, mivel kevés a klinikai tapasztalat egy (ismeretlenfarmakológiai hatású) metabolit felhalmozódásával kapcsolatban. Súlyos májkárosodásban szenvedô betegek esetén is óvatossággalkell eljárni, mivel a lakozamid farmakokinetikáját nem vizsgálták ilyen esetekben. A dózisemelést minden máj- és vesekárosodásbanszenvedô betegnél elôvigyázatosan kell végezni. Idôs betegeknél figyelembe kell venni az életkorral járó vese-clearancecsökkenést és az AUC-szintek emelkedését. A lakozamid biztonságosságát és hatásosságát 16 évesnél fiatalabb gyermekekesetében még nem igazolták.Nincsenek rendelkezésre álló adatok. Ellenjavallatok: A hatóanyaggal, illetve bármely segéd-anyaggal szembeni túlérzékenység. Ismert másod- vagy harmadfokú atrioventricularis- (AV) blokk. Különleges figyelmeztetésekés az alkalmazással kapcsolatos óvintézkedések: Lakozamiddal végzett kezelés során szédülést tapasztaltak, ami növelhetia véletlenszerû sérülés, illetve az elesések elôfordulását. Emiatt a betegeknek azt kell tanácsolni, hogy legyenek óvatosakmindaddig, amíg meg nem ismerik a gyógyszer esetleges hatásait. Klinikai vizsgálatokban azt tapasztalták, hogy a lakozamida PR-intervallum megnyúlását okozhatja. A lakozamidot elôvigyázatosan kell alkalmazni olyan betegeknél, akiknek ismertingerületvezetési zavarai vannak, vagy súlyos szívbetegségben szenvednek, például myocardialis infarctus vagy szívelégtelenségszerepel a kórtörténetükben. Különös óvatossággal kell eljárni idôs betegek kezelésekor, mivel náluk fokozott lehet a szív-betegségek kockázata, illetve amikor a lakozamidot olyan készítményekkel kombinálják, amelyek ismert módon kapcsolatbahozhatók a PR-megnyúlással.Posztmarketing tapasztalatok alapján másodfokú vagy súlyosabb AV-blokkot jelentettek. A betegekettájékoztatni kell az AV-blokk tüneteirôl (pl. lassú, szabálytalan pulzus, szédülés, ájulás), valamint a pitvarfibrilláció illetve re-megés tüneteirôl (pl. szívdobogásérzés, gyors vagy szabálytalan pulzus, légszomj). A betegeknek azt kell tanácsolni, hogyforduljanak orvoshoz, ha ezen tünetek bármelyikét észlelik. Antiepilepsziás gyógyszerekkel különbözô indikációkban kezeltbetegeknél öngyilkossági gondolatokat és öngyilkos viselkedést jelentettek. Ennek következtében a betegeket folyamatosanellenôrizni kell az öngyilkossági gondolatok és az öngyilkos viselkedés jelei tekintetében, és fontolóra kell venni a megfelelôkezelést. A betegek (és a betegek gondozóinak) figyelmét fel kell hívni arra, hogy kérjenek orvosi tanácsot, amennyiben ön-gyilkossági gondolatok vagy öngyilkos viselkedés jelei lépnének fel. Gyógyszerkölcsönhatások és egyéb interakciók: Alakozamidot elôvigyázatosan kell alkalmazni azon betegeknél, akiket olyan gyógyszerekkel kezelnek, amelyek ismert módonkapcsolatba hozhatók a PR-megnyúlással (pl. karbamazepin, lamotrigin, pregabalin), valamint I. osztályba sorolt antiarrhyth-miás gyógyszerekkel kezelt betegeknél. A CYP2C9, ill. a CYP3A4 erôs inhibitoraival (pl. flukonazol, ill. itrakonazol, ketokonazol,ritonavir, klaritromicin) történô egyidejû kezelés esetén elôvigyázatosság javasolt, mert ez a lakozamid szisztémás expozíci-ójának növekedéséhez vezethet. Erôs enzim-induktorok, például a rifampicin vagy az orbáncfû (Hypericum perforatum) kö-zepes mértékben csökkenthetik a szisztémás lakozamid expozíciót. Emiatt az ezen enzim-induktorokkal történô kezeléstelôvigyázatosan kell elkezdeni és befejezni. A lakozamid fehérjekötôdése alacsony, kisebb 15%-nál. Valószínûtlennek te-kinthetô tehát, hogy fehérjekötési helyekért történô versengés révén klinikailag jelentôs kölcsönhatások lépnének fel másgyógyszerekkel.Termékenység, terhesség és szoptatás: Terhes nôkön történô alkalmazásra nincs megfelelô adat a lako-zamid tekintetében. Emberben a potenciális veszély nem ismert. A lakozamidot a terhesség ideje alatt nem szabad alkalmazni,hacsak nem feltétlenül szükséges (ha az anyára gyakorolt elôny egyértelmûen nagyobb a magzatra gyakorolt esetleges koc-

kázatnál). Ha a nôk úgy döntenek, hogy terhességet vállalnak, a készítmény alkalmazását gondosan újra kell értékelni. Nemismert, hogy a lakozamid kiválasztódik-e az emberi anyatejjel. Elôvigyázatossági intézkedésként a szoptatást abba kell hagynia lakozamiddal végzett kezelés alatt. A készítmény hatásai a gépjármûvezetéshez és a gépek kezeléséhez szükségesképességekre: A Vimpat kis vagy közepes mértékben befolyásolhatja a gépjármûvezetéshez és gépek kezeléséhez szükségesképességeket. A Vimpat-kezelés során szédülést, illetve homályos látást észleltek. Ennek megfelelôen a betegeket figyel-meztetni kell arra, hogy ne vezessenek gépjármûvet, illetve ne kezeljenek potenciálisan veszélyes gépeket mindaddig, amígmeg nem ismerik a Vimpat hatásait az ilyen tevékenységek végzéséhez szükséges képességeikre. Nemkívánatos hatások,mellékhatások: A nagyon gyakori (a betegek több mint 10%-ánál elôforduló) mellékhatások a következôk: szédülés, fejfájás,kettôs látás, émelygés. Ezek intenzitása általában enyhe vagy közepes fokú volt. Egy részük dózisfüggô volt és a dózis csök-kentésével enyhíthetô volt. A központi idegrendszeri és az emésztôrendszeri mellékhatások elôfordulási gyakorisága és sú-lyossága általában csökkent az idô függvényében. A lakozamid-terápia abbahagyásához vezetô leggyakoribb mellékhatás aszédülés volt. Gyakori mellékhatások a következôk: depresszió, zavartság, álmatlanság, egyensúlyzavar, koordinációs zavar,memóriazavar, kognitív zavar, aluszékonyság, tremor, nystagmus, hypaesthesia, dysarthria, figyelemzavar, homályos látás,vertigo, tinnitus, hányás, székrekedés, flatulentia, dyspepsia, szájszárazság, pruritus, bôrkiütés, izomgörcsök, járászavar,asthenia, fáradtság, ingerlékenység, elesés, bôr laceratio. A lakozamid alkalmazásával összefügg a PR-intervallum dózisfüggônövekedése. A PR-intervallum megnyúlásával kapcsolatban "nem gyakori" mellékhatások (pl. atrioventricularis-blokk,syncope, bradycardia) léphetnek fel. További nem gyakori mellékhatásként pitvarfibrillációt illetve remegést, pszichiátriai tü-neteket (többek között öngyilkossági gondolatok és kísérlet, pszichotikus zavar, hallucináció, izgatottság, eufóriás hangulat,agresszivitás), angiooedemát, urticariát jelentettek. Kóros májfunkciós vizsgálati eredményeket figyeltek meg lakozamiddalvégzett kontrollos vizsgálatokban olyan, parciális görcsrohamokban szenvedô felnôtt betegek esetében, akik egyidejûleg 1-3 antiepilepsziás gyógyszert szedtek. Egyes antiepilepsziás szerekkel kezelt betegeknél több szervet érintô túlérzékenységireakciót jelentettek. Ezeknek a reakcióknak a megjelenési formája változatos, de típusosan lázzal és kiütéssel járnak, és kü-lönbözô szervrendszereket érintenek. A lakozamid kapcsán potenciális eseteket ritkán jelentettek, és amennyiben többszervet érintô túlérzékenységi reakció gyanúja áll fenn, a lakozamid kezelést abba kell hagyni. Túladagolás: A lakozamidembereknek történô túladagolásával kapcsolatban csak korlátozott klinikai tapasztalat áll rendelkezésre. Napi 1200 mg-osdózisokat követôen észlelt klinikai tünetek (szédülés és émelygés) fôként központi idegrendszeri és emésztôrendszeri jellegûekvoltak, és a dózis módosítására megszûntek. A lakozamiddal történt túladagolásnak nincs specifikus antidotuma. A lakozamidtúladagolás kezelésekor el kell végezni az általános szupportív beavatkozásokat, és sor kerülhet hemodialízisre is. Felhasz-nálhatósági idôtartam: 5 év (filmtabletták), 3 év (oldatos infúzió). Különleges tárolási elôírások: Ez a gyógyszer nemigényel különleges tárolást (filmtabletták). Legfeljebb 25°C-on tárolandó (odatos infúzió). Csomagolás: 50 mg filmtabletta:14 db; 100 mg filmtabletta: 56 db; 150 mg filmtabletta: 56 db; 200 mg filmtabletta: 56 db, oldatos infúzió: 5 x 20 ml injekciósüveg. Osztályozás: Korlátozott érvényû orvosi rendelvényhez kötött gyógyszerek (Sz). A forgalomba hozatali engedély jo-gosultja: UCB Pharma S.A., Allée de la Recherche 60, B-1070 Bruxelles, Belgium. A forgalomba hozatali engedély száma:EU/1/08/470/001 (50 mg, 14x); EU/1/08/470/005 (100 mg, 56x); EU/1/08/470/008 (150 mg, 56x); EU/1/08/470/011 (200mg, 56x); EU/1/08/470/017 (5 x 20 ml). Az alkalmazási elôírás jóváhagyásának dátuma: 2013. július 31. További infor-mációért/bôvebb tájékoztatásért kérjük, olvassa el a részletes alkalmazási elôírást. www.ema.europa.eu; www.ogyi.hu.

UCB Magyarország Kft.

1023 Budapest, Árpád fejedelem útja 26-28.

Tel.: 391-0060, Fax: 275-2998

Eng.szám: LCM-PRM-030025Lezárás dátuma: 2014.03.10

Készítmény megnevezése Kiszerelési Bruttó fogy. Emelt támogatási Emelt tám. Térítési díj emelt egység ár kategória összeg támogatás esetén

VIMPAT 50 MG FILMTABLETTA 14x 3 079 Ft 90% 2 771 Ft 308 Ft

VIMPAT 100 MG FILMTABLETTA 56x 21 560 Ft 90% 19 404 Ft 2 156 Ft



VIMPAT 10 MG/ML OLDATOS INF. 5x20 ml 47 080 Ft 0% 0 Ft 47 080 FtA VIMPAT 50 mg filmtabletta (14x), VIMPAT 100 mg filmtabletta (56x), VIMPAT 150 mg filmtabletta (56x), VIMPAT 200 mg filmtabletta (56x) köz-gyógyellátási igazolvánnyal rendelkezôknek a közgyógyellátási keret terhére rendelhetô. Részletes információt a www.oep.hu oldalon talál.

lakozamid

MÉG EGYSZERŰBB ALKALMAZÁS

oldatos infúzió

Alternatív készítmény olyan betegek számára, akiknél a szájon át történô alkalmazás

átmenetileg nem lehetséges

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OFFICIAL JOURNALof the

Hungarian Neurological Society,Hungarian Neurosurgical Society,

Hungarian Society of Clinical Neurophysiology,Hungarian Society of Child Neurology,Hungarian Society of Neuroradiology,

Hungarian Epilepsy League,Hungarian Spine Society,

Horányi Béla Hungarian Clinical Neuroscience Society,Hungarian Stroke Society,

Hungarian Neuroscience Society.•

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a Magyar Klinikai Neurofiziológiai Társaság,Magyar Gyermekneurológiai Társaság,a Magyar Neuroradiológiai Társaság,

a Magyar Epilepszia Liga,a Magyar Gerincgyógyászati Társaság,

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és a Magyar Idegtudományi TársaságHIVATALOS LAPJA.

S Z E M L EIDEGGYÓGYÁSZATI

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Ideggyógyászati Szemle/Clinical Neurosciencehavonta megjelenô szakfolyóiratISSN 0019-1442

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Elõfizetési díja egyéni elõfizetõk részére: 7900 Ft/évIntézmények részére: 12 000 Ft+áfa/évTámogatói elõfizetés, amely akár intézmény, akár magánszemély által történhet, és a lap fejlesztését szolgálja:minimum 15 000 Ft+áfa/évTámogatóink névsorát 2014. utolsó lapszámában, illetve azonline felületen jelezzükA lap egy példánya bruttó 2000 Ft

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László Solymosi Würzburg

Assistant Editor • Szerkesztôségi titkárKállai Éva Szeged

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Bereczki Dániel BudapestCsanda Endre BudapestCsiba László DebrecenCsibri Éva BudapestDeák György BudapestDóczi Tamás PécsElekes Károly TihanyFolyovich András BudapestFreund Tamás BudapestGyörgy Ilona DebrecenHalász Péter BudapestKenéz József BudapestKlauber András BudapestKomoly Sámuel PécsMechler Ferenc DebrecenNagy Zoltán BudapestNyáry István BudapestPalkovits Miklós BudapestPálffy György PécsSzirmai Imre BudapestTakáts Annamária BudapestTringer László Budapest

International Advisory Board • Nemzetközi tanácsadó testület

Alexander A. Borbély ZürichMaurice Choux MarseillesKarl Ekbom StockholmFranz Gerstenbrand WienGeorg Gosztonyi BerlinAndrew Kertesz London, OntarioCarl Hermann Lücking FreiburgFritz Magerl St. GallenJerzy Majkowski WarsawJoseph B. Martin BostonHans-Jürgen Möller MünchenAxel Perneczky MainzFrank Clifford Rose LondonHermann Stefan ErlangenArthur D. Steffee ClevelandKarsten Voigt Tübingen

Regional Editors • Regionális szerkesztôk

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TARTALOM CONTENTS

A folyóirat a következõ adatbázisokban szerepel/journal indexed and abstracted in:Science Citation Index Expanded (SciSearch®), Neuroscience Citation Index®, Journal Citation Report/Science Edition,

ISI Web of Science, MEDLINE, Index Copernicus, SCOPUS, Scirus, Google Scholar

Lapszámunk hirdetõi:UCB Magyarország Kft. 2. borítóoldal, Richter Gedeon Nyrt. (4. borítóoldal), Novartis Hungária Kft. (76. oldal),

Teva Gyógyszergyár Zrt. (128. oldal), Wörwag Pharma Kft. (144. oldal)

SELYE-SZIMPÓZIUMElôszóSomogyi Árpád, Szabó Sándor, Roger Guillemin . . . . . . . . . . .77Volker Jahnke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .79Milagros Salas-Prato . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .81Somogyi Árpád . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .87Szabó Sándor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .91Yvette Taché . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .95Lázár György . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .99Gyires Klára . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .103Vécsei László, Horváth Zoltán, Tuka Bernadett . . . . . . . . . . .107Dunai Magdolna . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .113Palkovits Miklós . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .116Ludmila Filaretova, Makara Gábor . . . . . . . . . . . . . . . . . . . . .121Giulio Gabbiani . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .124Kovács Kálmán, Fabio Rotondo, Horváth Éva, Luis V Syro . .126

EREDETI KÖZLEMÉNYAz MDS-UPDRS magyar validációja: Miért szükséges újabb Parkinson-pontozóskála? . . . . . . 129Horváth Krisztina, Aschermann Zsuzsanna, Ács Péter, Bosnyák Edit, Deli Gabriella, Pál Endre, Késmárki Ildikó, Horváth Réka, Takács Katalin, Komoly Sámuel, Bokor Magdolna, Rigó Eszter, Lajtos Júlia, Klivényi Péter, Dibó György, Vécsei László, Takáts Annamária, Tóth Adrián, Imre Piroska, Nagy Ferenc, Herceg Mihály, Hidasi Eszter, Kovács Norbert

ESETISMERTETÉSGyulladásos temporalis leukoencephalopathia együttes megjelenése két B-sejtes malignomával . . . . . . . . . . . . . . . . . . 135Garzuly Ferenc, Hahn Katalin, Iványi László János, Kereskai László, Gábor Valéria, Kovács G. Gábor, Budka Herbert, Kalman Bernadette

FÓRUMTerápiás továbblépés dilemmája relapszáló-remittáló sclerosis multiplexben az elsô vonalbeli kezelés hatástalansága esetén: fingolimod vagy natalizumab? . . . . . 141Lovas Gábor

TÁRSASÁGI MELLÉKLETA Magyar Epilepszia Liga Közgyûlése . . . . . . . . . . . . . . . . . . 142Szupera Zoltán

KONGRESSZUSI NAPTÁR . . . . . . . . . . . . . . . . . . . . . . . . . . 143

SELYE SYMPOSIUMForewordÁrpád Somogyi, Sándor Szabó, Roger Guillemin . . . . . . . . . . .77Volker Jahnke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .79Milagros Salas-Prato . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .81Árpád Somogyi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .87Sándor Szabó . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .91Yvette Taché . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .95György Lázár . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .99Klára Gyires . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .103László Vécsei, Zoltán Horváth, Bernadett Tuka . . . . . . . . . . .107Magdolna Dunai . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .113Miklós Palkovits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .116Ludmila Filaretova, Gábor Makara . . . . . . . . . . . . . . . . . . . . .121Giulio Gabbiani . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .124Kálmán Kovács, Fabio Rotondo, Éva Horváth, Luis V Syro . .126

ORIGINAL ARTICLEValidation of the Hungarian MDS-UPDRS: Why do we need a new Parkinson scale? . . . . . . . . . . . . . 129Krisztina Horváth, Zsuzsanna Aschermann, Péter Ács, Edit Bosnyák, Gabriella Deli, Endre Pál, Ildikó Késmárki, Réka Horváth, Katalin Takács, Sámuel Komoly, Magdolna Bokor, Eszter Rigó, Júlia Lajtos, Péter Klivényi, György Dibó, László Vécsei, Annamária Takáts, Adrián Tóth,Piroska Imre, Ferenc Nagy, Mihály Herceg, Eszter Hidasi, Norbert Kovács

CASE REPORTAssociation of temporal lobe inflammatory leukoencephalopathy with two B cell malignancies . . . . . . . . . 135Ferenc Garzuly, Katalin Hahn, László János Iványi, László Kereskai, Valéria Gábor, Gábor G. Kovács, Herbert Budka, Bernadette Kalman

FORUMDilemma of further therapeutic step in RRMS in case of ineffectivity of first line treatment: fingolimod ornatalizumab? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141Gábor Lovas

SOCIETY SUPPLEMENTMeeting of the Hungarian Epilepsy League . . . . . . . . . . . . . . 142Zoltán Szupera

CONGRESS CALENDAR . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

tartalomUJ_tartalomUJ.qxd 2014.03.24. 8:15 Page 75

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Kiemelkedô hatásosság1§,aktív élet2

A betegek kétharmada mentes a betegség aktivitásától (interferonról történt váltást követôen 1 évvel*)

1. Cohen JA et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Eng J Med 2010; 362: 402-415.

§ vs interferon beta-1a IM2. Hartung et al. Relationship between early disease activity and long-term clinical

outcome: Results from the phase 3 TRANSFORMS study extension at 4,5 years in relapsing-remitting multiple sclerosis. Poster presented at the 23rd European Neu-rology Society (ENS) Meeting, 8–11 June 2013, Barcelona, Spain. P380

*A törzskönyvezett indikáció országonként változhat.A napi 1x 0.5 mg fingolimoddózist kapó csoport eredményei alapján

1

Ez a gyógyszer fokozott felügyelet alatt áll, mely lehetôvé teszi az új gyógyszerbiztonsági információk gyors azonosítását. Az egészségügyi szakembereket arra kérjük, hogy jelentsenek bármilyen feltételezett mellékhatást.GILENYA 0,5 mg kemény kapszula (ATC: L04AA27) Hatóanyag: 0,5 mg fingolimod kemény kapszulánként (hidroklorid formájában).Terápiás javallatok: A Gilenya betegségmódosító kezelésként önmagában javallott nagyon aktív relapszáló‑remittáló sclerosis multiplex kezelésére a következô betegcsoportokban:– azon betegeknél, akiknél béta‑interferon‑kezelés ellenére nagyon aktív a betegség; Azok a betegek sorolhatók ide, akik nem reagáltak egy teljes és megfelelôen kivitelezett (általában legalább egy évig tartó) béta‑inter‑

feron kúrára. A betegeknél az elôzô év során a kezelés alatt legalább 1 relapszusnak kellett bekövetkeznie, és a koponya‑MRI‑n legalább 9, T2‑hiperintenzív lézió vagy legalább 1, gadolínium‑dúsulással járó lézió kellett, hogy legyen. A „nem reagáló” betegek úgy is definiálhatók, mint olyan betegek, akiknél az elôzô évhez képest a relapszusok gyakorisága változatlan, emelkedett, vagy folyamatban lévô súlyos relapszusban vannak.

vagy– azon betegeknél, akiknél a relapszáló‑remittáló sclerosis multiplex gyorsan súlyosbodik, azaz 2 vagy több funkcióvesztést okozó relapszus fordult elô egy év alatt, és 1 vagy több gadolínium‑dúsulással járó lézió volt

az agyi MRI‑n, vagy jelentôs növekedés volt a T2 léziókban a legutóbbi MRI‑hez képest.Adagolás és alkalmazás: A Gilenya javasolt adagja naponta egyszer egy 0,5 mg‑os kapszula, szájon át bevéve. Az enyhe ‑ súlyos fokban beszûkült vesemûködésû vagy az enyhén‑közepes fokban beszûkült májmûködésû betegeknél a dózis módosítása nem szükséges. A Gilenya biztonságosságát és hatásosságát 0‑18 éves gyermekek esetében nem igazolták. Ellenjavallatok: Ismert immunhiányos szindróma. Olyan betegeknél, akiknél fo‑kozott az opportunista fertôzések kockázata, beleértve a legyengült immunrendszerû betegeket is (köztük azokat, akik jelenleg kapnak immunszuppresszív kezelést vagy azokat, akiknek az immunrendszere korábbi kezelés miatt gyengült le). Súlyos, aktív fertôzések, aktív, krónikus fertôzések (hepatitis, tuberculosis). Ismert, aktív malignus megbetegedések, kivéve a bôr basalsejtes carcinomájában szenvedô betegek. Súlyosan beszûkült má‑jmûködés (Child‑Pugh C stádium). A készítmény hatóanyagával vagy bármely segédanyagával szembeni túlérzékenység. Különleges figyelmeztetések és az alkalmazással kapcsolatos óvintézkedések: Bradyarrhythmia: A Gilenya‑kezelés elkezdése a szívverésszám átmeneti csökkenését eredményezi, mely lassult atrioventricularis átvezetéssel is társulhat, beleértve az átmeneti, spontán megszûnô teljes AV‑blockról szóló izolált jelentése‑ket. Az elsô adag után a szívverésszám csökkenése egy órán belül elkezdôdik, és 6 órán belül a legkifejezettebb. A Gilenya negatív chronotrop hatása 6 órán túl is fennmarad, és a kezelés következô napjain progresszíven gyengül. Az adagolás folytatása mellett a szívverésszám egy hónapon belül visszatér a kiindulási szintre. Ugyanakkor egyes betegeknél elôfordulhat, hogy a szívverésszám az elsô hónap végére nem tér vissza a kiindulási szintre. A vezetési zavarok jellemzô módon átmenetiek és tünetmentesek voltak. A kezelésükre általában nem volt szükség, és a kezelés elsô 24 óráján belül megszûntek. A Gilenya elsô dózisa elôtt és 6 órával az után minden betegnél EKG‑vizsgálatot és vérnyomásmérést kell végezni. Minden betegnél óránkénti pulzusszám‑ és vérnyomásméréssel 6 órán keresztül monitorozni kell a bradycardia okozta panaszokat és tüneteket. Ez alatt a 6 órás idôszak alatt folyamatos (valós idejû) EKG‑monitorozás javasolt. Amennyiben az adagolást követôen bradyarrhythmiával összefüggô tünetek jelentkeznek, akkor megfelelô klinikai kezelést kell kezdeni, és a moni‑torozást a tünetek megszûnéséig folytatni kell. Amennyiben egy betegnél az elsô dózis monitorozásának ideje alatt gyógyszeres beavatkozásra van szükség, akkor egy egész éjszakán át tartó, egészségügyi intézményben végzett monitorozást kell kezdeni, és az elsô dózissal járó monitorozási stratégiát a Gilenya második dózisa után is meg kell ismételni. Ha a szívverésszám az elsô dózis beadása óta a 6. órában a legalacsonyabb, akkor a monitorozást legalább 2 órával meg kell hosszabbítani, mindaddig, amíg a pulzusszám újra emelkedni nem kezd. Ezen kívül, ha 6 óra múlva a percenkénti szívverésszám <45, vagy az EKG újonnan kialakuló másodfokú vagy magasabb fokú AV‑blockot vagy ≥500 msec‑os QTc‑távolságot mutat, akkor hosszabb ideig tartó monitorozást (legalább az egész éjszakán át tartó monitorozást) kell végezni, mindaddig, amíg ezek az eltérések meg nem szûnnek. Bármikor megjelenô harmadfokú AV‑block szintén hosszabb ideig tartó monitorozást (legalább az egész éjszakán át tartó monitorozást) kell eredményezzen.A súlyos ritmuszavarok kockázata miatt a Gilenya nem alkalmazható olyan betegeknél, akiknek másodfokú Mobitz II vagy magasabb fokú AV‑blockja, sick‑sinus szindrómája vagy sino‑atrialis blockja van, az anamnézisében tünetekkel járó bradycardia vagy visszatérô ájulás szerepel, vagy olyan betegeknél, akiknél a QT‑távolság jelentôsen megnyúlt (QTc >470 msec (nôk) vagy >450 msec (férfiak)). Mivel azok a betegek, akik ismert ischaemiás szívbetegségben (beleértve az angina pec‑torist is), cerebrovascularis kórképben szenvednek, akiknek az anamnézisében myocardialis infarctus szerepel, pangásos szívelégtelenségben szenvednek, vagy akiknek az anamnézisében szívleállás, nem beállított hyper‑tonia vagy súlyos alvási apnoe szerepel, rosszul tolerálhatják a jelentôs bradycardiát, ezért a Gilenya ezeknél a betegeknél nem alkalmazható. Az ilyen betegeknél a Gilenya‑kezelés csak akkor mérlegelhetô, ha a várható elônyök meghaladják a lehetséges kockázatokat. A kezelés mérlegelését követôen, a kezelés megkezdése elôtt a legmegfelelôbb monitorozás meghatározása érdekében kardiológus tanácsát kell kérni, a kezelés megkez‑déséhez legalább az egész éjszakán át tartó, meghosszabbított monitorozás javasolt. A Gilenya‑val szerzett tapasztalat korlátozott az olyan betegeknél, akik egyidejûleg béta‑blokkolókkal, pulzusszámcsökkentô kalciumcsa‑torna‑blokkolókkal (például verapamil, diltiazem vagy ivabradin) vagy más, olyan hatóanyagokkal végzett kezelést kapnak, amelyek csökkenthetik a szívverésszámot (pl. digoxin, antikolinészteráz szerek vagy pilokarpin). A szívverésszámra gyakorolt potenciális additív hatása miatt a Gilenya‑kezelést nem szabad elkezdeni olyan betegeknél, akiket egyidejûleg ezekkel a hatóanyagokkal kezelnek. Az ilyen betegeknél a Gilenya‑kezelés csak akkor mérlegelhetô, ha a várható elônyök meghaladják a lehetséges kockázatokat. A Gilenya‑kezelés mérlegelésekor a kezelés megkezdése elôtt kardiológus tanácsát kell kérni egy, a szívverésszámot nem csökkentô gyógyszerre történô átállítást illetôen. Ha a szívfrekvenciát csökkentô gyógyszert nem lehet abbahagyni, az elsô dózis megfelelô monitorozásának meghatározása érdekében kardiológus tanácsát kell kérni, legalább az egész éjszakán át tartó, meghosszabbított monitorozás javasolt. A szívverésszámra és az atrioventricularis átvezetésre gyakorolt hatások a Gilenya‑kezelés ismételt elkezdésekor újra visszatérhetnek a Gilenya‑kezelés megkezdése óta eltelt idô és a megszakítás hosszától függôen. Az elsô dózis esetén ugyanaz a monitorozás javasolt, mint a kezelés elkezdésekor, ha a kezelést az alábbiak szerint megszakították:1 vagy több nap a kezelés elsô 2 hete alatt, több mint 7 nap a kezelés 3. és 4. hete alatt, több mint 2 hét, egyhónapos kezelés után.Ha a kezelés félbeszakítása az elôzôeknél rövidebb ideig tart, akkor a kezelést a következô adaggal a tervezett szerint kell folytatni. QT‑távolság: Azoknál a betegeknél, akiknek releváns kockázati tényezôik vannak, mint amilyen a hypokalaemia vagy a QT‑távolság veleszületett megnyúlása, legjobb elkerülni azokat a gyógyszereket, amelyek megnyújthatják a QTc‑távolságot. Fertôzések: A Gilenya alapvetô farmakodinámiás hatása a perifériás lymphocyta‑szám dózisfüggô csökkentése a kiindulási érték 20‑30%‑ára. A súlyos, aktív fertôzésben szenvedô betegek Gilenya‑kezelésének elkezdését a fertôzés megszûnéséig halasztani kell. A Gilenya‑kezelés elkezdése elôtt meg kell vizsgálni és értékelni kell a varicella zoster vírus (VZV) elleni ellenanyagszintet az olyan betegeknél, akiknek az anamnézisében nem szerepel bárányhimlô vagy VZV elleni vakcináció. A Gilenya‑kezelés elkezdése elôtt gondoskodni kell az antitest‑negatív betegek VZV vakcinációjáról, ami után a Gilenya‑kezelés elindítását 1 hónapig halasztani kell, hogy az oltás teljes hatása kialakulhasson. A Gilenya immunrendszeri hatásai növelhetik a fertôzések kockázatát. Ezért a kezelés ideje alatt fertôzés tüneteit mutató betegeknél hatékony diagnosz‑tikai és terápiás stratégiákat kell alkalmazni. A Gilenya‑t kapó betegeket arra kell utasítani, hogy a kezelés alatt és az abbahagyást követô két hónapban jelentsék kezelôorvosuknak a fertôzések tüneteit. Macula oedéma: Vizuális tünetekkel járó vagy anélküli macula oedemát a 0,5 mg fingolimoddal kezelt betegek 0,4%‑ánál jelentettek, túlnyomórészt a kezelés elsô 3‑4 hónapja alatt. Ezért a kezelés megkezdése után 3‑4 hónappal szemésze‑ti vizsgálat javasolt. Azoknál a betegeknél, akiknek az anamnézisében uveitis szerepel, illetve a diabetes mellitusos betegeknél fokozott a macula oedema kockázata. Az ô esetükben javasolt, hogy a kezelés megkezdése elôtt szemészeti vizsgálaton essenek át, és a kezelés ideje alatt kontroll vizsgálatok történjenek náluk. Májfunkció: Ha májmûködési zavarra utaló tünetek jelentkeznek, a májenzimek szintjét ellenôrizni kell, és a Gilenya adását abba kell hagyni, ha jelentôs májkárosodás igazolódik (például a normálérték felsô határának 5‑szörösét meghaladó hepaticus transzaminázszintek). A fingolimod és potens CYP450 induktorok kombinációját óva‑tosan kell alkalmazni. Lyukaslevelû orbáncfûvel való egyidejû alkalmazása nem javasolt. Gyógyszerkölcsönhatások és egyéb interakciók: Daganatellenes, immunszuppresszív vagy immunmoduláló kezelések: Az additív immunrendszeri hatások kockázata miatt a daganatellenes, immunszuppresszív vagy immunmoduláló terápiákat nem szabad egyidejûleg alkalmazni. Akkor is elôvigyázatosság szükséges, amikor a betegeket immunrend‑szeri hatásokkal bíró, hosszú hatású kezelésekrôl, például natalizumabról vagy mitoxantronról állítják át. Vakcináció: A Gilenya‑kezelés ideje alatt és utána legfeljebb 2 hónapig elôfordulhat, hogy az oltás kevésbé hatásos. Élô, attenuált kórokozókat tartalmazó vakcinák alkalmazása a fertôzések kockázatát hordozhatja, ezért azt kerülni kell. Bradycardiát indukáló hatóanyagok: A béta‑blokkolókat vagy a szívverésszámot esetleg csökkentô, egyéb hatóanyagokat, például az Ia és a III. osztályba tartozó antiarrhythmiás gyógyszereket, kalciumcsatorna‑blokkolókat (például ivabradint, verapamilt vagy diltiazemet), digoxint, antikolinészteráz szereket vagy pilokar‑pint kapó betegeknél a szívverésszámra gyakorolt potenciális additív hatások miatt a Gilenya‑kezelést nem szabad elkezdeni. A Gilenya‑kezelés ilyen betegeknél történô mérlegelésekor kardiológus tanácsát kell kérni egy, a szívverésszámot nem csökkentô gyógyszerre történô átállítást vagy a kezelés elkezdésének megfelelô monitorozását illetôen, ha a szívverésszámot csökkentô gyógyszert nem lehet abbahagyni, akkor legalább az egész éjszakán át tartó monitorozás javasolt. Terhesség és szoptatás: A kezelés elkezdése elôtt a fogamzóképes nôk esetén negatív terhességi teszteredménynek kell rendelkezésre állnia. A kezelés ideje alatt a nôknek nem szabad teherbe esniük, és aktív fogamzásgátlás alkalmazása javasolt. Ha egy nô a Gilenya szedése alatt esik teherbe, a Gilenya abbahagyása javasolt. A Gilenya‑t kapó nôk nem szoptathatnak. A készítmény hatásai a gépjármûvezetéshez és gépek kezeléséhez szükséges képességekre: A Gilenya nem, vagy csak elhanyagolható mértékben befolyásolja a gépjármûvezetéshez és gépek kezeléséhez szükséges képességeket. Ugyanakkor a Gilenya‑kezelés elkezdésekor esetenként szédülés vagy álmosság fordulhat elô. A Gilenya‑kezelés megkezdésekor a betegek 6 órán át tartó megfigyelése javasolt. Nemkívánatos hatások, mellékhatások: Nagyon gyako-ri: influenza vírus okozta fertôzés, fejfájás, köhögés, hasmenés, hátfájás, emelkedett alanin‑transzamináz szint. Gyakori: herpes vírus okozta fertôzés, bronchitis, sinusitis, gastroenteritis, tinea fertôzés, limphopénia, leuko‑pénia, depresszió, szédülés, paraesthaesia, migrain, homályos látás, szemfájdalom, bradycardia, hypertonia, atrioventrikuláris blokk, dyspnoe, ekzema, alopecia, pruritus, gyengeség, emelkedett gamma‑glutamil–transz‑feráz szint, emelkedett májenzimszint, kóros májfunkciós eredmények, emelkedett triglicerid szint, testtömeg csökkenés. Nem gyakori: pneumónia, depressziós hangulat, makula oedema, csökkent neutrophil‑szám. Megjegyzés: A forgalomba hozatali engedély számai: EU/1/11/677/01‑05. Bôvebb információért olvassa el a gyógyszer alkalmazási elôírását (2013.12.18.)! Osztályozási alkategória: ,,SZ”, forgalmazott kiszerelés: 28x. Eü100 53/b Term. ár: 493056 Ft Fogy.ár: 541527 Ft Tér. díj: 300 Ft. A forgalomba hozatali engedély jogosultja: Novartis Europharm Limited, Wimblehurst Road, Horsham, West Sussex, RH12 5AB, Nagy‑Bri‑tannia. Forgalomba hozatali engedély jogosultjának magyarországi képviselôje: Novartis Hungária Kft., H‑1114 Budapest, Bartók Béla u. 43‑47.

1114 Budapest, Bartók Béla út 43–47.Tel.: 457–6500, Fax: 457–6600

GIL10/14FEB Lezárás dátuma: 2014. február 21.

