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Migraine: From clinic to bench
王署君國立陽明大學醫學院醫學系台北榮總神經醫學中心
2014/12/9
Edvard Munch - The Scream 1893
Headache
• Primary headache ( 原發性頭痛)– Migraine (偏頭痛)– Tension-type headache ( 緊縮型頭痛)– Cluster headache (叢發性頭痛)
• Secondary headache (續發性頭痛)– Post-traumatic headache (頭部外商後頭痛)– Headache due to tumor (腫瘤相關頭痛)– Headache due to CSF pressure changes (腦壓變化頭
痛)
常見原發性頭痛• 偏頭痛 (migraine)
– 門診最常見的頭痛• 緊縮型頭痛 (tension-type headache)
– 社區最常見的頭痛• 叢發性頭痛 (cluster headache)
Migraine
• Gr. ἡμικρανία (hemikrania) = ἡμι- (hemi-) (= half) κρανίον (kranion) (= skull)
什麼是偏頭痛?
Cephalalgia. 2004;24:9-160. N Engl J Med. 2006;354:158-165.
ICHD-2 1.1 Migraine without aura A. At least 5 attacks fulfilling criteria B-DB. Headache attacks lasting 4-72 h
(untreated or unsuccessfully treated)C. Headache has 2 of the following
characteristics:1. unilateral location2. pulsating quality3. moderate or severe pain intensity4. aggravation by or causing avoidance of
routine physical activity (eg, walking, climbing stairs)
D. During headache 1 of the following:1. nausea and/or vomiting2. photophobia and phonophobia
E. Not attributed to another disorder
偏頭痛之特徵
“Migraine, the Sick-headache” 偏頭痛是會想吐的頭痛
• 中度或重度的疼痛• 發病於 10 到 30 歲,女性為主,女比男 3:1• 通常是單側 unilateral 、搏動性 pulsating (throbbing) 、身體活動會加
劇、日常生活受影響或禁絕、伴隨噁心 nausea 、嘔吐 vomiting 、畏光 photophobia 、怕吵 phonophobia 。
• 發作時間 4 到 72 小時,頻率不同 ( 最常見 1/month)• 引發因子:低血糖,高血糖,睡眠不足或太多,月經、紅酒、壓力、 3C
食物、氣壓、冷熱• 分期: premonitory symptoms, aura, headache, postdrome
Cady R et al. Headache. 2002;42:204–216.Linde M. Acta Neurol Scand. 2006;114:71–83.Linde M. Cephalgia. 2006; 26; 712–721.
Headache
Post headache TimePreheadache ModerateMild Severe
Premonitory
Mood changes FatigueCognitive changesMuscle painFood craving
Fully reversibleNeurological changes: Visual somatosensory
Aura
Dull headacheNasal congestionMuscle pain
Early Headache
UnilateralThrobbingNauseaPhotophobiaPhonophobiaOsmophobia
Advanced Headache
FatigueCognitive changesMuscle pain
Postdrome
無預兆偏頭痛• A 、至少有 5 次能符合 B - D 項的發作。• B 、頭痛發作持續 4 - 72 小時。• C 、頭痛至少具下列二項特徵: PUMA
1. 單側 (Unilateral) 2. 搏動性 (Pulsating) 3. 程度中等或重度 (Moderate) 4. 日常身體活動加劇頭痛或導致避免此類活動如走
路或爬樓梯 (Physical Activities)• D 、當頭痛發作時至少有下列一情形:
1. 噁心或嘔吐 2. 畏光及怕吵
ABCD 四項皆有︰偏頭痛有其中三項:可能偏頭痛
盛行率 (%
)
大台北地區性別與年齡別偏頭痛盛行率
Wang SJ et al. Cephalalgia 2000;20:566-572
• 一年盛行率 :9.1%• 女性 :14.4% 男性 :4.5%• 預兆患者佔 12.5%
0
5
10
15
20
25
15-19
25-29
35-39
45-49
55-59
65-69
男性女性
頭痛病人如何診治• 頭痛病史• 身體檢查 • 實驗室檢查 • 神經放射檢查︰ CT 或 MRI ( 腦波 ?) • 脊髓穿刺 • 其他科醫生︰耳鼻喉、牙科、精神科、
復健科、風溼科
V
Pain intensity measurement
• Visual analogue scale (10cm) (VAS)
0 (no pain at all) 10 (worst pain)
10.0 cm
5.8 cm
Numerical rating scaleMost commonly used
• 0 to 10 scale• 0—no pain• 1,2,3—mild pain • 4,5,6—moderate pain • 7,8,9—severe pain• 10 extreme pain (the most severe pain)
Pain measurement
Sample of Headache Diary
Headache severity (mild:1, mod.:2, severe:3)
Accompanied symptoms, if yes mark “V”
Visual aura??
