HRVATSKE SMJERNICE ZA FARMAKOLOŠKO LIJEČENJE EPILEPSIJE Radna skupina Hrvatske lige protiv epilepsije, Hrvatskog neurološkog društva, Hrvatskog društva za dječju neurologiju, Hrvatske udruge za epilepsiju, Hrvatskog društva za EEG i kliničku neurofiziologi ju, Referentnog Centra Ministarstva Zdravlja za epilepsiju, Referentnog Centra Ministarstva Zdravlja za predoperativnu obradu bolesnika s farmakorezistentnom epilepsijom i Referentnog centra Ministarstva Zdravlja za epilepsiju i konvulzivne bolesti razvojne dobi (Bašić. S, Petelin Gadže Ž., Prpić I., Poljaković Z., Malenica M., Sporiš D., Jurić S., Gjerg ja Juraški R., Nanković S., Sabol Ž., Meštrović M., Šulentić V., Šarić Sučić J, Marković I., Šušak Sporiš I., Đuranović V., Jurin M., Barišić N., Zavoreo I., Čolak Romić Z., Kovač Šižgorić M, Mrđen A., Shihabi Aleksić A., Čengić Lj., Bitunjac M., Čandrlić M., Fajdetić D., Sruk A., Marčec R., Kostanjevec R., Vuković B., Cesarik M., Kerek V., Lojen G., Šapina L., Cindrić I., Smoljanac D., Papić S., Gržinčić T., Hlavati M., Penavin Kolarić D., Pejnović S., Novak N., Grbin M., Ivkić G.) UVOD Epilepsija je najčešća kronična neurološka bolest, a ujedno i jedina koja se lijekovima može u potpunosti staviti pod kontrolu, odnosno uvesti u dugotrajnu ili trajnu remisiju. Prema podacima Svjetske zdravstvene organizacije, smatra se da u svijetu preko 65 milijuna ljudi živi s epilepsijom. U općoj populaciji aktivnu epilepsiju ima 5 – 10 osoba na 1000 stanovnika, a dijagnoza epilepsije postavi se u oko 2,4 milijuna ljudi godišnje. Prema procjenama, u Hrvatskoj oko 40 000 ljudi boluje od epilepsije. Također se smatra da oko 10% ukupne populacije diljem svijeta doživi jedan epileptički napad u životu. Farmakološko liječenje epilepsija podrazumijeva primjenu antiepileptičkih lijekova (AEL), a u oko 50% bolesnika postiže se remisija primjenom prvog AEL. U slijedećih 20-ak% bolesnika remisija se postiže zamjenskom monoterapij om ili kombinacijskom terapijom. Bolesnici koji unatoč uzimanju dva ili više adekvatno odabrana AEL, primijenjena u adekvatnim dozama, i nadalje imaju napade, boluju od farmakorezistentnog oblika bolesti (farmakorezistentna epilepsija). Farmakorezistentni bolesnici su kandidati za neku od neurokirurškim metoda
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HRVATSKE SMJERNICE ZA FARMAKOLOŠKO
LIJEČENJE EPILEPSIJE
Radna skupina Hrvatske lige protiv epilepsije, Hrvatskog neurološkog društva, Hrvatskog društva za
dječju neurologiju, Hrvatske udruge za epilepsiju, Hrvatskog društva za EEG i kliničku neurofiziologiju,
Referentnog Centra Ministarstva Zdravlja za epilepsiju, Referentnog Centra Ministarstva Zdravlja za
predoperativnu obradu bolesnika s farmakorezistentnom epilepsijom i Referentnog centra Ministarstva
Zdravlja za epilepsiju i konvulzivne bolesti razvojne dobi
(Bašić. S, Petelin Gadže Ž., Prpić I., Poljaković Z., Malenica M., Sporiš D., Jurić S., Gjerg ja Juraški R.,
Nanković S., Sabol Ž., Meštrović M., Šulentić V., Šarić Sučić J, Marković I., Šušak Sporiš I., Đuranović
V., Jurin M., Barišić N., Zavoreo I., Čolak Romić Z., Kovač Šižgorić M, Mrđen A., Shihabi Aleksić A.,
Čengić Lj., Bitunjac M., Čandrlić M., Fajdetić D., Sruk A., Marčec R., Kostanjevec R., Vuković B.,
Cesarik M., Kerek V., Lojen G., Šapina L., Cindrić I., Smoljanac D., Papić S., Gržinčić T., Hlavati M.,
Penavin Kolarić D., Pejnović S., Novak N., Grbin M., Ivkić G.)