2014. marc 21 Gilenya 200x280 - 5 pontos betu.indd 1 3/21/14 1:38 PM


Ideggyogy Sz 2014;67(3–4):77–78. 77

SELYE SYMPOSIUM

FOREWORD TO THE PROCEEDINGS OF THE “SELYE SYMPOSIUM – 2013”, HELD AT THE HUNGARIAN

ACADEMY OF SCIENCES, BUDAPEST, HUNGARY, MAY 8, 2013

Hans Selye (Selye János) is mostly known forhis discovery & development of stress the

concept that he first described in a short article inNature, 1936. Yet, Selye made several other sem-inal discoveries & creative new observations, e.g.,the first scientific classification of steroid hor-mones, the introduction of notions such as ‘corti-coids’, glucocorticoids & mineralocorticoids, thefirst description of their anti- & pro-inflammatoryproperties, respectively, as well as the firstdescription of stress ulcers in humans. Since mostof these seminal articles were published in 1943,two of Selye’ almost last PhD students (i.e.,Árpád Somogyi & Sándor Szabó), with the help ofProf. László Vécsei, chair of the Medical Sectionof the Hungarian Academy of Sciences organizeda commemorative symposium on the 70th anniver-sary of the publication of these articles of HansSelye.

We invited Selye’s still active graduate studentswho obtained their PhD and/or MSc degree in hisinstitute at the University of Montreal, i.e., RogerGuillemin, Giulio Gabbiani, Volker Jahnke,Milagros Salas-Prato, Yvette Tache. Invited werealso Selye’s senior coworker Kálmán Kovács, oneof the famous “Claude Bernard Visiting Professors”in Selye’s institute, i.e., Sten Orrenius as well asformer visiting scientists who spent 1-2 years in theinstitute, i.e., István Berczi, Lóránd Bertók, GyörgyLázár, Gyula Zsigmond, & several ‘2nd generationof Selye students’ (i.e., investigators who collabo-rated with one of the‘1st generation of Selye stu-dents’), namely Magdolna Dunai, LudmilaFilaretova, Klára Gyires, Miklós Palkovits &László Vécsei. Unfortunately, not all invited speak-ers could join us on the day of the symposium, butwe are pleased that most of them submitted shortcontributions to these proceedings. We are espe-cially thankful to the Nobel laureate RogerGuillemin who wrote a short special introduction(see below.)

The program of the symposium was as follows:– László Vécsei (Budapest/Szeged): Old and

new neuroendocrine molecules: Somatostatin,pantethine and kynurenines

– Sándor Szabó (Long Beach/Irvine): Selye 70years later: Steroids, ulcers & H. pylori

– Sten Orrenius (Stockholm): On being a“Claude Bernard Visiting Prof.” in Selye’s Institute

– Miklós Palkovits (Budapest/Bethesda): TheAxelrod-Selye connection: Catecholamines &steroids

– Yvette Taché (Los Angeles): Hans Selye con-tributions from glucocorticoids to “the first brainmediator of the stress response”: The discovery ofCRF signaling pathways underlines Selye’s concept

– Ludmila Filaretova (St. Petersburg) & GáborMakara (Budapest): The surprising dual action ofglucocorticoids

– Volker Jahnke (Berlin): The relevance of HansSelye’s work for the field of otorhinolaryngology

– Árpád Somogyi (Berlin/Brussels/Budapest):Selye’s concept of pluricausal diseases and itsimpact on regulatory science

– Kálmán Kovács (Toronto): Stress in theclassification of pituitary tumors

– Klára Gyires (Budapest): Central neuroen-docrine mechanisms of gastroprotection

– Lóránd Bertók (Budapest): The effect of stresson natural immunity

– György Lázár (Szeged): Even visiting scien-tists could make discoveries in Montreal

– Magdolna Dunai (Palo Alto): A psychiatrist’sperspectives on stress & steroids

Round table discussion – Nyitott fórum kér -désekre, hozzászólásokra

The initiators of the Selye Symposium – 2013express their gratitude to Prof. Vecsei & the editorsof ‘Clinical Neuroscience’ for rapidly publishingthe accepted manuscripts.

Árpád [email protected]

Sándor Szabó[email protected]

External Members of the Hungarian Academyof Sciences

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Special introduction by RogerGuillemin, Nobel Laureate formerPh.D. student of Hans Selye

I am happy to write a few lines to appear with thetext of the Symposium commemorating Hans Selyeand his contribution to our understanding the biolo-gy of the response to stress.

I met Hans Selye on the occasion of three lec-tures he delivered in Paris at the Laenec Hospital in1949. I was so impressed that I decided to go to hisnewly created Institut de Médecine et Chirurgieexpérimentales in Montreal rather than continuingto practice medicine. I stayed in Selye’s Institute till1952 when I received a Ph.D. degree.

It is from the questions raised by Hans Selye thatI devoted my life as a physiologist and eventuallyisolated the first of these hypothalamic factors con-trolling pituitary functions as proposed by Selye inhis questions regarding the mechanism of theorganism’s response to stress. Neuroendocrinologyafter that became a major chapter of modern physi-ology and medicine.

I am happy to add these few lines of thanks tothis text in his memory.

Roger Guillemin, MD, PhDDistinguished Scientist

The Salk Institute for Biological StudiesLa Jolla, CA, USA

Nobel Prize for Physiology or Medicine, 1977

78 Selye Symposium

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Ideggyogy Sz 2014;67(3–4):79–80. 79

SELYE SYMPOSIUM

THE RELEVANCE OF HANS SELYE’S WORK IN THE FIELDOF OTORHINOLARYNGOLOGY

Volker JAHNKE

First of all I want to thank Professor Somogyivery much for arranging this tribute to Hans

Selye, with such great organising efforts. For my presentation today, I have no slides or

powerpoint because it is so long ago, and I will notread from a manuscript which certainly is in agree-ment with Hans Selye who never did that. He toldus the embarassing situation of a famous old pathol-ogist who instead of 15 minutes talked for one hour,since he had been reading the pages of his manu-script over and over again. For all of us, Hans Selyeis a hero, admired for his personality and the mon-umental work to which he devoted his life. It cer-tainly is noble to teach oneself as Hans Selye did,but it is still nobler to teach others as he did with hispostgraduate students. Born in Vienna, he did notpractice what allegedly has been the principle of theViennese Medical School: i.e. “primum nil nocere”,i.e. first of all don’t teach which I experienced inGermany being just out of Medical school. So muchto the contrary, he was indeed a very gifted andgenerous teacher.

In the beginning we postgraduate students werenothing, we were young and came from differentcountries. Hans Selye did not want us to know a lotor pride ourselves. He was the one to teach us basicresearch with emphasis on creativity and morpho-logic observations with simple techniques-and howto work hard. I did work hard with him for 10months from 1963 to 1964, with publications onstress and pathological calcification, the role ofmast cells as well as stress and aging. I also wrote athesis for my M.Sc. with the title, upon his sugges-tion, “Protective effect of restraint against intoxica-tion with serotonin”. The thesis described that therenal necroses, normally elicited by acute intoxica-tion with serotonin, can be prevented by strugglingin response to forced restraint both in intact and

adrenalectomized rats; hence, this protection is notmediated by an increased secretion of corticoids. –It is only in recent years that serotonin, as a neuro-transmitter, has been widely discussed, as well asdrugs which target this brain chemical. However,inspite of the growing awareness of serotonin’scentral role in mood and emotion and in re-vitaliza-tion, researchers are only beginning to understandits complex role in the functioning of the body andthe brain.

Now, what is the relevance of Hans Selye’s workfor the field of Otorhinolaryngology? I willapproach this question from two points of view:first his scientific influence and second how heinfluenced my life.

Hans Selye’s scientific relevance for the field ofotorhinolaryngology dates back to the 6th WorldCongress of Otorhinolaryngology May 5-10, 1957in Washington D.C.- exactly 56 years ago.According to his abstract with the title “The con-cept of stress in otorhinolaryngology” he placedspecial emphasis then on the diseases of adaptation,he discussed the role of corticoids in the collagendisorders of the respiratory tract and showed thathormones play an important participating role in thedevelopment of non-endocrine diseases.

Later on, in 1965, calciphylaxis has also beendiscussed in the diseases of the respiratory tract.

Now, what are my own contributions? After Ileft Montreal for the Department of Otorhi -nolaryngology at New York University we pub-lished the paper “Histopathology of the ear in theprogeria-like syndrome of the rat “in 1966. HansSelye wrote me that the reprint of this paper wasdiscussed at the weekly staff conference which weall remember so well. For a long time otologistshave been interested in certain aspects of calciummetabolism and the dynamics of bone, with special

Correspondent: Volker JAHNKE MD, Klinik für Hals-Nasen-Ohren Krankheiten; 14193 Berlin, Bernadottestr. 9,Germany. E-mail: [email protected]

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REFERENCES1. Jahnke V. Stress and pathological calcification. J Am

Osteopath Ass 1965;65:258.2. Jahnke V, Daly JF. Histopathology of the ear in a progeria

like syndrome of the rat. Arch Otolaryng 1966;84:497.

3. Jahnke V. Ultrastructure of the vestibular sensory epitheliain experimental lathyrism. Acta otolaryng 1969;68:336.

4. Jahnke V. Hans Selye 1907-1982. Münch Med Wschr1982;124:1094.

regard to otosclerosis. We described the histologicfeatures of the labyrintine capsule and of the middleear ossicles in this progeria-like syndrome of therat: greatley increased osteogenesis occured, withdeposition of excessive osteoid mainly in theendosteal spaces and on the ossicles. Since struc-turally comparable lesions are seen in certain typesof otosclerosis, the production of such changes wasdescribed as a useful model for the study af variousfactors that influence the course of otosclerosis, thecause of which is unknown until today and presum-ably varied.

We knew from studies of experimental lathyrismthat rats become kind of dizzy, with circling move-ments resembling waltzing. In our study of theultrastructure of the vestibular sensory areas inexperimental lathyrism in 1969 we described thedegenerative changes in the hair cells and less so inthe nerve endings. It was suggested that theseselected lesions were primarily due to a disturbancein protein metabolism, as a result of ototoxicity.These findings were considered relevant for ourspecialty, and I felt proud to receive the BasicResearch Award of the American Academy ofOthorhinolaryngology and Ophthalmology in 1969.

Interestingly, though Hans Selye was in favourof traditional research methods, he bought an elec-tron microscope and proudly showed it to me whenI visited- with a big smile because he knew that Ihad described experimental lathyrism in the innerear by means of electron microscopy.

In my later publications, questions occuredregarding the possible role of calciphylaxis inMorbus Osler-Rendu-Weber’s syndrome and inosteoma of the tongue. In my projects, mostly by

means of electron microscopy, I followed HansSelye’s advice to investigate what is a good subjectand what should be done.

There was another advice given by Hans Selye-which influenced my career and personal develop-ment: he wanted us to practice what he called altru-istic egoism, i.e. you have to look out for yourselffirst; in other words do what is best for you, do yourown thing. I did follow this advice: I liked tobecome a clinician in a surgical specialty; so I wentto New York University Medical Center for mytraining in othorhinolaryngology. This was verydifficult for a foreigner, but my time with HansSelye certainly helped. I continued basic researchand learned electron microscopy in Stockholm,Sweden.

I think, Hans Selye’s influence by teaching meto develop my personality and my potential mademe a better person, researcher and clinician. Lateron, when I became chairman of othorhinolaryon-gology at the university, first in West Berlin andafter the wall came down in addition at the Charitéin East Berlin, Hans Selye - by having influencedme - also had a relevance for my staff, the residentsin training and the students.

In closing, I want to emphasise that I am indeedvey thankful to Hans Selye as a scientist and for hisoutstanding, unique research mentioned in thismorning’s contributions by his students and by vis-iting professors. But most of all I appreciated hisgreat personality, his wisdom and his human quali-ties - how he lived and worked. That has influencedto a large extent both my career and private life.

Volker Jahnke

80 Jahnke: The relevance of Hans Selye’s work in the field of otorhinolaryngology

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Ideggyogy Sz 2014;67(3–4):81–86. 81

SELYE SYMPOSIUM

PERSONAL RECOLLECTIONS OF DR. HANS SELYE ANDOF HIS INSTITUT DE MÈDECINE ET DE CHIRURGIE

EXPÈRIMENTALES (IMCE) Milagros SALAS-PRATO

Hans Selye Foundation, Montreal, QC, Canada

SZEMÉLYES VISSZAEMLÉKEZÉS SELYE JÁNOSRA ÉS AZINSTITUT DE MÈDECINE ET DE CHIRURGIE EXPERIMENTALES-RE (IMCE)Salas-Prato M, MSc, PhDIdeggyogy Sz 2014;67(3–4):81–86.

Ez a cikk rövid személyes visszaemlékezés Selye Jánosra ésintézetére, hogy bemutassam elôször, hogy hogyan befolyá-solt bennünket; másodszor, ki volt ô mint személyiség,ember, orvos, tudós, professzor, mentor; harmadszor milyenvolt az Institut de Mèdecine et Chirurgie expèrimentales(IMCE) felépítése és mûködése, és negyedszer Selye Jánosszerepét és eredményeit.

Kulcsszavak: Selye János, Institut de Mèdecine et Chirurgieexpèrimentales (IMCE), általános adaptációs szindróma (GAS),vészreakció, stressz-szindróma, stressztriász, glükokor-tikoidok, mineralokortikoidok, nem specifikus, specifikus,homeosztázis, heterosztázis, akut, krónikus stressz, syntoxi-cus, katatoxikus szteroidok, distressz, eustressz, kísérleti állat-modellek, emberi betegség

This article is a short personal recollection of Dr. Hans Selye(HS) and of his institute in order to show, first, why and howhe influenced us; second, who he was as a person, humanbeing, physician, scientist, professor, mentor; third, whatwas the structure and functioning of the Institut de mèdecineet chirurgie expèrimentales (IMCE) and fourth, what HS’contributions and accomplishments were.

Keywords: Hans Selye, Institut de mèdecine et chirurgieexpèrimentales (IMCE), general adaptation syndrome (GAS),alarm reaction, stress syndrome, stress triad, glucocorticoids,mineralocorticoids, non-specificity, specificity, homeostasis,heterostasis, acute, chronic stress, syntoxic, catatoxicsteroids, distress, eustress, experimental animal models,human illness

Correspondence: Milagros SALAS-PRATO, MSc, PhD, Hans Selye Foundation; 4548 Coolbrook Ave. Montreal, QC H3X 2K6, Canada. Phone: 514-481-1873, e-mail: [email protected]

Érkezett: 2013. november 20. Elfogadva: 2014. február 10.

www.elitmed.hu

Imet Dr. Hans Selye (HS) at the age of 20 when Iwas continuing my studies (I had already begun

Experimental Mèdecine at McGill, B. Posner,M.Sc. Director) at the Institut de mèdecine et dechirurgie expèrimentales (IMCE) at the Faculty ofMèdecine (F of M) of the Universite de Montreal(U de M). I studied for my M.Sc. and Ph.D. degrees(B. Tuchweber, BT, research Director) at his insti-tute for five years. Subsequently, during my firstpostdoctoral studies at the Institut du Cancer ofNotre-Dame Hospital/Centre universitaire de l’Ude M (CHUM), I was also unofficially two moreyears part-time at the IMCE.

The principal aims of this article are: first, toshow why and how Dr. Hans Selye (HS) influencedus; second, who Dr. Hans Selye (HS) was as a per-son, human being, physician, scientist, professor,mentor; third, what was the structure and function-

ing of the IMCE and fourth, what HS’ contributionsand accomplishments were.

For general biographical and other information,please see text and video submitted by us in 2006with W. Feindel (former Montreal NeurologicalInstitute and Hospital, MNI, director/neurosurgeon,student of W. Penfield and also of HS in histologyat McGill) and P. Bois (former Dean, F of M, U deM, former President, Medical Research Council ofCanada, MRC/Canadian Institutes of HealthResearch, CIHR, HS/IMCE student, Institut derecherches cliniques de Montrèal, IRCM) for theinduction of HS into the Canadian Medical Hall ofFame (CMHF).1 Please note that the viewsexpressed in this short article are my own, basedupon my own experience and opinions. However,interestingly, many of us may recount similarimpressions of HS, his institute, and other matters.

salas_UJ ISZ TUKOR ALAP ANGOL.qxd 2014.03.21. 16:01 Page 81

His influence

In the current 2014 year, it will be: 107 years sinceHans Bruno Selye was born (Vienna, Austria), 78years ago since his first publication of the discoveryof the General adaptation syndrome (GAS), AlarmReaction or stress syndrome2, 69 years after hisfounding of the IMCE, 38 of the founding of theInternational Institute of Stress (IIS), 36 years fol-lowing his founding of the HS Foundation (HSF)and, 32 years since his untimely death.

Yet, for those graduate students at the IMCEwho greatly appreciated him and, even loved him asa great teacher/mentor/scientist, time has almoststood still and, he remains in our thoughts and livesas if he were alive.

Type of influence, his teachings, our studies

He had an incredible influence on all of us. He didthis by his way of being, his way of teaching, his wayof talking, his way of walking, his daily bicyclingand running up seven flights of stairs, as well as oftaking siestas, his way of seeing things, of observinglife, of evaluating experiments. Also, by his recount-ing the history of medical sciences, of his childhood,family, career and life memories, of his passion forscience, medecine, experimental medecine,endocrinology, steroids, neurosciences, histology,pathology (inflammation), philosophy of science andof life; his admiration of greatness, beauty, goodness,his tastes for good food, wines, travel, art, music, lit-erature, his love of languages, of people, of his fam-ily, close colleagues/friends, of Komarno, Vienna,Prague, his Russian journal, poem, stories of Russia,Latin-America, etc., etc., etc.

We were not only his students but, his academicchildren, indeed, part of his academic family andlife!

From him, we learnt1. Not only about medecine, science, neuro-

science, endocrinology, steroids, experimentalmedecine, stress, inflammation and life but to alsolove these areas/disciplines.

2. To be innovative, creative, original, andhardworking.

3. To admire, respect and aspire to scientificgreatness, yet to be humble, to be observant, to bedaring, to reach the highest possible goals, to showand explain what we knew and how we knew it.

4. To walk with giants and yet, to be as curious,questioning, content with experimenting and asobservant as children.

5. The greatness of medecine and of medical sci-ences, the effect of illness, of stress, of inflammation,and the use of experimental medecine/pathology ani-mal models to mimic, experiment, explore and probethe equivalent of human illnesses in chronologicalfashion in order to be able to understand the diseaseswe were trying to reproduce and study.

6. The power of hormones (the most importantregulators in the body), receptors, of growth fac-tors, of releasing factors, the effects of stress, theimportance of experimentally eliciting illnesses,elucidating their pathogenesis and treatment.

7. The importance of the brain and its regulationof all of the glands of the body and of the brain-body connection. The key role of interpretationduring stress.

8. About non-specificity and specificity, pluri-causality, homeostasis and heterostasis, acute andchronic stress, syntoxic and catatoxic steroids,distress and eustress.

9. The importance of determining dose-respons-es and of elucidating the time course ofexperimental illnesses.

10. That diseases should be experimentally pro-duced, treated, and thus, by so doing, we wouldunderstand their pathogenesis and possibleprevention.

11. About calcyphylaxis, progeria like-syn-drome, tissue scaffolding, steroid anesthesia, hor-monal shift hypothesis, cachexia, thombohemor-rhagic phenomena, periarteritis nodosa, endocrinekidneys, experimental cardiomyopathies, microso-mal enzyme inducers, etc., etc.

12. To carry out hypophysectomies, adrenalec-tomies, splenectomies, partial hepatectomies (hehad devised the first partial hepactectomy in 19313,before Higgins and Anderson 1931), gonadecto -mies, etc., etc., etc.

13. Discipline, hard work, honesty, the value oforiginality, the importance of innovative, unexpect-ed, generalizable scientific discoveries (three of thecharacteristics of great scientific ones).

14. In order to understand illness, we had to seeit from many points of view/angles utilizing asmany techniques of exploration as possible, such ashistology, biochemistry, electron microscopy, treat-ment with various drugs and agents, surgery, etc.,etc.

We were taught1. To observe, explore, and for doing this, we

had daily rounds in the various laboratories, observ-ing the various experiments being carried out by usand other colleagues and, moreover, to have, as agroup, autopsies of the animals with observation ofthese and daily discussions thereof.

82 Salas-Prato: Personal Recollections of Dr. Hans Selye and of his Institut (IMCE)


2. To think and present our experiments as pre-liminary plans (index cards, in a Symbolic Short -hand System, devised by him), for group review,discussion, consideration and critique.

3. To have these plans typed as protocolssequentially numbered, hanged on cage stands forreference and subsequently, archived for futureperusal and study.

4. To closely follow the literature, not only inour fields but in those of the other students’ andresearchers’ disciplines.

5. To have general interests, not only specificones in our own disciplines.

6. To have a holistic, pluricausal, point of viewof illnesses.

7. To learn all experimental and surgical proce-dures so that we would be able to subsequently fol-low them, understand their pitfalls and supervisethe assistants who carried these out.

8. To take many responsibilities, even while fol-lowing our graduate courses but to eventually dele-gate and to have tasks carried out by others, underour supervision.

9. The value of curiosity and of askingquestions.

10. Of viewing problems under different sourcesof light or lenses, as it were, by observing these andfinding unconventional solutions. This was taughtto us by giving us examples of serendipitous dis-coveries and of the keen observations and realiza-tions made by Bernard, Jenner, Koch, Pasteur, theCuries, Pavlov, Fleming, Pauling, Laborit, Szent-Gyorgyi, etc.

11. To work hard but yet, to also to love life andlive good ones, by eating well, exercising, moderat-ing our stress, meditating, loving art, music, litera-ture, languages, people, travelling, etc., etc., etc.

We were1. Given offices and great services and facilities

but were given great responsibilities and wereexpected to act as professionals and supervise tech-nical assistants and other personnel.

2. Trained in all of these disciplines, sequential-ly and in a series of rotations at the institute.

3. Considered as fellow researchers, even though,we were mere graduate students, and we were expect-ed to be in charge of welcoming Claude Bernard pro-fessors (Figures 1-2.) at the airport, meet with themin the institute, attend their conferences (Figure 3.),and the receptions at HS’ house (Figure 4.).

We becameAccustomed to talking to senior distinguished

researchers, Claude Bernard professors who couldhave been nominated (as HS) for Nobel prizes orwho may have obtained them.

The personality of Hans Selye

Many of the traits of his personality are listedabove. Moreover, it should be noted that by exam-ple and/or intent, he was coaching us to be like himand acquire the habits which had led him to success.Some of these were: enormous curiosity, originali-ty, stamina, creativity, industriousness, discipline, ahigh sense of order, organization, categorization,classification, an admiration of greatness, beauty,culture, music, literature, excellence, a love of sci-ence, neuroscience, medecine, endocrinology,steroids, pathology, clinical sciences, a love forpeople and for language/s, a witty personality,incredible productivity, impatient, loving to beentertained, prone to boredom if not occupied andinvolved all of the time, etc., etc., etc. Not to men-tion, his stamina, his medical sciences’ genius, hispublic relations savvy, his encyclopaedic knowl-edge and mind, his Renaissance man-like mentali-ty, world-wide interests, etc., etc., etc.

The IMCE

Some of the activities of the IMCE have alreadydescribed above. Moreover, the institute ran withthe discipline and rigour as if it had been in the for-mer Austro-Hungarian Empire. Also, it was pat-terned as if it were in a clinical setting in a hospital,

Ideggyogy Sz 2014;67(3–4):81–86. 83

Figure 1. Dr. M. Frimmer, Visiting C. BernardProfessor, Dr. Panos Kourounakis and myself in myoffice at the IMCE


with daily Grand Rounds, push button lights on aboard to denote our presence, daily autopsies of ani-mals, an intercom service with speakers calling outthe names of students, researchers or staff asrequired, timed tea breaks in the morning and after-

noon (tea push carts and all!), library and editingservices, various laboratory services/division, suchas histology, pharmacy, biochemistry, electronmicroscopy, surgery, etc., etc., etc.

The surgical rooms were state-of the art andresembled more an operating room in a clinical thanin an experimental setting.

There was marked respect, collegiality and col-laboration amongst the researchers, visiting re -searchers, scholars, students and assistants.

An international, European-flavoured cultured,learned and enriching atmosphere reigned at theinstitute, with researchers, students representingvarious countries around the globe speaking theircorresponding languages. Moreover, even thoughour courses at the university and the language ofwork was French, our discussions were also inEnglish or in other languages as required, so thatthe majority of the researchers/students could com-municate well. HS delighted in speaking Hun -garian, French, English, German or Spanish, etc.,etc. etc.

There existed an atmosphere of learning, schol-arship, collaborative team work,authorship with ample library,technical, laboratory and editorialservices available. Our writing(precursor of the computer andstick papers was done on “Rail”paper, invented by HS before thetime of the computer and stickypapers). This systematic approachaugmented our self-esteem andinduced us to carry out severalexperiments weekly, to write,present, publish, produce, attendlocal, national and internationalmeetings etc., etc.

One could observe a high senseof professionalism and perfection-ism in carrying out the experi-ments, research and the writing,even of everyday letters. All writ-ings (including letters) had to bestrictly edited, proofread in a char-acteristic style to HS and theIMCE.

Unfortunately, due to HS’ con-ventionally imposed retirement in1979, he had to leave his position

as Director and Professor of the IMCE. (Not beinga practicing clinician, it was unfortunate he had toretire at this age). Upon considering why his insti-tute could not survive past his retirement, as did theMNI or the IRCM, Dr. Bois commented that HS


Figure 2. Idem, showing some of our electron micro-graphs of phalloidin-treated rat hepatocytes to Dr.Frimmer

Figure 3. Dr. S. Orrhenius, Visiting C. Bernard Professor, sitting at the centre of thetable in our Conference room at the IMCE. To his right, Drs. H. Selye, P.Kourounakis, B. Tuchweber, S. Szabo, myself and to his left, Drs. B. Garg and G.Lazar


had mentioned to him that when he first movedfrom McGill to the U de M, the Dean had assuredhim he would be able to develop clinical researchand patient care at the institute. Indeed, these otherinstitutes may have survived because of their signif-icant contribution to the care of patients and to clin-ical research.

His contributions

Some of HS’ contributions have already been men-tioned. For statistics on his total number of publica-tions, books, honorary doctorates, degrees, etc.,etc., etc., please see our submission to the CMHFfor his induction1. It must be emphasized that foronly the years between the late 1940’s and the earlythe 1950’s, HS was nominated 17 times for theNobel prize4.

His most important discovery (please also seeDr. Guillemin’s introduction to these proceedings5

as well as6) may have been the discovery of theGAS, Alarm or stress syndrome, not only for this initself, but also because this led to his discovery ofthe glucocorticoids and their subsequent isolationand utilization in humans by others to alleviatearthritis (Kendall et al., Nobel prize for medecineand physiology, 19507). It also led to the conceptu-alization by him and the elucidation, isolation andcharacterization by others (one of these, his formergraduate student, Dr. R. Guillemin, please see his1977 Nobel Prize in Physiology or Mèdecine lec-

ture8) of the hypothalamic hormone releasing hor-mones or factors.

His discovery of the glucocorticoids and theirrole in stress also led to the ability to measure stressin experimental animals by weighing the adrenals,thymuses of the animals and, subsequently, by dos-ing the intensity of stress in these and in humans bycorticosterone and cortisol measurements, respec-tively.

Also, another of his great accomplishments wasthe recognition and classification of steroids intoglucocorticoids and mineralocorticoids, dependingupon their characteristic physiological effects onthe body.

Moreover, because the stress triad discovered byhim included the formation of gastroduodenalulcers, these also opened the door to the future dis-covery and Nobel prize by Warren & Marshall in1985 for the role of campylobacter in gastric ulcerformation9.

Not to mention the inclusion of the triad ofthymicolymphatic atrophy and, consequent im -munodepression which also opened avenues tomany other discoveries, possibly, Nobel prizereception or nominations.

His discovery of he GAS, alarm or stress triadwas also the first to point out solidly to a mind(brain)/body (glands/other organs) connectionwhich had been alluded to by others (Freud, soma-tization, see10) but had not yet been proven or ana-lyzed.

It also led to modern day acceptance of stressand trauma as causing, if not well adapted to,irreparable damage and sequelae, such as thoseobserved in post-traumatic stress disorder (PTSD),opening the door to possible utilization of CRHinhibitors during depression and of other neuropsy-chiatric illnesses11.

It also introduced the concept of adaptation inresponse to stress, its three various phases,resilience/exhaustion of the organism, to acute andchronic stress, etc., etc., etc.

Lastly, during his latter years, HS became inter-ested in philosophy of science and on the meaningof being human (in a Frankl manner12), and one ofhis conclusions, dictum, was that we should try to“Earn our neighbours’ love”13.

THE INTERNATIONAL INSTITUTE OF STRESS

In 1976, with the assistance of the StewartFoundation and Dr. Jean Tache (Director), HS(president) established the International Institute ofStress (IIS). It had its initial headquarters in PointeClaire, QC, subsequently, at his house on Milton

Ideggyogy Sz 2014;67(3–4):81–86. 85

Figure 4. Dr. S. Orrhenius, idem, reception.at Dr.Selye’s residence. To his immediate left, Dr. Hans Selyeand behind him, P. J. Araujo, myself and possibly, Dr. G.Lazar


REFERENCES1. Canadian Medical Hall of Fame (CMHF). http://cdnmed-

hall.org/dr-hans-selye. 2. Selye H. A syndrome produced by diverse nocuous agents.

Nature 1936;32:July 14. 3. Waelsch H, Selye H. Erwiderung auf vorstehende Bemer -

kung (Bedeutung der Leber bei der Avertinvergiftung).Arch Exp Patholog Pharmakol 1931;161:115.

4. Higgins GM, Anderson RM. Experimental pathology of theliver: Restoration of the liver of the white rat following par-tial removal. Arch Path 1931;12:186.

5. Guillemin R. Introduction to these Proceedings.6. Szabo S, Somogyi A, Tache Y. The legacy of Hans Selye

and the origins of stress research: A retrospective 75 yearsafter his landmark brief article in Nature. Stress 2012;15:472-8.

7. Kendall, EC Reichstein, T, Hench, PS. “The Nobel Prize inPhysiology or Medecine 1950”. Nobelprize.org. NobelMedia AB 2013. Web. 7 Feb 2014. http://www.nobel-prize.org/nobel_prizes/medecine/laureates/1950/

8. Guillemin R. Nobel Lecture: Peptides in the Brain. TheNew Endocrinology of the Neuron”. Nobelprize.org. Nobel

Media AB 2013. Web. 7 Feb 2014. http://www.nobel-prize.org/nobel_prizes/medecine/laureates/1977/guillemin-lecture.html.

9. Marshall BJ. “Nobel Lecture: Helicobacter Connections”.Nobelprize.org. Nobel Media AB 2013. Web. 7 Feb 2014.http://www.nobelprize.org/nobel_prizes/medecine/laure-ates/2005/marshall-lecture.html

10. Waitzkin H, Magaña H. The black box in somatization:unexplained physical symptoms, culture, and narratives oftrauma. Soc Sci Med 1997;45:811-25.

11. Zoumakis E, Chrousos GP. Corticotropin-releasing hor-mone receptor antagonists: an update. Endocr Dev2010;17:36-43.

12. Frankl VE. Man’s Search for Ultimate Meaning. NewYork: Basic Books; 2000.

13. Selye H. Stress Without Distress. New York: Lippincott;1974.

14. http://www.archiv.umontreal.ca/P0000/P0359.html;http://www.archiv.umontreal.ca/exposition/Hans_Selye/index.html


Avenue. He also assisted in forming the CanadianInstitute of Stress (CIS, A. Toffler) and theAmerican Institute of Stress (AIS, P. Rosch).

THE HANS SELYE FOUNDATION

The Hans Selye Foundation (HSF) was establishedin 1978 by HS (becoming its first president, L.Drevet, LD, his wife, the secretary-treasurer) topromote research of and education, history of stressand of neuroendocrinology. Additional aims are toameliorate and treat stress, as well as to promote HSdiscoveries/contributions.

Upon HS’ death in 1982, M. Cantin (another oneof his students, ICRM) became president. Upon M.Cantin’s death in 1991, BT (another one of HS’ stu-dents/former IMCE professor) became president;Y. Tache and S. Szabo, vice-presidents, I, secre-tary-treasurer. In 2008, BT retired and I becamepresident.

For the past few years, the HSF has been in -volved in organizing several international stresscongresses, including the one last year in Hungaryand in carrying out HS Memorial lectureships invarious World Stress congresses as well as aLaurentian HS History of Medecine conference.We have also in promoted HS student awards.

Following the death of HS and the sale of theMilton HS residence, LD donated to the HSF his col-lection of books, writings, memorabilia, medals,diplomas, photographs, personal articles. Sub -sequently, with the assistance of BT, the HSF Board

colleagues, myself, C. Minotto (former Director) andD. Baillargeon (present Director), Archives, U de Mand J-L. Rouleau (former Dean, F of M, U de M) wesucceeded in founding the Archives-fonds HansSelye14 at our Alma Mater and a virtual exhibitionwas done of HS and the IMCE.

ACKNOWLEDGEMENTSMy immense gratitude goes to Dr. Hans Selye forhaving accepted me to be part of the IMCE (to con-tinue my graduate studies) and of his academic lifeand for deeply influencing me. Similarly, to Dr. B.Tuchweber who was my professor, Director andMentor during all of those years and before that toDrs. B. Posner and J. Werringloer for influencingme, guiding me and initially accepting me to dograduate studies with them. Also, to my wonderfulcolleagues and great friends at the IMCE, particu-larly, Y. and J. Tache, S. Szabo and P. Kourounakiswho have continued to be great friends and exam-ples of industriousness and achievement throughoutthese years. Also, through our HS/IMCE/HSF fam-ily ties, to adopted mentors and friends, such asDrs. R. Guillemin and W. Feindel. Thanks to the H.Selye’s family, particularly, to his wife, L. Drevet,his daughter, Cathy Drew. Moreover, to HS’ for-mer colleague, Dr. M. Eisenberg, professors, D.Thomas, J. Bergeron, authors/historians, R. John -stone, M. Jackson, F. Stahnisch, W. Rostene, G.C.Bennett, etc. etc. etc. Last but not least, to C.Minotto, D. Baillargeon, M. Voyer, C. Champagne,Drs. C. Roy and J-L. Rouleau.


Ideggyogy Sz 2014;67(3–4):87–90. 87

SELYE SYMPOSIUM

SELYE’S CONCEPT OF PLURICAUSAL DISEASES AND ITSIMPACT ON REGULATORY SCIENCE

Árpád SOMOGYI Member of the Board of Directors, International Life Sciences Institute Europe, Brussels

SELYE ELMÉLETE A MULTIKAUZÁLIS BETEGSÉGEKRÔLÉS HATÁSA A SZABÁLYOZÁS TUDOMÁNYÁRASomogyi Á, MDIdeggyogy Sz 2014;67(3–4):87–90.

A tudomány az utóbbi évtizedekben egyre nagyobbszerephez jutott a szabályozás területén. A szabályozástudománya ma már elismert tudományág. A kutatásban ésa szabályozásban is komoly gondot jelentenek a zavaróanomáliák, a csaló adatok megjelenése. A MagyarTudományos Akadémián, Budapesten 2013 májusában tar-tott Selye Symposium – 2013 alkalmából Selye Jánosstresszel, a multikauzális betegségek különbözô formáivalés más kísérletes modellekkel kapcsolatos munkája kerültaz érdeklôdés középpontjába.

Kulcsszavak: Selye, stressz, multikauzális betegségek, a szabályozás tudománya

Science assumed in recent decades an increasingly impor-tant role in the regulatory field. Regulatory science is nowregarded as established specific brunch of science. A dis-turbing anomaly, the emergence of fraudulent data is ofmajor concern both in the field of research and in the regu-lation. Hans Selye’s work on stress, on several forms ofpluricausal diseases and on other experimental modelscame into the focus of interest on the occasion of the SelyeSymposium - 2013 held in May 2013 at the HungarianAcademy of Sciences in Budapest.