Headache duration in hours
Painkiller: name and dose
If the painkiller works?
If in menstrual cycle, mark “V”
Ethnicity and Photophobia?
Genetics of Migraine
• 70% positive family history (one parent: 46%, both parents: 66%)
• stronger relationship with migraine with aura
• multiple genes vs. monogene • Rs1835740->Glutamate homeostasis
(Anttila et al. Nat Genet 2010)
Familial hemiplegic migraine (FHM) FHM 1: 19p13 missense mutations in CACNA1A,
which encodes the pore-forming 1 subunit of voltage-gated neuronal Cav2·1 (P/Q-type) calcium channels. (Ophoff et al. Cell 1996)
FHM 2: 1q23 missense mutations in ATP1A2, which encodes the 2 subunit of the Na+/K+ pump (De Fusco et al. Nat Genet 2003)
FHM 3: 2q24 missense mutation in SCN1A, which encodes the neuronal voltage-gated sodium channel Nav1·1 (Dichgans et al. Lancet 2005)
Genetic studies in FHM: genes encode ion transporters
Lancet Neurol 2007; 6: 521–32
Common migraine: a complex disorder
Hum Genet 2009;126:115–132
Nature Genetics, published online 23 June 2013; doi:10.1038/ng.2676
On the threshold of understanding Adult height
Crohn’s Disease
Schizophrenia
Migraine
(per 5000/50
00)
(per 1000/10
00)
(per 3000/30
00)
(per 3000/60
00)
1X 0 2 1 1
2X 2 4 2 3
3X 7 5 6 8
9X 68 51 62 12
18X 180 - - -
Pathophysiology
• Cortical spreading depression• Vascular vs neuronal• Neurotransmitters and neuropeptides
Cortical Spreading Depression
Cortical spreading depression of Leao
Aristides Leao, PhD1914-1993
自發性偏頭痛發作時的 bilateral spreading cerebral hypoperfusion
N Engl J Med. 1994;331:1689-92. PET study
Vascular or Neuronal?
Nat Med. 1995;1:658-660.
PET carried out during attacks of MoA: pattern of increased blood flow not following a neurovascular distribution.
自發性偏頭痛的腦幹活化
偏頭痛發作和腦血管 / 腦膜血管擴張
Brain 2008; 131: 2192-2200
(A)maxillary artery, (B) middle meningeal artery.
With NTG infusion, but not with placebo, there was a transient 6.7–30.3% vasodilation (p<0.01) of all blood vessels, with no change in blood flow.
During migraine (6 hrs after infusion), there was NO vasodilation or change in blood flow.
偏頭痛血管變化的證據
MMA dilates on the headache side but not on the nonheadache side. After injection of sumatriptan, MMA contracts on both sides.
MCA dilates on the headache side but not on the nonheadache side. After injection of sumatriptan no contraction of MCA is observed.
Ann Neurol 2011; 69: 635–45
Migraine pain was not accompanied by extracranial arterial dilatation, and by only slight intracranial dilatation (migraine vs. non-migraine days)
Lancet Neurol 2013; 12: 454–61
NeuropeptideRelease
CentralSensitization
Pain SignalTransmission
Vasodilatation
Hargreaves RJ, Shepheard SL. Can J Neurol Sci. 1999;26(suppl 3):S12-S19.
