copy of migren 2.ppt
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TINJAUAN PUSTAKA
PATOFISIOLOGI MIGREN BERFOKUS PADA PERAN CALCITONIN GENE-RELATED PEPTIDE
PEMBIMBING : dr. H. Imam Rusdi SpS(K) dr. Indarwati Setyaningsih SpS
PRESENTAN : Tri Hastuti Hendrayani HARI/ TGL : Senin, 30 Mei 2005
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LATAR BELAKANG :
NYERI KEPALA
90% penddk nyeri kepala/ th9 dari 10 org/th 1 kali
• mengganggu aktivitas, produktiv.• menghentikan keg.sehari-hari• dampak sosial-ekonomi
MIGRENPrevalensi tidak banyak, namun merugikan (AS, 13jt dolar)
Tidak terdiagnosis, terapi kurang baik
Pemahaman patof, teori blm jelasVaskuler
Neurovaskuler
Sistem trigeminovaskuler CGRP
Peny.neurologi yg kompleks
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Peneliti,th Sumber/
metode
Prevalensi
Lipton, 2001 • Dt epid.th 1999, AS
•Usia > 12 th
• W/L: 3:1 (18,2%; 6,5%
•Puncak :25 dan 55 th
Rasmussen et al., 1995
• Denmark, sampel: 740
•Usia 25-64 th
•Insiden per-th: 7/1000
W(5,8), L(1,6)
Hagen et al., 2000 • Norwegia, sampel: 51383
•Usia 20 th
W (16%); L (8%)
Wang et al., 2000 •Taiwan, sampel: 3377
•Usia 15 th
W (14,4%); L (4,5%)
Henry et al., 2002 •Perancis, sampel: 10585
•Usia 15 th
W (11,2%); L (4%)
Kececi and Dener,
2002
•Turki, sampel: 1320 W (17,1%); L (7,9%)
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MASALAH
MIGREN : - Morbiditas sedikit dampak merugikan:
- aktivitas terganggu - pe produktivitas pekerjaan/ sekolah (dampak sos-ek)- tdk terdx/ tx :
- kurang dlm pemahaman patofisiologi- penyebab blm pasti- jrg yg periksa ke dokter
- teori neurovaskuler:- sistem trigeminovaskuler pelepasan- neuropeptida (CGRP)nyeri kepala migren?
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TUJUAN PENULISAN :
• pemahaman, pengetahuan peranan CGRP pd NK migren
MANFAAT PENULISAN :
• Patofisiologi dasar terapi rasional• mekanisme penyakit informasi adekuat, terapi tepat penderita + keluarga diuntungkan
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PEMBAHASAN :1.SEJARAH PERKEMBANGAN TEORI MIGREN:
Eber Papyrus (1200 SM) supranatural
•Hipocrates (400 SM) sesuatu dari perutmenjalar ke kepala aura•Gallen : hemikrania
Thomas Willis (1664) : migren ok dilatasi pemb.darah
(I kali teori vasc.diajukan) tdp beberapa kelemahan
Edward Liveing (1873) : migren ok gangg.saraf di talamus (neurogenik)
Moebius (1898): disfungsi otak & PD.
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DEFINISI :
MIGREN : • Konsep klasik : gg. Fungs. otak dg manifest.nyeri kepala unilateral, b’denyut, mendadak disertai mual atau muntah (Marquardt et al.,2000).
• Lance (1998) : NK episodik, disertai mual, fotofobia, mgkn didahului aura cit Harsono,1999
• Djoenaedi W (‘93): NK b’ulang, b’denyut, unilat, 2-72 jam, bebas nyeri ant. serangan dg gg.keprib,GIT, aura (Basjiruddin, 2004).