Keywords: Selye, stress, pluricausal diseases, regulatory science

Correspondence: Árpád SOMOGYI, MD, Member of the Board of Directors, International Life Sciences InstituteEurope, Brussels. E-mail: [email protected]


www.elitmed.hu

It was pure serendipity how I met Hans Selye. Inthe Spring of 1966, working as a young scientist

in Hannover, I have learned, literally in the lastmoment, that the discoverer and developer of thestress concept, the great Professor Selye will be thespeaker at a special evening meeting of the GermanPhysiological Society. Rushed to the big amphithe-ater of the university that was, beyond its normalcapacity, already full. Hence, I was very lucky tofind a spot, standing behind the last row of seats,where I was mesmerized by Selye’s stimulating lec-ture and the masterly constructed and presentedslides. This was the first time I realized how Selyeearned his reputation as an outstanding scientist anda magically effective communicator. After his talkthat was enthusiastically received by the audience,he was surrounded by many admirers, very eager toshake his hand and to talk to him. Somehow, Imiraculously managed to penetrate the formidable

human ring around him and got the chance to intro-duce myself; being in Hannover, naturally inGerman. Recognizing my unmistakable Hungarianname and accent, he continued the conversation inHungarian. What we were talking about exactly, Icannot recall. Toward the end of our short conver-sation of at most two to three minutes, I was sur-prised when he asked me whether I would be inter-ested to spend a year as a guest scientist in his insti-tute in Montreal, I exuberantly replied, joyfullyexclaiming “I would even swim there”. Whereupon,before turning to the next admirer in line, he gaveme his calling card suggesting that I should write tohim. I did . And a few months later, on the 1st ofNovember 1966, I started my one year at his insti-tute that miraculously failed to expire before theend of September 1970.

I was very fortunate that soon after my arrival inMontreal, Professor Selye included me into his own

somogyi_UJ ISZ TUKOR ALAP ANGOL.qxd 2014.03.21. 16:02 Page 87

multinational (Figure 1.) team working intensely atthe time on the concept of pluricausal diseases. Iwas intrigued by the fact that two or more agents,chemical or physical, when applied alone were voidof any discernible biological effect while in combi-nation with each other resulted in highly specificlesions. Therefore, I eagerly joined the group anddiligently tried to take an active part in planningand conducting as well as in the evaluation ofexperiments. By this exercise, at an early phase ofmy apprenticeship, I quickly gained insight andacquired some practical skills in various ongoingresearch projects of the institute. This quasi crash-course enabled me to gradually become a usefulmember in Selye’s group. The first major publica-tion with my coauthorship was entitled Inflam -mation, topical stress and the concept of pluri-causal diseases1. At this point Professor Selye sug-gested that I should stay on in the institute andurged me to formally enroll into the PhD programof the Faculty of Medicine of the University ofMontreal. In subsequent years, while pursuing myPhD degree with high priority, I participated inother diverse research projects mainly in the broadfield of pluricausal diseases that included or ledinto other areas, such as stress, experimental surgi-cal techniques, anaphylactoid edema, calciphylaxis,carcergy, thrombohemorrhagic phenomenon, justto mention a few.

It would be difficult, within the constraints of

this short account, to succinctly summarize or evensatisfactorily highlight the result of intensive workof four years. Suffice it to refer to a few selectedpublications listed in the section References2-8.Following the four years in Canada, I have spent sixmore years in North-America, notably in the USAdoing basic (cancer) research. In one way or theother, albeit using different methodologies9-15, I car-ried the spirit of “Montreal” with me. Toward theend of this period, I have received a generous offerfrom the German Federal Government to join at ahigh level executive position in Berlin at theiragency in the field of health. From here on my prin-cipal professional preoccupation centered aroundregulatory science, which I always related to theconcept of pluricausal diseases and the high ethicalstandard maintained by Selye in his institute.

Regulatory Science insidiously emerged aroundthe middle of the last century and is currently beingregarded as a separate branch of science. As itsname implies, it is, along with laws and social val-ues, one of the decisive factors of regulation. Withthe increase of international trade during the secondhalf of the twentieth century the need has arisen fora universally acceptable measure to ascertain both ahigh level of product (e.g., drug, food) safety andfair trading practices in international commerce.Science with its proverbial reputation of objectivityhas been identified and increasingly implementedin international agreements regulating trade aroundthe world. Henceforth, the pre-eminent role of sci-ence in regulatory decisions is undisputed.Regulatory decisions have a direct relevance foreach and every individual of a community, there-fore, it is not surprising that safety issues oftenoccupied in recent years centre stage in the scientif-ic, political and public arena.

According to Merriam-Webster’s CollegiateDictionary16 science is defined as “the state ofknowing: knowledge as distinguished from igno-rance or misunderstanding”. Knowledge is hardlyever complete and never a static state. It is rather adynamic concept, constantly in the process of devel-opment and refinement. Consequently, regulationbased on science must invariably be considered as atransitory stage reflecting current knowledge at agiven point in time. The history of science is full ofcontradictions, often of fierce competition of dia-metrically opposing views and ideas. The challengeto the knowledge of the day was always the mostpowerful propelling force for scientific progress.Therefore, it is often extremely difficult to deter-mine what, in a given field at a given time, contem-porary science is. Do the consolidated views of themajority or the unorthodox new ideas of the minor-

88 Somogyi: Selye’s concept of pluricausal diseases and its impact on regulatory science

Figure 1. From left to right: Giulio Gabbiani, Ung SooPahk, Gaston Coté, Selman A. Waksman (ClaudeBernard Visiting Professor, Nobel Price, 1952), LaurentSavoie, Árpád Somogyi, Hans Selye. 1967


ity, often of one single maverick, constitute “soundscience”? Many great discoveries and scientificbreakthroughs, also Selye’s stress concept, wereborn as bitterly contested ideas that initially wererejected by the mainstream scientific establishmentor even condemned as heresies by others. On theother hand, probably many more interesting, plausi-ble and ostensibly convincing ideas turned out laterto be illusions, hoaxes or the products of outrightfraud17, 18. Therefore, particularly if public health isat stake, it can easily become an awesome responsi-bility for decision-makers to opt for the opinion ofeither the majority or the minority. Democraticmechanisms do not lend themselves to resolve sci-entific issues! The sole arbiter in the case of discordin science can only be science itself, i.e., good sci-ence. In this respect, there cannot be a distinction asto basic, applied or regulatory science. This is alsoone of the principles I have learned from Hans Selyein countless discussions over the years. One of thesememorable conversations took place in May 1976when he came to Berlin to deliver the legendaryKeynote Lecture at the four-day festive centennialcelebration of the worldwide respectedBundesgesunheitsamt (Federal Health Office)19.

An important concern in using scientific data istheir reliability and integrity. Numerous measurestaken worldwide by international organizations, reg-ulatory bodies, professional societies or publishers ofscientific literature apparently failed to put a halt tothe emergence of fraudulent scientific data in globalcirculation. Unfortunately, fraud in science is a real,very disturbing and serious phenomenon. It can betraced back to ancient times18. But, most important-ly, it is also a contemporary bourgeoning anomaly17

Well publicized cases and the increasing number ofretraction of submitted manuscripts and even oldpublished papers are a sad indication for the dimen-sion of the problem. It is itself bad enough to produceand disseminate fraudulent data, but it could be cata-strophic if they unknowingly or inadvertently wereused as the basis for health-related decisions.

Despite these imponderables, there is no reason-able alternative to science. It must, therefore,become and firmly remain an indispensable ingre-dient of all regulatory decisions. It should, howev-er, be recognised that, as a rule, in order to be effec-tive, decisions aimed at protecting human or animalhealth often have to be made “here and now”,before scientific controversies can be resolved andthe verdict is in. In the face of uncertainties, regula-tors have to rely on risk assessment that is, as itsname implies, not an accurate process of measuringbut of approximation often based, particularly inthe absence of established facts, on scientifically

plausible hypotheses. It must, therefore, be clearlyunderstood by all stakeholders what, in general andin specific cases, science can deliver and what itcannot. The life-span of the scientific validity ofany regulatory decision will always be a function ofprogress in the pertinent disciplines and, thus, canoccasionally be extremely short. The scientificbasis for a particular regulation that universallydeemed rock solid today can, like sand, easily bewashed away already by tomorrow.

This brief excursion into the realm of regulationthat shows that Selye’s work remained not withouta discernible impact on that arcane world of scienceeither. Recently, we have dealt addressed in detailwith the legacy of Hans Selye20. Therefore, I wouldlike limit the following remarks on certain aspectsto my personal observations and impressions:

My close association with Hans Selye during theperiod from 1966 to 1970 gave me the uniqueopportunity to be involved, among others, in hisresearch on stress, on his concept of pluricausal dis-eases and on the interaction of antagonistic and syn-ergistic effects of xenobiotics in vivo. While I haveenormously benefited from being exposed toSelye’s approach to science in general, the way hedevised, conducted and evaluated his experimentsand how he arrived at his conclusions. I neverceased to be amazed by his work ethic, his extraor-dinary efficiency, his superb skills of communicat-ing his thoughts in his scientific and popular articlesas well as in his oral presentations.

In addition to his towering scientific compe-tence, Selye had brilliant organizational talents aswell. He created a structural and functional setup ofthe institute that made it uniquely suitable for thekind of work performed there. Different specializeddepartments (e.g., biochemistry, histology/electronmicroscopy, library/documentation, photography,editorial, animal experimentation etc facilities)were available to the researchers to allow them toconcentrate on the scientific rather than on the rou-tine technical aspects of their work.

Among his many talents Selye was also a veryprolific author with a high volume and an evenhigher quality of publications to his credit. His sev-eral thousand publications have been widely cited.By his account, his library service identified by1976 more than 100 000 publications (among thoseseveral hundred books) that dealt with differentaspects of what we regard today as the stress con-cept. Stress that was originally described as a phe-nomenon in medicine, conquered meanwhile otherdisciplines, such as behavioral and social sciences,as well. This is a clear indication for the signifi-cance and influence of this creative thinker and

Ideggyogy Sz 2014;67(3–4):87–90. 89


REFERENCES1. Selye H, Somogyi A, Vegh P. Inflammation, topical stress

and the concept of pluricausal diseases. BiochemPharmacol, Supp, Chemical Biology of Inflammation1968;107-22.

2. Selye H, Pahk US, Somogyi A. Prevention of renal necrosisby stress. JAMA 1967;201:1026-9.

3. Selye H, Somogyi A, Mecs I. Calcergy inhibited by calci-phylactic challengers. Science 1968;159:1361-62.

4. Selye H, Somogyi A, Cote G. Sensitization by corn oil forthe production of cardiac necrosis by various steroids andsodium salts. Amer J Cardiol 1968;23:719-22.

5. Somogyi A, Selye H. Tourniquet poditis, an experimentalpedal inflammation in the rat. Arzneim-Forsch (Drug Res)1969;19:977-81.

6. Selye H, Cunnington J, Somogyi A, Cote G. Accelerationand inhibition of wound healing by topical treatment withdifferent types of inflammatory irritants. Am J Surg1969;117:610-4.

7. Somogyi A, Berczi I, Selye H. Inhibition by salicylates ofvarious calcifying connective-tissue reactions. Arch intPharmacodyn 1969;177:211-23.

8. Somogyi A, Kovacs K, Selye H. Jejunal ulcers produced byindomethacin. J Pharm Pharmacol 1969;21:122-3.

9. Somogyi A, Kovacs K. Effect of stress on the adrenocorti-colytic and carcinogenic action of 7,12-dimethyl -benz(a)anthracene. Z Krebsforsch 1971;75:288-95.

10. Somogyi A, Kovacs K, Solymoss B, Kuntzman R, ConneyAH. Suppression of 7,12-dimethylbenz(a)anthracene-pro-duced adrenal necrosis by steroids capable of inducing arylhydrocarbon hydroxylase. Life Sciences 1971;10:1261-71.

11. Somogyi A, Conney AH, Kuntzman R, Solymoss B.Protection against dimethylnitrosamine toxicity by preg-nenolone-16a-carbonitrile. Nature 1972;237:61-3.

12. Somogyi A, Levin W, Banerjee S, Kuntzman R, Conney AH.

Inhibition of the acute toxicity and adrenocorticolyticeffect of 7,12-dimethylbenz(a)anthracene by isopropyl-valeramide and allylisopropylacetamide in the rat. CancerRes 1975;35:2500-5.

13. Grandjean CJ, Somogyi A. Effect of pregnenolone-16a-carbonitrile on the metabolism of dimethylnitrosamine andbinding to rat liver macromolecules. Biochem Pharmacol1976;25:2097-98.

14. Kuszynski C, Somogyi A, Nesnow S, Langenbach R.Inhibition of benzo(a)pyrene-induced transformation ofC3H/10T1 cells by allylisopropylacetamide and isopropy-lvaleramide. Cancer Res 1981;41:1893-97.

15. Kuszynski, C, Somogyi A, Langenbach R. Modification ofbenzo(a)pyrene-induced transformation of C3H/10T1/2cells by pregnenolone-16a-carbonitrile and dexametha-sone. Cancer Letters 1982;15:215-21.

16. Merriam-Webster’s Collegiate Dictionary, Tenth Edition.Springfield: Merriam-Webster, Inc.; 1998.

17. Lock S. Research misconduct 1974-1990: an imperfect his-tory. In: Lock S, Wells F, Farthing M (eds.). Fraud AndMisconduct In Biomedical Research, 3rd ed. London: BMJBooks; 2001.

18. Wade N, Broad W. Betrayers of the truth: Fraud and deceitin the halls of Science. New York, Simon & Schuster;1982.

19. Selye H. Gesundheit und Streß-Koncept. In: Fülgraff G(ed.). Bewertung von Risiken für die Gesundheit, p. 84.Stuttgart-New York: Gustav Fischer Verlag; 1976. p. 7-12.

20. Szabo S, Tache Y, Somogyi A. The legacy of Hans Selyeand the origins of stress research: A retrospective 75 yearsafter his landmark brief “Letter” to the Editor of Nature.Stress 2012;15:472-8.

21. Gabbiani G (ed.). Reflections on Biological Research. St.Louis: Warren H Green, Inc.; 1967.

inspiring teacher on diverse fields of contemporaryresearch and beyond.

As mentioned above, the stress concept had itsfans and foes. Meanwhile the controversy subsided,but Selye’s ideas keep reverberating and furtherexcite generations of scientists, most importantlyalso the young recruits from the current and pre-sumably thefuture generations. The measure forhow 30 renowned scientists of his own generationviewed Selye’s legacy is an anthology entitledReflections on Biological Research21 painstakinglycompiled and edited by Giulio Gabbiani who alsowrote the introduction to it.

Working in Selye’s institute was a fulltime occupa-tion characterized by long hours of hard work (sevendays a week) in a stimulating and competitive atmos-phere, spiced with the joy of success and occasionallyovercast by the frustration of failure. . But it was aprivilege that ultimately resulted in a lifelong remain-ing memory of an unbelievably rewarding experience.

I have had that privilege of working under theintellectual leadership of Professor Hans Selye, oneof the giants of medical research of the twentiethcentury. My association with him coined my entiresubsequent professional career as a research work-er, a university professor, and a regulatory execu-tive at national and international levels. I wasextremely fortunate to have learned from him howto initiate appropriate investigations and interprettheir results to ascertain safety while directing insti-tutions with the mission to protect the health andlife of the public against harm whether they derivedfrom medicinal substances, food, cosmetics, theenvironment or a wide variety of other consumerproducts and diverse other sources. But most of all,I learned from him the excitement of doing scienceand being found of it. Regrettably, the Institut deMédecine et de Chirurgie expérimentales that HansSelye founded and made world famous could notsurvive its creator.

90 Somogyi: Selye’s concept of pluricausal diseases and its impact on regulatory science


Ideggyogy Sz 2014;67(3–4):91–94. 91

SELYE SYMPOSIUM

HANS SELYE 70 YEARS LATER: STEROIDS, STRESS ULCERS & H. PYLORI

Sándor SZABÓDepartments of Pathology & Pharmacology, School of Medicine,

University of California-Irvine, & VA Medical Center, Long Beach, CA, USA

SELYE JÁNOS 70 ÉVVEL KÉSÔBB: SZTEROIDOK,STRESSZFEKÉLY ÉS HELICOBACTER PYLORISZABÓ S, MD, PhDIdeggyogy Sz 2014;67(3–4):91–94.

Bár Selye János fôleg a stresszelmélet felfedezéséért ésfejlesztéséért ismert, ô vezette be a szteroidok elsô, élettani-lag szilárd, struktúra-aktivitás osztályozását 1943-ban, amia szteroidok kémiai szerkezetén is alapult. Nemcsakbevezette a glükokortikoidok és mineralokortikoidok nevét,de felfedezte anti- és proinflammatorikus hatásaikat állat-modellben. Emellett nemcsak leírta az elsô stressz általindukált gyomorfekélyt patkányban (1936), de elôször jelle-mezte az emberi stresszulcust is a II. világháborúbanLondon bombázása idején (1943). Tehát Selye sokkal ter-mékenyebb és kreatívabb tudós volt, mint általában gon -dolják.

Kulcsszavak: Selye János, stresszelmélet, szteroidok osztályozása, glükokortikoidok, mineralokortikoidok, szteroidreceptorok, NSAID, stressz, gastroduodenalis fekélyek, H. pylori, krónikus gastritis,angiogen növekedési faktorok

Although Hans Selye is mostly known for his discovery &development of the stress concept, he also introduced thefirst physiologically sound, structure-activity classification ofsteroids that was also based on the chemical structure ofsteroids in 1943. He not only introduced the names of glu-cocorticoids & mineralocorticoids but discovered the anti- &pro-inflammatory properties, respectively, of these steroidsin animal models. Furthermore, he not only described thefirst stress-induced gastric ulcers in rats (1936) & character-ized the first human ‘stress ulcers’ during the air-raids inLondon during World War II (1943). Thus, Selye was amuch more productive & creative scientist than it is general-ly considered.

Keywords: Hans Selye, Stress concept, Steroid classification, Glucocorticoids, Mineralocorticoids, Steroid receptors, NSAID, Stress,Gastroduodenal ulcers, H. pylori, Chronic gastritis,Angiogenic growth factors

Correspondence: Sándor SZABÓ, MD, PhD, VA Med. Center/UCI; Long Beach, CA 90822, USA. Phone: 1-562-577-5088, e-mail: [email protected]


www.elitmed.hu

Dr. Hans Selye’s students & coworkers recentlycelebrated the 75th anniversary of his first arti-

cle on stress syndrome1, yet his other seminal con-tributions to this field came a few years later, most-ly in 1943. Namely, although his initial short articlein Nature in 1936 on the “general adaptation syn-drome” as it was then named, already included the“morphologic triad of stress” (e.g., adrenal hyper-trophy, thymo-lymphatic atrophy & hemorrhagicgastric erosions/ulcers), Selye was the first todescribe ‘stress ulcers’ as they are called today, in ashort article in Lancet in 19432. It turned-out morerelevant from today’s perspectives that the 1943

data did not come from animal experiments (vs. the“morphologic triad” that was seen rats exposed tosever stress), but from hospital & public health datafrom patients who had been admitted with acutelyperforated gastroduodenal ulcers after German air-raids on London during World War II2. In this arti-cle Selye was actually analyzing the data reportedin a clinical study published earlier also in Lancetthat demonstrated a huge increase in hospitaladmissions because of perforated ‘peptic ulcers’after air-raids in London & he put these ulcers inpatients in context with the animal observations hemade during the preceding about 10 years. Selye’s

szabo_UJ ISZ TUKOR ALAP ANGOL.qxd 2014.03.21. 16:03 Page 91

conclusion was obvious: ‘stress ulcers’ occur notonly in animals but in humans as well… I may addthat during my stay in his institute at the Universityof Montreal (1969-1973), Selye mentioned severaltimes in official meetings & in private conversa-tions that he didn’t like the name ‘stress ulcers’; hewould rather call them gastric and/or duodenalulcers caused by stress.

The naming & classification of steroids

Selye is mostly known for discovering & definingthe stress concept, yet he made a dozen of otherimportant & original discoveries (Table 1.).Among these, the most notable around this 70-yearanniversary is the classification & naming of

steroids – yet, most of the researchers & cliniciansat the beginning of 21st century do not know thatSelye didn’t only classify the naturally occurringsteroid hormones (based on their structure & glan-dular origins, but he introduced the names such as“corticoids”, “glucocorticoids” & “mineralocorti-coids”. Equally important is that he was the first todescribe the anti- & pro-inflammatory actions ofgluco- & mineralocorticoids, respectively, in ani-mal models about eight years1, 3, 4 (Figure 1.) muchbefore Dr. Phillips Hench & two of his colleaguesreceived the Nobel Prize in 1950 for the demonstra-tion of the SAME effect, i.e., the anti-inflammatoryproperties of cortisone & ACTH in rheumatoidarthritis patients1.

These steroid-related discoveries were describedin several excellent articles in the best scientific(basic research & clinical) journals of all time overabout 10 years period in the late 1930s & 1940s, themost important are probably those which appearedin 19433–5 (Table 1.). The confounding factor heremight be that the contemporary scientific literature& medical lingo use few of the original namesintroduced by Selye (e.g., corticoids, glucocorti-coids, mineralocorticoids), but the basis of classifi-cation is still the same he published first in &around 1943. Namely, his basis for the classifica-tion of these hormones had been not only the chem-ical structure but the glands of their origins; he gavethe name “corticoids” because these steroids aresynthesized in the adrenal cortex, “testoids”because they are secreted by the testis, “follicu-loids” from the follicles & “luteoids” since they aresynthesized in the corpus luteum of the ovary. Oneof the main reasons for the lack of appreciation forSelye’s steroid classification is that we now usemostly androgens for “testoids”, estrogens for “fol-liculoids” & progestins for “luteoids”.

Nowadays, there are a lot of unnecessary distor-tions with the inappropriate use of names ofsteroids. The most irritating for Selye had been(based on his weekend conversations with me) thefrequent & unnecessary use of “corticosteroids” for“corticoids” (indeed, because corticoid alreadyimplies steroids)… Even worse, the frequent men-tioning of “steroids” by medical experts & lay per-sons when they want to refer to the anti-inflamma-tory action of glucocorticoids – forgetting thatsteroids could mean androgens, estrogens or prog-estins… Selye was so irritated by these sloppy mis-uses of scientific terms that he would often write toeditors of scientific journals – until he realized thatit’s not worth arguing with people who read onlythe last 5-10 years of “modern” medical literature…Nevertheless, rather than being overly negativistic,

92 Szabo: Hans Selye 70 years later: Steroids, stress ulcers & H. pylori

Figure 1. An illustration of the anti- & pro-inflammato-ry actions of glucocorticoids & mineralocorticoids inrats*

*Modified & reproduced from Hans Selye: The Physiology &Pathology of Exposure to STRESS. Acta, Inc., Montreal, 1950, basedon his publications in the early 1940s.

Table 1. Hans Selye: Major original discoveries & con-tributions

– Stress syndrome (Nature, 1936; Lancet, 1943).– Classification & naming of steroids (Science, 1941;

Nature, 1943; Endocrinology, 1942; 1944).– Anti-inflammatory action of glucocorticoids & pro-

inflammatory effect of mineralocorticoids (Can MedAss J, 1942; Amer J Physiol, 1943; Lancet, 1943;1946; JAMA, 1944).

– Steroid anesthesia (Amer J Physiol, 1941;Endocrinology, 1942).

– Catatoxic steroids (Science, 1969; Can Med Ass J,1969).

– Distress vs. eustress (Book, 1974).


he went by a constructive pathway & in his lastmajor scientific monograph, published in 1971, heupdated & expanded his original classification &steroids (Figure 2.). It was a simplified classifica-tion that pointed out that steroids influence not onlyour growth (e.g., anabolic androgens), reproduction(e.g., estrogens, androgens, progestins), metabo-lism (e.g., corticoids), but our adaptation as well,based mostly on his discovery in 1969 of the cata-toxic & syntoxic action of steroids1 (Figure 2.).Unfortunately, Selye died in 1982, three yearsbefore my lab, in collaboration with JudahFolkman, at Harvard Medical School described yetanother independent biologic action of steroids, i.e.,the angiostatic & angiogenic effect of steroids6.Nevertheless, as an historic proof of the correctnessof Selye’s classification of steroids 70 years ago,we now know that naturally occurring steroid hor-mones & their synthetic analogues have their ownspecific nuclear receptors, with minimal or no over-lap in receptor specificity7, 8.

Gastroduodenal ulcers, stress &Helicobacter pylori

Despite the overwhelming evidence from the scien-tific literature of the last ¾ of century that largedoses of glucocorticoids produce hemorrhagic gas-tric erosions (i.e., superficial mucosal lesions) orulcers (i.e., deep lesions that penetrate the muscu-laris mucosae) in both rodents & humans (e.g.,patients treated with these steroids for diseases suchas rheumatoid arthritis, ulcerative colitis or otherautoimmune disorders), some “experts” doubt thecausative association of between severe distress &gastroduodenal ulcers, esp., after the first descrip-tion of high prevalence of H. pylori bacteria in the

epithelium of “active chronic gastritis” patients,many of who had ulcers in the stomach or duode-num9 (Table 2.).

Despite the initial controversy about the etiolog-ic role of this bacterium in gastritis & “peptic ulcer”over the subsequent decades, by the 1990s it wasinterpreted by a lot of clinicians that ‘H. pyloricauses gastroduodenal ulcers’… Yet, this might bea classic example of ‘true-true but unrelated’ falla-cy when the temporal or spatial parallel occurrenceof two phenomena doesn’t not mean causative oretiologic connection. In simplified terms, when wehave an evening discussion in well-lighted room, itdoes not mean we could not talk in dark… This isreinforced by the fact the “Koch postulate” (i.e., theisolated infectious agent from patients reproducedthe same disease in experimental animals fromwhich the same agent could be isolated again) wasreproduced only with gastritis, but not with gastro-duodenal ulcers. Namely, no animal models of gas-troduodenal ulcers induced by H. pylori exist (e.g.,only certain strains of specific gerbils developsuperficial gastric erosions (not ulcers!) after beingexposed to a large quantity of these bacteria – i.e.,when these bugs may represent nonspecific stres-sors… Thus, it can be stated with high degree ofcertainty, 70 years after the first description of‘stress ulcers’ in humans2, that the major primaryetiologic factors of gastroduodenal ulcers are, inaddition to sever distress, the clinical ‘side-effects’of steroidal & non-steroidal anti-inflammatorydrugs (NSAID) such as glucorticoids & aspirin-likedrugs1, 10. And as clinical experience & literatureshow us, even small doses of NSAID, esp. aspirin

Ideggyogy Sz 2014;67(3–4):91–94. 93

Figure 2. An updated classification of steroids by HansSelye (1971)*

*Adapted from Hans Selye: Hormones & Resistance, Springer Verlag,New York-Heidelberg-Berlin, 1971.

Table 2. The role of Helicobacter pylori in gastritis &ulcer pathogenesis

– Warren & Marshall (Lancet, 1983): high prevalenceof H. pylori (Hp) in “active chronic gastritis” patients,many of who had gastroduodenal ulcers.

– But temporal & local correlations my not provecausative/etiologic connection…

– The “Koch postulate” was satisfied only with Hpcausing gastritis (inflammation), NOT ulcers…

– Thus, Hp causes inflammation & cancer, NOTulcers…

– Hp delays the healing of gastroduodenal ulcerscaused by aspirin-like drugs, other chemicals orstress…

– Most likely because it decreases the bioavailability ofangiogenic growth factors (e.g., bFGF, VEGF, PDGF)that accelerate ulcer healing.


REFERENCES1. Szabo S, Somogyi A, Tache Y. The legacy of Hans Selye &

the origins of stress research: A retrospective 75 years afterhis landmark brief article in Nature. Stress 2012;15:472-8.

2. Selye H. Perforated peptic ulcer during air-raid. Lancet1943;20:252.

3. Selye H. Nephrosclerosis and tissue edema after desoxycor-ticosterone treatment. Anat Rec 1943;85:49.

4. Selye H, Pentz EI. Pathogenetical correlations betweenperiarteritis nodosa, renal hypertension and rheumaticlesions. Can Med Ass J 1943;49:264.

5. Selye H. An attempt at a natural classification of thesteroids. Nature 1943;151:662.

6. Crum R, Szabo S, Folkman J. A new class of steroidsinhibits angiogenesis in the presence of heparin or aheparin fragment. Science 1985;230:1375-8.

7. Lu NZ, Wardell SE, Burnstein KL, Defranco D, Fuller PJ,Giguere V, et al. “International Union of Pharmacology.LXV. The pharmacology and classification of the nuclearreceptor superfamily: glucocorticoid, mineralocorticoid,progesterone, and androgen receptors”. Pharmacol Rev2006;58(4):782-97.

8. Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC,Katzenellenbogen JA, Korach KS, et al. “InternationalUnion of Pharmacology. LXIV. Estrogen receptors”.Pharmacol Rev 2006; 58(4):773-81.

9. Warren JR, Marshall B. Unidentified curved bacilli on gas-tric epithelium in active chronic gastritis. Lancet1983;321:1273-5.

10. Selye H. Hormones and Resistance. Springer-Verlag, NewYork, Heidelberg, Berlin, 1971.

11. Szabo S, Shing Y, Fox J, Taylor N, Sandor Zs, Bishop J, etal. Inactivation of basic fibroblast growth factor (bFGF) bygastric helicobacters and not by E. coli. Gastroenterology1994;106:A190.

12. Sandor Z, Vincze A, Jadus M, Domek MJ, Wyle FA.Tarnawski A, et al. Effect of Vac+ and Vac- Helicobactorpylori supernatants on the bioactivity of basic fibroblastgrowth factor and platelet-derived growth factor in vitro.Gastroenterology 1996;110:A249.

13. Vincze A, Wyle FA, Domek MJ, Sandor Z, Jadus M,Tarnawski A, et al. Helicobacter pylori supernatant inter-fere with growth and proliferative response of fibroblasts tobFGF and PDGF. Gastroenterology 1996;110:A286.

14. Szabo S, Shing Y, Folkman J, Vincze A, Gombos Z, Deng X,et al. Angiogenesis and growth factors in ulcer healing. In:Tai-Ping D, Fan, Elise C. Kohn (eds.) The New Angio -therapy, Totowa, New Jersey: Humana Press, 2001. 199-211.

15. Khomenko T, Deng X, Ishikawa H, Sandor Zs, Szabo S.Peptide and gene therapy with angiogenic growth factorsbFGF, PDGF or VEGF in gastrointestinal ulcers in rats. In:Cho C-H (eds.) Gastrointestinal Mucosal Injury andRepair. Frontiers of Gastrointestinal Research. Basel: Kar -ger; 2002. 25, 1-18.

(e.g., 70 mg or less) may cause these ulcers if takenchronically for prevention of myocardial infarction& colon cancer.

Despite the initial confusion about the primaryetiologic role of H. pylori in gastroduodenal ulcer-ation, it cannot be denied that this bacterium isplaying a major role in this disease, - not because itcauses ulcers, but since it seems to delay the heal-ing of gastroduodenal ulcers caused by stress orglucocorticoids or NSAID. Thus, Warren &Marshall deserved the Nobel Prize in Physiology orMedicine in 1985 (Table 2.). Namely, the eradica-tion or decreased prevalence of H. pylori infectionreduced the incidence of not only severe gastritis

but also of certain forms of gastric lymphomas &carcinomas; - while the incidence of H. pylori -neg-ative ulcers was growing worldwide during the lastabout three decades1. More recent research revealedthat this bacterium although may not cause gastro-duodenal ulcers, but it delays the healing of theseinternal wounds, as any bacteria would delay thehealing of any external (e.g., skin) ulcers becauseH. pylori decreases the bioavailability of angio-genic growth factors (e.g., bFGF, VEGF, PDGF)that accelerate ulcer healing. Namely, the proteasesof this bacterium cut these peptide growth factors tomake them biologically inactive in the crucialprocesses of wound healing11-15.

94 Szabo: Hans Selye 70 years later: Steroids, stress ulcers & H. pylori


Ideggyogy Sz 2014;67(3–4):95–98. 95

SELYE SYMPOSIUM

HANS SELYE AND THE STRESS RESPONSE: FROM “THEFIRST MEDIATOR” TO THE IDENTIFICATION OF THE

HYPOTHALAMIC CORTICOTROPIN-RELEASING FACTOR Yvette TACHÉ

Department of Medicine, CURE Digestive Diseases Research Center, Center for Neurobiology of Stress, DigestiveDiseases Division UCLA and VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA

SELYE JÁNOS ÉS A STRESSZVÁLASZ: AZ „ELSÔMEDIÁTORTÓL” A HYPOTHALAMICUS CORTI-COTROPIN-RELEASING FAKTOR FELFEDEZÉSÉIGTaché Y, PhDIdeggyogy Sz 2014;67(3–4):95–98.

Selye vezette be a stresszelméletet, ami bekerült a minden-napi szótárunkba. Eredetileg azon a kísérletes megfi-gyelésen alapult, hogy a különbözô ártalmas ágensekhasonló endokrin (mellékvese-megnagyobbodás), immun-(thymusinvolúció) és bél- (gyomoreróziók) választ váltanakki, ahogyan arról a Nature-ben 1936-ban megjelent levél-ben beszámolt. Késôbb a háttérben álló mechanizmustkutatta és feltételezte, hogy a hypothalamusban lévô „elsômediátor” vezérli ezeket a testi változásokat. A mediátorazonosításához generációk munkája kellett. Selye korábbiPhD-hallgatója, a Nobel-díjas Roger Guillemin mutatta ki1955-ben az adrenokortikotrop hormon felszabadulásátkiváltó hypothalamicus faktort patkány hypophysisében, ésnevezte el kortikotropin releasing faktornak (CRF). 1981-ben Wylie Vale, Guillemin korábbi PhD-hallgatója írta le aCRF 41 aminosavját, és klónozta a CRF1- és CRF2-recep-torokat. Ez megnyitotta az utat azoknak a kísérleteknek,amelyek során kiderítették, hogy a CRF jelátvivô útvonalaktivációja az agyban kulcsszerepet játszik a stresszel össze-függô endokrin, viselkedési, autonóm és zsigeri válaszok-ban. A stressz biokémiai kódolásának felderítése Selyemunkásságában gyökerezve továbbra is jelentôs hatástgyakorol a tudományos közösségre.

Kulcsszavak: corticotropin-releasing faktor, hypothalamus,Selye, stressz

Selye pioneered the stress concept that is ingrained in thevocabulary of daily life. This was originally build on experi-mental observations that divers noxious agents can trigger asimilar triad of endocrine (adrenal enlargement), immune(involution of thymus) and gut (gastric erosion formation)responses as reported in a letter to Nature in 1936.Subsequently, he articulated the underlying mechanismsand hypothesized the existence of a “first mediator” in thehypothalamus able to orchestrate this bodily changes.However he took two generations to identify this mediator.The Nobel Laureate, Roger Guillemin, a former Selye’s PhDstudent, demonstrated in 1955 the existence of a hypothal-amic factor that elicited adrenocorticotropic hormonerelease from the rat pituitary and named it corticotropinreleasing factor (CRF). In 1981, Wylie Vale, a formerGuillemin’s Ph Student, characterized CRF as 41 amino acidand cloned the CRF1 and CRF2 receptors. This paves theway to experimental studies establishing that the activationof the CRF signaling pathways in the brain plays a key rolein mediating the stress-related endocrine, behavioral, auto-nomic and visceral responses. The unraveling of the bio-chemical coding of stress is rooted in Selye legacy continuesto have increasing impact on the scientific community.

Keywords: corticotropin releasing factor, hypothalamus,Selye, stress

Correspondence: Yvette TACHÉ PhD, Department of Medicine, CURE Digestive Diseases Research Center, Center for Neurobiology of Stress, Digestive Diseases Division UCLA and VA Greater Los Angeles Healthcare System;

Los Angeles, CA, USA. E-mail: [email protected]; [email protected]


www.elitmed.hu

Hans Selye was of Hungarian origin and born inVienna in 1907. He conducted his influential

scientific work in Montreal, first at McGillUniversity and then at the University of Montrealwhere he was Professor and Director of the Instituteof Experimental Medicine and Surgery from 1945

to his retirement in 1979. He passed away in 1982leaving an impressive scientific impact. He wasquoted as “One of the greatest scientists of the 20thcentury” or “the Einstein of medicine” and consid-ered as one of the pioneer of the field of endocrinol-ogy. His contributions resulted in 10 nominations

tache_UJ ISZ TUKOR ALAP ANGOL.qxd 2014.03.21. 16:04 Page 95

for the Nobel Price in Physiology/Medicine startingsince19461.

