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 Anexa 4 Managementul sindroamelor neurologice paraneoplazice: raportul grupului de lucru EFNS C.A.Vedeler a,b , J.C. Antoine c , B.Giometto d , F.Graus e , W. Grisold f , I.K. Hart , J. Honnorat ! , ". A.# . $il le%is $mitt i , J.J.G.&. Ve rsc!uuren  '  and (.Vo l) *  +entr u "arane o+last ic euroloical $-ndrome #uronetor* a Depar tment of Neur ology , Haukeland Univ ersi ty Hospi tal, Bergen, Nor way; b Department of Clinical Medic ine, Universi ty of Berge n,Ber gen, Norway; c Department of Neurology, Hopital Bellevue, aint !tie nne, "ranc e; d Department of Neurology and #syc$iatry %&Neurologic Clinic' University of #adua, #ad ua, (tal y; e erv ice of Neur ology , (nsti tut d)( nvesti gacio Biomedica *ugu st #i i uny er%(D (B*# ', Hospit al Cl inic, Univer si ty of Barc el ona, Barcel ona, pai n; f  +udwig Bolt mann (nst it ut fur  Neuroonkologie, -ienna, +in,*ustria; g  Neuroimmunology .roup, Department of Neurological cience, +iverpool, U/; $  *ta0ia 1esearc$ C enter, N eurology B, Hospit al Neurologi2ue, +y on, "rance; ( Department of Neur ol ogy, !r asmus Univer si ty Medi cal Center, 1ott er dam, 3$e Net$er lands;  4 Department ofNeurology, +eiden University Medical Center, +eiden, 3$e Net$erlands; and k Department of #alliative Medicine, University of Cologne, Cologne, .ermany Cuvinte cheie/ cancer, in%estiatie, neuroloie, +araneo+la)ic, tratament $indroamele neurol oi ce +ar ane o+l a)i ce 0"$1 re+re)int 2 efe cte le la dis tan 32 ale cancerului asu+ra sistemului ner%os. "re)entul ra+ort re+re)int2 o +re)entare eneral2 a manaementului "$ clasice ca encefalita limbic2 +araneo+la)ic2, neurono+atia sen)orial2 sub acut2, deener escen3 a cer ebeloas2 +ar aneo+la)ic 2, mioclonusul o+soclonusul +araneo+la)ic, sindromul miastenic 5ambert#aton 6i !i+erexcitabilitatea ner%oas2 +eriferic2 +araneo+la)ic2. &iastenia ra%is 6i neuro+atiile +ara+roteinemice nu sunt incluse 7n acest ra+ort. u au fost +osibile recomand2ri ba)ate +e do%e)i dar sa a'uns la un consens +ri%ind reuli de bun2 +ractic2 medical2. $unt indicate in%estia3iile urente, 7n s+ecial 7n sindroamele ce afectea)2 sistemul ner%os central, astfel 7nc8t s2 +oat2 fi +osibil un tratament c8t mai +recoce al tumorii si s2 +oat2 fi +re%enite distruc3ia neuronal2 +roresi%2 6i deficitele neuroloice ire%ersibile. Anticor+ii onconeuronali sunt de mare im+ortan32 7n in%estiarea "$ 6i sunt utili 7n de+istarea tumorii subiacen te. "9G"# : est e fol osi toa re atunci c8nd screeninul radiol oi c tumoral ini3ial a fost neati%. 9etec3ia 6i tratamentul +recoce al tumorii +ar s2 ofere cea mai mare sans2 +entru stabili)area "$. :era+ia imun2 nu are de obicei nici un efect 1

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Managementul sindroamelor neurologice paraneoplazice: raport grupului de lucru EFNS

Anexa 4

Managementul sindroamelor neurologice paraneoplazice: raportul grupului de lucru EFNS