• Rapoport et al.,(2004) dokter umum : “Migren: NK, intensitas sedang-berat, pola stabil, hilang timbul, kemampuan, normal 48 jam, perburukan (-), Sampai ada bukti bahwa itu bukan migren”
• The Research group on Migraine and Headache of the World Federation of Neurology: “familial, serangan berulang, intensitas, frek,lama bervariasi. NK unilateral, disertai anoreksia, mual, muntah, bbrp diawali gejala neurologik, gangguan mood” (Evan & Mathew, 1999)
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KRITERIA DIAGNOSTIK:
Gambaranklinik
•Fase prodromal/ premonitori•F. serangan utama: aura & nyeri kepala•F. postdromal
Klasifikasi formal
ICHD th 2004:1. MWO paling sering dijumpai2. MWA3. Childhood periodic syndromes that are commonly precursors of migraine
4. Retinal migraine 5. Complications of migraine 6. Probable migraine
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Gambaran klinik:
Fase karakteristik Gejala/ bukti penelitianProdromal •Trigger
•60% pend.migren•Bbrp jam-hari
25%:•Sensitif (mdh marah)•Euforia, ngantuk, depresi,lapar, haus
Aura •30% pend.migren•5-20mnt (b’akhir 60’)•Visual (V), sensorik (S), mtrk (M), g.btg otak, gg.bicara/afasia (A)
Thomsen (Denmark):
1881 sampel,72% ♀; 28%♂ :•VSMA : 70% pasien•VS : 17% ; SMA : 7%•SM : 4%; AM : 1%; VMA : 1%
Nilai median memberatnya g/ aura:•V 10’(1-180’); S 15’(1-720’); M 15’(1-720’); Nilai median lamanya aura:•V 45’ (1-1440’) ; S 90’ (10-2880’)•M 120’ (10-4320’); A 60’ (5-1440’)
Nyeri kepala •Onset unilat, b’denyut, Sedang – Berat, aktiv. m’brt •4-72 j,Frek : 1-3 x/bln
postdromal •Lelah, iritabel, gg.mood, gg.konsentr, NT klt kpl.
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Migren dengan aura Migren tanpa aura