UVOD
Epilepsija je najčešća kronična neurološka bolest, a ujedno i jedina koja se
lijekovima može u potpunosti staviti pod kontrolu, odnosno uvesti u dugotrajnu ili
trajnu remisiju. Prema podacima Svjetske zdravstvene organizacije, smatra se da u
svijetu preko 65 milijuna ljudi živi s epilepsijom. U općoj populaciji aktivnu epilepsiju
ima 5 – 10 osoba na 1000 stanovnika, a dijagnoza epilepsije postavi se u oko 2,4
milijuna ljudi godišnje. Prema procjenama, u Hrvatskoj oko 40 000 ljudi boluje od
epilepsije. Također se smatra da oko 10% ukupne populacije diljem svijeta doživi
pregabalin, fenitoin, fenobarbital, tiagabin, rufinamid i
vigabatrin
DOOSOV SINDROM (MIOKLONO-ASTATSKA EPILEPSIJA)
AEL prvog izbora natrij valproat
AEL drugog izbora etosuksimid, topiramat, zonisamid, levetiracetam*
lamotrigin*, ketogena dijeta
AEL trećeg izbora klobazam, acetazolamid, sultiam, bromidi, rufinamid,
felbamat
Ne preporučuju se
karbamazepin, okskarbazepin, eslikarbazepin, fenitoin i
vigabatrin
*Oprez: mogu agravirati mioklone napade
Napomena: Iako je upotrebu lamotrigina u liječenju epilepsija s mioklonim napadima preporučljivo izbjegavati, poglavito u Dravet sindromu, male doze lamotrigina u kombinaciji s valproatom pokazale su se učinkovite u liječenu Doosova sindroma.
LENNOX – GASTAUT SINDROM
AEL prvog izbora natrij valproat, lamotrigin, topiramat
AEL drugog izbora zonisamid, levetiracetam, klobazam, rufinamid
AEL trećeg izbora felbamat*, vigabatrin§ i kanabidiol
* Felbamat se rijetko primjenjuje zbog toksičnosti (aplastična anemija, zatajenje jetre
i drugo)
§ Primjenu vigabatrina treba razmotriti samo iznimno zbog retinalna toksičnost čime
je ograničena dugotrajna primjena, a prije upotrebe potrebno je učiniti oftalmološki
pregled te rutinske kontrole tijekom korištenja, kao i moguće agravacije apsansa i
mioklonih napada
Napomena:
Benzodijazepini mogu inducirati tonički status.
Lakozamid može egzacerbirati mioklone, toničke i atoničke napada, ali može biti učinkovit u kupiranju žarišnih i generaliziranih toničko-kloničkih napada
Ekspertno mišljenje: Temeljem kontroliranih randomiziranih kliničkih studija nema
dovoljno dokaza koji bi preferirali jedan AEL u odnosu na druge. Većina eksperata
sugerira natrijev valproat kao lijek prvog izbora. Lamotrigin i topiramat se smatraju
alternativnim lijekom prvog izbora ili prvom dodatnom terapijom. Rufinamid se
preferira nad ostalim AEL druge linije u slučaju čestih atoničkih napada. U liječenju
LGS često se primjenjuje rana kombinacija dva ili maksimalno tri AEL. Više autora
sugerira ranu kombinaciju VPA i LTG, a anegdotalni izvještaj u literaturi sugerira
učinkovitost kombinacije VPA, CLB i LEV. U slučaju neuspjeha može se razmotriti
ketogena dijeta, hormonska terapija, intravenski imunoglobulini i kirurška terapija
(korpus kalozotomija i stimulator živca vagusa)
BENIGNA EPILEPSIJA S CENTROTEMPORALNIM ŠILJCIMA
AEL prvog izbora levetiracetam
AEL drugog izbora zonisamid, topiramat, natrijev valproat, pregabalin,
gabapentin, sultiam, lamotrigin, okskarbazepin,
karbamazepin, klonazepam
AEL trećeg izbora lakozamid, eslikarbazepin, klobazam, fenobarbital,
tiagabin i vigabatrin
Ekspertno mišljenje: Iako se u neke djece može izbjeći upotreba AEL, općenita je
preporuka uvođenje terapije. Nema dovoljno dokaza potkrijepljenih randomiziranim
klničkim studijama o superiornosti pojedinih AEL. Obzirom na farmakološki profil u
novije vrijeme sugerira se levetiracetam kao AEL prvog izbora. Natrijev valproat se
zbog farmakološkog profila više ne sugerira kao AEL prvog izbora. Kao racionalni
AEL drugog izbora sugerira se zonisamid, topiramat, sultiam, pregabalin i
gabapentin, dok se lamotrigin, okskarbazepin i karbamazepin, unatoč učinkovitosti,
primjenjuju s oprezom budući mogu agravirati nove vrste napada.