The legacy of Selye’s scientific contributions iswell documented by the impressive number of hisoriginal articles reaching 1700 throughout his sci-entific career and the writing of 39 monographbooks. This begs the question what was the secretof Hans Selye’s creativity and productivity? Wecan delineate a combination of a number of factors.Early on, he had an outstanding training withendocrinologist leaders in Europe and Canadawhich rooted his focus on the endocrinology relat-ed scientific quest. Selye was gifted with a keensense of observation and synthetic mind andapplied an effective discipline to reach his goals. Hewas a voracious reader of scientific literature, tal-ented communicator and writer, and had a relent-less and passionate scientific curiosity but most ofall he had VISION to interpret facts. This is exem-plified in his seminal article “Syndrome producedby diverse nocious agents”2. In this report, he con-ceptualized the “stress response” based on a “triad”of endocrine (adrenal enlargement), immune (thy-mus involution), and gastrointestinal (gastric hem-orrhagic erosions) responses occurring in rats irre-spective of the noxious agents applied on them. Onthis basis, he defined stress as the “non-specificresponse of the body to any demand”. He furtherdeveloped this entity as the “general adaptationsyndrome” which encompasses three phases: thealarm reaction, the phases of resistance, andexhaustion reflecting the various phases of the bodyreaction linked with the duration and intensity ofstress exposure3.

The legacy of Selye in the stress field is illustrat-ed in the Oxford Dictionary quoting him as “havingintroduced the word stress in the medical literature,borrowing the term from the engineers who used itto refer to the physical changes happening to somemetal or otherwise solid structure when submittedto whatever conditions would tend to affect its rest-ing state. Actually it is the engineers who had bor-rowed the term (1547 AD, later) from its original(1303 AD, 1400 AD) use, referring to hardship,adversity, affliction (stress being possibly an aphet-ic form of distress). So, Selye was actually usingthe word in its original sense and implications.”However since then, attempts have been made todefine stress by other names such as “al lostasis“defined by Sterling and Eyer, in 1988 as “achievingstability through change” i.e. the active process bywhich the body responds to daily events and main-tains homeostasis4. Allostatic overload was referredto the wear and tear that results from dysregulated

allostasic response under conditions of sustainedstress by McEwen5. Chrousos6 more recentlycoined the term eustasis as the ability of the organ-ism to return to basal homeostasis and cacostasis asthe inappropriate response (inadequate or exces-sive)6. However it is clear that the word stresscoined by Selye still remained the main stay asshown by the vast literature (56,5883 citations inpub med) and is part of the daily vocabulary.

In parallel with his scientific fame, Selye standsas an inspirational scientific mentor to more thansixty MSc & PhD students; including the NobelLaureate of Medicine, Roger Guillemin MD whowrote after listening to Selye’s lecture in Paris “Themagnetism of the man was extraordinary.” Hundredof visiting scientists from all over the world flockedthe Institute of Experimental Medicine and Surgeryin Montreal over decades. I was privileged to be hislast PhD student from 1970 to 1974 and then post-doctoral fellow for one year. Selye encapsulated inhis mentorship several aspects that he exemplifiedincluding pursuing research training with promi-nent leaders; to unravel and connect scientificobservations; to be well versed in scientific litera-ture; to wrap up findings for publications; to setback and assess whether findings will have broadimplications and significance if not change topic!

From the “first mediator” to the identification of the corticotropinreleasing factor (CRF) signaling pathways in the stress response

In 1950, Selye referred to “a first mediator’ in thebrain that triggers the bodily adaptive response tostress (Figure 1.)7. Roger Guillemin MD, then aPhD student in Selye Institute from 1949 to1952,stated “It is from the questions raised by Hans Selyethat I devoted my life as a physiologist and eventu-ally isolated the first of these hypothalamic factorscontrolling pituitary functions as proposed by Selyein his questions regarding the mechanism of theorganism response to stress. Neuroendocrinologyafter that became a major chapter of modern physi-ology and medicine”. After his recruitment atBaylor College, Guillemin demonstrated the exis-tence of a hypothalamic factor that elicited adreno-corticotropic hormone (ACTH) release from the ratpituitary that he named CRF in keeping with itsadrenocorticotropic releasing property and the factthat the molecular structure was not yet known8.Although CRF was one of the first hypothalamic-releasing factor to be named9, the elucidation of its

96 Taché: Hans Selye and the stress response


structure lingered nearly three decades. Only in1981, a former Guillemin’S PhD student, WylieVale and his group succeeded in characterizing the41-amino acid peptide from ovine hypothalamus10

and thereafter the cognate receptors CRF1 andCRF2

11. This historical developments illustrated theimportance of strong mentoring linkage (Figure 2.)as proned by Selye. After these biochemical andmolecular discoveries, the physiological impor-tance of CRF expended quickly beyond the estab-lished action to mount ACTH release in response tovarious stressors. Convergent experimental studiesdemonstrated that the administration of CRF actingthrough CRF-R1 in the brain was able to recapitu-late a variety of stress-like response on the behav-ior, autonomic nervous system, immune and viscer-al function commonly induced by various acutestressors12, 13 (Figure 3.). Moreover CRF antago-nists prevented the stress-related bodily changes.These studies provided the framework for CRF sig-naling pathwats to fulfill the insightful conceptadvanced by Selye regarding the “the first media-tor”.

Ideggyogy Sz 2014;67(3–4):95–98. 97

Figure 1. Principal pathways mediating the stressresponse to stressors and conditioning factors that mod-ulate this response as described by Selye7

Figure 2. From Selye concept of first mediator to the identifica-tion of CRF signaling pathways: the mentoring linkage

Figure 3. The endocrine, behavioral, autonomic, viscer-al and immune responses induced by the activation ofCRF-CRF-R1 receptor in the brain


REFERENCES1. Szabo S, Taché Y, Somogyi A. The legacy of Hans Selye

and the origins of stress research: a retrospective 75 yearsafter his landmark brief “letter” to the editor# of nature.Stress 2012;15:472-8.

2. Selye H. Syndrome produced by diverse nocuous agents.Nature 1936;138:32.

3. Selye H. Study on adaptation. Endocrinology 1937;21:169-88.

4. Sterling P, Eyer J. Allostasis: a new paradigm to explainarousal pathology. In: Fisher S, Reason J (eds.). Handbookof Life Stress, Cognition and Health. New York: JohnWiley & Sons; 1988. p. 629-49.

5. McEwen BS. Stress, adaptation, and disease. Allostasis andallostatic load. Ann N Y Acad Sci 1998;840:33-44.

6. Chrousos GP. Stress and disorders of the stress system. NatRev Endocrinol 2009;5:374-81.

7. Selye H. Theories. Stress in health and disease. Boston-London: Butterworths; 1976. p. 928-1148.

8. Guillemin R, Rosenberg B. Humoral hypothalamic controlof anterior pituitary: a study with combined tissue cultures.Endocrinology 1955;57:599-607.

9. Guillemin R. Neuroendocrinology: a short historicalreview. Ann N Y Acad Sci 2011;1220:1-5.

10. Vale W, Spiess J, Rivier C, Rivier J. Characterization of a41-residue ovine hypothalamic peptide that stimulatessecretion of corticotropin and b-endorphin. Science1981;213:1394-7.

11. Vale W, Vaughan J, Perrin M. Corticotropin-releasing fac-tor (CRF) family of ligands and their receptors. TheEndocrinologist 1997;7:S3-S9.

12. Bale TL, Vale WW. CRF and CRF receptor: Role in stressresponsivity and other behaviors. Annu Rev PharmacolToxicol 2004;44:525-57.

13. Taché Y, Bonaz B. Corticotropin-releasing factor receptorsand stress-related alterations of gut motor function. J ClinInvest 2007;117:33-40.

98 Taché: Hans Selye and the stress response


Ideggyogy Sz 2014;67(3–4):99–102. 99

SELYE SYMPOSIUM

EVEN VISITING SCIENTISTS COULD MAKE DISCOVERIESIN MONTREAL

György LÁZÁR Institute of Pathophysiology, Faculty of Medicine, University of Szeged, Szeged

MÉG A VENDÉGTUDÓSOK IS TEHETTEKFELFEDEZÉSEKET MONTREALBANLázár Gy, MD, DSc Ideggyogy Sz 2014;67(3–4):99–102.

Közleményemben összefoglalom Selye Jánossal kapcsolatostudományos élményeimet, kiemelten a ritka fémsóknak areticuloendothelialis funkciókra kifejtett specifikus hatásávalkapcsolatos ismeretekre. A ritka földfémek ionjai jelentôshatást fejtenek ki a gyulladásos és immunjelenségekbenrészt vevô sejtek funkciójára. A GdCl3 által kiváltott Kupffer-sejt-blokád a Kupffer-sejtek élettani és kórélettani szerepévelkapcsolatos kutatások általánosan elfogadott módszere.Különbözô sokkállapotokban, májkárosodásban és obstruk-ciós sárgaságban kimutattuk a macrophagblokád poten-ciális elônyös hatásait.

Kulcsszavak: Selye János; Kupffer-sejtek, macrophag-blokád, obstrukciós sárgaság

This publication summarizes the scientific adventure withProfessor Selye, and focuses on the specific effect of raremetal salts on reticuloendothelial functions. Rare earthmetal ions markedly affect the functions of cells involved ininflammatory and immunological phenomena. The Kupffercell blockade induced by GdCl3 is a generally acceptedmethod for investigation of the physiological and patho-physiological roles of Kupffer cells. Potential beneficialeffects of macrophage blockade have been demonstrated indifferent shock states, liver injury and obstructive jaundice.

Keywords: Dr. Hans Selye; Kupffer cells, macrophage blockade, obstructive jaundice

Correspondent: György LÁZÁR Jr. MD, DSc, Department of Surgery, Faculty of Medicine, University of Szeged; 6720 Szeged, Pécsi u. 4. Phone:+36 62 545 444, fax: +36 62 545 701, e-mail: [email protected]


www.elitmed.hu

One of my early dreams as a young scientistengaged in biomedical research was to meet

professor Selye and to visit the famous Institute ofProfessor Hans Selye in Montreal, and even workwith Selye professor. Although, I did not know himpersonally, for me he was the scientist who incar-nated creativity and originality. I knew his basicdiscoveries and his concept of stress, the exhaustionof the organism, pluricausal diseases, and the adap-tation syndrome1-5. I was particularly excitedbecause the focus of my interest was very close tothat of the research topics in Selye Institute.

When I received an invitation from professorSelye in 1967, we had described that a rare earthmetal complex, “Phlogodym” with anticoagulantand antiphlogistic properties, aggravates theintravascular coagulation during different forms ofshock6.

At the same time it was demonstrated in the

Institute of Professor Hans Selye that the rare earthmetals, which exhibited an anticoagulant property,sensitize the organism to the development of athrombo-haemorrhagic phenomenon induced bycatecholamine administration7. The thrombo- hem-orrhagic phenomenon was therefore the bridge thatled me to Montreal. Even the four-year-delaybefore I received my exit permit is vivid in mymemory.

I was always afraid that Professor Selye wouldbecome weary of waiting for me and his invitationwould not be valid forever. When I wrote a letter toProfessor Selye in 1971 saying that it seems Iwould finally make it within two months, ProfessorSelye reply was the following, and here I quotefrom his letter:

“I was very glad to learn that you will now beable to come about two months. During the summermonths the life somewhat less stressful at our

lazar_UJ ISZ TUKOR ALAP ANGOL.qxd 2014.03.21. 16:05 Page 99

Institute, it would be most appropriate time for youto arrive. Looking forward to pleasure of meetingyou soon here on Canadian soil.” Szívélyes üd -vözlettel: János bátyád. Professor Selye wouldnever miss writing couple of sentence Hungarian atthe bottom of his letter written in English or French.

Nevertheless, finally I was there. When I arrivedin Montreal late afternoon in September, ProfessorSelye received me in his office. At this first meet-ing Professor Selye already presented me with theresearch options.

“I gladly join in the research work of theInstitute- I replied- yet I believe I will have enoughtime to realize my own research plans as well.”

Hans Selye demonstrated that stress from a vari-ety of sources causes adrenal enlargement and thy-mus atrophy. The idea that stress alters the immunefunction gained notable interest among cliniciansand scientist and has led to the development of themodern concept of psychoneuroimmunology.

My research conducted in Selye’s institutebecame the basis of my later research and hasproved that the macrophages are the “alarm” cellsof the organism, which play a key role in theimmune system and the cytokines, the mediatorsproduced by macrophages may start off unwantedreactions damaging the organism similarly to thereactions elements of chronic shock.

Effect of rare metal salts on reticuloendothelial activity

One of my first papers published from Selye insti-tute reported that the rare earth metal salts, amongthe gadolinium chloride, depress the reticuloen-dothelial activity8-10, and selectively interfere withthe function of the Kupffer cells11.

These works became determinant in my furtherscientific work. How is our research work related tothe stress concept? Macrophages are the body’s“alarm” cells that synthesize and excrete highlyreactive materials. The biological active materialsare very important in killing bacteria and tumorcells. However, macrophages not only act as a firstline of defense and have pivotal role in regulatingimmune response.

Nowadays the Kupffer cell blockade induced byGdCl3 became a generally accepted method forinvestigation of the physiological and pathophysio-logical roles of Kupffer cells (Figure 1.). Mac -rophage blockade has the theoretical advantage ofabrogating inflammatory responses at an earlierstage of disease and in a specific fashion. It has alsobeen reported that GdCl3 inhibits the secretion of

biologically active substances from the liverKupffer cells, and decreases the liver-damagingeffects of hepatotoxins12, ischemia-reperfusion13.Furthermore the ablation of the functions of theliver’s macrophages inhibits the development ofanaphylaxis14, lethal septic15 and endotoxin shock16,

17. GdCl3 also influences the hypotension inducedby immunoglobulin aggregates18, and prolongs thesurvival of a human insulinoma cell xenograft inthe liver19.

Pathophysiological rules of Kupffercells in obstructive jaundice

Despite advances of intensive care, survival of crit-ically ill patients with obstructive jaundice did notimprove over the last decades - and septic compli-cations are still the leading cause of mortality20, 21.The Kupffer cell functions are changing after bil-iary obstruction as well22-24 and Kupffer cell-dependent immune modulation may lead to diver-gent outcomes25-28. Defects in crucial elements ofRES function after cholestasis are leading to hyper-sensitivity to bacterial endotoxin with high rate ofseptic complications in the long run. However, ithas been demonstrated that attenuation of Kupffercell activity with GdCl3 might decrease endotoxin-induced lethality and morbidity in obstructive jaun-dice29-30.

Previously it has been shown that biliaryobstruction enhances the inflammatory andmicrovascular response of the liver to endotox-emia29, 31. Our recent observation clearly demon-strates that hepatic microcirculatory dysfunction issignificantly exaggerated if obstructive jaundice is

100 Lázár: Even visiting scientists could make discoveries in Montreal

Figure 1. The physiological and pathophysiologicalroles of Kupffer cells

Kupffer Cells


followed by endotoxin administration32. The resultsalso show that hepatic Kupffer cells have a pivotalrole in this process. Our results that the inhibition ofa Kupffer cell-dependent inflammatory responsereduces the endotoxin-induced lethality and organinjury in obstructive jaundice suggest a novel appli-cation for this experimental treatment modality.

Conclusions

In his book “From dream to discovery” Selye statesthat timing makes a huge difference, and as far ashe was concerned he was fresh and active, and mostoptimistic especially in the morning. Indeed, Selyearrived at the institute at 6 a.m. before any ofemployees usually after an early swimming orcycling. The picture shows Selye professor return-ing cycling around the university campus (Figure2.). From 6 to 8.30 a.m. he was the most intensiveand focused work of writing various papers ensued.His productivity is proved by numbers publications,more than 30 books and nearly 2000 articles. Ouroffices of Sándor Szabó and me were closed to eachother. And Professor Selye very frequently visitedus in our offices for a short conversation. He veryfrequently said “Only the Hungarians know thehard-working Hungarian farmers, who start workevery day early in the morning when the day is justbreaking and stopped at exactly six o’clock in theevening.” At 3 p.m. Selye would start his autopsymeeting, during which he would analyze the resultsof experiments with his characteristic magnifyingglass and head lamp. Usually, these times ProfessorSelye was invited to deliver a lecture about hisexperiments concerning the stress. He asked us,Sanyi, Gyuri do you want to accompany me? Andwe willingly went with him to hear his excellentlectures.

During one year scholarship 15 relevant ownpapers were prepared in Montreal In Selye’sInstitute. After this fruitful scientific year I returnedhome and continued my work at home with my co-workers.

My work in Montreal has determined my scien-tific carrier and has been motivated continuously.When I try to recall our life in the company of HansSelye, my feeling is always that time has stoppedand we are young again, full of energy and ambitionas we were so many years ago in the old SelyeInstitute.

Ideggyogy Sz 2014;67(3–4):99–102. 101

Figure 2. Professor Selye returning from cycling

REFERENCES1. Selye H. A syndrome produced by diverse nocuous agents.

Nature 1936;138:32.2. Selye H. The significance of the adrenals for adaptation.

Science 1937;85:247-8.3. Selye H. Pharmacological classification of steroid hor-

mones. Nature 1937;148:84-5.4. Selye H. Role of hypophysis in the pathogenesis of the dis-

eases of adaptation. Can Med Assoc 1944;50:426-33.5. Selye H. The general adaptation syndrome and the diseases

of adaptation. J Clin Endocr 1946;6:117-230.6. Lázár G, Karády I, Husztik E. Effect of phlogodym on the

tourniquet shock. Thromb Diath Haemorrh 1966;21:159-65.

7. Solymoss B, Selye H, Gabbiani G. Predisposition to throm-bosis not reflected by the blood coagulogram. J Clin Pathol1966;19:332-3.

8. Lazar G. The reticuloendothelial blocking effect of rareearth metals in rats. J Reticuloendoth Soc 1973;13:231-3.

9. Lazar G. Effect of reticuloendothelial stimulation anddepression on rare earth metal chloride-induced spleniccalcification and fatty degeneration of the liver. Experientia1973;29:818-9.

10. Lázár G, Serra D, Tuchweber B. Effect on cadmium toxic-ity of substances influencing reticuloendothelial activity.1974;29:367-76.

11. Husztik E, Lazar G, Párducz Á. Electron Microscopic


Study of Kuppfer Cell Phagocytosis Blockade induced bygadolinium chloride. Br J Exp Path 1980;61:624-30.

12. Barriault C, Audet M, Yousef IM, Tuchweber B. Effect ofagents which modify reticuloendothelial system functionon acute phalloidin-induced lethality and hepatotoxicity inmice. Toxicol. Appl. Pharmacol 1995;131:206-15.

13. Suzika S, Toledo-Pereyra LH, Ridriguez F, Lopez F. Roleof Kupffer cells in neutrophil activation and infiltration fol-lowing total hepatic ischaemia and reperfusion. Circ Shock1994;42:204-9.

14. Lázár G Jr, Lázár G, Kaszaki J, Oláh J, Kiss I, Husztik E.Inhibition of anaphylactic shock by gadolinium chloride-induced Kupffer cell blockade. Agents Actions 1994;41:C97-C98.

15. Lázár G Jr, Husztik E, Lázár G. Effects of endotoxin andgadolinium chloride in acute septic peritonitis end septicshock in rats. Prog Clin Biol Res 1986;236B:323-8.

16. Vollmar B, Rüttinger D, Wanner GA, Leiderer R, MengerMD. Modulation of Kupffer cell activity by gadoliniumchloride in endotoxemic rats. Shock 1996;6:434-41.

17. Iimuro Y, Yamamoto M, Kohno H, Itakura J, Fujii H,Matsumoto Y. Blockade of liver macrophage by gadolini-um blockade reduces lethality in endotoxic rats: analysis ofmechanism of lethality in endotoxemia. J Leukocyte Biol1994;55:723-31.

18. Iimuro Y, Yamamoto M, Kohno H, Itakura J, Fujii H,Matsumoto Y. Blockade of liver macrophage by gadolini-um blockade reduces lethality in endotoxic rats: analysis ofmechanism of lethality in endotoxemia. J Leukocyte Biol1994;55:723-31.

19. Lázár G Jr, Farkas Gy, Csanádi J, Lázár G. Gadoliniumchloride-induced macrophage blockade prevents rejectionof human insulinoma cell xenograft in rats. Transplantation1997;63:729-32.

20. Diamond T, Dolan S, Thompson RL, Rowlands BJ.Development and reversal of endotoxemia and endotoxin-related death in obstructive jaundice. Surgery 1990;108(2):370-4; discussion 374-5.

21. Greig JD, Krukowski ZH, Matheson NA. Surgical morbid-ity and mortality in one hundred and twenty-nine patientswith obstructive jaundice. Br J Surg 1988;75(3):216-9.

22. Kennedy JA, Clements WD, Kirk SJ, McCaigue MD,Campbell GR, Erwin PJ, et al. Characterization of theKupffer cell response to exogenous endotoxin in a rodentmodel of obstructive jaundice. Br J Surg 1999;86(5):628-33.

23. O’Neil S, Hunt J, Filkins J, Gamelli R. Obstructive jaun-dice in rats results in exaggerated hepatic production oftumor necrosis factor-alpha and systemic and tissue tumornecrosis factor-alpha levels after endotoxin. Surgery1997;122(2):281-6; discussion 286-7.

24. Harry D, Anand R, Holt S, Davies S, Marley R, FernandoB, et al. Increased sensitivity to endotoxemia in the bileduct-ligated cirrhotic Rat. Hepatology 1999;30(5):1198-205.

25. Ding JW, Andersson R, Norgren L, Stenram U, BengmarkS. The influence of biliary obstruction and sepsis on retic-uloendothelial function in rats Eur J Surg 1992;158(3):157-64.

26. Ball SK, Grogan JB, Collier BJ, Scott-Conner CE.Bacterial phagocytosis in obstructive jaundice. A microbi-ologic and electron microscopic analysis. Am Surg1991;57(2):67-72.

27. Katz S, Grosfeld JL, Gross K, Plager DA, Ross D, Ro -senthal RS, et al. Impaired bacterial clearance and trappingin obstructive jaundice. Ann Surg J 1984;199(1):14-20.

28. Tomioka M, Iinuma H, Okinaga K. Impaired Kupffer cellfunction and effect of immunotherapy in obstructive jaun-dice. J Surg Res 2000;92(2):276-82.

29. Lazar G Jr, Paszt A, Kaszaki J, Duda E, Szakacs J,Tiszlavicz L, et al. Kupffer cell phagocytosis blockadedecreases morbidity in endotoxemic rats with obstructivejaundice. Inflamm Res 2002;51(10):511-8.

30. Minter RM, Fan MH, Sun J, Niederbichler A, Ipaktchi K,Arbabi S, et al. Altered Kupffer cell function in biliaryobstruction. Surgery 2005;138(2):236-45.

31. Ito Y, Machen NW, Urbaschek R, McCuskey RS. Biliaryobstruction exacerbates the hepatic microvascular inflam-matory response to endotoxin. Shock 2000;14(6):599-604.

32. Ábrahám S, Szabó A, Kaszaki J, Éder K, Duda E, Lázár G,et al. Kupffer cell blockade improves the endotoxin-induced microcirculatory inflammatory response inobstructive jaundice. Shock 2008;30(1):69-74.

102 Lázár: Even visiting scientists could make discoveries in Montreal


Ideggyogy Sz 2014;67(3–4):103–106. 103

SELYE SYMPOSIUM

CENTRAL NEUROENDOCRINE MECHANISMS OF GASTROPROTECTION

Klára GYIRES Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest

A GYOMORVÉDELEM CENTRÁLIS NEUROENDOKRINMECHANIZMUSAIGyires K, MD, PhDIdeggyogy Sz 2014;67(3–4):103–106.

Selye ismerte fel a hypothalamus-hypophysis-mellékvesetengely stressz alatti aktivációjának a jelentôségét, és akapcsolatot a központi idegrendszeri és a neuroendokrinszabályozás között. Ez az elmélet képezte a kutatásokelkezdésének az alapját, amelyekben feltárták az agy-béltengely jelentôségét a gyomornyálkahártya integritásának aszabályozásában. Számos neuropeptidrôl, így a thyreotropreleasing hormonokról, adrenomedullinról, peptid YY-ról,amylinrôl, opioid peptidekrôl nociceptinrôl, nocisatinról P-anyagról, ghrelinrôl, leptinrôl, orexin-A-ról, angiotenzin II-rôl kimutatták, hogy centrálisan injektálva gyomorvédôhatású. Jól dokumentált a dorsalis vagusköteg és a nervusvagus szerepe a központ perifériára kifejtett hatásában, detovábbi mechanizmusok is felmerültek. A neuropeptidekközötti kölcsönhatások jelentik azt a további komponenst,amely módosíthatja a gyomornyálkahártyának az ártalmasstimulusokkal szembeni ellenállását.

Kulcsszavak: hypothalamus-hypophysis-mellékvese tengely,neuropeptidek, gyomorvédelem

Selye recognized the importance of activation of hypothala-mic-pituitary-adrenal axis during stress and the connectionbetween central nervous system and neuroendocrine regu-lation. This concept basically contributed to initiation of thestudies, which revealed the importance of brain gut axis inregulation of gastric mucosal integrity. Several neuropep-tides, such as thyreotrop releasing hormones,adrenomedullin, peptide YY, amylin, opioid peptides, noci-ceptin, nocisatin, substance P, ghrelin, leptin, orexin-A,angiotensin II were shown to induce gastroprotective effectinjected centrally. Though the involvement of dorsal vagalcomplex and vagal nerves in conveying the central action tothe periphery has been well documented, additional mech-anisms have also been raised. The interaction between neu-ropeptides further component that may modify the gastricmucosal resistance to noxious stimulus.

Keywords: hypothalamic-pituitary-adrenal axis, neuropeptides, gastroprotection

Correspondent: Professor Klára GYIRES, Department of Pharmacology and Pharmacotherapy, Faculty of Medicine,Semmelweis University; 1089 Budapest, Nagyvárad tér 4. Phone: 36-1-210-4416, fax: 36-1-210-4412,

e-mail: [email protected]


www.elitmed.hu

Selye’s breakthrough ideas about stress openedan entirely new medical field – the study of bio-

logical stress and its effects. He recognized, that notonly catecholamines, but also corticoids arereleased in stress reaction under the influence ofadrenocorticotropic hormone (ACTH) and hypo-thalamic releasing hormones, and activation ofhypothalamic-pituitary adrenal axis basically con-

tribute to the pathomechanism of stress. The triad ofthe general alarm reaction characterized by adrenalhypertrophy, thymus atrophy and gastric mucosalerosions are the consequences of the activation ofhypothalamic pituitary-adrenal axis. However, it isless known that Selye demonstrated first the anti-and proinflammatory effects of corticosteroids, andhe classified the adrenal steroids as gluco- and min-

gyires_UJ ISZ TUKOR ALAP ANGOL.qxd 2014.03.21. 16:06 Page 103

eralocorticoids. He also reveled connectionbetween central nervous system (CNS) and neu-roendocrine regulation. His pioneering findings ini-tiated series of experiments, which lead directly, orindirectly to the discovery of ACTH, GRH, somato-statin and further hypothalamic, hypophyseal hor-mones and neuropeptides.

The activation of hypothalamic-pituitary-adrenalaxis affects also gastric mucosal integrity and gas-tric mucosal erosion is part of the classic triad ofgeneral alarm reaction as mentioned above1, 2.

On the other hand Filaretova suggested that glu-cocorticoids released during stress or by variousulcerogenic stimuli have gastroprotective effect andhelp the gastric mucosa to resist against a harmfulaction of ulcerogenic stimuli. Moreover, deficiencyof glucocorticods was shown to aggravate themucosal damage in experimental ulcer models3, 4.The dual actions of glucocorticoids and stress ongastric mucosa might be explained e.g. by differ-ences of the dose of glucocorticoids, by differencein the intensity, duration of stress stimulus, as wellas whether their role is analyzed under physiologi-cal or pathophysiological condition.

Neuropeptides and gastric mucosalprotection

During the last 15-20 years the role of central nerv-ous system in regulation of gastrointestinal func-tions has been intensively analyzed and evidencewas obtained that brain gut axis has determiningrole in regulation of gastric mucosal integrity. Thepreviously described hypothalamic-pituitary-adre-nal axis can be considered as one of the first exper-imental evidence for the role of CNS on gastricmucosal damage/ protection.

Increasing number of evidence have demonstrat-ed that different neuropeptides e.g. thyreotropreleasing (TRH), adrenomedullin, peptide YY,amylin, opioid peptides, nociceptin, nocistatin, sub-stance P, ghrelin, leptin, orexin-A, angiotensin II(Ang II), and the non-neuropeptide endocannabi-noids injected centrally to different brain areas ofthe rat may initiate a chain of events which is result-ed in gastric mucosal protection against differentulcerogenic stimulus5-15.

However, several differences can be observed inthe gastroprotective profile of neuropeptides. Forexample differences can be observed in their poten-cy, effectiveness against different types of gastricmucosal damage, in the mechanism how the centraleffect is conveyed to the periphery, in their addi-tional gastrointestinal actions, in the site of injec-

tion and brain areas potentially involved in mucos-al protective effect, as well as in their interactionwith other neuropeptides.

According to their potency the neuropeptidescan be divided into four groups: the effective dose-range a. below 0.01 nmol: e.g. TRH, endomorphins,β-endorphin and partly substance P; b. between0.01 and 0.1 nmol: e.g. angiotensin II, adrenom-ledulin, PYY, substance P; c. between 0.1-1 nmol:e.g. amylin, nociceptin, nocistatin, leptin, partlyghrelin and TLQP-21; d. between 1-10 nmol: e.g.TLQP-21, ghrelin (Review: 7). Some neuropep-tides, such as substance P, TLQP-21, ghrelin, havea wide effective dose range, therefore they are indi-cated not only in one group.

Moreover, above the effective dose range, thegastroprotective effect of some neuropeptides isreduced, and even aggravation of the lesions can beobserved. For example TRH in 1.5-3 ng givenintracisternally results in gastroprotective effectagainst ethanol-induced lesions, however in thedose of 1-3 µg it induced mucosal damage9.Similarly, e.g. Ang II (956 pmol i.cv.) nociceptin,nocistatin (2-5 nmol i.c.v), substance P (74-148pmol i.c.v.) exert reduced gastroprotective effectabove the effective dose range (11.9-191 pmol, 0.5-1 nmol and 9.3-18.5 pmol, respectively)12-14.

The mechanism of the dual effect neuropeptidesin gastroprorection has not been fully clarified.Most probable in higher dose range activation ofadditional receptors and induction of additionaleffects might be responsible for the reduced gastro-protective activity. E.g. TRH in higher dose rangestimulates gastric acid secretion, which might coun-teract the protective effect of TRH induced by lowdose range9. Or in the case of Ang II the higherdoses may induce increased sympathetic tone andincreased vascular resistance by activation of type 1angiotensin (AT1) receptors16. The increased vascu-lar resistance might results in reduced gastricmucosal flow and consequently, aggravation of thelesions.

Interaction between neuropeptides

In addition, the effect of neuropeptides on gastricmucosa may be affected by the wide range of inter-actions among them, as well as with other neuro-transmitter/modulators. For example, paracrinetransactivation of CB1 receptors by co-expressedAT1 receptors in Chinese hamster ovary cells wasobserved17. In vivo evidence for the interactionbetween Ang II and cannabinoid system in gastro-protection was recently published, namely it was

104 Gyires: Neuroendocrine system and gastroprotection


found that Ang II-induced gastroprotection wasreversed by cannabinoid CB1 receptor antagonist aswell as by blocking tetrahydrolipstatin, the enzymeresponsible for the formation of endocannabinoid2-arachidonoylglycerol (2-AG) in the rat. In addi-tion, while Ang II proved to be protective also inwide type mice, its protective effect was dramati-cally reduced in CB1 cannabinoid receptor deficientmice12. Ang II, however, has interaction with otherneuropeptides, e.g., anatomical evidence suggeststhat Ang II binding sites in the medial nucleus ofthe solitary tract (NTS) are located presynapticallyon vagal afferent fibers that may contain SP and areco-distributed with SP binding sites located postsy-naptically on intrinsic medial NTS neurons18.Experiments are in progress to reveal the potentialrole of this interaction in gastroprotection.Additional interactions between neuropeptideswhich might play a role in their gastroprotectiveactions, e.g.: TRH-enkephalin interactions wasdescribed in the amygdaloid complex during gastricstress ulcer formation in rats19, or stress induced therelease of corticotropin-releasing hormone, argi-nine vasopressin, the proopiomelanocortin-derivedmelanocyte-stimulating hormone and β-endor-phin20. This later finding might explain, at leastpartly, why stress can be not only aggressive butalso protective for gastric mucosa, namely, β-endorphin was shown to mediate protective actionon gastric mucosa11.

Convey of central action to the periphery

The centrally initiated gastroprotective effect maybe conveyed to the periphery by vagal dependentpathway5, 8, 9. However, the role of sympathetic

nervous system has also been raised. For example,recently it was found that the gastroprotective effectof opioid peptides besides bilateral cervical vagoto-my11 was reduced also following chemical sympa-thectomy by 6-OH dopamine (600 nmol i.c.v.). Thenoradrenaline content in the nucleus of the solitarytract was decreased in a significant manner in 6-OHdopamine-treated rats indicating that the decreaseof the mucosal protective effect of opioid peptidesafter 6-OH dopamine treatment relates to the reduc-tion of noradrenaline content in the nucleus of soli-tary tract7. Similarly, gastroprotective effect ofnociceptin against ethanol administered either i.c.v.or intaperitoneally was blocked by atropine, subdi-aphragmatic vagotomy and the adrenerg neuronblocking bretylium, suggesting that both vagal cho-linergic and sympathetic pathways mediate thecentral activity of this peptide21. In contrast, themucosal protective effect of Ang II given into para-ventricular nuclei against gastric ischemia/reperfu-sion-induced injury, was not affected by subdiaph-ragmatic vagotomy or atropine, but was abolishedby propranolol or disconnection of the nerves inner-vating the adrenal glands indicating the role ofsympathetic-adrenal gland/β- adrenoceptor path-way in gastroprotection15.

In conclusion, the integrity of gastric mucosa isregulated not only by peripheral (e.g. bicarbonate,mucus, nitric oxide, prostaglandins, calcitonin-gene related peptide production) but also by cen-tral mechanisms. Though different brain areasmay play a role in in the centrally originated gas-tric mucosal defense, the hypothalamus and dorsalvagal complex seem to have a particular impor-tance. Further studies are needed to clarify the roleof endogenous neuropeptides in gastric mucosalhomeostasis under physiological and pathologicalcondition.

Ideggyogy Sz 2014;67(3–4):103–106. 105

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the origins of stress research: a retrospective 75 years afterhis landmark brief “letter” to the editor# of nature. Stress2012;15:472-8.

2. Selye H. Perforated peptic ulcer during air-raid. Lancet1943;20:252.

3. Filaretova LP. The hypothalamic-pituitary-adrenocorticalsystem: Hormonal brain-gut interaction and gastroprotec-tion. Autonomic Neuroscience 2006;125:86-93.

4. Filaretova LP. Gastroprotective role of glucocorticoidsduring NSAID-induced gastropathy. Curr Pharm Des2013;19:29.

5. Gyires K. Neuropeptides and gastric mucosal homeostasis.Curr Top Med Chem 2004;4:63-73.

6. Shujaa N, Zadori ZS, Ronai AZ, Barna I, Mergl Z, MozesMM, et al. Analysis of the effect of neuropeptides and can-nabinoids in gastric mucosal defense initiated centrally inthe rat. J Physiol Pharmacol 2009;7:93-100.

7. Gyires K, Németh J, Zádori ZS. Gastric mucosal protectionand central nervous system. Curr Pharm Des 2013;19:34-9.

8. Tache Y. Brainstem neuropeptides and vagal protection ofthe gastric mucosal against injury: Role of prostaglandins,nitric oxide and calcitonin-gene related peptide in capsaicinafferents. Curr Med Chem 2012;19:35-42.


9. Tache Y, Yoneda M. Central action of TRH to induce vagal-ly mediated gastric cytoprotection and ulcer formation inrats. J Clin Gastroenterol 1993;17:58-63.