A. Min.2 serangan yang sesuai kriteria B
B. Min.3 dari 4 kriteris dibawah ini:
1. Satu/ lebih gjl aura yg reversibel, mengarah ada kel.dikorteks serebri dan/ disf.otak
2. Plg t’ tdp 1 gjl aura yg makin m’brt dlm 4 mnt, atau 2/ lbh gjl yg tjd b’samaan
3. Aura < 60 menit
4. NK tjd dlm wkt 60 mnt sth aura berakhir
C. min.1 dari kriteria berikut:
1. Ggn.NK sekunder (-), pd: p.neuro,fsk, r.peny.
2. Pem.neuro, fsk, r.peny.mengarah NK sekunder, tp disimgkirkan oleh pem.yg teliti
3. NK sekunder (+), tapi serangan migren yg pertama kali tdk bersamaan dengan timbulnya gangg.tersebut.
A. Min. 5 serangan yg memenuhi kriteria B-D
B. NK 4-72 jam (tidak membaik dengan tx)
C. Karakter.NK plg tdk memenuhi 2 dibwh:
1. Lokasi unilateral
2. Nyeri berdenyut
3. Intensitas sedang-brt (sedang: mengganggu aktiv.sehari-hari; berat: tdk dpt melaks.keg)
4. Memberat bl jalan naik tangga/ aktiv.fisik
D. Selama NK min.disertai:
1. Mual dan atau muntah
2. Fotofobi dan fonofobi
E. Min.1 dari kriteria berikut:
1. Ggn.NK sekunder (-),pd: p.neuro,fsk,r.peny.
2. Pem.neuro, fsk, r.peny.mengarah NK sekunder, tp disimgkirkan oleh pem.yg teliti
3. NK sekunder (+), tapi serangan migren yg pertama kali tdk bersamaan dengan timbulnya gangg.tersebut.
Klasifikasi Formal (ICHD 2004): Olesen et al., 2003)
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PREVALENSI KARAKTERISTIK NYERI KEPALA MIGREN MENURUT IHS
Migren tanpa aura Migren dengan aura
Laki-laki (%) Wanita (%) Laki-laki (%) Wanita (%) N=197 N=145 N=92 N=64
Lokasi unilateral
Memberat pada- aktivitas fisik
Nausea
Vomiting
Fotofobia
Fonofobia
48,2 64,3 55,4 64,1
98,0 95,8 87,0 80,0
85,8 88,9 70,7 81,5
41,6 49,3 37,0 44,6
92,4 92,4 82,6 90,8
78,7 85,4 64,1 78,5
Sumber : Lipton et al., (2000)
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TRIGGERS / PENCETUS MIGREN :
Bukti kuat pencetus migren
Diduga pencetus migren
• Stres• menstruasi• caffeine withdrawal• rangsang visual• perubahan cuaca
• nitrat• perut kosong• gangguan tidur• alkohol• monosodium glutamat
Sinclair, 1999; Lipton, 2000
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PATOFISIOLOGI MIGREN :
A. FASE TRIGGER
Landy, 2003
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B. FASE AURA:
CSD rCBF oligemia iskemik disfungsi neuronal aura
Olesen, 1991
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Peneliti, th Metode Hasil • Lauritzen et al., 1983
•Bednarzyk et al., 1998
(membandingkan
pengukuran CBF
selama serangan
migren dan saat bebas serangan)
•Migren klasik: 13
•Inj. Xenon 133 i.a
•Diukur rCBF
•Alat : PET
•Migren t’ aura, diukur:
CBF,CBV, ekstrkasi O2, metab saat ser. Migren
•Ukur ulang: 48 jam saat bebas NK
•CBF: mL/min/100gr (SD)
•CBV: mL/100gr (SD)
8 pasien:
Tdp pe rCBF asal dari post ant otk.
Terdpt perbedaan bermakna pe CBF/ CBV saat serangan dibdg bebas serangan:
CBF: 52,70(6,9) vs 59,65(10,6), p=0,028
CBV: 3,6(0,43) vs 3,8(0,55), p=0.047
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DeVries et al., 1999
C. FASE NYERI KEPALA :
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Lanjutan…
MercMedicus Modules, 2001
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CALCITONIN GENE-RELATED PEPTIDE (CGRP) :
• Kelomp.kalsit (5): kalsitonin, amilin,CGRP( dan ), adrenomedulin• neuropeptida 37-asam amino hsl pengolahan/ penyambungan alternatif mRNA• di kromosom 11• tdp 2 btk CGRP :
: di sistem saraf sensorik : di sistem saraf enterik
• pertama kali ditemukan th 1983 (pd tikus)• merupakan vasodilator poten.
1.Definisi dan karakteristik :
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2. Molekuler genetik :CGRP…
Ma, 2004
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CGRP… 3. Struktur CGRP dan hub. aktivitas
• N-terminal loop (disulphide) memicu transduksi sinyal dan aktivitas reseptor• Struktur -helix interaksi molekul dg reseptor.• Residu 19-27 daerah pengatur perlekatan dg reseptornya• C-terminal memastikan interaksi yg sesuai dg reseptornya.
(Conner et al.,2002; Ma, 2004)
(Dikutip dari: Nimmagadda & Ghatta, 2004).
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CGRP…
4. DISTRIBUSI :
• SUSUNAN SARAF PERIFER:- Sel kornu post.ganglia sensorik- srg berhub.dg P.D. otot polos ( GIT, gld.parotis, sel endokrin duod, ileum, gangl.mienterik, paru, gld.tiroid, sinusoid dan vena lienalis, kulit manusia, kelj.pituitari.
• KARDIOVASKULER:- Arteri > vena- Arteri: disambungan ant.T.adventisia dan T.media- atrium > ventrikel- otot jantung
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RESEPTOR CGRP….
1. Klasifikasi :• CGRP1 dan CGRP2
2. struktur reseptor• CRLR• RAMP(1,2,3)RCP: as.amino 148 +Prot.G
Transduksi sinyal
Department of Neurobiology & AnatomyIan Dickerson's Lab
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RESEPTOR CGRP…..
3. DISTRIBUSI DAN IKATAN ;
• Afinitas tertinggi : serebelum dan medula spinalis• diserebelum :
- lap. Molekuler : CGRP densitas tinggi- lap. Purkinje : sedang- lap. Granuler : CGRP (-).