Trigeminovascular Migraine Pain Pathways
Preventive medication target
Acute medication target
CGRP, Substance P
Neurotransmitters & Neuropeptides
Neurology 2008;70:431–439
Scan 1: headache phase Scan 2: after sumatriptan Scan 3: interictal (between attacks)
偏頭痛的腦部 serotonin 合成
偏頭痛發作時外頸靜脈血中神經傳導物質濃度
Brain Res Rev. 2005; 48: 438–56.
NPY VIP Substance P CGRPMigraine without aura
± 0 ± 0 ± 0 ↑
Migraine with aura ± 0 ± 0 ± 0 ↑
Trigeminal neuralgia ± 0 ± 0 ± 0 ↑
Cluster headache ± 0 ↑ ± 0 ↑
Chronic paroxysmal headache
± 0 ↑ ± 0 ↑
± 0 = no change from before headache.↑ = significant increase in neuropeptide level.
Pain Signaling to CNS
Durham. N Engl J Med. 2004;350:1073-1075; Pietrobon. Neuroscientist. 2005;11:373-386Ramadan et al. Pharmacol Ther. 2006;112:199-212; Mitsikostas et al. Pain. 1998;76:239-248.Longoni et al. Neurol Sci. 2006;27 Suppl 2:S107-110.
1 MARCH 2013 VOL 339 SCIENCE www.sciencemag.org
頭痛藥物使用
頭痛藥服用的方式:有 2 種
① 止痛藥:「有痛才吃」
② 頭痛治療 ( 預防 ) 用藥:「需天天服用」
急性發作處理– 大部分病患,只需要急性治療。– 不同程度的頭痛,止痛藥物也不盡相同– 除了頭痛外,其他相關症狀如噁心、嘔
吐也須處理。– 急性用藥每星期不能超過兩天,否則可
能會藥物過度使用頭痛。
急性發作處理:有許多 ( 頭痛 ) 止痛藥可選擇
• 翠普登 (triptans): 如英明格 (Imigran)• 輕度止痛藥(普拿疼、百服寧)• 非固醇性抗炎症藥物 (NSAIDs)• 麥角胺鹼 (ergotamine) ︰加非葛 (Cafergot)
Triptans ( 翠普登 )
• 選擇性血漿胺 5- HT1B/ID-like 接受器催動劑。• 全世界上市的已超過七種廠牌。• Imigran ( 英明格 ), Migoff ( 邁歐芙)是台灣上市的翠普登。• 作用在抑制 Trigeminovascular system 三叉神經血管系統活性。 • 專門用來治療偏頭痛,最有效藥物。• 且不需其他藥物共同使用。• 價格昂貴。• 孕婦、冠狀動脈心臟病與高血壓控制不良患者禁止使用。• Imigran ( 英明格 ) 每個月限用四次,一次劑量不超過 100 mg
( 兩顆 ) ( 一個月最多八顆 )• Gr I 中到重度偏頭痛
NEJM 2004; 350: 1073-5
Decreasing blood flow in cerebral vessels
Blocking neurogenic inflammation
Inhibition of pain transmission
BIBN 4096 BS
CGRP-Receptor Antagonist 作用機轉
Telcagepant (MK-0974) Phase III Clinical Efficacy Results
2 Hr Pain ReliefPN11 PN16
50.255.4 56.1
26.8
0
10
20
30
40
50
60
70
MK-0974 150mg (N=333)
MK-0974 300mg (N=354)
Zolmitriptan 5mg (N=345)
Placebo(N=348)
Pe
rce
nt
pa
tie
nt ***
*** ***
*** p<0.001 vs. Placebo
Pe
rce
nt
pa
tie
nt
44.5
53.8 56
32.7
0
10
20
30
40
50
60
70
MK-0974 50mg (N=177)
MK-0974 150mg (N=381)
MK-0974 300mg (N=371)
Placebo(N=365)
*** ***
***p<0.001
頭痛治療 ( 預防 ) 用藥
1. 有許多不同種類的藥物可以減少偏頭痛發作。
2. 80% 病人至少減少 50% 發作次數。3. 用機轉仍不明。4. 需二至三星期,才會見效。5. 超過四到六 個月,發作情形已控制,
可開始減藥。
「頭痛預防用藥」有那幾種?多數藥物原本不是用於頭痛病人
– 乙型阻斷劑 (抗高血壓)• 天諾敏、康佳爾多
– 鈣離子阻斷劑 (頭暈)• 血裨益
– 抗抑鬱劑 (治憂鬱症)• 特定腦、妥富腦• 速悅• 樂活憂
– 抗癲癇藥物(治療癲癇)• 妥泰 (可以減重)• 帝拔癲
Inhibiting Neurotransmitter Release By Botulinum toxin A
BoNT/A SNAP-25
Light Chain
Adopted from Breidenbach: TRENDS in Molecular Medicine Vol.11 No.8 August 2005