C.A.Vedelera,b, J.C. Antoinec, B.Giomettod, F.Grause, W. Grisoldf, I.K. Hartg, J. Honnorath, P.A.E. Sillevis Smitti, J.J.G.M. Verschuurenj and R.Volzk pentru Paraneoplastic Neurological Syndrome Euronetwork

a Department of Neurology, Haukeland University Hospital, Bergen, Norway; b Department of Clinical Medicine, University of Bergen,Bergen, Norway; c Department of Neurology, Hopital Bellevue, Saint Etienne, France; d Department of Neurology and Psychiatry (2Neurologic Clinic) University of Padua, Padua, Italy; e Service of Neurology, Institut dInvestigacio Biomedica August Pi i Sunyer(IDIBAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain; f Ludwig Boltzmann Institut fur Neuroonkologie, Vienna, Linz,Austria; g Neuroimmunology Group, Department of Neurological Science, Liverpool, UK; h Ataxia Research Center, Neurology B, Hospital Neurologique, Lyon, France; I Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands; j Department ofNeurology, Leiden University Medical Center, Leiden, The Netherlands; and k Department of Palliative Medicine, University of Cologne, Cologne, Germany

Cuvinte cheie: cancer, investigatie, neurologie, paraneoplazic, tratament

Sindroamele neurologice paraneoplazice (PNS) reprezint efectele la distan ale cancerului asupra sistemului nervos. Prezentul raport reprezint o prezentare general a managementului PNS clasice ca encefalita limbic paraneoplazic, neuronopatia senzorial subacut, degenerescena cerebeloas paraneoplazic, mioclonusul-opsoclonusul paraneoplazic, sindromul miastenic Lambert-Eaton i hiperexcitabilitatea nervoas periferic paraneoplazic. Miastenia gravis i neuropatiile paraproteinemice nu sunt incluse n acest raport. Nu au fost posibile recomandri bazate pe dovezi dar s-a ajuns la un consens privind reguli de bun practic medical. Sunt indicate investigaiile urgente, n special n sindroamele ce afecteaz sistemul nervos central, astfel nct s poat fi posibil un tratament ct mai precoce al tumorii si s poat fi prevenite distrucia neuronal progresiv i deficitele neurologice ireversibile. Anticorpii onconeuronali sunt de mare importan n investigarea PNS i sunt utili n depistarea tumorii subiacente. PDG-PET este folositoare atunci cnd screening-ul radiologic tumoral iniial a fost negativ. Detecia i tratamentul precoce al tumorii par s ofere cea mai mare sans pentru stabilizarea PNS. Terapia imun nu are de obicei nici un efect sau are un efect moderat asupra sindroamelor ce implic sistemul nervos central ins acest tip de terapie este benefic pentru PNS ce afecteaz jonctiunea neuromuscular. Toti pacientii cu PNS ar trebui sa primeasc tratament simptomatic.

IntroducereSindroamele neurologice paraneoplazice (PNS) au fost iniial definite ca sindroame neurologice de cauz necunoscut care de obicei antedateaz diagnosticul unui cancer care st la baza acestui sindrom i care nu este de obicei evident clinic. In ultimele dou decade, s-a descoperit c multe dintre PNS sunt asociate cu anticorpi impotriva unor antigene neuronale exprimate de tumor (anticorpi onconeuronali) ceea ce a sugerat ca unele dintre SNP sunt mediate imun. PNS sunt rare si apar la 20Hz produce o cretere important, dar este dureroas i de obicei nu este necesar. Anticorpii anti VGCC de tip P/Q sunt prezeni n ser la peste 85% din pacieni [56]. Aceti anticorpi apar n ambele forme de LEMS, cu sau far prezena cancerului pulmonar cu celule mici. S-au gsit n ser i anticorpi VGCC de tip N, dar contribuia lor la slabiciunea muscular sau disfuncia autonomic este probabil mic; nu sunt folosii n scop diagnostic.