•Afinitas sedang- tinggi : korteks piriformis insula•Af rendah-sedang : area preoptik medial.•Di gangl.radiks dorsalis dan neuron lain CGRP bergab. dg reseptor lain sbg: Neurotransmiter dan neuromodulator
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RESEPTOR CGRP….
4. MEKANISME TRANSDUKSI SINYAL :
Wimalawansa, 1996
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PEMERIKSAAN KADAR & POTENSI CGRP:
KADAR CGRP POTENSI CGRP
• Radioreceptor Assay :
• Radioimmuno Assay
- plasma
- LCS
• uji pembentukan cAMP
• ukur relaksasi aorta tikus
• uji efek inotropik & krono-
tropik pd jtg tikus
• uji fungsi CV : ukur MAP
Wimalawansa, 1996
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Fungsi Fisiologis CGRP :
SISTEM SARAF SISTEM PULMO
• tersebar merata di jar. otak:
sistem motorik & sensorik
• informasi auditorius
•Sist.trigeminovaskuler: letak resept=letak respt 5-HT
•Degranulasi sel mast
•Vasodilatasi A-V pulmo,ok resept.tdp di endotel P.D pulmo-CGRP relaks. A.pulmo dilat.a.pulmo
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Sistem kardiovaskuler Fungsi lain
•Kontrol tonus P.D perifer
•Vasorelaksasi kuat
•me kontraksi denyut jtg
•>> di jar perivask: dilat.mesenterium, ginjal, ot.skelet jlr endotel dependen/ indep
•Efek inotropik/ kronotopik positif
•Sekresi hormon pertumb.
•Hipertermia
•Aktivitas motorik
•Respon nosiseptik
•Memodulasi Ach
•Tulang: hipokals, prolif.osteoklas,
hbt resorpsi tlg intak
•mepermeab.mikrovask: hiperemia inflam, akumul. netrof, edema lokal
•Inflam neurogenik: kebocoran vaskuler
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PERAN cgrp PADA NYERI KEPALA MIGREN:
CGRP :• di prod.di ganglion saraf trigeminal•dilepas, sth terjadi aktivasi saraf•vasodilator poten P.D.serebral dan dural punya peran ptg dlm pengaturan aliran drh ke otak dan meningen.•P.D meningen vasodilat; sel mast :degranulasi inflam. steril •nilai Normal : 2-35 pmol/L
A. CGRP dan MIGREN :
Wimalawansa, 1996; Durham, 2004
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TRIGGER / Pencetus
rCBF <23ml ml
CSD
vol.darah tiap denyut jtg
Oligemia
Impuls nosiseptik
Aktivasi btg otak/ migren generator
Nukl. saraf trigeminalyg lebih tinggi
iskemik
korteks
pulsasi P.D
talamus
rCBF
Aura (-)
Disfungsi neuronal (+)
Aktivasi saraf trigeminal
NK migren
Refleks vasodilatasi P.D.& anast.A-V
rCBF >23ml ml
Disfungsi neuronal (-)
Aura (+)
Degranulasi
Sel mast
Pemb. Darah intraserebral
p.darah
meningen
Pelepasan neuropeptida(CGRP)
Vasodilat.
Vasodilatasi Vol.darah ,Pengaliran
cepat
Inflamasisteril
Hipo-talamus
Nausea,vomiting
CTZ
Foto/fonofobia
Dikutip dari:• Olesen, 1991• Goadsby et al., 2002• Villalon et al., 2002• Durham, 2004
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Bukti-bukti klinis peran CGRP pd migren:
Studi Metode Hasil/ kesimpulan
• Mengetahui hub. sistem TG dg perub. CV dan Neuropeptida(Goadsby & Edvinsson, 1993)
•Membandingkan CGRP plasma interiktal pend. migren (M) dg org sehat (S)(Ashina et al., 2000)
• sampel: kucing
ambil drh vena jug. ext
•Stim. gangl.trigeminal
•ukur CGRP,CBF
•Sampel: 20 (M), 20 (S)
•Ukur CGRP plasma .