10. Yamada H, Tanno S, Takakusaki K, Okumura T. Intra -cisternal injection of orexin-A prevents ethanol-inducedgastric mucosal damage in rats. J Gastroenterol 2007;42(5):336-41.

11. Gyires K, Rónai AZ. Supraspinal delta- and mu-opioidreceptors mediate gastric mucosal protection in the rat. JPharmacol Exp Ther 2001;297:1010-5.

12. Gyires K, Rónai AZ, Zádori ZS, Tóth VE, Németh J,Szekeres M, et al. Angiotensin II-induced activation of cen-tral AT1 receptors exerts endocannabinoid-mediated gas-troprotective effect in rats. Mol Cell Endocrinol 2013[Epub ahead of print].

13. Zádori ZS, Shujaa N, Köles L, Király KP, Tekes K, GyiresK. Nocistatin and nociceptin given centrally induce opioid-mediated gastric mucosal protection. Peptides 2008;29:2257-65.

14. Brancati SB, Zádori ZS, Németh J, Gyires K. Substance Pinduces gastric mucosal protection at supraspinal level viaincreasing the level of endomorphin-2 in rats. Brain ResBull 2013;91:38-45.

15. Zhang YM, Wei EQ, Hu X, Xu M, Shi Y, Zhang JF.Administration of angiotensin II in the paraventricularnucleus protects gastric mucosa from ischemia-reperfusioninjury. Brain Res 2008;1212:25-34.

16. Marc Y, Llorens-Cortes C. The role of the brain renin-angiotensin system in hypertension: implications for newtreatment. Prog Neurobiol 2011;95:89-103.

17. Turu G, Varnai P, Gyombolai P, Szidonya L, Offertaler L,Bagdy G, et al. Paracrine transactivation of the CB1cannabinoid receptor by AT1 angiotensin and other Gq/11protein-coupled receptors. J Biol Chem 2009;284:16914-21.

18. Barnes KL, Diz DI, Ferrario CM. Functional InteractionsBetween Angiotensin II and Substance P in the Dorsal.Medulla Hypertension 1991;17:1121-6.

19. Ray A, Henke PG. TRH-enkephalin interactions in theamygdaloid complex during gastric stress ulcer formationin rats. Regul Pept 1991;35:11-7.

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21. Polidori C, Massi M, Guerrini R, Grandi D, Lupo D,Morini G. Peripheral mechanisms involved in gastricmuco-sal protection by intracerebroventricular and intraperitone-al nociceptin in rats. Endocrinology 2005;146:3861-7.

106 Gyires: Neuroendocrine system and gastroprotection


Ideggyogy Sz 2014;67(3–4):107–112. 107

SELYE SYMPOSIUM

OLD AND NEW NEUROENDOCRINE MOLECULES:SOMATOSTATIN, CYSTEAMINE, PANTETHINE AND

KYNURENINE László VÉCSEI1,2, Zoltán HORVÁTH1, Bernadett TUKA2

1Department of Neurology, Faculty of Medicine, University of Szeged, Szeged 2MTA-SZTE Neuroscience Research Group, University of Szeged, Szeged

RÉGI ÉS ÚJ NEUROENDOKRIN MOLEKULÁK:SZOMATOSZTATIN, CISZTEAMIN, PANTETHIN ÉS KINURENINVécsei L, MD, DSc; Horváth Z, MD; Tuka B, MScIdeggyogy Sz 2014;67(3–4):107–112.

Az összefoglaló célja, hogy megemlékezzünk Selye Jánosról,az endokrinológusról, a stressz leghíresebb kutatójáról, ésröviden összefoglaljuk a szomatosztatin (SST), a ciszteamin(CysA) és a pantethin (PAN) legfontosabb jellemzôit neuroen-dokrinológiai szempontból, amelyek szoros összefüggésbenálllnak tudományos munkájával. Emellett megemlítjük a kin-urenin (KP) -útvonal néhány metabolitját is mint a neuroen-dokrinológia néhány lehetséges célmolekuláját.R. Guillemin és A. V. Schally jártak elôl az SSTfelfedezésében az 1970-es években. Az SST-t fôként anövekedésihormon-elválasztás inhibitoraként ismerjük,emellett csökkenti a gyomosav és a pepszin felszabadulásátés a gastroduodenalis nyálkahártya véráramlását. Ezek ahatások nagyon fontosak a peptikus fekély vérzésénekkórélettanában, ami összefügg a CysA által kiváltott per-foráló duodenalis fekély kísérletes stresszmodelljével,patkányban, amit Selye és Szabó fejlesztettek ki. A CysA atermészetben elôforduló duodenalis ulcerogen anyag, amiSST-depléciót okoz a gyomornyálkahártyában és egyes agyirégiókban. Az SST-depléció mellett a CysA adrenocorticalisnecrosist is okoz, ami kölcsönhatásra utal a centrális/peri -fériás idegrendszer és a neuroendokrin rendszer között. ACysA mellett képzôdô antioxidáns PAN hatása hasonló:csökkenti az SST és a prolaktin szintjét az agykéregben és ahypothalamusban az által, hogy a CysA testszerte felhal-mozódik a sejteken belül. Új szempontként a KP részt veheta neuroendokrin folyamatok modulációjában: a glu-tamátreceptorok különbözô agonistái és antagonistái sza -bályozzák a hypothalamus-hypophysis-mellékvese tengelyt,és a kinurénsav fokozza újszülött csibékben az anxiolyticusstresszválaszt. A KP proinflammatorikus citokin által indukáltés a toxikus nehézolaj-szennyezôdés által kiváltott változásaiközvetetten hozzájárulnak a neuroendokrin zavarokhoz. Összességében nagyon fontos fejlôdés ment végbe a neu-roendokrinológiában Selye elsô eredményei óta. Bár mégviszonylag kevés adatunk van a kinureninek potenciálisszerepérôl a neuroendokrinológiában, a már elért ered-mények különösen értékesek és nagyon ígéretesek.

Kulcsszavak: szomatosztatin, ciszteamin, pantethin, kinurenin

The aim of this review is to commemorate Hans Selye,endocrinologist, the most famous researchers of stress andto briefly summarize the major features of somatostatin(SST), cysteamine (CysA) and patethine (PAN) in neuroen-docrinological aspect, which are closely related to his scien-tific work. In addition, some metabolites of kynurenine path-way (KP) were also mentioned in this paper, as new, possi-ble target molecules in neuroendocrinology. R. Guillemin and A. V. Schally were the main pioneers ofthe discovery of SST in the 1970’s. SST primarily is knownas an inhibitor of growth hormone secretion and additional-ly reduces the gastric acid and pepsin release and also thegastroduodenal mucosal blood flow. These effects are veryimportant in the pathophysiology of peptic ulcer bleeding,which is related to the CysA-evoked perforating duodenalulcer experimental stress model in rats developed by Selyeand Szabo. CysA is a naturally occurring duodenal ulcero-gen, which depletes SST in the gastric mucosa and certainbrain regions. Furthermore, in addition to depleting SST,CysA also causes adrenocortical necrosis, suggesting aninteraction between the central/peripheral nervous systemand the neuroendocrine system. The antioxidant PAN, for-mulated besides the CysA, has similar effects: it attenuatesthe levels of SST and prolactin in the cerebral cortex andhypothalamus through the accumulation of CysA within cellsthroughout the body. As new perspectives the KP may beinvolved in the modulation of neuroendrocrine processes:different agonists and antagonists of glutamate receptorsregulate the hypothalamic-pituitary-adrenal axis andkynurenic acid augments the anxiolytic stress responses inneonatal chicks. The pro-inflammatory cytokine-inducedand the toxic heavy oil contaminations-evoked alterations inthe KP indirectly contribute to the development of neuroen-docrine disorders. In summary, there have been highly important develop-ments in neuroendocrinology since the early findings ofSelye. Although there are as yet relatively few data aboutthe potential role of kynurenines in neuroendocrinology, theresults already achieved are extremely noteworthy andimmensely promising.

Keywords: somatostatin, cysteamine, pantethine, kynurenine

Correspondent: László VÉCSEI MD, DSc, Department of Neurology, Faculty of Medicine, University of Szeged; H-6725 Szeged, Semmelweis u. 6. Phone: +3662/545351, e-mail: [email protected]


www.elitmed.hu

vecsei_UJ ISZ TUKOR ALAP ANGOL.qxd 2014.03.21. 16:07 Page 107

The hormone somatostatin (SST) was isolatedfrom the hypothalamus in the 1970’s1-3. It was

originally regarded only as an inhibitor of growthhormone (GH) release (and was previously calledsomatotropin release inhibiting factor), but it is nowknown that SST has a number of biological effects.Burgus et al. observed that the addition of crudeextracts of the ovine hypothalamus to anterior pitu-itary cells maintained in vitro inhibited the secre-tion of GH and they isolated a compound thataccounted for all the GH-release inhibiting activityof the crude extract1. After sequencing and synthe-sis the peptide displayed biological activity both invitro and in vivo. SST, a small cyclic peptide, existsin two biologically active forms: SST-14 and SST-28, which are produced by the alternative post-translational cleavage of the single prehormone.SST release can be stimulated by a variety of hor-mones (growth hormone- and corticotropin-releas-ing hormone, neurotensin), neuropeptides, neuro-transmitters, cytokines, growth factors and nutrientsin several tissues4. On the other hand, the neuro-transmitter GABA and opiates generally inhibitSST secretion5. Inflammatory cytokines, such asinterleukin-1, tumor necrosis factor alpha and inter-leukin-6, are potent stimulators of SST release6,while transforming growth factor beta and leptin7

inhibit the secretion of the peptide. The develop-ment of synthetic analogs has led to the effectivetreatment of clinical disorders including acro -megaly, hormone-secreting tumors of the gastroin-testinal tract and portal hypertensive bleeding4. Asa general inhibitor of gastrointestinal endocrinesecretion, SST inhibits both gastric acid and pepsinrelease8. Moreover, it combines these effects with areduction in gastroduodenal mucosal blood flow,which appears to be important in the pathophysiol-ogy of peptic ulcer bleeding. These results weredemonstrated by several experimental stress mod-els; one of the earliest of these was the cysteamine-evoked perforating duodenal ulcer model in ratsdeveloped in 1973 by Selye and Szabo9.

Cysteamine (CysA) is a small aminothiol gener-ated by hydrolysis of the lipid-lowering drug pan-tethine (PAN), together with two pantothenic acids(vitamin B5). It is assumed that CysA is involved inthe production of cholesterol and triglycerides bymeans of its binding to inactivate sulfur-containingamino acids in liver enzymes. Moreover, CysA is anaturally occurring duodenal ulcerogen and has theability to cause adrenocortical necrosis too10. CysAand its derivatives deplete SST in the gastricmucosa, causing significant increases in gastricacidity and pepsin activity, alterations that con-tribute to the development of duodenal ulcer9. The

ulcerogenic activity of these derivatives is signifi-cantly correlated with their SST-depleting activi-ty11. In accordance with these findings, the admin-istration of SST prevents the development of CysA-induced duodenal ulcer. However, the effects ofCysA in causing duodenal ulcer and adrenal lesionssuggest an interaction between the central/peripher-al nervous system and the neuroendocrine system.In 1982, Palkovits et al. demonstrated that a singlesubcutaneous (sc.) injection of CysA (300 mg/kg)resulted in a quite selective SST depletion in thebrain. An approximately 70–80% decrease in SSTlevels was observed in those areas where SST-pro-ducing neurons (periventricular nucleus) and SST-ergic nerve terminals (median eminence) are locat-ed, whereas the CysA did not produce changes inthe levels of other neuropeptides12.

The naturally occurring antioxidant PAN is astable disulfide precursor of pantetheine. The latteris an intermediate in the production of coenzyme A(CoA) in the organism (Figure 1.). From a bio-chemical aspect, the enzymatic cleavage of PANproduces CysA (and later taurine) and pantothenicacid. After absorption from the food, 4’-phospho-pantetheine is reformed by the action of pantothen-ate kinase, after which ribose and adenine mole-cules attach to it in the mitochondrium to createCoA or bind to acyl carrier protein13. CoA and acylcarrier protein function as acyl or acetyl carriers.CoA facilitates the transfer of acetyl groups frompyruvate to oxaloacetate, thereby initiating theSzent-Györgyi–Krebs (tricarboxylic acid) cycle.CoA is involved in several ways in the fat metabo-lism, including the synthesis, transportation anddegradation of fatty acids. Several clinical studies

108 Vécsei: Old and new neuroendocrine molecules: Somatostatin, cysteamine, pantethine and kynurenine

Figure 1. Metabolic pathway of pantethine (ImageCLEF2011-Medical Datasheet)


have demonstrated its moderate benefits on dyslipi-demic subjects14 and also its inhibition of plateletaggregation, which offers an effective therapeuticoption for the treatment of patients with differentforms of atherosclerotic vascular disease15.

From a neuroendocrinological aspect, theadministration of PAN attenuates the levels of SST-and prolactin-immunoreactivity in the cerebral cor-tex and hypothalamus16 through the accumulationof CysA within cells throughout the body. It hastherefore been suggested that this substance may bea useful pharmacological tool for elucidation of therole of SST in the central nervous system. The func-tion of catecholaminergic pathways cannot beexcluded completely since PAN or possibly theforming CysA inhibits dopamine beta-hydroxy-lase17. In 1989, Sellini et al. observed that a singlehigh dose of PAN increased the levels of adreno-corticotropic hormone and cortisol (still within thenormal range), but had no effect on the GH and Prolevels. This might be explained by a PAN-inducedstimulus of the pituitary–adrenal axis or anincreased synthesis of acetylcholine18.

There is evidence that CysA and PAN havebehavior-modulating functions and other hormonaleffects too. CysA can more effectively diminishlocomotor, rearing and grooming activities than anequimolar dose of PAN. PAN influences severalother behavioral responses in animals19: it stimu-lates the food intake in satiated rats, dependingupon the stage of the circadian rhythm, but inhibitsthe food intake in fasted animals17. This effect ispossibly mediated through the disinhibition of cen-tral appete-regulating SST-ergic pathways. It influ-ences shuttle box learning20 and causes locomotorinhibition (4 h after sc. treatment) and activation(24 h after repeated sc. injection) in open-fieldtest21, 22. It leads to the attenuation of SST-inducedbarrel rotation23. From the aspect of passive avoid-ance behavior, there is no effect after sc. adminis-tration and merely a slight disruption after intrac-erebroventricular (icv.) treatment21. CysA, and to alesser extent PAN, reduced the concentration ofnoradrenaline and increased those of dopamine and3,4-dihydroxyphenylacetic acid in the hypothala-mus. Pantothenic acid itself did not influence eitherthe hypothalamic catecholamine concentrations orthe behavior of rats22.

Kynurenines, as ligands of glutamate (Glu)receptors may also be important modulators of theneuroendocrine system. In 1976, Coyle andSchwarcz revealed that kainic acid (KA) is associ-ated with lesions of the striatal neurons, as inHuntington’s disease (HD) and it depletes SST24. In1989, Beal et al. demonstrated that the striatal exci-

totoxin lesions caused by the injection of quinolin-ic acid (QA), resulted in relative sparing of the SSTand neuropeptide-Y (NPY) levels in rats25. Corticalinjections of certain agonists acting at the Glureceptors depleted the Glu and GABA levels, whilethe SST- and NPY immunoreactivity were eitherunchanged or significantly increased. Other N-methyl-D-aspartate (NMDA) excitotoxins, such asKA and alpha-amino-3-hydroxy-5-methyl-4-isoxa-zolepropionic acid (AMPA) caused significantdecreases in the concentration of SST26. ChronicQA-induced lesions resulted in similar alterations:elevated SST and NPY concentrations and reducedGABA, substance P-ir and choline acetyltrans-ferase activity27. The pattern of selective neuronaldamage caused in the cerebral cortex by NMDAreceptor agonists was similar to that observed inHD. However, there are contradictions, becausethere were no changes in SST, NPY or SP-ir withaging in the cerebral cortex or hippocampus follow-ing QA-induced striatal lesions28, but there are dif-ferent behavioral effects of KA- or QA-inducedstriatal lesions29.

Preclinical studies have indicated that thekynurenine pathway (KP) may be involved in themodulation of neuroendrocrine processes. Espe -cially the function of kynurenic acid (KYNA) as anew, potential neuroendocrine molecule is empha-sized. The main branch (approx. 95%) of the tryp-tophan (Trp) metabolism is the formation ofkynurenines. Trp may be converted to L-kynure-nine (KYN) by Trp- or indoleamine 2,3-dioxyge-nase (IDO) via a transition product. KYN serves asa key molecule between the neurotoxic and neuro-protective directions of the pathway. The neurotox-ic QA is produced from KYN via additional toxicmetabolites, which generate toxic free radicals,oxidative stress and lipid peroxidation, and henceexcitotoxicity. In contrast, the characteristicallyneuroprotective KYNA is formed directly fromKYN catalyzed by kynurenine aminotransferase(KAT) (Figure 2.)30. Most of the neuroprotective,antiexcitotoxic effects of KYNA are explained bythe inhibition of excitatory amino acid receptors. Ithas been proposed to act primarily as an antagonistat ionotropic AMPA and KA receptors, and as anoncompetitive antagonist at the strychnine-insen-sitive glycine-binding site of the NMDA receptors.KYNA can be an antagonist of the alpha7-nicotinicacetylcholine receptors, and a ligand for the orphanG protein-coupled receptors and the recentlyrevealed aryl hydrocarbon receptors31. There isextensive literature on the role of the KP in differ-ent neurological diseases. Its protective impacts areemphasized in HD32, Parkinson’s disease33,

Ideggyogy Sz 2014;67(3–4):107–112. 109


migraine34, 35, multiple sclerosis36, 37, schizophre-nia38, stroke39, 40 and epilepsy41, but its action inendocrine/neuroendocrine mechanisms has not yetbeen fully investigated.

In 1985, Rogers and Evangelista observed thatleucine-stimulated insulin release from rat pancre-atic islets can be inhibited by kynurenine metabo-lites (3-hydroxykynurenine and 3-hydroxyan-thranilic acid)42. The regulatory effects of QA wereinvestigated in ovariectomized, estradiol-primedrats. It was shown that icv. administered QAevoked an acute, dose-dependent increase of serumluteinizing hormone concentrations, which wasblocked by KYNA. Brain morphologic distur-bances were not detected in consequence of thetreatments43. The agonists and antagonists of Glureceptors regulate the hypothalamic-pituitary-adre-nal axis (HPA) by different subtypes of amino acidreceptors. Glu, KA and L-aspartate (Asp) signifi-cantly diminished the release of corticotropin-releasing hormone, while Asp and NMDA signifi-

cantly enhanced arginine-vasopressin release,whereas this was decreased by KA and quisqualicacid. KYNA completely abolished the effects ofAsp in connection with both neurohumoral activa-tors44. A human study has indicated that cytokinessuch as interferon- and interleukin-10 regulate theexpression of IDO in cells of hypothalamic andpituitary origin in connection with sickness behav-ior of patients45. In 2010, Oxenkrug observed simi-lar results: the pro-inflammatory cytokines facili-tate the activity of IDO, which shifts the Trp metab-olism to the formation of kynurenines. These mole-cules indirectly contribute to the development ofmetabolic syndromes and age-associated neuroen-docrine disorders via apoptotic, neurotoxic and pro-oxidative effects (Figure 3.). A genetic predisposi-tion to the presence of certain polymorphisms ofpro-inflammatory cytokine genes might lead to the“superinduction” of IDO46. The anxiolytic effects ofKYNA were recently evaluated in neonatal chicks.A stress model was developed by social isolation,which was augmented by icv. corticotropin-releas-ing hormone. The stress responses were decreasedby the icv. administration of Trp and (more effec-tively) KYNA. Attenuated distress vocalization,active wakefulness and increased time of sleepingposition were observed after the KYNA treatment.Moreover, a depressed plasma corticosterone con-centration was measured47. When the toxic rever-berations of the heavy oil spill near the northwestcoast of Spain (2002) were examined seven yearsafter the disaster from the aspects of endocrine andimmunological alterations, the biomarker analysesrevealed a significantly increased plasma level ofcortisol, and decreased level of KYN andCD16+56+lymphocytes in exposed vs. unexposedindividuals. More serious changes were observed inthe chronically contaminated subjects, which sug-gested a chronic elevation of HPA activity and thepossibility of endocrine diseases48.

In summary, it may be stated that there havebeen highly important developments in neuroen-


Figure 3. Relationship between kynurenines, metabolicsyndromes (MetS) and age-associated neuroendocrinedisorders (AAND) (Oxenkrug, G.F. Ann N Y Acad Sci,2010)

Figure 2. Main pathway of tryptophan-kynureninemetabolism


Ideggyogy Sz 2014;67(3–4):107–112. 111

docrinology since the early findings of Selye.Although there are as yet relatively few data aboutthe potential role of kynurenines in neuroen-docrinology, the results already achieved areextremely noteworthy and immensely promising.

ACKNOWLEDGEMENTThis work was supported by the following grants:TÁMOP-4.2.2. A-11/1/KONV-2012-0052, Neuro -science Research Group of the Hungarian Academyof Sciences and University of Szeged.

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39. Brouns R, Verkerk R, Aerts T, De Surgeloose D, Wauters A,Scharpe S, et al. The role of tryptophan catabolism alongthe kynurenine pathway in acute ischemic stroke. Neuro -chem Res 2010;35(9):1315-22.

40. Gigler G, Szenasi G, Simo A, Levay G, Harsing LG, Jr.,Sas K, et al. Neuroprotective effect of L-kynurenine sulfate

administered before focal cerebral ischemia in mice andglobal cerebral ischemia in gerbils. Eur J Pharmacol2007;564(1-3):116-22.

41. Demeter I, Nagy K, Gellert L, Vecsei L, Fulop F, Toldi J.A novel kynurenic acid analog (SZR104) inhibits pen -tylenetetrazole-induced epileptiform seizures. An electro-physiological study :special issue related to kynurenine. JNeural Transm 2012;119(2):151-4.

42. Rogers KS, Evangelista SJ. 3-Hydroxykynurenine, 3-hydroxyanthranilic acid, and o-aminophenol inhibit leu -cine-stimulated insulin release from rat pancreatic islets.Proc Soc Exp Biol Med 1985;178(2):275-8.

43. Johnson MD, Whetsell WO, Jr., Crowley WR. Quinolinicacid stimulates luteinizing hormone secretion in femalerats:evidence for involvement of N-methyl-D-aspartate-preferring receptors. Exp Brain Res 1985;59(1):57-61.

44. Patchev VK, Karalis K, Chrousos GP. Effects of excitato-ry amino acid transmitters on hypothalamic corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP)release in vitro:implications in pituitary-adrenal regulation.Brain Res 1994;633(1-2):312-6.

45. Tu H, Rady PL, Juelich T, Smith EM, Tyring SK, HughesTK. Cytokine regulation of tryptophan metabolism in thehypothalamic-pituitary-adrenal (HPA) axis:implicationsfor protective and toxic consequences in neuroendocrineregulation. Cell Mol Neurobiol 2005;25(3-4):673-80.

46. Oxenkrug GF. Metabolic syndrome, age-associated neuroen-docrine disorders, and dysregulation of tryptophan-kynure-nine metabolism. Ann N Y Acad Sci 2010;1199:1-14.

47. Yoshida J, Tomonaga S, Ogino Y, Nagasawa M, Kurata K,Furuse M. Intracerebroventricular injection of kynurenicacid attenuates corticotrophin-releasing hormone-augment-ed stress responses in neonatal chicks. Neuroscience 2012;220:142-8.

48. Laffon B, Aguilera F, Rios-Vazquez J, Garcia-Leston J,Fuchs D, Valdiglesias V, et al. Endocrine and immunolog-ical parameters in individuals involved in Prestige spillcleanup tasks seven years after the exposure. Environ Int2013;59:103-11.



Ideggyogy Sz 2014;67(3–4):113–115. 113

SELYE SYMPOSIUM

A PSYCHIATRIST’S PERSPECTIVES ON STRESS, STEROIDSAND MENTAL ILLNESS

Magdolna DUNAI Department of Psychiatry, Stanford University School of Medicine, USA

A STRESSZ, A SZTEROIDOK ÉS A MENTÁLISBETEGSÉGEK PSZICHIÁTRIAI SZEMPONTBÓLDunai M, MDIdeggyogy Sz 2014;67(3–4):113–115.

Kiterjedten vizsgálták az összefüggést a stressz és a mentálisbetegségek között, és egyre inkább egyetértés van abban,hogy a mentális betegségek kialakulása inkább bizonyosfaktorok kombinációjától, nem pedig stresszt jelentô külsôeseményektôl függ. A major depresszióban és bipoláriszavarban szenvedôk esetében a hypothalamus-hypophy sis-mellékvese tengely jelentôs rendellenességeit figyelték meg.Mindkét zavarban a kortizolszint változásának a mértékeösszefüggésben állt a betegség súlyosságával és a kognitívváltozásokkal. A szintetikus szteroidok exogén használatagyakran súlyos pszichiátriai tüneteket eredményez. Tehát aszteroidhormonok szintjének a változása agyi károsodástokozhat.

Kulcsszavak: stressz, mentális betegség, szteroidhormonok,major depresszív zavar, bipoláris zavar, exogén szteroidok, kognitív tünetek

The relationship between stress and mental illness has beenextensively studied and there is a growing consensus thatthe occurrence of mental illness rather depends on a com-bination of factors than is caused by stressful externalevents. Significant hypothalamus pituitary adrenal axisabnormalities were observed among others in majordepressive disorder and bipolar disorder. In both disorders,the extent of change in cortisol level was related to theseverity of illness and to cognitive changes. Exogenous useof synthetic steroids also frequently resulted in severe psychi-atric symptoms. In conclusion changes in the level of steroidhormones may cause impairments in the brain.

Keywords: stress, mental illness, steroid hormones, major depressive disorder, bipolar disorder, exogenous steroids, cognitive symptoms

Correspondent: Magdolna DUNAI, MD, Department of Psychiatry, Stanford University School of Medicine; USA, E-mail: [email protected]


www.elitmed.hu

Among the subspecialties of medicine it is inpsychiatry that patients present most frequent-

ly with the subjective experience of being in astressful state and attribute their symptoms to that.Psychological stress indeed has an important role inboth the onset and course of mental illness. Thisincludes the whole spectrum of diagnostic cate-gories, but it is most significant for the mood andanxiety disorders, schizophrenia, substance abuseand eating disorders. Does it cause mental illness?

Stress steroids and mental illnesses

In order to evaluate the impact of stress it is impor-tant to separate the event, namely the stressor fromthe resulting subjective strain, which is theresponse1.

Stressors have been most studied related to lifeevents with attempts to classify them. According tosome the severity of a stressor has been the mostimportant, and life events were scored, with a prog-

dunai_UJ ISZ TUKOR ALAP ANGOL.qxd 2014.03.21. 16:08 Page 113

nostic value to develop an illness e.g. SocialReadjustment Rating Scale by Holmes, Rahe2.Others emphasized the importance of certain quali-ties of stressors, like desirable or undesirable byPaykel3. Events resulting in a loss with long termconsequences, or those causing feelings of humilia-tion, being trapped, or eliciting a sense of dangerwere thought to have the greatest impact. Theresponse to stressors though can vary to a greatextent among different individuals, and not every-one will develop psychiatric symptoms. One of thereasons for that may be that a particular stress willnot hold the same importance for everybody4. It isalso true that both positive and negative events canprecipitate most mental disorders, and the severityof mental illness can be quite disproportionate tothe stressor. More than that, most psychiatric symp-toms also present without a stressor.

Therefore there is a growing consensus thatexternal events by themselves may not be sufficientto cause mental disorders. Rather a combination offactors has to coexist.

The occurrence of mental disorder depends onthe combination of such factors as: genetics, childrearing practices, psychological and social stres-sors, and physical disorders, with a unique combi-nation for the person and time of his lifespan5.

Stress elicits an endocrine response resulting inelevated cortisol levels and changes in the levels ofsteroid hormones have been also observed in multi-ple forms of mental illness. A correlation betweenthe hypersecretion of cortisol and depression is oneof the oldest observations in biological psychiatry.The most severe form of depression, the psychoticmajor depression (PMD) is a model of chronichypercortisolemic state.

Dr Alan Schatzberg, in his study (Figure 1.) atStanford, has shown that evening cortisol levels

were highest in the psychotic depressed group, andhigher than normal in the depressed group.

The Dexamethason Suppression Test alsodemonstrates increased resistance to the negativefeedback of the exogenously administered gluco-corticoid dexamethasone.

In Figure 2, about 40% of depressed patientsand 60% of psychotic depressed patients fail tohave a normal suppression response. This findingsuggests that the hormonal response seems to corre-late with the severity of depression7.

Major cognitive, neuropsychological deficitswere found in psychotic depression. Specifically,working memory, attention, and executive functionwere affected with a correlation regarding elevatedcortisol levels8. Another proof for glucocorticoidinvolvement in depression is the new therapeutictrial with the glucocorticoid receptor blockerMifepristone. It demonstrates promising results inreducing both depressive symptoms and improvingcognitive function9.

There is an even higher level of endocrine abnor-mality in bipolar disorder10.

In this illness depressed, manic and euthymicstates alternate and the manic phase can presentwith elated or irritable or sad mood. This last formof mania with sad mood is called the mixed state.Characteristics of Hypothalamus Pituitary Adrenal(HPA) axis abnormalities in bipolar disorder are thefollowing: Endocrine dysfunction is more pro-nounced in the depressed state of bipolar disorderthan in unipolar depression. Circadian hyper-secre-tion of cortisol occurred in all phases of bipolar dis-order. This means that higher levels of cortisol arenot characteristic of the depressed state; they arenot state markers. The severity of clinical symp-

114 Dunai: A psychiatrist’s perspectives on stress, steroids and mental illness

Figure 1. Stanford PMD study6

Figure 2. DST non-suppression in 14 comparison stud-ies


Ideggyogy Sz 2014;67(3–4):113–115. 115

toms correlates with basic cortisol levels. In irrita-ble and mixed forms of mania, HPA changes aresimilar to the depressed state, while in elated maniaresults are variable. Endocrine abnormalities maynot normalize even with successful treatment.Recurrence of endocrine abnormalities duringremission is indicative of a new relapse. Based onthese findings HPA dysfunction may be a potentialtrait marker in bipolar disorder10.

Severe psychiatric symptoms can be seen as aresult of treatment with synthetic steroids e.g. glu-cocorticoids, androgens11, 12. These medications areused to treat a multitude of disorders and frequent-ly cause psychiatric symptoms as a side effect. Theweighted incidence of severe psychiatric symptomswhen treated with synthetic glucocorticoids is 6%with a distribution of: major depression (40%),mania (25%), paranoid psychosis (15%), and delir-ium (10%) of all cases.

Three percent of patients commit suicide, butearly treatment is efficient for most cases.

Symptoms are dose dependent (BostonCollaborative Surveillance Study). Mental changescan occur at any time during treatment, and no rela-tionship exists between symptoms during the firstand subsequent courses of treatment. Previous psy-chiatric history does not predict development ofpsychiatric symptoms, and the majority of patientsdo not even have a prior psychiatric history.

In conclusion we can state that changes in thelevels of steroid hormones due to stress or otherpathophysiology may impair the brain13. It is due totheir wide-ranging metabolic effects that the pre-sentations and course of steroid psychoses maychange so dramatically. More cross-disciplinaryresearch is needed between clinical studies and neu-roscience in order to better understand the underly-ing biology of mental illness.

REFERENCES1. Herbert J. Stress, the brain, and mental illness. BMJ 1997;

315:530-5.2. Holmes ThH, Rahe RH. The social readjustment. Scale J

Psychosom Res 1967;11:213-8.3. Paykel ES. Life events and social stress. Handbook of

affective disorders. 2nd ed. London: Churchill Livingstone;1992. p. 149-70.

4. Fisher S, Reason J. Handbook of life, cognition and health.Chichester: Wiley; 1988.

5. Kaplan and Saddock’s Synopsis of Psychiatry 2007.6. Schatzberg A, Posener J, De Battista C. Neuro -

psychological deficits in psychotic vs nonpsychotic majordepression and no mental illness. Am J Psych2000;157:1095-100.

7. Nelson JC, Davis JM. Dexamethason studies in psychoticdepression a meta-analysis. AJP 1997;154;1497-503.

8. Belanoff JK, Kalehzan M. Cortisol activity and cognitivechanges in psychotic major depression. Am J Psych2001;158:1612-6.

9. Flores BH, Kenna H, Keller J, Solvason B, Schatzberg A.Clinical and biological effects of Mifepristone treatmentfor psychotic depression. Neuropsychopharmacology2006;31(3):628-36.

10. Daban C, Vieta E, Mackin P, Young A, Phil M.Hypothalamic-pituitary-adrenal. Axis and BipolarDisorder. Psychiatr Clin N Am 2005;28:469-80.

11. Hall RCW, Beresford TP. Psychiatric Manifestations ofPhysical Illness. Psychiatry Vol 2. Philadelphia, Chapter88. 1989.

12. Lewis DA, Smith RE. Steroid induced psychiatric syn-dromes. J Affect Dis 1983;5:319-32.

13. Sapolsky RM. Why stress is bad for your brain. Science1996; 273:749-50.


116 Palkovits: Catecholamines and stress

SELYE SYMPOSIUM

CATECHOLAMINES AND STRESS Miklós PALKOVITSHuman Brain Tissue Bank and Laboratory, Semmelweis University, Budapest

A KATECHOLAMINOK ÉS A STRESSZPalkovits M, MD, DsCIdeggyogy Sz 2014;67(3–4):116–120.

A közlemény rövid áttekintést ad a stresszvizsgálatok ésstresszelméletek két régóta vitatott kérdésérôl: 1. a stressz,illetve a stresszre adott válasz alapjában véve specifikusnakvagy heterogénnek tekinthetô-e, és 2. mi a funkcionálisszerepe és jelentôsége a központi idegrendszeri kate-cholaminneuronoknak a stressz-szignál továbbításában és astresszre adott válasz realizálódásában?

Kulcsszavak: stressz, ascendáló katecholamin-rendszer,descendáló katecholamin rendszer, hypothalamus-hypophysis-mellékvese (HPA-) tengely

A brief survey is offering of debates on two long-standingquestions in stress studies and theories: 1) question of stressnonspecificity (i.e. homo- or heterogeneity in stress respons-es), and 2) what is the functional role of central cate-cholamines in stress mechanisms, especially in stress signal-transduction and in the realization of stress responses.

Keywords: stress, ascending catecholamine system,descending catecholamine system, hypothalamo-pituitary-adrenal (HPA) axis

Correspondence: Miklós PALKOVITS, MD, DSc, Human Brain Tissue Bank and Laboratory, Semmelweis University; H-1094 Budapest, Tûzoltó u. 58.

Phone: +36-1-216-0488, fax number: +36-1-218-1612E-mail: [email protected]


www.elitmed.hu

During the first half of the 20th century, withinten years, two theories were introduced about

external and internal factors that may influence thebody homeostasis. One of the theories was intro-duced by Cannon1 who used the term fight-or-flight, the other theory was published by Selye2 whocalled this phenomenon stress. The basic idea ofthese two theories was almost the same: the organ-ism may react somehow to the extremely variablestimuli that arise either from outside or inside thebody. Their explanations on the mechanisms ofresponses however, were completely different.Cannon underlined the role of the sympatheticnervous system, the adreno-medullary cate-cholamines, while Selye preferred the anterior pitu-itary-adrenocortical system that produces corticos-teroids. Selye considered the adrenal cortex to bethe organ of integration during stress.

Selye’s view on catecholamines in the stress was

“minimal”. Although, he recognized fromCannon’s work that stressors elicit neuronallymediated sympatho-adrenal responses, he neverincorporated this finding properly in his stress the-ories.

Cannon was the first to introduce the term“homeostasis”. He concentrated on the role of theadrenal medulla in fight-or-flight reaction1 (thisphrase was used for all type of reactions that maychange body homeostasis before the term stress hasbeen introduced by Selye in 19362), Selye turned tothe adrenal cortex, as a key participant of the ante-rior pituitary-adrenocortical (HPA) axis. Thus,Selye’s studies were focused to corticosterone withrelatively minor respect to adrenaline or noradrena-line. Cannon never used the term “stress”.