La jumtate dintre pacienii cu LEMS va fi diagnosticat cancerul pulmonar cu celule mici n mai puin de doi ani. Un studiu retrospectiv pe 77 de pacieni cu LEMS a artat c pacienii fumtori (actuali sau foti), HLA-B8 negativi au avut o ans de 69% de a dezvolta cancer pulmonar cu celule mici. n contrast, nici unul dintre cei 24 de pacieni, care nu au fumat niciodat i erau HLA-B8-pozitivi, nu au dezvoltat acest tip de cancer [57]. Oricum, se recomand ca toi pacienii s fie examinai prin tomografie computerizat toracic de nalt rezoluie, bronhoscopie atunci cnd este cazul i, dac tomografia nu arat modificri, prin PDG-PET. Acest protocol de investigaie este important n mod special pentru pacienii cu risc crescut (fumtori, HLA-B8 negativi). Pacienii ar trebui urmrii pentru o perioad de 4 ani prin efectuarea tomografiilor la fiecare 6 luni.

Tratament

La pacienii cu cancer pulmonar cu celule mici este important terapia oncologic. Rezultatele desprinse dintr-un studiu retrospectiv pe o serie mic de pacienii arat c dup tratamentul specific al tumorii, sindromul neurologic s+a remis n 6-12 luni [58]. Un pacient la care s-au efectuat rezecie local i radioterapie nu a avut recderi timp de 12 ani. Chimioterapia, care este prima opiune de tratament, are efect imunosupresiv n LEMS. S-a demonstrat c prezena LEMS la pacienii cu cacncer pulmonar cu celule mici crete supravieuirea [59]. Tratamentul simptomatic const n administrarea de 3,4-diaminopiridin [60] i dac se adaug i piridostigmin se poate obine un efect terapeutic adiional. Dac aceast terapie nu este suficient pot fi luate n considerare steroizii, azatioprina,plasmafereza i imunoglobulinele administrate intravenos.

Hiperexcitabilitatea nervoas periferic paraneoplazic (PPNH)

Manifestri clinice

Cea mai obinuit form de hiperexcitabilitate nervoas periferic (PNH) (numit i neuromiotonie sau sindrom Isaacs) este autoimun i este cauzat de obicei de anticorpii VGKC [61]. PPNH apare la pn la 25% din pacieni i poate antedata detecia tumorii cu pn la 4 ani [62]. ntr-un studiu pe 60 de pacieni, apte (12%) au avut timom i miastenia gravis, doi (3%) au avut timom fr a avea i miastenia gravis, patru (7%) au avut cancer pulmonar cu celule mici i unul (2%) a avut adenocarcinom pulmonar [62]. PPNH poate s apar i la pacienii cu boal Hodgkins [63,64] sau la cei cu plasmocitom [65].

Caracteristica hiperexcitabilitii nervoase periferice este hiperactivitatea spontan i continu a muchilor scheletici, de obicei sub form de mioclonii i crampe dureroase uneori acompaniate de variate combinaii de rigiditate, pseudomiotonie, pseudotetanie i slbiciune [66]. Aproximativ 33% din pacieni au i tulburri de sensibilitate i pn la 50% au hiperhidroz sugernd afectarea sistemului nervos autonom. Poate fi afecatat i sistemul nervos central, cu apariia tulburrilor de personalitate, insomniei, psihozei cu idei iluzorii, halucinaiilor i disfunciei autonomice (Sindromul Morvans).

Investigaii

Electromiografia este util n confirmarea diagnosticului de hiperexcitabilitate nervoas periferic i n excluderea altor cauze de hiperactivitate muscular continu ca sindromul stiff al membrelor. Studiul conducerii nervoase poate s evidenieze o neuropatie periferic subiacent [62,66].

Nu exist nici un anticorp care s indice dac hiperexcitabilitatea nervoas periferic este de origine paraneoplazic. Anticorpii VGKC sunt prezeni la 35% dintre pacienii cu hieprexcitabilitate nervoas periferic dobndit, acest procent crescnd la 80% la cei cu timoame [61]. Aceti anticorpi sunt prezeni i la cei cu PLE i timom fr PNH i la cei cu encefalit limbic non-paraneoplazic [9-11]. Anticorpii Hu pot fi de ajutor n cazul n care un pacient cu PPNH a avut cancer pulmonar cu celule mici [67]. Cutarea paraproteinelor n ser i urin poate ajuta la identificarea plasmocitoamelor [65].