• Stim.frek.20/dtk:
pe rerata CBF: 43±9%
• Stim.frek. 5/dtk:
pe kdr CGRP : 67 ±3 –
82 ±5 pmol/L
• CGRP v.cubiti: M>S
(75±8 : 49±3 pmol/L)
(p=0,005)
• MWO > S :
(82±10 : 49 ±3, p=0,001)
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B. Penatalaksanaan farmakologis berdasarkan peran CGRP pada migren:
Inhibisi pelepasan CGRP Antagonis reseptor CGRP
Gol. Triptan:(1) vasokonstriksi P.D arteri kranial
dan anastomosis arteri-vena yang mengalami dilatasi melalui stimulasi reseptor 5-HT 1B (Villalon et
al., 2002)
(2) inhibisi pelepasan CGRP dan transmisi nosiseptif pada saraf sensorik trigeminal sentral dan perifer melalui reseptor 5-HT 1B/1D
(Bigal et al., 2002; Goadsby et al., 2002; Swidan, 2002; Tepper et al., 2002).
BIBN4096BS:
1. Menghbt inflamasi neurogenik
2. Menurunkan blood flow di P.D serebral
3. Menghambat transmisi nyeri
(Durham, 2004).
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Penelitian sumaptriptan: inhibisi pelepasan CGRP
Peneliti Sampel/ metode Hasil/ kesimpulan
Juhasz et al., 2005 •Sampel: 19 wanita mgr sth induksi NTG sumaptrip spray 120 sth onset serangan
•Ukur sampel drh:
60 mnt sth diberi sumaptriptan
• tdp penurunan konsentrasi plasma CGRP yg bermakna
(p< 0,005)
•Kesimpulan: slh satu efek gol. triptan adl menurunkan pelepasan CGRP.
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Penelitian BIBN4096BS: reseptor antagonis CGRP
Peneliti,th Sampel/ Metode Hasil/kesimpulan
• Olesen et al., 2004 •126 pasien
•IHS; MWA/MWO
•RCT,DB,MC
•0,25 mg
• 0,5 mg
•1 mg
• 2,5 mg
• 5 mg
•10 mg
• iv,10 mnt
• Efektif: 2,5 mg
• 60% : 27% (p=0,001)
• Perbedaan bermakna:
(1) nyeri menghilang dalam waktu 2 jam setelah pemberian obat;
(2) hilang nyeri hingga 24jam;
(3) kekambuhan nyeri kepala kelompok terapi menurun;
(4) perbaikan dalam hal fotofobia, nausea, dan kegiatan fisik.
• Efek spg terbyk :parestesi.
Kesimpulan : BIBN4096 efektif utk tx migren akut
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TARGET
OBAT
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RINGKASAN
MIGREN
•Morbiditas rendah•Dampak nyeri: - kualitas hdp - produktivitas kerja/ sklh
Teori terbaru neurovaskuler sistem trigeminovaskuler pelepasan CGRP ke reseptor vasodilatasi, inflamasi neurogenik nyeri kepala migren
•Klinis; sulit dx•Pemahaman patof << penanganan krg
BIBN4096BS iv sbg antagonis reseptor CGRP efektif mengurangi NK migren, sbg obat alternatif gol.triptan
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SARAN
• Sth tahu peran CGRP pada migren & terbukti efektif BIBN4096BS iv. untuk terapi migren, tanpa ES yg bermakna perlu penelitian lbh lanjut pemberian BIBN4096BS per-oral utk mengetahui apakah efektivitas dan efikasinya sebanding dengan triptan.
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PREVALENSI MIGREN:
AstraZeneca Medicines (2005)
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what do you do when you are in pain? You stop using that limb, which leads to decreased mobility and reduces your functional status. As you start to not do the things you used to do, there can be a loss of self-esteem and self-efficacy. You start to limit yourself, and this vicious cycle goes on and on. Another way that I like to try and describe it to clinicians is this: as an infant, you are born as this groping little thing trying to find your feet, putting everything into yourmouth, getting sensory awareness. You then grow up as a member of a family; you get integrated into that family; you learn that you are not the only entity that exists. You develop into a mature adult and hopefully you become a viable, contributing member of your community and society. (Brennan, 2002)
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Four Headache Questions that can help Diagnose Migraine1. Do you have headaches that interfere with work, social, or family functions?
chronic, periodic, disabling headaches should be considered as migraine.2. Has your headache pattern been stable over the past six months?
any headache pattern that changes over a six-month interval should be investigated as a possible secondary headache disorder.
