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？
ICHD-2 1.1 Migraine without aura
A. At least 5 attacks fulfilling criteria B-D
B. Headache attacks lasting 4-72 h
(untreated or unsuccessfully treated)
C. Headache has 2 of the following
characteristics:
1.
2.
3.
4.
unilateral location
pulsating quality
moderate or severe pain intensity
aggravation by or causing avoidance of
routine physical activity (eg, walking,
climbing stairs)
D. During headache 1 of the following:
1.
E.
nausea and/or vomiting
2. photophobia and phonophobia
Not attributed to another disorder
Cephalalgia. 2004;24:9-160. N Engl J Med. 2006;354:158-165.
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
Premonitory
Aura
Early Headache
Mood changes
Fully reversible
Dull headache
Fatigue
Neurological changes:
Nasal congestion
Cognitive changes Visual somatosensory
Muscle pain
Muscle pain
Food craving
Preheadache
Mild
Moderate
Advanced Headache
Postdrome
Unilateral
Throbbing
Nausea
Photophobia
Phonophobia
Osmophobia
Severe
Fatigue
Cognitive changes
Muscle pain
Post headache
Headache
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.
Time
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
大台北地區性別與年齡別偏頭痛盛行率
25
• 一年盛行率:9.1%
(%)
• 女性:14.4%
男性:4.5%
• 預兆患者佔 12.5%
盛
行
率
20
15
男性
女性
10
5
0
1519
2529
3539
4549
5559
Wang SJ et al. Cephalalgia 2000;20:566-572
6569
頭痛病人如何診治
•V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
Pain intensity measurement
• Visual analogue scale (10cm) (VAS)
10.0 cm
0 (no pain at all)
5.8 cm
10 (worst pain)
Numerical rating scale
Most 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
Headache severity (mild:1, mod.:2, severe:3)
Accompanied symptoms, if yes mark “V”
Sample of
Visual aura??
Headache Diary
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
Crohn’s Schizoph Migraine
height
Disease
renia
(per
(per
(per
(per
5000/500 1000/100 3000/300 3000/600
0)
0)
0)
0)
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, PhD
1914-1993
自發性偏頭痛發作時的bilateral spreading cerebral
hypoperfusion
PET study
N Engl J Med. 1994;331:1689-92.
Vascular or Neuronal?
自發性偏頭痛的腦幹活化
PET carried out during attacks of MoA: pattern of increased blood flow not
following a neurovascular distribution.
Nat Med. 1995;1:658-660.
偏頭痛發作和腦血管/腦膜血管擴張
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.
(A) maxillary artery,
(B) middle meningeal artery.
Brain 2008; 131: 2192-2200
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
Trigeminovascular Migraine
Pain Pathways
Preventive medication target
Neuropeptide
Release
CGRP, Substance P
Vasodilatation
Central
Sensitization
Pain Signal
Transmission
Acute medication target
Hargreaves RJ, Shepheard SL. Can J Neurol Sci. 1999;26(suppl 3):S12-S19.
Neurotransmitters & Neuropeptides
偏頭痛的腦部serotonin合成
Scan 1: headache phase
Scan 2: after sumatriptan
Scan 3: interictal (between attacks)
Neurology 2008;70:431–439
偏頭痛發作時外頸靜脈血中
神經傳導物質濃度
NPY
±0
VIP
±0
Substance P
±0
CGRP
↑
±0
±0
±0
↑
Trigeminal neuralgia
±0
±0
±0
↑
Cluster headache
±0
↑
±0
↑
Chronic paroxysmal
headache
±0
↑
±0
↑
Migraine without
aura
Migraine with aura
± 0 = no change from before headache.
↑ = significant increase in neuropeptide level.
Brain Res Rev. 2005; 48: 438–56.