Este indicat examenul computer tomografic mediastinal cu contrast ntruct pn la 15% din pacieni au un timom, uneori n absena miasteniei gravis sau a anticorpilor AchR [62]. Este util i efectuarea unuei examinri tomografice toracice de nalt rezoluie ntruct aproximativ 10% din pacienii cu PNH au cancer pulmonar cu celule mici sau adenocarcinom pulmonar [62]. Examinarea CT poate de asemenea identifica pacienii cu boal Hodgkins [63,64]. PDG-PET este investigaia de elecie atunci cnd exist suspiciunea unei maligniti dar investigaiile iniiale nu o detecteaz. La cei ce au risc crescut de cancer pulmonar este indicat urmrirea pe o perioad de pn la 4 ani [62].

Tratament

PPNH se amelioreaz de obicei sau se poate chiar remite dup tratamentul oncologic adecvat [63,65-67]. Observaia c majoritatea cazurilor de PPNH sunt autoimune a dus la ncercarea administrrii medicamentelor imunomodulatoare, inclusiv la civa pacieni cu timoame [66,68] ale cror simptome erau dizabilitante sau refractare la terapia simptomatic. Plasmafereza produce de obicei o ameliorare clinic semnificativ ce dureaz n medie 6 sptmni i este nsoit de o scdere a activitaii electromiografice [66] i de o scdere a titrurilor de anticorpi VGKC [69]. Experiena sugereaz c i imunoglobulinele administrate intravenos pot ajuta [70] dei s-a raportat agravarea PNH la un pacient dup administrarea lor i eficien inferioar plasmaferezei la altul [72]. Prin analogie cu LEMS, anumii pacieni cu PPNH refractar la alte forme de tratament pot beneficia de edine repetate de terapie imunomodulatorie la fiecare 6-8 sptmni.

Prednisolonul, cu sau fr azatioprin, a fost util la unii pacieni cu PNH autoimun [66,73], inclusiv la civa pacieni cu PPNH asociat timomului a cror simptomatologie nu s-a mbuntit dup timectomie [66]. Toate formele de hiperexcitabilitate nervoas periferic, inclusiv cele paraneoplazice, se amelioreaz de obicei dup tratamentul simptomatic cu medicamente anti-epileptice [66].

Recomadri de bun practic medical

Pacienii cu PNS prezint de obicei simptome neurologice nainte de detecia tumorii subiacente. Anticorpii onconeurali ar trebui s fie cutai seriat la pacienii cu suspiciune de PNS. Anticorpii sunt importani pentru diagnosticul i localizarea tumorii.

Sunt importante investigaiile radiologice pentru detecia tumorii (ex: examinarea tomografic de nalt rezoluie pentru cancerul pulmonar cu celule mici), dar acestea ar trebui urmate de PDG-PET dac nu se gsete tumora.

Pacienii trebuie urmrii la intervale regulate, de exemplu la fiecare 6 luni pe o perioad de pn la 4 ani, cu scopul de a detecta tumora atunci cnd screening-ul iniial a fost negativ.

Cea mai de succes abordare n vederea stabilizrii PNS este detecia i tratamentul precoce al tumorii subiacente. Aceasta presupune colaborarea cu oncologi, pneumologi, ginecologi sau pediatri, n funcie de tipul tumorii asociate.

Terapia imunologic (steroizi, plasmaferez, imunoglobuline administrate intravenos) nu are de obicei nici un efect sau are un efect modest n PLE, SSN i PCD.

Copiii cu POM pot rspunde bine la terapie imunologic; la adulii cu POM ns, nu exist dovezi clare ale eficienei acestei terapii.

Terapia imunologic la pacienii cu LEMS sau PPNH duce la ameliorarea simptomatologiei.

Toi pacienii cu PNS ar trebui s beneficieze de tratament simptomatic.

Declaraie

Accest studiu a fost finanat prin Grant-ul Uniunii Europene cu numrul QLG1-CT-2002-01756.

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