3. How frequently do you experience headaches?an increase in the frequency, intensity, and duration of headaches may indicate transformed migraine. Patients who at one time experienced an intermittent disabling headache and now suffer from near-daily headaches may be overusing symptomatic medications. The primary medical focus for these individuals should be headache prevention and avoidance of medication overuse.
4. How effective is your current headache treatment?patients who successfully treat their headaches are rarely seen by physicians.Those who treat their headaches with symptomatic medication more than twiceweekly may note that over time their analgesics become less effective. Headacheeducation, lifestyle changes, and preventive medications are necessary to alleviatethese headaches and restore normal daily function.
Unger et al, Emerg Med, 2003
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Unger et al., 2003
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Unger et al., 2003
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The Calssification of Headache :
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Characteristics of three common types of headaches
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Wagner, 2005
Secondary Headache Disorders :
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PATOGENESIS TENSION TYPE HEADACHE:
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Schachter, 2004
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From Headache, The Newsletter of ACHE. Spring 2002,
Studies of Migraine Trigger Factors
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Menstrual migraine:• terjadi 3 hr I fase mens estrogen + progesteronHow so many different migraine triggers can produce such similar disabling headaches? • A migraine trigger is any factor that can lead to the development of a migraine headache. How a specific trigger brings on a head- ache is becoming more clear, thanks to recent scientific studies on the subject. One leading theory suggests that migraine occurs because of an inherited hyperactivity of the nervous system. Individuals with migraine are genetically programmed to be more vulnerable to irritating stimuli such as flickering lights or sudden changes in weather. When one, two, or several of these irritating stimuli occur, their hyperactive nervous systems respond with a full-blown migraine attack.
Philip Bain, Wilkinson Medical Clinic
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Diamond, www.Medscape.com
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Diamond, www.Medscape.com
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“Falling Estrogen Theory”“Serotonin Theory”
SerotoninEstrogen
Trigeminal
Neuron CGRP
-
+
HO
CH3OH
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“Falling Estrogen Theory”“Serotonin Theory”
Serotonin Menstruation
Estrogen Serotonin
Trigeminal
Neuron CGRP, SP Vasodilation
Pain & Inflammation
HO
CH3OH
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One explanation for the onset of migraine when estrogen levels drop is that estrogen influences the serotonin receptors, which is believed to be an important part in headache pain. Other factors that may play a role in the development of menstrual migraine include:
1.the relative proportions of estrogen and progesterone; 2.dysfunction of platelets, a compenent of the blood which contains serotonin; 3.decreased levels of brain magnesium (which increases brain excitability); 4.decreased natural brain endorphines; and 5.increased secretion of prostaglandins (substances that sensitize pain receptors and cause inflammation around the cerebral blood vessels).
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SENSORY
PATHWAYS
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the trigeminal nucleus caudalis are the key relay neurons for nociceptive input in head and neck.
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There is correlation between input from the trigeminal system and the cervical routes. So there are neurons in this complex that receive convergent input from the trigeminal cutaneous fibers, from the supratentorial dura,
from the posterior routes in the deep musculature, or from the cutaneous dermatome served by the greater occipital nerve. It's sensitization of these neurons that have received convergent input
that may result in the clinical syndromes of spread
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Referred pain and perhaps hypersensitivity, central sensitization, and allodynia.
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Goadsby et al., 2002
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www.medscape.com
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Trigeminal nerve activity during migraine and with the addition of a serotonin agonist. During a migraine, the trigeminal nerve releases CGRP, substance P, and neurokinin A, which are vasodilators. The addition of a serotonin agonist inhibits the release of these neuropeptides,
inhibiting vasodilation and migraine pain.