The first description of adrenaline3 (this is amilestone study. Unfortunately, the contribution ofKálmán Lissák in the first description of brain

palkovics_UJ ISZ TUKOR ALAP ANGOL.qxd 2014.03.21. 16:09 Page 116

adrenaline neurons has been almost forgotten),noradrenaline4 in nerve fibers, and their present andactivation in the brain5, as well as their inactivationby both neuronal reuptake and/or by enzymaticdegradation6, 7 clearly demonstrated the functionalsignificance of these substances in neuronal mech-anisms that basically influence the body homeosta-sis. Selye recognized these studies, he admired thework of Axelrod. Although, he did not spent toomuch time with working on catecholamines, hadhigh respect to Julius’s work. Fair, almost friendlyconnection existed between these two giants.Axelrod never performed studies on any kind ofstress but he favored Selye’s idea. I remember to hisshort comment about Selye: “He introduced some-thing very important in science that always existedin life. He is fantastic, a genius, but somewhat he isa very complicated man.”

The obvious question has been raised: Why didSelye make a relatively little attention on brain-born adrenaline and noradrenaline in stress? It ismost probably that the lack of routine techniquesfor measuring micro quantities of released cate-cholamines from the sympathoneural or adreno -medullary systems that time, Selye whose mind andworking attitude preferred the exact, visible andmeasurable parameters in his studies, did not con-sider central catecholamines as major factors in thestress mechanism, at least not that time when heintroduced his stress story.

Stress specificity or nonspecificity

Hans Selye was an extraordinarily active researcherwho was able to brilliantly popularize his theory asa medical and scientific idea. In 1936, when Selyeformulated his stress definition, he named threeobjective indicators that could be recognized nomatter how stress was produced: the activation ofthe HPA axis, involution in the thymicolymphaticsystem, and gastrointestinal peptidergic ulcer. Thisstatement became later the “stress nonspecificity”or “stress homogeneity” theory. This dogma be -came extraordinarily popular, it is hard to find anysimilar in the neuroscience.

When Selye’s doctrine was formulated, onlythree objective indicators existed that could be rec-ognized no matter how stress was produced. Latermore and more data and observations have beenpublished indicating the existence of a variety typeof stressors with different targets and differenteffects on the homeostasis. For review, seeKvetnansky et al., 20098 and Pacak and Palkovits,20019. In 1998, the Selye’s doctrine of nonspecifici-

ty underwent systematic experimental testing,which failed to confirm it10.

Based on measurements of plasma levels ofadrenaline, noradrenaline, catecholamine precur-sors, and metabolites in stress, it is generallyaccepted that sympatho-adrenomedullary systemand sympatho-neuronal system (HPA axis) arespecifically, and somewhat independently, activat-ed by different stressors. Exposures to cold evoke aselective activation of sympatho-neuronal system,as indicated by elevated plasma noradrenaline lev-els, whereas insulin-induced glucoprivation oremotional stressors activate sympatho-adreno -medullary system, as indicated by plasma adrena-line responses. Other stressors, such as restraint orformalin-induced pain, activate both systems.Immobilization represents a severe stress that elic-its an extremely large increase in plasma adrenalineand noradrenaline. Results from a variety of studiesindicate that not only the peripheral but also thecentral catecholamine system and the hypothalam-ic-pituitary-adrenal (HPA) axis respond specifical-ly to different stressful stimuli. An intact HPA axisis essential for the activity of PNMT, the enzymeresponsible for adrenaline synthesis in the adrenalmedulla. Thus, depending on the nature and the tar-get sites of various stressors, the two systems maybe regulated by different central pathways10, 11.

One point, however, should be mentioned. Selyehimself treated and explained his doctrine of non-specificity different way in 1936 than in 1980. Hewrote in 1980: „Stress is nonspecific. This does notmean that all stress situations are identical becausestress is never seen in isolation. You cannot pro-duce stress in pure form without using a stressor,and the latter necessarily always has specificeffects12.” … “The fact that all stress situations areapparently different does not nullify their nonspeci-ficity. … This is explained by two circumstances:(A) the stressor is always accompanied by specificside effects; (B) both internal and external predis-posing factors modify the response12.”

Brain catecholamines in stress

To maintain homeostasis, the sympathetic nervoussystem responds to several different types of senso-ry inputs. Brain adrenergic and noradrenergic neu-rons are involved in the central processing of stressresponses. For review, see Kvetnansky et al., 20098

and Pacak and Palkovits, 20019. Activation of thesympathetic nervous system leads to the outflow ofadrenaline from the adrenal medulla and outflow ofnoradrenaline from the varicosities of the sympa-

Ideggyogy Sz 2014;67(3–4):116–120. 117



thetic postganglionic axons. In response to acutestressor, large amounts of adrenaline and noradren-aline are released. Depending on the nature, theintensity, the duration of stressful stimuli, levels ofadrenaline and noradrenaline in the plasma mayincrease from ten to several hundred folds.

The brain catecholamine system can be dividedinto two major parts, according to their projectionsand innervation patterns. One group, the ascendingcentral catecholamine system constituted by theA1, A2, noradrenaline, C1 caudal and C2 adrena-line cell groups, and the major part of the locuscoeruleus in the lower brainstem innervates theforebrain, the hypothalamus including the paraven-tricular nucleus (Figure 1A, 1C). Axons from theseneurons receive direct somato- and viscerosensoryinputs. Their activation is stressor-specific, thesefibers represent a part of the stress-signal routes.That constitute a part of the ascending reticular acti-vating system innervate – among many otherregions – the HPA axis. The paraventricular nucle-

us, as the central part of the HPA axis receives,beside catecholamines several neuronal inputs fromlimbic and cortical brain areas and humoral inputs,i.e. CRH, ACTH or corticosteroid feedback(Figure 2.).

High number of noradrenaline (A5, A7, caudallocus coeruleus) and adrenaline (C1) neurons con-stitute the descending central catecholamine sys-tem, that project to the sympathetic preganglionicneurons in the intermediolateral cell column of thethoracic spinal cord (Figure 1B and Figure 3.).Neurons of this descending system receive neuronalinput from the paraventricular nucleus (Figure 3.).Neurons in the paraventricular nucleus have alsodirect projections to the sympathetic preganglionicneurons (Figure 3.), i.e. they may act directly, assympathetic premotor neurons.

The sympathoadrenal system is composed ofsympathetic preganglionic neurons in the IML cellcolumn and the chromaffin cells of the adrenalmedulla (Figure 3.). The activation of sympathetic

Figure 1. Stress signal routes and pathway in stress response. Figure A and B: red – noradrenaline projections;green – adrenaline projections. Figure B: blue – paraventricular projections to the locus coeruleus and A5 cellgroup. Figure C: 1. stressful stimuli; 2. projections to higher brain centers – ascending catecholamine projectionsfrom the lower brainstem; 3. hypothalamo-anterior pituitary-adrenal cortex axis (HPA axis); 4. anterior pituitary-adrenomedullary connection (ACTH action on the adrenal medulla); 5. PVN projections to descending CA-projec-tion neurons (to premotor sympathetic neurons); 6. direct PVN projection to spinal preganglionic sympathetic neu-rons; 7. projections of premotor sympathetic neurons to the spinal preganglionic sympathetic neurons (descendingcatecholamine pathway); 8. sympathetic preganglionic fibers to the adrenal medulla; 9. preganglionic sympatheticfibers; 10. postganglionic sympathetic fibers

A1-A7: A1-A7 noradrenaline cell groups (A6c – caudal portion of the locus coeruleus); C1-C3: C1-C3 adrenaline cell groups (C1c – caudal, C1r– rostral portions of C1 cell group); CA: catecholamines; CORT: corticosterone; EPI: adrenaline; LC: locus coeruleus; NA: noradrenaline; PVN:paraventricular nucleus; SC: subcoeruleus area


Ideggyogy Sz 2014;67(3–4):116–120. 119

preganglionic neurons is controlled by distinct neu-ronal cell groups, called premotor sympathetic cellgroups, probably by distinct neurotransmitters. Thepremotor sympathetic neurons used to be classifiedas catecholaminergic and non-catecholaminergic.

Although, most of the forebrain regions, includ-ing those are classified into the “limbic system”

control the sympathetic outflow, they do not direct-ly innervate spinal preganglionic sympathetic neu-rons. They exert their actions through by way of thehypothalamus, actually through paraventricularneurons (PVN). Cortical projections to the PVNmainly arise in the prefrontal cortex and the anteri-or cingulate cortex. The hippocampus and theamygdala reach the PVN through the bed nucleusof the stria terminalis. The paraventricular premotorsympathetic neurons are peptidergic.

For detailed description of the sympathoadrenalsystem, as neuronal arm of the stress response,please see the Encyclopedia of Neuroscience.11

Just one further note: Introducing new imageanalyzing techniques, especially the functionalmagnetic resonance imaging one, brought new pos-sibilities in stress studies. These techniques provideus unique information about the activity of the “liv-ing” human brain.

To complete this brief overview, may cite two

Figure 2. Neuronal connections of the paraventricularnucleus (PVN). 1-3. Hypothalamo-anterior pituitary-adrenal medullary (HPA) axis; 4. glucocorticoid feed-back; 5. corticoids in the circulation; 6. ascending cate-cholamine projections from brainstem NA and EPI neu-rons to the PVN; 7. PVN projections to premotor sympa-thetic preganglionic neurons (locus coeruleus, A5 NAand C1 EPI cell groups) in the lower brainstem; 8.ascending CA projections from the lower brainstem tolimbic and cortical areas; 9. central amygdala + BSTprojections to the lower brainstem; 10. stria terminalis;11. direct amygdala projections to the PVN; 12. pre-frontal projections to the amygdala; 13. prefrontal pro-jections to the BST; 14. prefrontal projections to peri-PVN GABAerg neurons; 15. hippocampal projections toperi-PVN GABAerg neurons; 16. hippocampal projec-tions to the BST; 17. fimbria/fornix; 18. direct BST pro-jections to the PVN; unlabeled arrows – projections toperi-PVN GABAerg neurons; unlabeled double arrows –peri-PVN GABAerg projections to the PVN

BST: bed nucleus of the stria terminalis; CA: catecholamine; EPI:adrenaline; NA: noradrenaline

Figure 3. Sympathetic premotor projections in the sym-patho-adrenal and sympatho-neuronal system11 with modifica-

tions. Blue-red-violet: HPA axis; red: paraventricularprojections to brainstem sympathetic premotor neuronsand direct projections to sympathetic preganglionic neu-rons; black: locus coeruleus and A5 catecholamine pro-jections to sympathetic preganglionic neurons; yellow:sympatho-adrenal system – preganglion projections tothe adrenal medulla; green: preganglionic sympatheticfibers; blue: postganglionic sympathetic fibers; red:release of noradrenaline and adrenaline from the adre-nal gland

A: adrenaline; A5: A5 catecholamine cell group; C: corticosterone; C1:C1 adrenaline cell group; CRH: corticotropin-releasing hormone; IML:intermediolateral cell column (with sympathetic preganglionic neu-rons); LCc: caudal cell group in the locus coeruleus; PVN: paraventric-ular nucleus; SG: sympathetic ganglion; V: varicosities on noradrener-gic axons; VP: vasopressin



sentences from Selye12 which express his objectivesin stress studies and thinking about stress and life:

1) “From laboratory and clinical work on stresswe have tried to arrive at a code of ethics founded,not on the traditions of our society, not inspirationor blind faith in the infallibility of the teachings ofany particular prophet, or religious leader or man-made political doctrine, but on the scientificallyverifiable laws of Nature that govern the body’sreactions in maintaining homeostasis and living insatisfying equilibrium with its surroundings.”

2) “Find your own natural stress level and runtoward what you accept as your own goal. …

Granted, this is difficult and takes much time, buttoo many people suffer all their lives because theyare too conservative to risk a radical change andbreak with tradition.”

ACKNOWLEDGEMENTThis paper is based on the lecture untitled TheAxelrod-Selye connection: Catecholamines andsteroids presented in the Selye-Szimpózium 2013 atthe Hungarian Academy of Sciences.

The author is grateful for Magdolna Toronyay-Kasztner for her technical help to complete both thepresented and written materials.

REFERENCES1. Cannon WB. Organization for physiological homeostasis.

Physiol Rev 1929;9:399-431.2. Selye H. A syndrome produced by diverse nocious agents.

Nature 1936;138:32.3. Cannon WB, Lissak K. Evidence for adrenaline in adrener-

gic neurons. Am J Physiol 1939;125:765-77.4. von Euler US. A specific sympathomimetic ergone in

adrenergic nerve fibres (sympathin) and its relations toadrenaline and noradrenaline. Acta Physiol Scand1946;12:73-96.

5. Vogt M. Norepinephrine and epinephrine in the centralnervous system. Pharmacol Rev 1954;6:31-2.

6. Axelrod J. O-methylation of (epinephrine and other cate-cholamines) catecholamines in vitro and in vivo. Science1957;126:400-1.

7. Axelrod J, Weil-Malherbe H, Tomchick R. The physiologi-cal disposition of H3-epinephrine and its metabolitemetanephrine. J Pharmacol Exp Ther 1959;127:251-6.

8. Kvetnansky R, Sabban EL, Palkovits M. Catecholaminergicsystems in stress: structural and molecular geneticapproaches. Physiol Rev 2009;89:535-606.

9. Pacak K, Palkovits M. Stressor specificity of central neu-roendocrine responses: implications for stress-related dis-orders. Endocr Rev 2001;22:502-48.

10. Pacak K, Palkovits M, Yadid G, Kvetnansky R, Kopin IJ,Goldstein DS. Heterogeneous neurochemical responses todifferent stressors: a test of Selye’s doctrine of nonspeci-ficity. Am J Physiol Regul Integr Comp Physiol1998;275:R1247-R1255.

11. Palkovits M. Sympathoadrenal system: Neural arm of thestress response. In: Squire LR (ed.). Encyclopedia ofNeuroscience. Oxford: Academic Press; 2009. p. 679-84.

12. Selye’s Guide to Stress Research. Selye H (ed.). NewYork: Van Nostrand Reinhold; 1980.


Ideggyogy Sz 2014;67(3–4):121–123. 121

SELYE SYMPOSIUM

THE SURPRISING DUAL ACTION OF GLUCOCORTICOIDSLudmila FILARETOVA1, Gábor MAKARA2

1Pavlov Institute of Physiology, Russian Academy of Sciences, St. Petersburg, Russia2Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary

A GLÜKOKORTIKOIDOK MEGLEPÔ KETTÔS HATÁSAFilaretova L, PhD, DSci; Makara G, MDIdeggyogy Sz 2014;67(3–4):121–123.

A glükokortikoid hormonok kettôs hatást fejtenek ki agyomorra: élettani gyomorvédô és kóros proulcerogénhatást. Élettani körülmények között, még akut stressz -helyzetben is, a glükokortikoidok adaptív hatást, ezáltalvédelmet fejtenek ki a gyomorra. A most áttekintett ered-mények azt mutatják, hogy az akut stressz során felsza -baduló glükokortikoidok természetesen elôforduló védôfak-torok, amelyek fontos szerepet játszanak a gyomornyálka-hártya integritásának a fenntartásában.

Kulcsszavak: Selye János, stressz, hypothalamus-hypophysis-mellékvese tengely, glükokortikoidok, nemszteroid gyulladásgátlók, gyomoreróziók, gyomorvédelem

Glucocorticoid hormones may have dual action on thestomach: physiological gastroprotective and pathologicalproulcerogenic one. In physiological conditions, even inacute stress situations, glucocorticoids have an adaptiveeffect on the stomach and, therefore, are gastroprotective.The findings that we review in this article suggest that gluco-corticoids released during acute stress are naturally occur-ring protective factors that play an important role in mainte-nance of the gastric mucosal integrity.

Keywords: Hans Selye, stress, the hypothalamic-pituitary-adrenocortical axis, glucocorticoids, non-steroidalanti-inflammatory drugs, gastric erosion, gastroprotection

Correspondent: Ludmila FILARETOVA PhD, DSci, Pavlov Institute of Physiology; Nab. Makarova 6, St. Petersburg,199034, Russia. Fax: +7-812-328-05-01, e-mail: [email protected]


www.elitmed.hu

The gastrointestinal tract in general and the stom-ach in particular is extremely sensitive to a vari-

ety of stress situations. Gastric ulcer disease, whichis a very common pathology, is regarded as a“stress disease”. Despite indubitable advances inelucidation of the pathogenesis of gastric ulcera-tion, there are gaps in our understanding of ulcero-genesis, particularly, the role of key hormonal sys-tem of adaptation: the hypothalamic-pituitary-adrenocortical (HPA) axis, and consequently, glu-cocorticoid hormones.

Glucocorticoids and gastric ulceration have beendiscussed in many contexts. The action of acute andchronic treatment of patients or experimental ani-mals with glucocorticoids as well as the effects ofbasal and stress-induced glucocorticoid productionon the gastric mucosa has been considered.Although there is a long-standing debate overwhether glucocorticoid therapy by itself leads to

peptic ulcer disease in human, it is established thatadministration of glucocorticoids to experimentalanimals can result in an acute gastric erosion forma-tion1. In the same time, in some cases administra-tion of glucocorticoids to animals can attenuate gas-tric erosion2, 3. It is also known that basal glucocor-ticoid production contribute to the maintenance ofthe gastric mucosal integrity. The glucocorticoidsmay have a permissive role in allowing gastropro-tective mechanisms to exert their full potential. Apermissive role of glucocorticoids in gastric mucos-al protection induced by prostaglandins, sulfhyd -ryls, cimetidine was demonstrated for the first timeby Szabo et al4.

The most controversial question is the questionabout the action of stress-produced glucocorticoids.For several decades it was generally accepted thatglucocorticoids released during stress are ulcero-genic hormones. Main approach used to support

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this view was a groundless extrapolation of theulcerogenic properties of exogenous glucocorti-coids observed at high pharmacological doses to theproperties of endogenous glucocorticoids releasedduring stress.

As the widely held view about the ulcerogenicrole of glucocorticoids released during stress is dif-ficult to reconcile with the adaptive role of HPAaxis hormones, we performed experiments in rats toclarify the validity of this view. The resultsobtained do not support the traditional view andsuggest that glucocorticoids released during acuteactivation of the HPA axis are important gastropro-tective factors.

Gastroprotective action of glucocorticoids released during acuteactivation of the HPA axis

Stressful stimuli activate the HPA axis, and conse-quently, the production of glucocorticoids andsevere stress stimuli may also induce gastric ero-sion, called “stress ulcers”. Hans Selye, the“Father” of the field of research into stress, attract-ed attention to these signs of stress. His greatestcontributions were the demonstration of the stresstriad (gastrointestinal ulceration, thymico-lymphat-ic atrophy, and adrenal hypertrophy) and of the roleof the hypothalamus in activating the hypophysis,which, in turn, stimulates the adrenals to producecorticoids5, 6.

From the very outset, researchers have focusedon the idea that stress-produced glucocorticoids arecausally related with gastric ulcerogenesis. Thispossibility was also investigated in hypophysec-tomized and adrenalectomized animals by Selyehimself, who observed that although stress-inducedthymico-lymphatic atrophy was inhibited in theseanimals, “stress ulcers” were not prevented, andconcluded that the formation of “stress ulcers”depends on not only the pituitary-adrenal axis butother factors as well5. Nevertheless for a long timestress-produced glucocorticoids were considered asulcerogenic hormones.

From the beginning7, we have focused on theidea that glucocorticoids released during acutestress also have an adaptive effect on the stomachand, therefore, are gastroprotective rather thanulcerogenic. To test this hypothesis, we examinedthe effect of glucocorticoid deficiency or the gluco-corticoid receptor antagonist RU-38486 on waterand immersion-restraint-induced or cold-restraint-induced gastric erosion in rats. Different approach-es were used to inhibit the stress-induced release of

corticosterone: the inhibition of corticotropin-releasing hormone synthesis in the hypothalamicparaventricular nucleus by intrahypothalamicimplantation of dexamethasone, the creating alesion on the hypothalamic paraventricular nucleus,the immunoneutralization of ACTH by pretreat-ment with ACTH antiserum, and the inhibition ofthe HPA axis at the hypothalamic and the pituitarylevels by pretreatment with a pharmacological doseof cortisol one week before stress. Corticosteronereplacement, that is, the injection of corticosteroneat a dose mimicking the stress-induced rise in corti-costerone was used in our experiments7-9.

The data obtained show that the reduction in thestress-induced corticosterone release (by anyapproaches as stated above), as well as preventionof its actions (by glucocorticoid receptor antago-nist), aggravates stress-caused gastric erosion7-9. Itis suggested that an acute increase in corticosteroneduring stress protects the gastric mucosa againststress-induced injury.

Further support for the point of view that gluco-corticoids released during acute stress are gastro-protective factors came from our results demon-strated that glucocorticoids contribute to gastropro-tective effect of preconditioning mild stress.Indeed, we demonstrated that mild stress decreasedthe gastric ulceration caused by severe stress andthis effect was prevented by glucocorticoid defi-ciency during mild stress10.

Non-steroidal anti-inflammatory drugs (NSAIDs)as well as stressful lifestyle make significant contri-butions to gastric ulcer disease. We demonstratedthat NSAIDs, similar to stress, induce an increase inglucocorticoid production that in turn helps the gas-tric mucosa to resist the harmful actions of thesedrugs11-13. It has been considered previously thatcombined NSAIDs treatment with therapeuticdoses of glucocorticoid increases the risk of gastriculceration. The results obtained in our studies11-13

suggest that the increased risk of adverse gastricreactions should be considered when NSAIDs areused in patients with impaired glucocorticoid pro-duction.

According to our data gastroprotective effect ofglucocorticoids may be mediated by multipleactions, including maintenance of gastric mucosalblood flow, mucus production, and attenuation ofenhanced gastric motility and microvascular perme-ability14, 15. In addition, glucocorticoids releasedduring acute activation of the HPA axis may con-tribute to protection of the gastric mucosa by main-taining general body homeostasis, including glu-cose levels and systemic blood pressure, whichcould be fundamental to their beneficial influence

122 Filaretova: The surprising dual action of glucocorticoids


on gastric mucosal integrity14, 15. Furthermore, glu-cocorticoids exert a compensatory gastroprotectiverole in the case of impaired gastroprotective mech-anisms provided by prostaglandins, nitric oxide,and capsaicin-sensitive sensory neurons16. Thesefindings support idea that gastroprotective action ofglucocorticoids is an essential element of their gen-eral adaptive action.

Thus, the results obtained in our studies suggestthat glucocorticoids released during acute activa-tion of the HPA axis are naturally occurring protec-tive factors that play an important role in mainte-nance of the gastric mucosal integrity.

Conclusions

An acute stress-induced increase of glucocorticoidshas a gastroprotective action against stress-inducedgastric injury but is not ulcerogenic, as it has gener-ally been considered for some decades. Beneficial

action of high levels of endogenous glucocorticoidsreleased during acute stress on the gastric mucosa isopposite to the deleterious actions of exogenousglucocorticoids at pharmacological doses used as ahormonal therapy.

Thus, in general glucocorticoid hormones mayhave dual action on the stomach: physiological gas-troprotective and pathological proulcerogenic one.In physiological conditions, even in acute stress sit-uations, glucocorticoids have an adaptive effect onthe stomach and, therefore, are gastroprotective,while in some situations their action on the gastricmucosa may become proulcerogenic. It is importantto understand how physiological gastroprotectiveaction can be transformed to pathological proul-cerogenic effect. This question is under our consid-eration [Filaretova et al. 2009].

ACKNOWLEDGEMENTSThis work was supported by Programs of PresidiumRAS 7P and 5P, grant of RFBR-13-04-01680-a.

Ideggyogy Sz 2014;67(3–4):121–123. 123

REFERENCES 1. Bandyopadhyay U, Biswas K, Bandyopadhyay D, Ganguly

CK, Banerjee RK. Dexamethasone makes the gastricmucosa susceptible to ulceration by inhibitingprostaglandin synthetase and peroxidase - two importantgastroprotective enzymes. Mol Cell Biochem 1999;202:31-6.

2. Hernandez DE, Adcock JW, Nemeroff CB, Prange AJ. Therole of the adrenal gland in cytoprotection against stress-induced gastric ulcers in rats. J Neurosci Res1984;11(2):193-201.

3. Filaretova L, Morozova O, Bagaeva T, Podvigina T. Fromgastroprotective to proulcerogenic action of glucocorti-coids on the gastric mucosa. J Physiol Pharmacol2009;60(Suppl 7):79-86.

4. Szabo S, Callagher GT, Horner, et al. Role of the adrenalcortex in gastric mucosal protection by prostaglandins,sulfhydryls, and cimetidine in the rat. Gastroenterology1983;85:1384-90.

5. Selye H. In Vivo. The case for supramolecular biology pre-sented in six informal, illustrated lectures. New York:Liveright; 1967.

6. Szabo S, Tache Y, Somogyi A.The legacy of Hans Selye andthe origins of stress research: a retrospective 75 years afterhis landmark brief “letter” to the editor# of nature. Stress2012;15:472-8.

7. Filaretova L. The dependence of the formation of stressgastric ulcers on the function of hypothalamo-hypophy-seal-adrenocortical system. Sechenov Physiol J USSR1990;76:1594-600.

8. Filaretova LP, Filaretov A, Makara GB. Corticosteroneincrease inhibits stress-induced gastric erosions in rats. AmJ Physiol 1998;274:G1024-G1030.

9. Filaretova LP. The hypothalamic-pituitary-adrenocorticalsystem: hormonal brain-gut interaction and gastroprotec-tion. Autonomic Neurosci: Basic and Clinical 2006;125:86-93.

10. Filaretova L, Bagaeva T, Amagase K, Takeuchi K.Contribution of glucocorticoids to protective influence ofpreconditioning mild stress against stress-induced gastricerosions. Ann N Y Acad Sci 2008;1148:209-12.

11. Filaretova L, Podvigina T, Bagaeva T, Makara G.Gastroprotective action of glucocorticoids during the for-mation and the healing of indomethacin-induced gastricerosions in rats. J Physiol Paris 2001;95:201-8.

12. Filaretova LP, Bagaeva TR, Makara GB. Aggravation ofnonsteroidal antiinflammatory drug gastropathy by gluco-corticoid deficiency or blockade of glucocorticoid receptorin rats. Life Sci 2002;71:2457-68.

13. Filaretova L. Gastroprotective role of glucocorticoids dur-ing NSAID-induced gastropathy. Curr Pharm Des2013;19(1):29-33.

14. Filaretova L, Tanaka A, Miyazawa T, Kato S, Takeuchi K.Mechanisms by which endogenous glucocorticoids pro-tects against indomethacin-induced gastric injury in rats.Am J Physiol 2002;283:G1082-G1089.

15. Filaretova LP, Podvigina TT, Bagaeva TR, Tanaka A,Takeuchi K. Mechanisms underlying gastroprotectiveaction of glucocorticoids released in response to ulcero-genic stress factors. Ann NY Acad Sci 2004;1018:288-93.

16. Filaretova L, Bobryshev P, Bagaeva T, Podvigina T,Takeuchi K. Compensatory gastroprotective role of gluco-corticoid hormones during inhibition of prostaglandin andnitric oxide production and desensitization of capsaicin-sensitive sensory neurons. Inflammopharmacology2007;5:146-53.


124 Gabbiani: Hans Selye: an inspiring teacher

SELYE SYMPOSIUM

HANS SELYE: AN INSPIRING TEACHER Giulio GABBIANI Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

SELYE JÁNOS, AZ INSPIRÁLÓ OKTATÓGabbiani G, MDIdeggyogy Sz 2014;67(3–4):124–125.

Az írás Selye János, az egyetemisták és posztgraduális hall-gatók oktatójának eredményeit ismerteti. Tanításának fôcélja az volt, hogy a hallgatókat az eredmények jelentôségeés eredetiség irányába orientálja.

Kulcsszavak: eredetiség, oktatás, perifériás látás, myofibroblast

The souvenirs of Hans Selye as a teacher of graduate andpost graduate students are presented and discussed. Themain aim of his teaching was to orient the student towardimportance and originality of findings.

Keywords: originality, teaching, peripheral vision, myofibroblast

Correspondent: Giulio GABBIANI, MD, Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. E-mail: [email protected]


www.elitmed.hu

Ihave no doubts that my stay at the “Institute ofExperimental Medicine and Surgery” of the

University of Montreal (1961-1969) has shapedirreversibly my attitude toward research and sci-ence in general. Hans Selye wanted to be a success-ful teacher and placed enormous amounts of energyin this task. He liked undergraduate teaching, butmost of all graduate and postgraduate teaching thathe accomplished at several levels. He wanted tomeet students and coworkers every day during theweek and, frequently, during the week-end, creat-ing sometime problems for family life…1. Thisallowed the members of the Institute to witness hisway of making observations, planning experimentsand producing generalizations; eventually it waspossible for the coworker to confront his or her ownideas with those of the “boss” and in this way toparticipate in the progress of a given research proj-ect. Hans Selye was very critical and, while collab-orating with him could represent a difficult experi-ence, it could also be a unique opportunity of learn-ing and applying very demanding criteria for

research planning and execution. The main point inthis respect was “originality” as the evaluation cri-terion of an observation or a hypothesis. In order toproduce original observations and hypotheses anessential tool according to him was the “peripheralvision” i.e. “the ability not only to look straight atwhat you want to see, but also to watch continual-ly, through the corner of your eye, for the unexpect-ed”2.

In my experience it was more difficult to work inthe Institute as an independent researcher than as astudent: Hans Selye was clearly less interested infollowing research of other people even when theywere young Faculty members in the Institute.However, he was ready to listen and give a criticaladvice, when presented with a new result or idea. Iexperienced his availability when I asked his opin-ion about my first electron microscopic observationof the myofibroblast that was made in Toronto dur-ing a year (September 1967- September 1968) spentin Boston, Toronto and Geneva in order to special-ize in electron microscopy techniques, thanks to a

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REFERENCES1. Gabbiani G. On the stress of living with Dr. Selye.

Experientia 1985;41:562-3. 2. Selye H. From Dream to Discovery. New York: McGraw-

Hill Book Company; 1964. p. 78.

3. Gabbiani G, Ryan GB, Majno G. Presence of modifiedfibroblasts in granulation tissue and their possible role inwound contraction. Experientia 1971;27:549-50.

4. Gabbiani G. Citation Classic. Current Content 1988;16:16.

fellowship of the Medical Research Council ofCanada3, 4. This year changed my life because ofthis observation and of the fact I worked during 8months with Dr. Guido Majno at the Department ofPathology of Harvard Medical School, who at thattime was asked to direct the Department ofPathology at the University of Geneva. He pro-posed to me to move with him and I accepted, afterhaving spent a year (1968-1969) in Montreal inorder to help Dr. Selye to find an academic electronmicroscopist replacing me. In Toronto I was twomonths with Dr. W. S. Hartroft at the Departmentof Pathology of the Hospital for Sick Children andI worked on the mechanisms of ceroid deposit for-mation during inflammation. For this purpose Iused a well-established experimental modeldescribed by Dr. Selye, i.e. the “granuloma pouch”produced by injecting croton oil into an air pouch inthe back of the rat; this resulted in a typical abscesswhose wall was containing many fibroblasts. It wasin these fibroblasts that I noticed bundles of micro-filaments suggesting their similarity with smoothmuscle. This observation was later confirmed inmany situations where granulation tissue or activefibrotic lesions were present. Immediately I real-ized that this observation could lead to a new wayof interpreting wound contraction, which at thattime was mainly related to collagen rearrangement.I wanted to ask the opinion of experts in this field:contrary to other well-known scientist I consulted at

that time, who clearly did not catch the possibleimplications of such an observation, Hans Selyerealized instantly the possible relevance of the find-ing and advised me to continue following this field.His advice was crucial for my decision to dedicatemyself to what has become my main research topicfor the next 45 years.

Another feature of the Institute that greatly con-tributed to student formation was the “ClaudeBernard Conferences” that allowed coworkers tocome in contact with well-known scientists, amongwhich there were several Nobel Prize winners, thusallowing them to directly learn how important dis-coveries were made and developed. I still remembervividly the presentations by Selman Waksman (dis-coverer of streptomycin, Nobel Prize winner in1952), Rita Levi-Montalcini (discoverer of thenerve growth factor, Nobel Prize winner in 1986),Baruj Benacerraf (discoverer of dominant auto-somic transmission of immunological response andcontributor to the discovery of the histocompatibil-ity complex, Nobel Prize winner in 1980) and EarlP. Benditt (discoverer of the presence of serotoninin mast cell granules and proposer of the monoclon-al theory for atheroma formation) and the discus-sions about the evolution of their discoveries.

In conclusion, life with Hans Selye was not easyevery day, but represented an excellent opportunityto develop a rigorous research method and to appre-ciate the importance and beauty of original thinking.

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126 Kovács: Stress in the classification of pituitary tumors. Focus on aggressive pituitary adenomas

SELYE SYMPOSIUM

STRESS IN THE CLASSIFICATION OF PITUITARY TUMORS.FOCUS ON AGGRESSIVE PITUITARY ADENOMAS Kálmán KOVÁCS1, Fabio ROTONDO1, Éva HORVÁTH1, Luis V SYRO2

1Department of Laboratory Medicine, Division of Pathology, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada 2Department of Neurosurgery, Hospital Pablo Tobon Uribe and Clinica Medellin, Medellin, Colombia

A STRESSZ A HYPOPHYSISTUMOROK OSZTÁLYOZÁSÁBAN. FÓKUSZBAN AZ AGRESSZÍVHYPOPHYSISADENOMÁKKovács K, MD, Rotondo F, MD, Horváth É, MD, Syro LV, MDIdeggyogy Sz 2014;67(3–4):126–127.

A stresszelmélet és Selye János munkásságának rövid össze-foglalása után a hypophysisdaganatok osztályzására és akülönbözô hypophysistumorok prognózisáról adható infor-mációk nehézségeire fokuszálunk. Bevezetjük az „agresszívhypophysistumor” kifejezést. Ezekben a daganatokbangyors ütemû a sejtosztódás. Jelenleg a Ki-67 nukleárisjelölés index felmérése tûnik a legyegyszerûbb és legmeg-bízhatóbb módszernek a daganatsejtek osztódásánakfelmérésére. További vizsgálatokra van szükség a hypophy -sistumorok biomarkereirôl.

Kulcsszavak: biomarkerek, dr. Selye János, hypophysis,hypophysistumorok, stressz

After a brief summary of the stress concept and the contri-bution of Dr. Hans Selye, this publication focuses on theclassification of pituitary neoplasms and the difficulties toprovide conclusive information on the prognosis of variouspituitary tumor types. The term “aggressive pituitary tumors”was introduced. These tumors have a rapid cell proliferationrate. At present, the assessment of Ki-67 nuclear labelingindex appears to be the simplest and most reliable methodto evaluate tumor cell multiplication. Further studies on pitu-itary tumor biomarkers are needed.

Keywords: biomarkers; Dr. Hans Selye, pituitary, pituitary tumors; stress

Correspondent: Kálmán KOVÁCS, MD, PhD, Department of Laboratory Medicine, Division of Pathology, St. Michael’s Hospital; 30 Bond Street, Toronto, ON, Canada, M5B 1W8. Phone: 416-864-6060, fax: 416-864-5648.

E-mail: [email protected]


www.elitmed.hu

Dr. Selye was an excellent leader, a creative anddevoted scientist1. I was very fortunate to have

been invited to work with him at the Université deMontreal. His department was really cosmopolitan.Researchers worked there from Canada, Italy,Germany, Brazil, Japan, Yugoslavia, Hungary, etc.

When I arrived in his department, I greeted him:‘Professor Selye’. He responded to me inHungarian: “do not call me Professor Selye, callme, János bácsi.”

My main interest in research was the study of thestructure and function of the pituitary gland. Iplanned to do research related to the pituitary. Dr.

Selye told me that I had to join the team and theirarea of research was myocardial necrosis. I had toinvestigate the heart of rats that had been poisonedwith various chemicals. I reluctantly accepted therole. A few weeks later, I realized that every newarea is exciting and provides intellectual satisfac-tion. Subsequently, I worked on the effect of drugson the liver, various tumors and to my pleasure, Icould do research on the pituitary.

Every research is “stress” and every researcher isexcited whether he/she will succeed. This stress isthe “good stress” which may lead to happiness.

After leaving Dr. Selye’s department, I moved to

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REFERENCE1. Kovacs K. Hans Selye. The original and creative scientist.