Prilikom prve primjene lijeka (uvođenja u terapiju), nema razlike između
korištenja originalnih ili generičkih lijekova.
Tijekom titracije terapije i kasnije, nakon postizanja stabilne doze ili ukidanja
terapije, strogo se ne preporučuje međusobna zamjena generičkih
pripravaka, zbog mogućih velikih odstupanja u bioraspoloživosti aktivne tvari,
što značajno povećava rizik od javljanja nuspojava ili relapsa (epileptičkih
napada).
Zamjena generika i originatora ili obrnuto, također se ne preporučuje.
Iznimno, u slučaju neophodne zamjene AEL (nedostupnost na tržištu i sl.),
preporuča se zamjena originalnog lijeka i generičkog oblika ili obrnuto, budući
je rizik od nuspojava ili relapsa napada u ovom slučaju manji nego pri
međusobnoj zamjeni dva generička oblika AEL.
PREPORUKE ZA UKIDANJE ANTIEPILEPTIČKE TERAPIJE Ne postoje jasne i sigurne smjernice za ukidanje terapije, stoga se ova odluka donosi
na individualnoj razini, u dogovoru s bolesnikom i njegovom obitelji uz informiranje o
koristima i rizicima ukidanja AET. Rizik relapsa nakon ukidanja terapije je velik, a
najveći je tijekom smanjivanja doze i unutar godine dana od prestanka uzimanja
AEL. U donošenju odluke o ukidanju terapije potrebno je razmotriti slijedeće:
Duljina perioda bez napada – što je period dulji manji je rizik od relapsa
nakon ukidanja terapije. Ukidanje terapije ne treba razmatrati prije isteka
perioda od minimalno 2 godine bez epileptičkih napada.
Dob bolesnika – djeca općenito imaju manji rizik relapsa od odraslih. U
odrasloj populaciji, manji rizik relapsa imaju bolesnici kod kojih je kompletna
remisija nastupila prije 30. godine života.
Trajanje aktivne bolesti – dulji period od početka bolesti do postizanja
remisije i veća frekvencija napada povećavaju rizik od relapsa nakon ukidanja
terapije.
Vrsta epileptičkih napada i etiologija - miokloni napadi, žarišni napadi s
prelaskom u bilateralne toničko kloničke napade, istovremena pojava više
vrsta napada povezani su s povećanim rizikom od relapsa. Epilepsijski
sindromi za koje je karakteristična spontana remisija primjerice dječja apsans
epilepsija i benigna epilepsija s centrotemporalnim šiljcima imaju manji rizik od
relapsa, za razliku od juvenilne mioklone epilepsije i refleksnih epilepsija i
epilepsija strukturalne etiologije koji imaju veliki rizik od relapsa.
Neurološki deficit kao i kognitivno oštećenje (mentalna retardacija)
povećavaju rizik od relapsa nakon ukidanja terapije.
Elektroencefalografija – abnormalni EEG nalaz u trenutku ukidanja i
neposredno nakon ukidanja povećavaju rizik od relapsa.
Duljina perioda redukcije terapije - Nema jasnih preporuka od duljini
perioda ukidanja. Dulji period ukidanja nosi manji rizik od relapsa. Terapija se
ukida postupno i sporo, preporučljivo tijekom perioda ne kraćeg od 6 mjeseci,
a često i duljeg. Ukoliko je bolesnik na politerapiji, treba ukidati jedan po jedan
lijek postupno.
Stav bolesnika prema ukidanju terapije – Odluka o ukidanju terapije donosi
se u dogovoru s bolesnikom. Bolesniku je potrebno objasniti koristi i rizike
ukidanja terapije te ga uputiti o životnim ograničenjima koja bi trebala trajati
barem godinu dana nakon potpunog ukidanja terapije.
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