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Trigeminal innervation of cranial structures. The ophthalmic division of the trigeminal nerve innervates meningeal, cerebral, and cranial vessels. It is the ophthalmic nerve that is thought to be responsible for the pain associated with migraines. The superior sagittal sinus runs between the meninges and is the primary vein draining the cranial vasculature
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Algorithm for the symptomatic and prophylactic treatment of migraine headache
(adapted from Capobianco13).
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Rami Burstein uses a brush to check skin sensitivity.
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www.ncbi.nlm.nih.gov/genemap
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DNA to protein
http://cellbio.utmb.edu/cellbio/ribosome.htm
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Poly A site choice and alternative splicing produce either Calcitonin or CGRP (Calcitonin Gene Related Peptide) (hormones) in the calcitonin gene transcript from rats depending on
tissue type:
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Amino acid sequences of human and -CGRP
Endocrine Reviews; 1996
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Endocrine Reviews; 1996
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Endocrine Reviews; 1996
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PENATALAKSANAAN MIGREN:
Terapi abortif Terapi preventif
menghilangkan nyeri kepala serta gejala-gejala yang menyertai ketika serangan migren sedang berlangsung
(1) mengurangi frekuensi, durasi, dan intensitas serangan;
(2) memperbaiki reaksi terhadap pengobatan akut;
(3) memperbaiki fungsi dan mengurangi disabilitas.
Silberstein, 2000; American Academy of Neurology
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Obat Mekanisme kerja - asetaminofen
- aspirin
-Ergot (ergotamine tartrate, dihydroergotamine)
-Opioid
-triptans (sumatriptan, rizatriptan, zolmitriptan)
-steroid
- beta bloker (propanolol, timolol)
-Ca channel antagonis (nimodipin, flunarisin)
-Antikonvulsan :
- Asam divalproat
- Gabapentin
- Inhibisi sintesa prostaglandin di CNS, inhibisi aktifitas nosiseptif via reseptor 5HT
- Inhibisi sintesa prostaglandin
- Selektif arterial konstriktor yang kuat dan mempunyai daya ikat yang kuat pd otot dinding arteri
- Stimulasi reseptor opioid endogen
- Berikatan dengan reseptor 5HT1B, 5HT 1D, 5HT 1F, menginhibisi
neuronal dengan cara blokade sensoris pada n. trigeminal, blokade pelepasan vasoaktif peptide dan juga proses inflamasi neurovaskuler di dura maupun meningen.
- Anti inflamasi-Inhibisi pelepasan NE dg cara blokade prejunctional beta bloker reseptor, efek agonis pada 5HT1 reseptor, efek antagonis pada 5HT2
- Mempengaruhi Ca influks dalam mencegah vasokonstriksi dan pelepasan SP
- Menambah kadar GABA di sinap, menghambat enzin GABA di otak, menambah konduktansi kalium yang memberi hiperpolarisasi neuronal, menghentikan letupan dari neuron 5HT dari nukleus raphe dorsalis.
