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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