Ann NY Acad Sci 1998;851:13-5. 2. Kovacs K, Horvath E. Atlas of tumor pathology. Series 2,

Fasc. 21. Tumors of the pituitary gland. DC: Armed ForcesInstitute of Pathlogy. Washington DC; 1986.

3. Sav A, Rotondo F, Syro LV, Scheithauer BW, Kovacs K.Biomarkers of pituitary neoplasms. Anticancer Res 2012;32:4639-54.

4. Suhardja A, Kovacs K, Rutka J. Genetic basis of pituitaryadenoma invasiveness: a review. J Neurooncol 2001;52:195-204.

5. World Health Organization Classification of Tumors.Pathology & genetics. Tumors of endocrine organs. In:DeLellis RA, Lloyd RV, Heitz PU, Eng C (eds.). Lyon:IARC Press; 2004. pp. 1-320.

6. Thapar K, Kovacs K, Scheithauer BW, Stefaneanu L,Horvath E, Pernicone PJ, et al. Proliferative activity andinvasiveness among pituitary adenomas and carcinomas:an analysis using MIB-1 antibody. Neurosurgery 1996;38:99-107.

St. Michael’s Hospital, one of the major teachinghospitals affiliated with the University of Toronto.We studied several thousand pituitary tumors2 andtumors of other endocrine glands. In this paper wefocus on the significance, diagnosis, classification,prognosis and treatment of aggressive pituitarytumors3, 4.

Pituitary adenomas are not easy to classify. Inmany cases, it is a diagnostic challenge to assessbiologic behavior and prognosis. Our focus is onaggressive pituitary tumors. Approximately 70% ofpituitary adenomas are expansively growing benignneoplasms with slow cell proliferation rate. Theyare not encapsulated but are well demarcated by apseudocapsule consisting of adjacent compressednon-tumorous adenohypophysial cells, capillaries,fibroblasts and collagen fibers. Approximately 30%of pituitary adenomas are invasive. They spreadinto adjacent tissues, penetrate the sphenoid andcavernous sinuses and expand to suprasellar areas.Less than 1% of pituitary neoplasms are malignantand are regarded as carcinomas. According to thecurrently accepted classification5, the diagnosis ofcarcinoma can only be made when distant cere-brospinal and/or systemic metastases are document-ed. Pituitary carcinomas produce most often PRL orACTH. Very rarely, they may synthesize GH, TSH,FSH, LH or alpha subunit or they may be unassoci-ated with secretion of adenohypophysial hormones.

Recently, the terms “aggressive pituitary adeno-ma” and “atypical pituitary adenoma” were intro-duced2. According to our interpretation, they repre-sent the same tumor type. In our view “aggressivepituitary adenoma” provides a more relevant name.

The questions can be asked: do aggressive pitu-itary adenomas represent a distinct entity and whatare the criteria of their conclusive recognition.

We believe that the most important criterion ofaggressive pituitary adenomas is the rapid cell pro-liferation rate. Aggressive pituitary adenomas arefrequently macroadenomas, invasive and, occurmore often in younger patients associated withincreased hormone secretion. However, evidenceindicates that large tumor size, invasion, youngerage, and hormone secretion may also be noted inpatients with slowly growing pituitary neoplasms.Tumor size, invasiveness, age, gender, hormonesecretion, hormone content, cellular pleomorphismand local symptoms such as headache, visual dis-turbances are not decisive diagnostic features ofaggressive pituitary adenomas.

More work is needed to find specific biomarkersand molecular/genetic abnormalities which wouldpermit to conclusively recognize aggressive pitu-itary adenomas. These studies would be extremelyimportant not only theoretically but also practicallybecause it would make possible to identify thosepatients whose tumor is rapidly proliferating andhave malignant potential. At present, we recom-mend the application of the Ki-67 nuclear labelingindex6. This is a simple immunohistochemicalapproach, reliable in most cases. If the Ki-67nuclear labeling index is above 10%, the diagnosisof aggressive pituitary adenoma appears to be justi-fied.

We are grateful to the Jarislowsky and LloydCarr-Harris Foundations for their generous sup-port.

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Azilect 1mg tabletta 30x 26 691 Ft 24 022 Ft 2 669 FtEmelt (90%) támogatás jogcíme: 6/b Parkinson kórban (BNO: G20). Parkinson-kór esetén, az alkalmazási előírásban szereplő monoterápiában, illetve L-DOPA és selegilinnel, illetve amantadinnal való kombinált kezelésben kiegészítő kezelésként is, ha súlyos motoros fl uktuáció jelentkezik - a fi nanszírozási eljárásrendekről szóló miniszteri rendeletben meghatározott fi nanszírozási protokoll alapján. 2014. március 01. (www.oep.hu). Lezárás dátuma : 2014/03/01


Ideggyogy Sz 2014;67(3–4):129–134. 129

EREDETI KÖZLEMÉNY

AZ MDS-UPDRS MAGYAR VALIDÁCIÓJA: MIÉRT SZÜKSÉGES ÚJABB PARKINSON-PONTOZÓSKÁLA?

HORVÁTH Krisztina1, ASCHERMANN Zsuzsanna2, ÁCS Péter2, BOSNYÁK Edit2, DELI Gabriella2, PÁL Endre2, KÉSMÁRKI Ildikó3, HORVÁTH Réka2, TAKÁCS Katalin2, KOMOLY Sámuel2, BOKOR Magdolna4,

RIGÓ Eszter4, LAJTOS Júlia5, KLIVÉNYI Péter6, DIBÓ György6, VÉCSEI László6, 7, TAKÁTS Annamária8,TÓTH Adrián8, IMRE Piroska9, NAGY Ferenc10, HERCEG Mihály10, HIDASI Eszter11, KOVÁCS Norbert2, 12

1Pécsi Tudományegyetem, Klinikai Idegtudományok Doktori Iskola, Pécs2Pécsi Tudományegyetem, Neurológiai Klinika, Pécs

3Egyesített Egészségügyi Intézmények, Neurológia Szakrendelés, Pécs4Nyírô Gyula Kórház-OPAI, Neurológiai Osztály, Budapest

5Kenézy Gyula Kórház, Neurológiai Osztály, Debrecen6Szegedi Tudományegyetem, Neurológiai Klinika, Szeged

7MTA-SZTE, Idegtudományi Kutatócsoport, Szeged8Semmelweis Egyetem, Neurológiai Klinika, Budapest

9Csolnoky Ferenc Kórház, Neurológiai Osztály, Veszprém10Kaposi Mór Megyei Kórház, Neurológiai Osztály, Kaposvár

11Debreceni Egyetem, Neurológiai Klinika, Debrecen12MTA-PTE, Klinikai Idegtudományi Képalkotó Kutatócsoport, Pécs

VALIDATION OF THE HUNGARIAN MDS-UPDRS:WHY DO WE NEED A NEW PARKINSON SCALE? Horváth K, MD; Aschermann Zs, MD; Ács P, MD; BosnyákE, MD; Deli G, MD; Pál E, MD; Késmárki I, MD; Horváth R,MD; Takács K, MD; Komoly S, MD; Bokor M, MD; Rigó E,MD; Lajtos J, MD; Klivényi P, MD; Dibó Gy, MD; Vécsei L,MD; Takáts A, MD; Tóth A, MD; Imre P, MD; Nagy F, MD;Herceg M, MD; Hidasi E, MD; Kovács N, MDIdeggyogy Sz 2014;67(3–4):129–134.

Background – The Movement Disorder Society-sponsoredrevision of the Unified Parkinson’s Disease Rating Scale(MDS-UPDRS) has been published in 2008 as the successorof the original UPDRS. The MDS-UPDRS organizing teamdeveloped guidelines for the development of official non-English translations consisting of four steps:translation/back-translation, cognitive pretesting, large fieldtesting, and clinimetric analysis. The aim of this paper wasto introduce the new MDS-UPDRS and its validation processinto Hungarian.Methods – Two independent groups of neurologists transla-ted the text of the MDS-UPDRS into Hungarian and subse-quently back-translated into English. After the review of theback-translated English version by the MDS-UPDRS translati-on administration team, cognitive pretesting was conductedwith ten patients. Based on the results of the initial cognitivepretesting, another round was conducted. For the large fieldtesting phase, the Hungarian official working draft versionof MDS-UPDRS was tested with 357 patients withParkinson’s disease (PD). Confirmatory factor analyses (CFA)determined whether the factor structure for the English-lan-

Bevezetés – Az 1986-os Egységesített ParkinsonPontozóskála (UPDRS) utódjaként kifejlesztett, a MovementDisorder Society által fémjelzett Egységesített ParkinsonPontozóskálát (MDS-UPDRS) 2008-ban véglegesítették. Askála egyéb nyelvre történô hivatalos fordításához az MDSnégy lépésbôl álló szigorú validálási módszert dolgozott ki:1. fordítás/visszafordítás, 2. kognitív elôtesztelés, 3. nagybeteganyagon történô tesztelés és 4. klinimetrikus analízis.Vizsgálatunk célja az MDS-UPDRS ismertetése és a magyarnyelvi validáció folyamatának és eredményeinek bemutatá-sa.Módszertan – Elsô lépésben az MDS-UPDRS-t magyarralefordítottuk, amit független munkacsoport angolra vissza-fordított. Miután a visszafordított szöveget az MDS-UPDRSbizottsága elemezte, a magyar szöveg érthetôségét két kog-nitív elôteszteléssel ellenôriztük. A validálási folyamat har-madik fázisában a magyar verziót 357 Parkinson-kórosbetegen vettük fel. Ezt követôen ellenôrzô faktoranalízissegítségével megvizsgáltuk, hogy a magyar MDS-UPDRSfaktorszerkezete mennyire illeszkedik az angol verzió faktor-szerkezetéhez. Az általunk lefordított skálát akkor tekinthet-

Levelezô szerzô (correspondent): Dr. KOVÁCS Norbert, Pécsi Tudományegyetem, Általános Orvostudományi Kar, Neurológiai Klinika;

7623 Pécs, Rét u. 2. Telefon: (06-72) 535-900, fax: (06-72) 535-911, e-mail: [email protected]

Érkezett: 2014. február 1. Elfogadva: 2014. február 17.

www.elitmed.hu

horvath_UJ ISZ TUKOR ALAP.qxd 2014.03.21. 16:12 Page 129

http://www.elitmed.hu/kiadvanyaink/ideggyogyaszati_szemle/kezelesi_lehetosegek_a_parkinson_kor_elorehaladott_stadiumaban_11719/

Az Egységesített Parkinson Pontozóskálát(Unified Parkinson’s Disease Rating Scale,

UPDRS) az 1980-as években fejlesztették ki Fahnés munkatársai1, hogy a Parkinson-kór (PK) súlyos-ságának mérésére addig elérhetô több tucat mérô-eszközt egységes skálával váltsák ki2. Mivel aUPDRS megalkotásáig a különbözô vizsgáló cent-rumok egymástól eltérô skálákat alkalmaztak, akülönbözô vizsgálatok nem voltak egymással jólösszehasonlíthatók2. A megalkotása óta eltelt idô-szakban a UPDRS a PK súlyosságának megítélésé-re szolgáló tesztek arany standardjává vált2.

A UPDRS alapvetôen négy részbôl áll: AUPDRS-1 a gondolkodás, a magatartás és a hangu-lat vizsgálatára szolgál, a UPDRS-2 a mindennapiéletvitelt pontozza, a UPDRS-3 a motoros tüneteksúlyosságát, míg a UPDRS-4 a kezelés szövôdmé-nyeit méri fel. A UPDRS egyik legnagyobb elônyeaz, hogy a PK több dimenzióját egymástól külön-külön értékeli. Egyaránt képes felmérni a motorostünetek súlyosságát (UPDRS-3) és az ebbôl fakadókorlátozottság mértékét (UPDRS-2). Külön foglal-kozik bizonyos nem motoros tünetek jelenlétének(UPDRS-1) és a gyógyszeres kezelés szövôdmé-nyeinek és mellékhatásainak megítélésével is(UPDRS-4). A UPDRS a gyakorlatban 15-20 percalatt felvehetô. További elônye, hogy megfelelôintra- és interrater megbízhatóságát és validitásátszámos klinimetrikus vizsgálat is alátámasztotta.

Felmerülhet a kérdés, hogyha a UPDRS ennyielônyös tulajdonsággal rendelkezik, akkor miértszükséges újabb változatot kifejleszteni. Az eredetiUPDRS megalkotása óta eltelt két évtizedben a PK-val kapcsolatos tudásanyagunk is jelentôsen bôvült.Példaként említhetjük, hogy csak az utóbbi évekbenismertük fel a nem motoros tünetek szerepét az élet-minôség kialakításában. Az eredeti UPDRS nem

foglalkozik számos, a megalkotása óta ismertté váltés egyre nagyobb hangsúlyt kapó, nem motorostünettel, úgymint az impulzuskontroll-zavarral, aszorongással, a fáradékonysággal, és a vegetatívproblémákkal.

A UPDRS alkalmazásának egyéb gyenge pontjaiis akadnak, melyeket a Movement DisordersSociety (MDS) Pontozóskálákat Vizsgáló Bizott -sága részletesen elemzett2, 3.

A motoros tünetek vizsgálata során a UPDRS-3nem látja el a vizsgálót pontos utasításokkal, hogymit kérjen a betegtôl a feladat elvégzéséhez, illetvehogy pontosan hogyan értékelje a látottakat. Annakellenére, hogy ezek a hiányosságok egy késôbbkifejlesztett videotréning segítségével részben áthi-dalhatóvá váltak4, 5, a UPDRS-3 felvétele során szá-mos olyan kérdéssel is találkozhatunk, melyekintra- és interrater megbízhatósága elmarad a kívá-natostól. Az egyik legkevésbé következetesenelvégzett feladat a testtartási instabilitás vizsgálata.Mivel a UPDRS nem definiálja, hogy hogyan ésmilyen erôkifejtéssel vizsgáljuk a beteget, ezértugyanazon beteg vizsgálatakor gyakran egymástólmerôben eltérô eredményt is kaphatunk6. A UPDRSmásik jellegzetes hibája a posturalis és kinetikustremor mértékének összevont és összemosott érté-kelése.

A UPDRS klinimetrikai értékét jelentôsen ront-ja, hogy például a szövôdményeket felmérôUPDRS-4 egyaránt tartalmaz ötfokozatú válaszle-hetôséggel rendelkezô és dichotom kérdéseket is.Dichotomnak tekinthetô például az alvászavar vagyorthostaticus hipotenzió jelenlétét vagy hiányátvizsgáló kérdés (igen/nem). Ezek a kérdésekazonban inkább csak szûrésre, mintsem a súlyosságmérésére alkalmasak. Ráadásul a UPDRS-4 ahányingert és az alvászavart a gyógyszeres kezelés

130 Horváth: Az MDS-UPDRS magyar nyelvi validációja

tük validnak, ha az összehasonlító illeszkedési mutató (CFI)mind a négy részben ≥0,90 feletti.Eredmények – A CFI értéke a magyar MDS-UPDRS minda négy részénél ≥0,94 volt. Következtetés – A magyar nyelvû MDS-UPDRS faktorstruk-túrája a magas CFI-értékek alapján jó illeszkedést mutatottaz eredeti angol MDS-UPDRS felépítésével. A fentiek alap-ján az általunk elkészített és validált verziót a hivatalosmagyar MDS-UPDRS verzióként fogadták el.

Kulcsszavak: Parkinson-kór, pontozóskálák, faktoranalízis

guage MDS-UPDRS could be confirmed in data collectedusing the Hungarian Official Draft Version. To become anofficial translation, the Comparative Fit Index (CFI) had tobe ≥0.90 compared to the English-language version.Results – For all four parts of the Hungarian MDS-UPDRS,the CFI was ≥0.94.Conclusion – The overall factor structure of the Hungarianversion was consistent with that of the English versionbased on the high CFIs for all the four parts of the MDS-UPDRS in the CFA; therefore, this version was designatedas the ‘OFFICIAL HUNGARIAN VERSION OF THE MDS-UPDRS.’

Keywords: Parkinson’s disease, rating scales, factor analysis


szövôdményéhez sorolja, annak ellenére, hogy ezeka nem motoros tünetek a gyógyszeresen nem kezeltPK-betegeknél is elôfordulhatnak7.

A régi UPDRS további hátránya, hogy angolonkívül egyéb hivatalos nyelvi fordítása nem létezik2.Magyar nyelven is legalább három, egymástóltöbbé-kevésbé eltérô szövegezésû verzió elérhetô.A különbözô nyelvi variánsok használata pedig akülönbözô centrumok eredményeinek összehason-líthatóságát is negatívan befolyásolhatja.

Klinikai szempontból további hátrányt jelent,hogy a UPDRS-pontszámban bekövetkezô válto-zást nem lehet kongruens módon összehangolni aklinikai relevancia mértékével. A gyakorlatban aterápiás hatékonyság mértékének megítélésébenegyre nagyobb szerepet kap a klinikailag relevánsmértékû minimális különbség (minimal clinicallyrelevant difference, MCRD) nagyságának meghatá-rozása. Az MCRD mértékét el nem érô változás(javulás) klinikai szempontból irrelevánsnak tekint-hetô. A UPDRS MCRD-értéke nem egységes, vizs-gálatról vizsgálatra változó mértékû8, 9.

A UPDRS-t ért kritikák alapján az MDS új, akorábbinál konzekvensebb, a PK különbözô dimen-zióit jobban elkülönítô, de az eredeti UPDRStagoltságát megôrzô skála kifejlesztése mellett dön-tött10, 11. Az MDS által szponzorált UPDRS-skálát(MDS-UPDRS) már eleve jól körülhatárolt klini-metrikus irányelvek alapján alkották meg (faktor -analízissel verifikált összetettség). Szintén a köve-telmények között szerepelt, hogy minden egyeskérdéshez megfelelô útmutató és értékelési irányelvtartozzon, ami növeli a vizsgálók közötti konkor-danciát. A feladatokat úgy dolgozták ki, hogy askála megalkotásának idôpontjában ismert mindenfôbb klinikai tünetet felmérjen és alkalmas legyen akülönbözô kultúrák egységes szempontú megköze-lítésére is. Az MDS-UPDRS II. részébe a korábbankülön kezelt Hoehn–Yahr Skálát is beemelték12,miközben az MDS-UPDRS IV. részét úgy alakítot-ták ki, hogy kizárólag a motoros komplikációkatértékelje13.

Az MDS-UPDRS publikálásával egy idôbenmeghatározták azokat az irányelveket is, melyekalapján elvégezhetô a további nyelvekre történônyelvi fordítás és validáció10. A jelen munkánkbana hivatalos magyar nyelvi validáció fôbb állomása-it és eredményeit mutatjuk be.

Betegek és módszerek

Az MDS-UPDRS hivatalos validálása négy részbôlállt: Az 1. fázisban került sor a hivatalos angol ver-zió magyarra fordítására, majd az így elkészült szö-

veg angolra történô visszafordítására. A visszafor-dított angol szöveget a Movement DisordersSociety (MDS) nyelvi fordításokért felelôs munka-csoportja ellenôrizte és véleményezte. A 2. fázis akognitív elôtesztelés folyamata, amikor a lefordítottmagyar szöveg érthetôségét ellenôriztük betegeken.A kognitív elôtesztelés során elsôsorban azokra akérdésekre koncentráltunk, melyek visszafordítottszövegezését az MDS munkacsoportja túlságosaneltérônek vélte az eredeti angol verziótól. A validá-lási folyamat 3. fázisában a minimumfeltételeknekmegfelelôen legalább 350 Parkinson-kóros betegenkellett a kognitív elôtesztelés alapján véglegesítettmagyar verziót felvenni, majd a 4. fázisban kerültsor a klinimetrikus analízisre.

BETEGEK

A validálási folyamatba minimum 350, maximum710, Parkinson-kór miatt gondozott beteg bevoná-sát terveztük. A kognitív elôtesztelés megkezdéseelôtt ETT-engedélyt kértünk (582/PI/2012,36102/2012/EKU), melyet az újabb vizsgálócentru-mok csatlakozásával módosítottunk (184/2013.14437/2013/EKUl).

MÓDSZEREK

A vizsgálati beleegyezô nyilatkozat aláírását köve-tôen elôször a betegek demográfiai és Parkinson-kórral kapcsolatos adatait vettük fel (nem, születéséve, iskolázottság, PK kezdete, PK típusa, levodo-pakezelés és a fluktuációk megjelenésének éve, akezesség, a tüneti aszimmetria és az aktuálisanhasznált gyógyszerek). Az útmutató alapján elvég-zett vizsgálat eredményeit az MDS-UPDRS ponto-zólapon rögzítettük.

A betegek demográfiai és betegséggel kapcsola-tos adatait, illetve az MDS-UPDRS pontokat abetegek azonosítására alkalmatlan anonim módon apécsi munkacsoport két tagja (HK és KN) rögzítettea vizsgálat céljára kifejlesztett adatbázisban. Abetegségtartam hosszát a vizsgálat évének és abetegség kezdetének különbségébôl számítottuk ki,míg a levodopakezelés hosszát a vizsgálat événekés a levodopakezelés kezdeti évének különbségeadta. A gyógyszerelés mennyiségét levodopaekvi-valens dózisban határoztuk meg14.

Az adatok minôségének javítása érdekében azadatbázisban történô rögzítést követôen az alábbiszempontok szerint logikai ellenôrzést végeztünk:

– Ha bármilyen pótolható adat hiányzott (példá-ul iskolázottság vagy gyógyszerelés), ezt utó -lagosan bekértük.

– Mivel a bevont betegeknek legalább egy érté-

Ideggyogy Sz 2014;67(3–4):129–134. 131


kelhetô parkinsonos tünetet kellett mutatniuk, aHoehn–Yahr Skála értéke nem lehetett 0.

– Ha a motoros vizsgálat pontszámai alapján abetegnek kétoldali tünetei voltak, akkor a HYSértéke nem lehetett 1.

– Ha a betegnek a motoros vizsgálat alapjánkizárólag féloldali tünetei voltak, akkor néhányritka kivételtôl eltekintve (például kerekes székhezkötött parapleg beteg kezdôdô Parkinson-kórral), aHYS értéke nem lehetett 2.

– Ha a testtartási instabilitás súlyos fokú (a 3.12feladat értéke >2), akkor definíció szerint a HYSnem lehet ≤3.

– Ha nyugalmi tremor jelen van (a 3.17 a–e kér-dések bármelyike >0), akkor a nyugalmi tremoridôtartama (3.18) nem lehet 0 pont.

– Ha a nyugalmi tremor idôtartama (3.18) >0pont, akkor a 3.17 a–e kérdések valamelyikének 0-ánál nagyobbnak kell lennie.

– Ha a vizsgáló bejelöli, hogy a vizsgálat alattdyskinesia észlelhetô, akkor a vizsgálat napját isbeleértve az elmúlt hét napban a dyskinesiával töl-tött idô (4.1) nem lehet 0 pont.

– Ha nincs off állapot (az off állapot idôtartama4.3=0), akkor az off állapot életvitelre gyakorolthatását, komplexitását és az off állapotban jelentke-zô dystoniát felmérô (4.4–4.6) kérdésekre adottválasz egyik esetben sem lehet >0 pont.

Hiányzó adatok, vagy a fenti szempontokalapján inkoherensnek tûnô pontozás esetében avizsgálóval egyeztettünk. A statisztikai elemzéselvégzése elôtt az adatbázisban szereplô értékeketmég egyszer összevetettük a papír alapú pontozóla-pon szereplô értékekkel (TK), hogy minimalizáljuka gépelési hibák elôfordulását.

STATISZTIKA

A statisztikai számításokat az M-Plus program (7.verzió) segítségével végeztük. Mivel az MDS-UPDRS változói kategorikusak, ezért az ellenôrzôfaktorelemzést (confirmatory factor analysis, CFA)súlyozott négyzetes megközelítéssel végeztük. Astatisztikai vizsgálatok elsôdleges célja az volt,hogy tisztázza, az eredeti angol MDS-UPDRS adat-bázisban szereplô faktorstruktúra megfelel-e amagyar nyelvû MDS-UPDRS segítségével felvettadatoknak10. Az MDS-UPDRS skála mind a négyalrészét külön-külön értékeltük.

A CFA alapján nyert adatokat az ÖsszehasonlítóIlleszkedési Mutató (Comparative Fit Index, CFI)alapján értékeltük15. A CFI az adatok és a hipoteti-kus modell közti különbséget elemzi úgy, hogyközben korrigálja a χ2-próba elemszám-érzékeny-

ségét és a normalizált illeszkedési mutatót. A CFIértéke 0 és 1 közé eshet; minél nagyobb, annál jobbaz illeszkedés. Általában a 0,90-es, vagy nagyobbérték igazolja a jó modellilleszkedést. Az MDS-UPDRS validálási protokoll szerint akkor tekinthe-tô a fordítás elfogadhatónak, ha a CFI értéke a skálamind a négy részében 0,9 feletti.

Az illeszkedés minôségének megítélése céljábólMegközelítési négyzetes középérték hiba (Root MeanSquare Error of Approximation, RMSEA) számítástis végeztünk. Az RMSEA értéke 0 és 1 között lehet-séges, minél kisebb, annál jobb az illeszkedés. AzRMSEA ≤0,1 értékeket tekintettünk elfogadhatónak.

Eredmények

FORDÍTÁS ÉS VISSZAFORDÍTÁS

Az MDS-UPDRS hivatalos angol verziójánakmagyarra fordítását (KN) követôen a PTE, KK,Neurológiai Klinika munkatársai véleményezték aszöveget (AZs, ÁP és BE). Az észrevételekkelmódosult szöveget angol nyelvre visszafordítottuk(HK és NF), melyet a Movement Disorders SocietyMDS-UPDRS Translation Administrative Teamtagjai (Christopher Goetz, Glenn Stebbings, NancyLaPelle és Barbara Tilley) véleményezték. A nyel-vi és kulturális sajátságok miatt számos észrevételérkezett a magyar nyelvû és a visszafordított angolszöveggel kapcsolatban, melyek szükségességéttöbb fordulóban egyeztettük.

KOGNITÍV ELÔTESZTELÉS

Az egyeztetéseket követôen módosult szöveggel 10betegen végeztük el a kognitív elôtesztelést (AZs,BE, TK és ÁP). A kognitív elôtesztelés célja az volt,hogy a visszafordítás alapján kiválasztott kérdésso-ron keresztül mind a betegek, mind a vizsgálókvéleményét kikérdezzük arról, hogy a magyar szö-veg mennyire könnyen érthetô, jól strukturált ésegyértelmû. A tesztelést az I–IV. részek bevezetôszövegén, az IA rész befejezô szövegén, az 1.1, az1.4, a 2.7, a 2.13, a 3.5, a 3.9, a 4.1 és 4.2 kérdése-ken végeztük el. A kognitív elôtesztelés során szer-zett észrevételek alapján a magyar szöveg kisfokúmódosítására is sor került, majd a kognitív elôtesz-telést újabb 10 betegen megismételtük.

NAGY ESETSZÁMÚ TESZTELÉS

A validálási folyamat 3. fázisában nyolc vizsgáló-centrum vett részt. A 2013. február és november



közötti idôszakban 361 skála került felvételre, 28esetben vizsgálóval történô egyeztetés vált szüksé-gessé hiányzó adatok vagy inkongruensnek tûnôpontozás miatt. Négy esetben az utólagos egyezte-tés alapján sem sikerült megbízható módon felolda-ni a felmerült ellentmondásokat.

Az analízis fázisába csak azokat az eseteketvontuk be, ahol a betegre vonatkozó klinikai ada-tok és az MDS-UPDRS pontozólap hiánytalanulkitöltésre került, illetve az MDS-UPDRS pontozá-sa az elôzetes logikai elemzésnek megfelelt(n=357, 233 férfi, életkor: 65,8±9,2 év, betegség-tartam: 8,3±6,2 év). Összesen 113 beteg részesültmély agyi stimulációs, míg 10 levodopa/carbidopaintestinalis gél kezelésben. Tizennégy beteg avizsgálat során még nem részesült dopaminergkezelésben (de novo beteg), míg 88 beteg csakdopaminagonista monoterápiában részesült. Alevodopaekvivalens dózisban számított gyógy-szeradag 214 mg volt (medián, 25–75 percentilér-tékek: 14–324 mg).

Az MDS-UPDRS I. részén (Mindennapi életvi-tel nem motoros tünetei) átlagosan 13 pontot mér-tünk (medián, 25–75 percentilértékek: 8–18), míg aII. részen (Mindennapi életvitel motoros tünetei) 14pontot (medián, 25–75 percentilértékek: 9–21). Askála Motoros Tünetek Vizsgálata részén (III.) 35pontot (medián, 25–75 percentilértékek: 23–45),míg a Motoros Komplikációk Vizsgálata részen(IV.) 4 (medián, 25–75 percentilértékek: 1–6) pon-tot kaptunk. Az MDS-UPDRS összesített pontszám65 (medián, 25–75 percentilértékek: 48–87) pont-nak adódott.

KLINIMETRIKUS ELEMZÉS (FAKTORANALÍZIS)

Az eredeti angol és magyar adatok összevetésébôlszámított CFI-értékek ≥0,94-nak bizonyultak (I.rész: CFI=0,94, RMSEA=0,08, I. rész: CFI=0,97,RMSEA=0,10, II. rész: CFI=0,95, RMSEA=0,08,míg a IV. résznél: CFI=0,99, RMSEA=0,20).

Az MDS-UPDRS Motoros KomplikációsVizsgálata részében az RMSEA meghaladta azelfogadható mértéket. Ennek okaként azt feltételez-tük, hogy a magyar adatbázisban a súlyosan fluktu-áló betegek aránya jelentôsen elmaradt az amerikaiadatokhoz képest. Ezért a CFA modelljét úgymódosítottuk, hogy a súlyos fluktuációt mutatóbetegek aránya közel hasonló legyen az eredetiamerikai és a magyar mintában. A betegpopulációeltéréseinek figyelembevételével elvégzett módosí-tott CFA-analízis során már mind a CFI, mind azRMSEA értéke megfelelô tartományban került(CFI=1,00, RMSEA=0,08).

Megbeszélés

Eredményeink alapján az általunk validált magyarnyelvû MDS-UPDRS a nyolcadik hivatalos idegennyelvû verzióként került elfogadásra, illetve ezzelegy idôben a MDS honlapjáról is elérhetôvé vált(http://www.movementdisorders.org/publications/rating_scales/). A klinikai gyakorlatban az MDS-UPDRS alkalmazása ingyenes; online tréningprog-ram is segíti megismerkedést az új skálával és amég megbízhatóbb pontozást16.

Az MDS-UPDRS az eredeti UPDRS számoshibáját és gyenge pontját korrigálja. Legfontosabbelônye a korábbi verzióhoz képest, hogy egysége-sen (nem pedig összemosva a motoros kompliká -ciókkal) kezeli a mindennapi életvitel motoros ésnem motoros tüneteit, illetve a motoros tünetekobjektív vizsgálata is sokkal megbízhatóbbá éskoherensebbé vált a megfelelô utasítások és értéke-lési szempontok alkalmazásával10, 13, 17.

Az MDS-UPDRS egyik legnagyobb hátránya,hogy nem kompatibilis a korábbi UPDRS-verzió-val. Az MDS-UPDRS I. és II. része számos olyantünetet is vizsgál (például dopamin-diszregulációsszindrómát, szorongást, kóros mértékû fáradékony-ságot), melyet a korábbi UPDRS nem tartalmazott.

Az eredeti UPDRS 3. részének (Motoros Tüne tekVizsgálata) egyik nagy elônye az, hogy megfelelôprotokoll alapján rögzített videofelvételrôl a rigiditáskivételével egy késôbbi idôpontban ismételten felve-hetô. Ezáltal a UPDRS 3. részét a vizsgálatra és abetegre nézve vak értékelô is újra tudja pontozni18, 19.Az új MDS-UPDRS III. része is megtartotta ezt atulajdonságot, azaz a rigiditás kivételével videofelvé-tel alapján újraértékelhetô. Azon ban az MDS-UPDRS III. része olyan elemeket is tartalmaz (példá-ul lábujjdobolást), amit a régi UPDRS nem vizsgált,ezért a régebbi vizsgálatokhoz (UPDRS-hez) készültvideoprotokoll alapján már az új skála nem vehetôfel teljes egészében. A probléma áthidalására azMDS szakértôi kidolgoztak egy olyan képletet, ami-nek az alkalmazásával a UPDRS-3 pontszámokbólmegközelíthetô módon kiszámolhatóvá válik azMDS-UPDRS III. pontszám20.

A UPDRS és az MDS-UPDRS pontszámok kli-nikai értékelése több szempontból is eltérô lehet.Ugyanazon beteg motoros tüneteinek vizsgálatasorán az MDS-UPDRS III. részén rendszerint többpontot kapunk, mint a UPDRS 3. részén. Ez akülönbség részben a megnövekedett kérdésszám-mal, részben az eltérô pontozási szisztémávalmagyarázható. Példaként említhetô, hogy a validá-lásban részt vevô betegeink MDS-UPDRS III. sze-rinti súlyossága 35 pontnak (medián) bizonyult,

Ideggyogy Sz 2014;67(3–4):129–134. 133


IRODALOM1. Fahn S, Elton R, UPDRS program members. Unified Parkinson’s

Disease Rating Scale. In: Fahn S, Marsden C, Goldstein M, CalneD, eds. Recent Developments in Parkinson’s Disease. FlorhamPark, NJ: Macmillan Health care Information; 1987. p. 153-163and 293–304.

2. The Unified Parkinson’s Disease Rating Scale (UPDRS): statusand recommendations. Mov Disord 2003;18(7):738-50.

3. Goetz C. Re: UPDRS: Status and recommendations. Mov Disord2004;19(5):605.

4. Goetz CG, Stebbins GT. Assuring interrater reliability for theUPDRS motor section: utility of the UPDRS teaching tape. MovDisord 2004;19(12):1453-6.

5. Goetz CG, LeWitt PA, Weidenman M. Standardized training toolsfor the UPDRS activities of daily living scale: newly available tea-ching program. Mov Disord 2003;18(12):1455-8.

6. Munhoz RP, Li JY, Kurtinecz M, et al. Evaluation of the pull testtechnique in assessing postural instability in Parkinson’s disease.Neurology 2004;62(1):125-7.

7. Kim HJ, Park SY, Cho YJ, et al. Nonmotor symptoms in de novoParkinson disease before and after dopaminergic treatment. JNeurol Sci 2009;287(1-2):200-4.

8. Hauser RA, Auinger P. Determination of minimal clinicallyimportant change in early and advanced Parkinson’s disease. MovDisord 2011;26(5):813.

9. Schrag A, Sampaio C, Counsell N, Poewe W. Minimal clinicallyimportant change on the unified Parkinson’s disease rating scale.Mov Disord 2006;21(8):1200-7.

10. Goetz CG, Tilley BC, Shaftman SR, et al. Movement DisorderSociety-sponsored revision of the Unified Parkinson’s DiseaseRating Scale (MDS-UPDRS): scale presentation and clinimetrictesting results. Mov Disord 2008;23(15):2129-70.

11. Goetz CG, Fahn S, Martinez-Martin P, et al. Movement DisorderSociety-sponsored revision of the Unified Parkinson’s DiseaseRating Scale (MDS-UPDRS): Pro cess, format, and clinimetric tes-ting plan. Mov Disord 2007;22(1):41-7.

12. Goetz CG, Poewe W, Rascol O, et al. Movement Disorder SocietyTask Force report on the Hoehn and Yahr staging scale: status andrecommendations. Mov Disord 2004;19(9):1020-8.

13. Goetz CG, Stebbins GT, Chung KA, et al. Which dyskinesia scalebest detects treatment response? Mov Disord 2013;28(3):341-6.

14. Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE.Systematic review of levodopa dose equivalency reporting inParkinson’s disease. Mov Disord 2010;25(15):2649-53.

15. Goetz CG, Tilley BC, Stebbins GT. Dopamine dysregulationsyndrome item from the MDS-UPDRS. Mov Disord 2012;27(1):166.

16. Goetz CG, Stebbins GT, Chmura TA, Fahn S, Poewe W, TannerCM. Teaching program for the Movement Disorder Society-spon-sored revision of the Unified Parkinson’s Disease Rating Scale:(MDS-UPDRS). Mov Disord 2010;25(9):1190-4.