- Merubah aktivitas glutamic acid decarboxylase sehingga mampu meningkatkan GABA, menghambat pelepasan monoamin neurotransmiter (termasuk noradrenalin, dopamin dan serotonin)
Silberstein, 2001;Headache Council Philippne Neurological Association, 2000
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Wagner, 2005
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British Journal of Pharmacology (2000) 129, 420-423
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(Olesen et al., 2004)
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(Olesen et al., 2004)
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(Olesen et al., 2004)
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(Olesen et al., 2004)
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Silberstein, 2000; American Academy of Neurology
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Silberstein, 2000; American Academy of Neurology
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Silberstein, 2000; American Academy of Neurology
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Silberstein, 2000; American Academy of Neurology
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Silberstein, 2000; American Academy of Neurology
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Silberstein, 2000; American Academy of Neurology
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Silberstein, 2000; American Academy of Neurology
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Goadsby et al., 2002
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Indications for Hospitalization When outpatient treatment has been unsuccessful, hospitalization may be necessary for:
•Severe dehydration, for which inpatient parenteral therapy may be necessary •Diagnostic suspicion (confirmed by appropriate diagnostic testing) of organic etiology, such as:
1.infectious disorder involving the CNS (ie, brain abscess or meningitis) 2.acute vascular compromise (ie, aneurysm, subarachnoid hemorrhage) 3.structural disorder with accompanying symptoms (ie, brain tumor)
•Prolonged, unrelenting headache with associated symptoms, such as nausea and vomiting, which, if allowed to continue, would pose a further threat to the patient's welfare •Status migraine, or dependence on analgesics, ergots, opiates, barbiturates, or tranquilizers •Pain that is accompanied by serious adverse reactions or complications from therapy continued use of such therapy aggravates or induces further illness •Pain that occurs in the presence of significant medical disease -- but appropriate treatment of headache symptoms aggravates or induces further illness •Failed outpatient detoxification, for which inpatient pain and psychiatric management may be necessary •Intractable and chronic cluster headache, for which inpatient administration of histamine or dihydroergotamine may be necessary •Treatment requiring co-pharmacy with drugs that may cause a drug interaction, thus necessitating careful observation (monoamine oxidase inhibitors and ß-blockers)
Drug Benefit Trends, 1999
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Jenis migren karakteristik
Typical aura with migraine headache
Migren dg aura spt tanda-tanda:
-aura visual : (+):chy kilat, berkedip, bintik2/ garis2. (-) : gelap
-aura sensorik: (+) : spt ditusuk jarum, (-): parestesi
Gradual > 5 mnt; < 1 jam, reversibel; diikuti NK yg memenuhi kriteria migren WO aura
Typical aura with non-migraine headache
diikuti NK yg tidak memenuhi kriteria migren WO aura
Familial hemiplegic migraine (FHM)
-bersifat autosomal, dominan
-Sergn.di t/ oleh NK jns migren dg foto/ fonopobia, N,V
-Didahului/ disertai hemiparesis bbrp mnt-mgg, membaik tanpa g/ sisa.
-Tjd sergn.awal masa kanak-kanak, atau < 30 th
-20% keluarga dg FHM
Cyclical vomiting N,V, episodik, berulang, pucat, lethargi
Abdominal migraine Nyeri di tengah abdomen, episodik, berulang, selama 1-72 jam, diikuti N,V, dg masa diantara serangan pasien dlm kead. Normal
Benign paroxysmal vertigo of childhood
Sergn. Vertigo tiba2 saat interval anak sehat
Multipel, tiba2, gangg.keseimb(+), nistagmus, muntah, Pem.Neuro(N), EEG (N)
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Chronic migraine NK migren t/ aura selama 15 hr/> per-bulan; selama 3 bln/ > tanpa ada tanda-tanda overdosis obat
Persistent aura without infarction
Gejala aura menetao selama > 1 minggu, tanpa ada kelainan infark pada rontgen
Migrainous infarction Gjl aura 1 atau lebih sehubungan dg lesi iskemik otak sesuai dg teritori daerahnya pd pem. Imaging
Migraine-triggered seizure
Timbulnya kejang yg dipicu oleh adanya aura migren
Probable migraine Serangan migren yg disertai/ tdk NK dimn tdk adanya salah satu gjl, shg tdk memenuhi kriteria migren yg sebenarnya; baik migren dg/ tanpa aura
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Kaplan et.al., 1997
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Kaplan et.al., 1997
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Kaplan et.al .,1997
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Serotonin ReceptorsClassClass LocalizationLocalization Synaptic ActionSynaptic Action Signalling Signalling
MechanismMechanism5-HT1A Raphe nuclei
Hippocampus
Inhibition (↑ K+) ↓ cAMP
Direct K+ open
5-HT1B Cranial Blood Vessels
Cerebral vasoconstriction ↓ cAMP
5-HT1D Cranial Blood Vessels
Autoreceptor-mediated ↓ 5-HT release
↓ cAMP
5-HT1E/F Cortex
Striatum
↓ cAMP
5-HT2A Platelets
Smooth Muscle
Cerebral Cortex
Platelet aggregation
Contraction
Excitation (↓ K+)
IP3 production