Inhibition of peripheral peptides release
CGRP
Substance P
Acetylcholine
Postsynaptic Receptor
Axon Terminal
Norepinephrine
Fixed-site, fixed-dose injection site locations (155U)
PREEMPT primary endpoint
Diener et al. Cephalalgia 2010 Epub
NYMU-TVGH Headache Research Group
Migraine GWAS
GWASTDT: 1 wkHaplotype: 2wks
Annotation+ pathway analysis: 1wk
Clinical Genomics Bioinformatics
Subject recruitmentDiscovery cohort - 2000 migraine pt’ - 2000 controls*Replication cohort - 600 trios
Endophenotyping
GWASAffymetrix Axiom Genome-Wide CHB Array Plate
BiostatisticsMethods: gPLINKTDT, parenTDT
Gene annotationEnsembl
Pathway analysisPINKQuasiPro
*controls from Academia Sinica
GWAS results
NUP98 rs7945156
DLG2 rs655484rs2651732 rs1117243
GFRA1 rs3781545 rs17653752SLC1A3 rs60115512
Future plan
• Select potential SNPs/Gene loci for replication studies-- Single point genotyping by TagMan SNP genotyping assay-- Independent samples with 1000 MO patients and 1000 controls
• Fine mapping of SNPs/Gene loci significantly related to migraine in both screening and replicative dataset.-- purpose: (1) to identify Taiwan Chinese-specific variants/SNPs (2) to identify real causal SNPs
• Functional validation of significant genes using cellular and animal models-- Validate its biological functions in neurons and elucidate its role in migraine pathogenesis
Team MembersClinical Medicine
Shuu-Jiun WangJong-Ling FuhShih-Pin ChenWei-Ta ChenYen-Feng WangKwan-Lin Lai
Genetics/ Bioinformatics
Ming-Yi ChungCathy Sheng-Jiuan FannMing-Wei LinUeng-Cheng Yang Yi-Chu LiaoChia-Lin HsuHsien-Yang Lee
Investigators • Prof. Jung-Ling Fuh• Dr. Wei-Ta Chen• Dr. Kuan-Lin Lai• Dr. Albert C. Yang• Dr. Fu-Jung Hsiao• Dr. David M. Niddam
• Prof. Chin-Teng Lin• Dr. Li-Wei Ko• Pei-Hua Huang• Bo-Yuan Wu• Prof. John K. Zao
• Prof. Tzyy-Ping Jung
Headache Electrophysiology team
Visual evoked magnetic field: P100m
• Stimuli 120’ check size6 reversals/s
• 1500 trials• Sampling rate = 500 Hz• Bandpass = 0.1-130 Hz• Source modeling: single equivalent current dipole (ECD) for P100m activity
Chen et al., Can J Neurol Sci 2005
視覺刺激黑白棋盤方格 ( 左半視野 )
MEG studyIctal-like Visual Cortex Excitability in Chronic Migraine
Grand-average P100m:*CM or EM (ictal) vs. EM (interictal) or Control
Sub-average P100m:*EM (interictal) vs. CM, EM (ictal) or Control
**
Chen WT et al. Pain 2011
Visual cortex excitability in different types of migraine
Chen et al., Brain 2011
SSVEP Experiment
Baseline Recording Open Close Open Close Open Close
30 sec. 30 sec. 150 sec.