17. Martinez-Martin P, Rodriguez-Blazquez C, Alvarez-Sanchez M, etal. Expanded and independent validation of the MovementDisorder Society-Unified Parkinson’s Disease Rating Scale(MDS-UPDRS). J Neurol 2013;260(1):228-36.

18. Fehér G, Balás I, Komoly S, et al. A kétoldali szubtalamikus sti-muláció hatékonysága az antiparkinson gyógyszerelés változtatá-sának tükrében. Ideggyogy Sz 2010;63(9-10):314-9.

19. Deli G, Balás I, Komoly S, et al. Korábban és hatékonyabban: Amély agyi stimuláció szerepe a munkaképesség megôrzésében.Ideggyogy Sz 2014;67:közlésre elfogadva.

20. Goetz CG, Stebbins GT, Tilley BC. Calibration of unifiedParkinson’s disease rating scale scores to Movement DisorderSociety-unified Parkinson’s disease rating scale scores. MovDisord 2012;27(10):1239-42.

21. Kovács N, Balás I, Llumiguano C, et al. Mély agyi stimuláció: egyúj perspektíva a mozgászavarok kezelésében. Lege Artis Me -dicinae 2009;19(2):119-26.

22. Lang AE, Houeto JL, Krack P, et al. Deep brain stimulation: pre-operative issues. Mov Disord 2006;21(Suppl 14):S171-96.

23. Merello M, Gerschcovich ER, Ballesteros D, Cerquetti D.Correlation between the Movement Disorders Society UnifiedParkinson’s Disease rating scale (MDS-UPDRS) and the UnifiedParkinson’s Disease rating scale (UPDRS) during L-dopa acutechallenge. Parkinsonism Relat Disord 2011;17(9):705-7.

ami a UPDRS 3. részén megközelítôleg 27 pontnak(medián, 25–75 percentilértékek: 15–37 pont) feleltvolna meg. A klinikai gyakorlatban a UPDRS-3részén 30 pont felett tekintjük a motoros tüneteket„súlyos” fokúnak; az MDS-UPDRS-en a közelítôszámítások szerint ez a határ 37–40 pont közöttiretehetô a HYS-értéktôl függôen20. Mély agyi stimu-látor beültetése elôtt elvégzett levodopateszteléskora nemzetközi gyakorlathoz igazodva legalább 30%-os javulást várunk el on állapotban az off állapothozképest21, 22. Ez a mérték az MDS-UPDRS III. részénpéldául 24,5%-os javulásnak felel meg az eltérôpontozási szisztéma miatt23.

Összefoglalás

Az MDS-UPDRS hivatalos magyar nyelvi validá -ciójával lehetôvé vált, hogy mind a klinikai gyakor-

latban, mind a kutatásban nemzetközileg is elfoga-dott PK-pontozóskálát használhassunk. Mivel aUPDRS és az MDS-UPDRS nem kompatibilisekegymással és az elért pontszámok sem vethetôkössze egymással teljes mértékben, ezért gyakorlatotés óvatosságot is igényel az új skála bevezetése aklinikai rutinba.

KÖSZÖNETNYILVÁNÍTÁSA vizsgálat kivitelezését az OTKA PD103964, aMagyar Neuroimaging Alapítvány, a TÁMOP-4.2.2.A-11/1/KONV-2012-0017 és a TÁMOP-4.2.2.A-11/1/KONV-2012-0052 illetve a KTIA-NAP-13-1-2013-0001 támogatta.

Köszönettel tartozunk az MDS-UPDRS teamtagjainak a magyar nyelvi validációhoz nyújtottsegítségükért (Christopher G. Goetz, Glenn T.Stebbins, Barbara C. Tilley, Nancy LaPelle, ShengT. Luo, Lu Wang).



Ideggyogy Sz 2014;67(3–4):135–139. 135

ESETISMERTETÉS

ASSOCIATION OF TEMPORAL LOBE INFLAMMATORYLEUKOENCEPHALOPATHY WITH TWO B CELL

MALIGNANCIES Ferenc GARZULY1, Katalin HAHN2, László János IVÁNYI3, László KERESKAI5, Valéria GÁBOR1,

Gábor G. KOVÁCS6, Herbert BUDKA6, Bernadette KALMAN4

1Markusovszky University Hospital, Department of Pathology; Szombathely2Markusovszky University Hospital, Department of Neurology; Szombathely

3Markusovszky University Hospital, Department of Hematology; Szombathely4Markusovszky University Hospital, Center for Molecular Medicine; Szombathely

5University of Pécs, Institute of Pathology; Pécs6Medical University of Vienna, Institute of Neurology; Austria

GYULLADÁSOS TEMPORALIS LEUKOEN-CEPHALOPATHIA EGYÜTTES MEGJELENÉSE KÉT B-SEJTES MALIGNOMÁVAL Garzuly F, MD, PhD; Hahn K, MD; Iványi LJ, MD, PhD; KereskaiL, MD; Gábor V, MD; Kovács GG, MD, PhD; Budka H, MD,MSc, Dhc; Kalman B, MD, PhD, DScIdeggyogy Sz 2014;67(3–4):135–139.

A klinikus idônként olyan beteggel is találkozik, akinekegyszerre többféle, látszólag egymástól független betegségevan. Ilyenkor az esetleges kapcsolat felderítése komolykihívást jelenthet számára. Ilyen bonyolult esetet mutatunkbe, amelyben két malignus B-sejtes betegség és gyulladásosleukoencephalopathia fordult elô együtt. Az idôs férfi afelvételt megelôzôen három nappal gyengeségre kezdettpanaszkodni, fejét fájdította, ismételten hányt, feledékenylett, étvágytalanná, deprimálttá, majd aluszékonnyá vált.Klinikai, laboratóriumi, képalkotó és hisztológiai vizsgálatoktörténtek, melyek során primer központi idegrendszeri lym-phoma, a temporalis lebeny gyulladásos leukoen-cephalopathiája és lappangó myeloma multiplex derült ki.A beteg korábban kemoterápiában nem részesült. Korábbigenomikai tanulmányok eredményei alapján feltételezhetô,hogy a molekuláris abnormalitások B-sejtekben történôszekvenciális akkumulációja vezetett elôször a myelomamultiplex, majd a primer központi idegrendszeri lymphomakialakulásához, míg a temporalis lebeny leukoen-cephalopathiája a lappangó myeloma multiplex paraneo-plasiás következményeként értelmezhetô.

Kulcsszavak: myeloma multiplex, primer központi idegrendszeri lymphoma, B-sejtes malignoma, paraneoplasticus gyulladásos leukoencephalopthia,szomatikus mutációk

Identification of etiological connections among virtually dis-tinct diseases in a patient may be sometimes challenging.We report a unique case with two B cell malignancies andan inflammatory leukoencephalopathy. Three days prior toadmission, the elderly male patient developed fatigue,headaches, recurrent vomiting, memory disturbances,depression and somnolence. Clinical, laboratory and imag-ing evaluations as well as post mortem histological studieswere performed. Simultaneous presence of primary centralnervous system B cell lymphoma, temporal lobe inflamma-tory leukoencephalopathy and multiple (smoldering) myelo-ma, was revealed by the detailed work up in the treatment-naïve patient. Based on recent data from genomic studies,we propose that a sequential evolution of molecular pathol-ogy lead to the co-occurrence of multiple myeloma and pri-mary central nervous system B cell lymphoma in thispatient, and interpret the development of the temporal lobeleukoencephalopathy as a likely paraneoplastic complica-tion of smoldering myeloma.

Keywords: multiple myeloma, primary CNS lymphoma, B cell malignancy, paraneoplastic inflammatory leukoencephalopathy, somatic mutations

Correspondent (levelezô szerzô): Ferenc GARZULY, MD, PhD, Department of Pathology, Markusovszky UniversityHospital; 9700 Szombathely, Markusovszky Street 5. Phone: 36-94-515-412, e-mail: [email protected]

Érkezett: 2013. február 27. Elfogadva: 2013. március 26.

www.elitmed.hu

garzuly_UJ ISZ TUKOR ALAP ANGOL.qxd 2014.03.21. 16:14 Page 135

http://www.elitmed.hu/kiadvanyaink/ideggyogyaszati_szemle/progressziv_multifokalis_leukoencephalopathia-720/

The co-occurrence of common diseases is fre-quently seen in clinical practice and causes no

diagnostic or therapeutic difficulties. In contrast,the co-occurrence of rare and apparently independ-ent conditions may pose major challenges in clini-cal practice. It is particularly difficult to proceedwith the therapeutic intervention without knowingwhether or not there is a causal link among theassociated conditions. Here we report such a com-plex case of a patient who presented with subacutememory loss, personality and behavioral changesand somnolence in our neurology department.

Case report

A 73 year old man was previously treated forhypertension and atrial fibrillation. His new com-plaints began three days prior to admission to theneurology department, and included fatigue,headaches, vomiting, memory problems, depres-sion and personality changes. Neurological examrevealed no focal findings, but lack of facial expres-sions, psychomotor slowing, partial disorientationin time, memory difficulties with encoding of newinformation and somnolence when left alone.

Abnormal laboratory results: cerebrospinalfluid: protein 0.83 g/l (normal 0.12-0.6), WBC10/µl (normal 0-10) with 90% lymphocytes, 10%monocytes and no lymphoblasts; glucose 2.65mmol/L (normal 2.20-3.90).

3 Tesla MRI: A symmetric space occupyinglesion with edema, contrast enhancement anddecreased average diffusivity is visualized in themedial thalami and inter-thalamic regions. Theright temporal lobe appears with narrowed gyri andenlarged horn of the lateral ventricle. T1-weightedimages show a hypointense, and T2-weightedimages show a hyperintense lesion in this areaextending to the insular region, but excluding theposterior part of the temporal lobe. In addition,increased diffusion is noted on the DWI images inthe white matter, while equivocal diffusion alter-ations are seen in the amygdale and hippocampus ofthe right temporal lobe. T1-weighted images dis-play no pathological changes in the hippocampaland parahippocampal cortices (Figure 1A, B).

These findings raised the suspicion of viral(Herpes simplex virus - HSV) encephalitis ortumor. Acyclovir, dexamethasone and enoxaparinewere initiated. However, subsequent tests were neg-ative for HSV, tick borne encephalitis and West-Nile viruses.

MRI-guided stereotactic biopsy of the right thal-amus was performed at the Institute of

Neurosurgery, University of Pécs (UP), Dr. F.Vetô. Histology: Primary large B cell lymphoma ofthe brain with CD20+, Mum-1+, CD3-, and CD10-immunophenotype.

For further management the patient was trans-ferred to the Hematology Department of our hospi-tal.

Abdominal, mediastinal and pelvic computertomography revealed moderate hepatomegaly with-out splenomegaly or mediastinal and abdominallymphadenomegaly. The cranium, vertebrae andpelvis were free of osteolytic lesions.

Laboratory findings: Serum immune-elec-trophoresis: IgG 21.10 g/l (normal 8.0-17.0), IgA0.29 g/l (normal 1.00-4.9), IgM 0.31 g/l (normal0.50-3.2), Kappa-K chain 5.67 g/l (normal 2.00-4.40), lambda-k chain 0.24 g/l (normal 1.1-2.4).Interpretation: (1) 22.2% paraprotein in the gammaregion, (2) IgG Kappa monoclonal gammopathy.

Bone marrow aspirate: > 20% clonally expandedplasma cells; IgG kappa monoclonal gammopathyand 22.2 g% M-protein. Interpretation: Multiplemyeloma.

136 Garzuly: Association of temporal lobe inflammatory leukoencephalopathy with two B cell malignancies

Figure 1A Postgadolinium T1 weighted coronal imageof the thalamic lesion. The image shows bilateralenhancing lesions representing the PCNSL

Figure 1B. T1 weighted native coronal image of righttemporal lobe. Thinning of the cortex, hypointensitywithin the atrophied white matter and the enlargement ofthe temporal horn are depicted


Bone marrow (iliac crest) biopsy (Institute ofPathology, PTE): The cellularity is below 20-30%in many areas. Moderate CD138+ plasma cell pro-liferation with mostly CD20+, CD56- co-staining isseen in an uneven diffuse and cluster-like distribu-tion occasionally reaching 10-15%. IgG kappachain positivity is abundant.

Comparison of the bone marrow and thalamusbiopsies: The brain biopsy (PCNSL) contained cellsof markedly more immature phenotype, predomi-nantly immunoblastoid cells with central nucleolus,a few with plasmocytoid features, but repeatedlywith CD138- and strongly CD20+ staining and witha proliferation rate of >70% that would be veryunusual in MM. Analyses of IgG heavy chain generearrangements in the brain - and bone marrow -derived specimens revealed multiple, but distinctrearrangement patterns, supporting two clonallydifferent processes (B cell PCNSL in the brain andplasma cell myeloma in the bone marrow).

The patient received 1x intravenous (3 g/m2) and3x intrathecal methotrexate treatment for thePCNSL. In a week, severe myelosuppression devel-oped. The anemia was treated with RBC concen-trate, while the neutropenia was managed with agranulocyte colony-stimulating factor preparation.For the treatment of MM, dexamethasone wasadministered. His neurological condition wasunchanged, but he developed fever and died of sep-sis.

Autopsy: The immediate cause of death waspneumonia with abscesses accompanied by a hema-tological spread. Bone fragments showed decalcifi-

cation and hypocellular marrow with significantlydecreased erythro- and myelopoesis. Atypia wasobserved among megakariocytes. Plasma cell pro-liferation was seen with cytomorphological atypiaand uneven distribution. Internal organs were freeof MM (“smoldering myeloma”).

Both thalami were moderately swollen.Lymphocytic parenchymal infiltration accompaniedby astrogliosis, and perivascular infiltration at thelesion edges, were seen in the medial nuclei of boththalami (Figure 2.). The tumor cells were small andmedium sized with fine chromatin structure, roundshape and occasionally prominent nucleoli. Thecytoplasm appeared thin and slightly eosinophilic.Immunohistochemistry revealed almost 100%CD20+ and CD79a+ tumor cells. There were a fewCD8+ T lymphocytes localized around blood vesselsand in inflammatory infiltrates.

Ideggyogy Sz 2014;67(3–4):135–139. 137

Figure 2. H&E stained section and IHC of the PCNSLfrom the thalami. Small and medium size tumor cellswith fine chromatin structure and round shaped, occa-sionally prominent nucleoli are demonstrated. The cyto-plasm appears thin and slightly eosinophilic. Inset: IHCreveals strong CD20 positivity of the cells

Figure 3A. Woelcke stained section of the right hemi-sphere. Extensive loss of myelin is demonstrated in thetemporal lobe

Figure 3B. Anti-CD8 immunohistochemistry of the tem-poral lobe. Perivascular and parenchymal infiltration ofCD8 lymphocytes is seen in the white matter of the righttemporal lobe


The right temporal lobe had thin gyri and gray-ish, softened WM. The WM was rarified and cystic(Figure 3A) with only a few remaining fragmentsof SMI31+ axonal and myelin fragments amidstprominent glial scarring involving gemistocytes,fibrillary astrocytes and scattered macrophages.Strong CD68+ staining was noted in lipid-ladenmacrophages. Predominantly CD8+ cytotoxic Tand CD20+ B cell infiltration occurred in perivas-cular distribution, without signs of malignancy.CD8 cells diffusely infiltrated the parenchyma(Figure 3B). The cortical gray matter was rarifiedand focally spongiform with some inflammatoryactivity extending from the WM, but withoutmicroglial nodules or gliosis. Immunohisto che -mistry was negative for HSV-1,-2, JC and SV40viruses. These observations suggested an inflam-matory leukoencephalopathy of non-viral origin.Epstein-Barr virus detection was equivocal due topoor RNA quality. Direct immunfluorescencerevealed no IgG and complement C3 deposition inthe temporal WM specimens.

Discussion

The clinical work up established that the patient hadtwo diseases of the CNS: 1. a primary B cell CNSlymphoma occupying both thalami and 2. a whitematter disease affecting almost the entire right tem-poral lobe and causing atrophy. In addition to theCNS pathology, this case was further complicatedby the clinical recognition of a smoldering multiplemyeloma that only affected the bone marrow andcaused no apparent complaints. Unfortunately, thepatient died from sepsis after 1.5 months of immunesuppressive therapy.

In our work up two major questions arose1. Could the co-occurrence of two B cell malig-

nancies (PCNSL and MM) be a co-incidence, orrelated to a common molecular cause in this patientwho was treatment naive at the time of clinicalrecognition? Unless treatment of MM bychemotherapy induced immune suppression and asecondary cancer (e.g. PCNSL), the simultaneousdetection of two B cell malignancies in a singlepatient is unusual (1). Searching Pubmed, wefound a single report describing a tri-lineage hema-tological disease with sideroblastic anemia, MMand B-cell non-Hodgkin’s lymphoma (2). TheMultiple Myeloma Genomics Initiative using mas-sively parallel sequencing of tumor genomes andthe corresponding normal DNAs revealed that thenumber of somatic point mutations in the tumor ishigh (2.9 / million bases translating into 7,450mutations in a tumor), and the mutations involve

several functionally important genes that define amechanistic framework of tumorgenesis (3).Relevant to our case, mutations were detected inregions of known somatic hypermutations whichcomprise immuno globulin-coding genes and alymphoid oncogene, BCL6. Further, mutationswere observed within non-coding regions ofBCL7A, a putative tumor suppressor gene involvedin the B-cell malignancy, Burkitt lymphoma. In thelight of these findings we propose that the accumu-lation of somatic mutations in malignant cells ofthe bone marrow may result in some clonal diver-sity over time. Mutations affecting lymphoid onco-genes or tumor suppressor genes may occur inmyeloma subclones and drive the genesis of a new,phenotypically different B cell malignancy. Ifthese mutated daughter clones express appropriateadhesion molecules, they may migrate to the CNSand give rise to PCNSL. Therefore, the PCNSL inthis patient could be explained as a result of thesomatic molecular changes evolving in the bonemarrow B cell lineages which primarily cause MMand subsequently also PCNSL.

2. What could be the cause of the observed tem-poral lobe leukoencephalopathy? Vascular, trau-matic, metabolic or inherited disorders could bereadily excluded based on clinical and histologicalfeatures. Despite the absence of characteristic signsof Herpes Simplex (HS) encephalitis (the patienthad no fevers, the MRI showed a chronic lesionpredominantly in the white matter without theinvolvement of the cortex, and there was no hemor-rhagic transformation in this lesion), this diagnosiswas assumed as a potential, treatable cause of tem-poral lobe pathology and empirically treated untilserological, virological and / or histopathologicalstudies from the stereotactic brain biopsy unequiv-ocally excluded the presence of this and severalother viruses (HSV-1, -2, West Nile, JC, SB40).When PCNSL in the thalami was recognized, thepossibility of paraneoplastic origin of the temporallobe pathology arose. The association betweenparaneoplastic limbic encephalitis and peripheral Bcell lymphomas is well known (4). However, aparaneoplastic mechanism requires chronic expo-sure to and priming of the adaptive immune systemby the lymphoma antigens in the peripheralimmune system. Therefore, it is difficult to associ-ate a paraneoplastic mechanism with a lymphomarestricted to the CNS, and the literature is alsorather spares in this regard.

Could the temporal lobe pathology still be para-neoplastic in origin? The bone marrow malignancycaused no complaints, but the disease probably per-sisted for years as a smoldering myeloma, allowingthe development of a long-standing, secondary

138 Garzuly: Association of temporal lobe inflammatory leukoencephalopathy with two B cell malignancies


Ideggyogy Sz 2014;67(3–4):135–139. 139

pathology in the CNS. However, both the MRimages and the pathology work up showed that thelimbic system was largely spared, while the whitematter of the right temporal lobe was predominant-ly affected in this patient. The histological studiesalso suggested that it was the inflammatory andspongiosus white matter lesion that extendedtowards the gray matter of the right temporal lobe,not the other way around, and beside the extensivewhite matter involvement, the gray matter patholo-gy was sparse. Such a temporal lobe leukoen-cephalopathy, would not be compatible with para-neoplastic limbic encephalitis that primarily affectsthe mesial temporal lobe region and gray matterstructures (5). In the absence of IgG kappa parapro-tein, C3 complement, viruses and malignant B cellsin the right temporal lobe, the inflammatoryleukoencephalopathy with many infiltrating CD8cells and myelin and axonal loss was likely a T celldriven paraneoplastic leukoencephalopathy andmostly resembled the histological characteristics ofADEM (acute demyelinating encephalomyelitis).The lesion’s MRI characteristics were also compat-ible with this conclusion. ADEM-like paraneoplas-tic leukoencephalomyelitides in association withMM were described without the presence of com-mon paraneoplastic antibodies or microorganisms(6–8). However, in the light of the long standingnature of and lack of anti-myelin paraproteins in theCNS WM lesion, our observation, similar to thepreviously published cases, only provides circum-stantial evidence for the existence of a paraneoplas-tic ADEM-like pathology and may be more appro-priate to call it inflammatory leukoencephalopathyassociated with MM.

As inflammatory CNS lesions can be caused byEpstein-Barr virus (EBV) infection in both pedi-atric (9, 10) and adult patients (11, 12), the ethio-logical involvement of EBV in the temporal lobepathology of this patient also had to be considered.However, PCNSLs are typically negative for EBVin immunocompetent patients, as was our patienttoo at the time of PCNSL diagnosis. Nevertheless,a recent report described EBV detection in a verylow frequency of PCNS in immunocompetent indi-viduals (13). Unfortunately, testing for EBV in thePCNSL lesion failed to provide unequivocal resultin our patient. Considering the typically EBV nega-tive nature of PCNSL in an immunocompetentpatient, the cause of the temporal lobe lesion in ourcase appears unlikely to be EBV-related and ismainly compatible with an inflammatory leukoen-cephalopathy, possibly of paraneoplastic origin, inassociation with MM.

Conclusions

The current case exemplifies the complexity of MMpathology and suggests that clonal diversity andautoimmune processes may contribute to associatedneurological complications.

ACKNOWLEDGEMENTS The authors thank for the scientific discussions andconsultations by Prof. Dr. Zs. Illés, Department ofNeurology, UP, Pécs, Dr. A. Vadvári, RadiologyDepartment, Markusovszky Hospital, Szombathely,and Dr. P. Barsi, MR Research Institute, Semmel -weis University, Budapest.

REFERENCES1. Dispenzieri A, Kyle RA. Neurological aspects of multiple

myeloma and related disorders. Best practice & research.Clinical Haematology 2005;18:673-88.

2. Ianotto JC, Tempescul A, Eveillard JR, et al. Tri-lineagedisease involving sideroblastic anaemia, multiple myelomaand B-cell non-Hodgkin’s lymphoma in the same patient.Ann Hematol 2009;88:273-4.

3. Chapman M, Lawrence MS, Keats JJ, et al. Initial genomesequencing and analysis of multiple myeloma. Nature2011;471:467-72.

4. Kawashima S, Okita K, Yamawaki T, et al. Case of parane-oplastic limbic encephalitis associated with malignant Bcell lymphoma. Brain Nerve 2009;61:208-12.

5. Sakai K, Yoshita M, Samuraki M, Yamada M. Acute dis-seminated encephalomyelitis with medial temporal lesionsmimicking acute limbic encephalitis. Clin NeurolNeurosurg 2011;113:72-4.

6. Sheng B, Mak VW, Lee HK, et al. Multiple myeloma pre-senting with acute disseminated encephalomyelitis: causalor chance link? Neurology 2006;67:1893-4.

7. Vokaer M, De Beyl D Z, Bier JC. Multiple myeloma pre-senting with acute disseminated encephalomyelitis: causalor chance link? Neurology 2007;68:1873-4.

8. Alkatan H, Shuckett P. Diffuse leukoencephalitis associat-ed with retinoblastoma: case report of a presumed parane-oplastic syndrome. Can J Ophthalmol 2008;43:490-2.

9. Ozbek O, Koç O, Paksoy Y, Aydin K, Nayman A. Epstein-Barr virus encephalitis: findings of MRI, MRS, diffusionand perfusion. Turk J Pediatr 2011;53:680-3.

10. Jang YY, Lee KH. Transient asymptomatic white matterlesions following Epstein-Barr virus encephalitis. Korean JPediatr 201;54:389-93.

11. Westergaard CG, Risum M, Lunding S. Primary Epstein-Barr virus infections with neurological complications intwo middle-aged men. Ugeskr Laeger 2012;174:1240-2.

12. Takeuchi S, Takasato Y, Masaoka H. Epstein-Barr virusencephalitis with a reversible splenial lesion. Intern Med2012;51:341-2.

13. Saglam A, Akyurek N, Soylemezoglu F, Uner A. Epstein-Barr virus frequency in primary central nervous systemlymphomas in Turkey. APMIS 2013;121:232-8.


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Relapszáló-remittáló, elsô vonalbeli kezelés mel-lett is relapszusokat szenvedô sclerosis multip-

lexes (SM-) betegek esetében a klinikusnak terápi-ás dilemmát jelent, hogy a hatékonyságot és a biz-tonságosságot is figyelembe véve milyen terápiásdöntéssel haladjon tovább a beteg kezelésében,melyik másodvonalbeli készítményt használja.

Stefan Braune németországi SM-kohorsztanul-mányban számolt be a kezelési alternatívák mellettszerzett tapasztalatokról a Journal of Neurology2013. szeptemberi számában.

A tanulmányban németországi SM-klinikákonelsô vonalbeli szerekrôl másodvonalbeli szerekreállított betegek adatait dolgozták fel (2009. február1. és 2011. január 31. között átállított és 2012. janu-ár 30-ig legalább 12 hónapon át kezelt betegek ada-tainak elemzésével).

Az adatgyûjtést 237, natalizumabra és 190, fin-golimodra átállított beteg követésével végezték. Akét csoportban elôzôleg nem mutatkozott jelentôskülönbség az éves relapszusrátában. Az átváltástkövetôen a relapszusráta már az elsô három hónap-ban drasztikusan csökkent mind a két csoportban. Aklinikai hatékonyság mértékében, és annak fennma-radásában nem találtak a csoportok között szignifi-káns különbséget az egyéves megfigyelés alatt.Mindkét csoportban hasonló volt a változatlan,illetve a javuló EDSS-sel rendelkezôk aránya (fin-golimod: 80,53%, natalizumab: 79,32%). A relap-szusmentes betegek arányában sem találtak statisz-tikailag szignifikáns különbséget (fingolimod:75,79%, natalizumab: 71,73%). Ugyanígy a prog-

ressziómentes (fingolimod: 87,39%, natalizumab:82,70%), illetve relapszus- és progressziómentesbetegek aránya (fingolimod: 71,05%, natalizumab:62,03% ) is hasonló volt.

A fingolimodot az FDA elsô vonalbeli szerként,míg az EMA második vonalban törzskönyvezte re -lapszáló-remittáló sclerosis multiplexben (RRMS).A németországi valós körülmények között (azaz amindennapi rutinban és nem klinikai vizsgálatban)gyûjtött adatok azt mutatták, hogy úgy a natalizu-mab, mint a fingolimod kedvezôen befolyásolta abetegség lefolyását, körülbelül hasonló mértékbenstabilizálták az EDSS-t és csökkentették a relapszu-sokat az elsô 12 hónapban. Mindkét gyógyszerrel abetegek körülbelül kétharmada lett betegségaktivi-tástól mentes, holott ezt az elsô vonalbeli szerekkelnem sikerült elérni. Ez a hatás függetlennek tûnt akiindulási EDSS-tôl, illetve a relapszusrátától.

Hosszabb megfigyelési idejû, több beteg bevo-násával végzett vizsgálatban szükséges tisztázni,hogy a mindennapi alkalmazás során milyenkülönbség mutatkozik a másodvonalbeli szerekközött hatékonyság és biztonságosság vonatkozásá-ban.

Mindenképpen kiemelendô azonban, hogy azadatok alapján az elsô vonalbeli szerek mellettiállapotromlás esetén érdemes másodvonalbelikezelést megfontolni relapszáló-remittáló sclerosismultiplexben.

dr. Lovas Gábor PhDJahn Ferenc Dél-pesti Kórház és Rendelôintézet,

Neurológiai Osztály

Ideggyogy Sz 2014;67(3–4):141. 141

FÓRUM

TERÁPIÁS TOVÁBBLÉPÉS DILEMMÁJA RELAPSZÁLÓ-REMITTÁLÓ SCLEROSIS MULTIPLEXBEN AZELSÔ VONALBELI KEZELÉS HATÁSTALANSÁGA ESETÉN:

FINGOLIMOD VAGY NATALIZUMAB?

Kivonatos tartalmi ismertetés. Eredeti megjelenés: Braune S, Lang M, Bergmann A; NTC Study Group J Neurol.Second line use of Fingolimod is as effective as Natalizumab in a German out-patient RRMS-cohort.

2013 Dec;260(12):2981-5.

lovas_UJ ISZ TUKOR ALAP.qxd 2014.03.22. 21:39 Page 141

142 Társasági melléklet

TÁRSASÁGI MELLÉKLET

AXXX. gyôri Epileptológiai Továbbképzô Munka -kon ferencia keretében tartotta meg éves közgyûlését

a Magyar Epilepszia Liga (MEL). Prof. dr. Janszky József elnöki beszámolója a

vezetôség elmúlt évi munkájáról:– Pénzügyi mérleg. A MEL elôzô évi induló egyen -

lege 36 942 116 Ft volt. Az elôzô éves ciklus bevétele 1 693 632 Ft volt: tagdíj 74 000 Ft, kamat 1 619 632 Ft.A kiadás 160 307 Ft: ILAE-tagdíj 10 303 Ft, telefon 10 000 Ft, könyvelôi díj 105 000 Ft, banki költségek 29 307 Ft, honlap 2387 Ft, reprezentáció 3000 Ft. AMEL jelenleg 38 475 441 forinttal rendelkezik.

– Az elmúlt idôszak pozitív eseményei a következôkvoltak. A 2009. évi Epilepszia Világkongresszus szerve-zéséért járó összeget átutalta az ILAE, ami jelentôsenjavította a MEL pénzügyi helyzetét. A MEL képviseltet-te magát az idei MIET és MKNT kongresszusain. Idénmár 30. alkalommal került megrendezésre a gyôri Epi -leptológiai Továbbképzô Munkakonferencia. A MELszakmai segítségével idén is sikeresen rendezte meg azUCB Magyarország Kft. a továbbképzô konferenciátHerceghalmon. Az epilepsziaellátással kapcsolatos szak-mai irányelv megújítása folyamatban van, és jövô év ele-jén megjelenik. Hamarosan megindul és mindenki általelérhetô az új honlap (epilepszia.hu). Megújult a kapcso-latfelvétel a betegszervezetekkel.

– Negatívumok az elmúlt idôszakban. A MEL-neknincs érdemi beleszólása a jogalkotásba, a kormányzatidöntések a véleményünk figyelembevétele nélkül történ-nek. Nincs megfelelô párbeszéd a Sportorvosi Kollé -giummal. Változatlanul gond a neurológus szakorvosok

elvándorlása és az utánpótlás hiánya. Idén továbbcsökkentek a szponzorálások.

– A jövô legfontosabb középtávú terve az epilepto-lógusképzés javítása. Ezért a MEL létre kívánja hozniaz Epilepszia Ösztöndíjat. Az ösztöndíjjal a képzéstszemélyes oktatáson keresztül, mentor-rezidensi rend-szerben lehet megvalósítani. A képzés hároméves. Azösztöndíj mértéke bruttó 4 millió forint. Az átadásrahárom részletben kerül sor: sikeres „EpilepsziábanJártas Orvos” vizsga (elsô év végén, 1 millió forint),sikeres „Epilep tológiai EEG Jártasság” vizsga (a máso-dik év végén, 1 millió forint), sikeres „EpilepsziaSpecialista” vizsga (a harmadik év végén, 2 millióforint). Az ösztöndíjasnak vállalni kell azt, hogy a mun-kahelyén minimum heti 8 órában epilepszia-szakrende-lést folytat, valamint a képzés ideje alatt és utána háromévig nem távozik külföldre munkavállalás céljábólhárom hónapnál hosszabb idôre. Az ösztöndíj részletesfeltételrendszere és a pályázás módja külön meg fogjelenni a honlapon és az Ideggyógyászati Szemlében.Az elsô ciklusban két fô részére tervezi a MEL az ösz-töndíj kiírását. Az ösztöndíj finanszírozására a MELalapítványt kíván létrehozni.

– A közgyûlés egyhangú szavazással elfogadta avezetôség beszámolóját. Ezután a közgyûlés egyhangúszavazással elfogadta, hogy a MEL alapítványt hozhas-son létre az Epilepszia Ösztöndíj finanszírozására,amennyiben ezt az aktuális jogszabályok megengedikvagy lehetôvé teszik.

Dr. Szupera Zoltántitkár

A MAGYAR EPILEPSZIA LIGA KÖZGYÛLÉSE

Gyôr, 2013. október 18.

IDEGGYÓGYÁSZATI SZEMLE LEGJOBB KÖZLEMÉNYE DÍJÁT 2013-BAN

Fogarasi András, Tobias Loddenkemper, Cecilia Mellado, Ingrid Tuxhorn, Georg Evers, Dean Sarco,Richard C. Burgess, Halász Péter, Barsi Péter, Gyorsok Zsuzsanna, Gyimesi Csilla, Kóbor Jenõ,Siegler Zsuzsanna, Janszky József, Jakus Rita. Sturge-Weber-szindróma: klinikai és radiológiai kor-relátumok 86 beteg esetében. Ideggyógyászati Szemle 2013;66(1-2):53-57. kapta. A nyerteseknekszívbôl gratulálunk.

A díj átadásának várható helye és ideje:Magyar Epilepszia Liga XII. Kongresszusa 2014. június 5-7. Szeged

szupera tarsasagi_tarsasmell MEL.qxd 2014.03.21. 16:15 Page 142

Kongresszusi naptár 143

KONGRESSZUSI NAPTÁR

Hazai rendezvények

2014. május 9–10. A Magyar Fejfájás Társaság XXI. Kongresszusa – Siófok Inf.: www.fejfajas-tarsasag.hu és www.top-congress.hu

2014. június 5–7. Magyar Epilepszia Liga XII. kongresszusa – SzegedInf.: www.epilepszia.hu és www.congress-service.hu

2014. október 2–4. A Magyarországi Fájdalom Társaság és a IV. NeurostimulációsSzimpozium közös Kongresszusa – Pécs Inf.: [email protected]

2014. november 29. Az Idegtudományi Doktori Iskola V. PhD Szimpóziuma – Debrecen Inf.: [email protected]

Külföldi rendezvények

May 04 2014–May 09 ESC – European Stroke Conference 2014 – Nice, FranceInf.: http://www.eurostroke.org/

May 07 2014–May 10 2014 7th World Congress of the World Institute of Pain (WIP 2014) –Maastrich, The NetherlandsInf.: www.kenes.com/wip2014

May 08 2014–May 11 2014 8th World Congress on Controversies in Neurology (CONy) – Berlin,GermanyInf.: http://comtecmed.com/cony/2014/

May 18-20, 2014 2014 Society of Neurological Surgeons` Annual Meeting – -Rochester(MN), Minnesota, United StatesInf.: http://www.comtecmed.com/

May 31 2014–June 03 2014 Joint Congress of European Neurology (EFNS-ENS) – Istanbul,TurkeyInf.: http://efns2014.efns.org/

June 8-12, 2014 Movement Disorder Society Annual Congress 2014 – Stockholm,SwedenInf.: http://www.movementdisorders.org/congress/past_and_future.phpInf.: http://www.worldneurologyonline.com/article/mark-your-calen-dars/#sthash.dPLD7YLw.dpuf

June 29–July 3, 2014 11th European Congress on Epileptology – Stockholm, SwedenInf.: http://epilepsycongress.org/

July 05 2014–July 09 2014 9th FENS Forum of Neuroscience – MilanInf.: http://fens2014.neurosciences.asso.fr/index.php

kongr_kongr.qxd 2014.03.21. 16:16 Page 143

worwa_levetiragamma_sajto_200x280_140319.indd 1 2014.03.19. 16:22:30


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NEUROreal-j.mtak.hu/2885/4/isz 2014 3-4 e-mag.kicsi.pdf2014. március 30. Ideggyógyászati Szemle/Clinical Neuroscience 2014;67(3–4):73–144. NEUROSCIENCE CLINICAL SZEMLE IDEGGYÓ