Baseline Recording
Preparation
13Hz . . .
10 s 160 sec.
5 Hz Rest 7 HzRest Rest 21Hz 18 Hz ENDRest
10 s 10 s 10 s 10 s
9Hz 11 Hz Rest 13 HzRest Rest 15Hz 17 Hz RestRest 19 Hz Rest
2 min.
SSVEP Experiment – Nicolet-One Clinical EEG recording
Normal Interictal Preictal Ictal Postictal17
74
13 11 10
Normal Inter-ictal Pre-ictal Ictal Post-ictal0.65
0.7
0.75
0.8
0.85
0.9
0.95
1
Normal and Migraine States
13H
z H
abitu
atio
n
13Hz Habituation O1 channel of Low
Accuracy(%)
QDC PARZENDC kNNC LDC
QDC 88.224 97.024 98.432 59.776
PARZENDC 62.336 71.84 66.24 59.648
kNNC 59.2 59.264 46.464 59.2
LDC 85.568 95.552 97.344 60.896
Classifier for Leave-One-Out Evaluation
ForwardFeature
SelectionCriterion
Prediction of Headache Status by Habituation Parameter(Low-frequency Migraine Patients)
New Experiment – Using MINDO
13Hz
10 s
Repeat 5 timesRest
80 s10 s
Rest
1 min.
18Hz
10 s
Repeat 5 timesRest
80 s10 s
Rest
1
min.
24Hz
10 s
Repeat 5 timesRest
80 s10 s
Rest
1 min.
Open-Eye
Resting
2 min.
2 min.
Closed-Eye
Resting
SSVEP
T0(2 wk)
T1(2 wk)
T2(2 wk)
T3(2 wk)
Start Medication (Topiramate [TPM] or Sibelium [Sib])
1st MRI scan 2nd MRI scan
titration for 1 wk
Yang-Ming Chronic migraine study
Structure image Resting fMRI Single voxel MRS Mid-wall 2D MRS
Current Recruitment Status
Patient Screened (n=51)
VPA (N=3) TPM (N=19) Sib (N=21)
Failure to meet CM criteria (n=2)Refuse to participate (n=2)MRI incompatibility (n=4)
TPM (n=19)
Lost follow-up due to S.E. (n=2: #12, #27)
Lost follow-up without reason(n=1: #21)
Complete intervention (n= 16)T0-T3: 12
T0-T2: 1 (#26)T0-T1: 3 (#13, #19, #30)
Sib (n=21)
Lost follow-up due to S.E. (n=1: #37)
Lost follow-up without reason(n=1: #34)
Complete intervention (n=19)T0-T3: 14
T0-T2: 1 (#42)T0-T1: 4 (#14, #23, #43, #44)
Neuroimage Findings
Impaired functional connectivity between PAG and OFC in naïve CM patients compared to control.
Enhanced functional connectivity (PAG OFC) in CM responders after a 2-week treatment.
CTL CM-PreTx CM-PostTx
Investigators – animal studiesShuu-Jiun WangLung-Sen Kao Jiin-Cherng Yen
Bai-Chuang Shyu
Jong-Ling FuhShih-Pin ChenYen-Feng Wang
SD rats
頭痛的動物模式• Electrophysiology (under anesthesia)• Awake rats• Facial expressions in pain
硬腦膜電刺激及電生理記錄
J Neurophysiol 1998; 79:964-982.
清醒狀態下的大鼠模式
Headache 2007; 47: 1026-1036
Epidural cannula for inflammatory
soup infusion
von Frey monofilament
Rat grimace scale
Mol Pain. 2011; 7: 55.
Cortical spreading depression
Veh
LEV
Medication-overuse headache- Behavior
Electronic von Frey anesthesiometer
Forehead withdrawal threshold Two-bottle choice test
Osmotic minipump
Medication-overuse headache- Immunohistochemistry
CGRP in TG
C-fos in TNCCGRP in dural afferents