Pain Signaling to CNS
Durham. N Engl J Med. 2004;350:1073-1075; Pietrobon. Neuroscientist. 2005;11:373-386
Ramadan 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
 止痛藥：「有痛才吃」
 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
CGRP-Receptor Antagonist作用機轉
Blocking neurogenic inflammation
BIBN 4096 BS
Decreasing blood flow in cerebral
vessels
Inhibition of pain transmission
NEJM 2004; 350: 1073-5
Telcagepant (MK-0974) Phase III
Clinical Efficacy Results
2 Hr Pain Relief
PN11
PN16
70
*** p<0.001 vs. Placebo
50
***
***
55.4
***
56.1
50.2
40
30
26.8
20
***p<0.001
60
10
Percent patient
Percent patient
60
70
***
50
40
53.8
***
56
44.5
30
32.7
20
10
0
0
MK-0974 150
mg (N=333)
MK-0974 300
mg (N=354)
Zolmitriptan 5
mg (N=345)
Placebo
(N=348)
MK-0974 50
mg (N=177)
MK-0974 150
mg (N=381)
MK-0974 300
mg (N=371)
Placebo
(N=365)
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
Light Chain
BoNT/A
SNAP-25
Adopted from Breidenbach: TRENDS in Molecular Medicine Vol.11 No.8 August 2005
Inhibition of peripheral peptides release
Acetylcholine
Substance P
Axon
Terminal
CGRP
Norepinephrine
Postsynaptic
Receptor
Fixed-site, fixed-dose injection site
locations (155U)
PREEMPT primary endpoint
Diener et al. Cephalalgia 2010 Epub
NYMU-TVGH Headache Research
Group
Migraine GWAS
Clinical
Subject recruitment
Discovery cohort
- 2000 migraine pt’
- 2000 controls*
Replication cohort
- 600 trios
Genomics
GWAS
Affymetrix Axiom
Genome-Wide CHB
Array Plate
Endophenotyping
Biostatistics
Methods: gPLINK
TDT, parenTDT
*controls from
Academia Sinica
GWASTDT: 1 wk
Haplotype: 2wks
Bioinformatics
Gene annotation
Ensembl
Pathway analysis
PINK
QuasiPro
Annotation+ pathway
analysis: 1wk
GWAS results
NUP98 rs7945156
DLG2 rs655484
rs2651732
SLC1A3 rs60115512
GFRA1 rs3781545
rs17653752
rs1117243
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 Members
Clinical Medicine
Shuu-Jiun Wang
Jong-Ling Fuh
Shih-Pin Chen
Wei-Ta Chen
Yen-Feng Wang
Kwan-Lin Lai
Genetics/ Bioinformatics
Ming-Yi Chung
Cathy Sheng-Jiuan Fann
Ming-Wei Lin
Ueng-Cheng Yang
Yi-Chu Liao
Chia-Lin Hsu
Hsien-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. Tzyy-Ping Jung
•
•
•
•
•
Prof. Chin-Teng Lin
Dr. Li-Wei Ko
Pei-Hua Huang
Bo-Yuan Wu
Prof. John K. Zao
Headache Electrophysiology team
Visual evoked magnetic field: P100m
• Stimuli
120’ check size
6 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 study
Ictal-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 – Nicolet-One Clinical EEG recording
Preparation
Baseline
Recording
Open
Close
30 sec.
2 min.
SSVEP Experiment
Close
Open
Open
150 sec.
30 sec.
9Hz
Rest
11 Hz
Rest
13 Hz
Rest
15Hz
13Hz
Rest
5 Hz
Rest
7 Hz
Rest
...
10 s
10 s
10 s
10 s
Baseline
Recording
Close
10 s
Rest
160 sec.
21Hz
17 Hz
Rest
Rest
18 Hz
19 Hz
END
Rest
Prediction of Headache Status by Habituation Parameter
(Low-frequency Migraine Patients)
13Hz Habituation O1 channel of Low
1
0.95
Accuracy(%) Classifier for Leave-One-Out Evaluation
13Hz Habituation
0.9
0.85
QDC
PARZENDC kNNC
LDC
0.8
Forward
Feature
Selection
Criterion
0.75
QDC
88.224
PARZENDC 62.336
97.024
98.432
59.776
71.84
66.24
59.648
0.7
0.65
Normal
Inter-ictal
Pre-ictal
Normal and Migraine States
Ictal
74
17
13
Normal Interictal Preictal
kNNC
59.2
59.264
46.464
59.2
LDC
85.568
95.552
97.344
60.896
Post-ictal
11
10
Ictal
Postictal
New Experiment – Using MINDO
OpenEye
Resting
2 min.
ClosedEye
Resting
SSVEP
2 min.
13Hz
Repeat
5 times
Rest
10 s
10 s
80 s
18Hz
Rest
1 min.
Repeat
5 times
Rest
10 s
10 s
80 s
24Hz
Rest
1 min.
Repeat
5 times
Rest
10 s
10 s
80 s
Rest
1 min.
Yang-Ming Chronic migraine study
Start Medication (Topiramate [TPM] or Sibelium [Sib])
titration for 1 wk
T0
T1
T2
T3
(2 wk)
(2 wk)
(2 wk)
(2 wk)
1st MRI scan
Structure image
Resting fMRI
2nd MRI scan
Single voxel MRS
Mid-wall 2D MRS
Current Recruitment Status
Patient Screened
(n=51)
Failure to meet CM criteria (n=2)
Refuse to participate (n=2)
MRI incompatibility (n=4)
VPA (N=3)
TPM
TPM (n=19)
(N=19)
Sib
Sib(N=21)
(n=21)
Lost follow-up due to S.E.
Lost follow-up due to S.E.
(n=2: #12, #27)
(n=1: #37)
Lost follow-up without reason
Lost follow-up without reason
(n=1: #21)
(n=1: #34)
Complete intervention (n= 16)
Complete intervention (n=19)
T0-T3: 12
T0-T3: 14
T0-T2: 1 (#26)
T0-T2: 1 (#42)
T0-T1: 3 (#13, #19, #30)
T0-T1: 4 (#14, #23, #43, #44)
Neuroimage Findings
Impaired functional
connectivity between PAG
and OFC in naïve CM patients
compared to control.
CTL
Enhanced functional
connectivity (PAG  OFC)
in CM responders after a 2week treatment.
CM-PreTx
CM-PostTx
Investigators – animal studies
 Shuu-Jiun Wang
 Lung-Sen Kao
 Jiin-Cherng Yen
 Jong-Ling Fuh
 Shih-Pin Chen
 Yen-Feng Wang
 Bai-Chuang Shyu
 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
von Frey monofilament
Epidural cannula
for inflammatory
soup infusion
Headache 2007; 47: 1026-1036
Rat grimace scale
Mol Pain. 2011; 7: 55.
Cortical spreading depression
Veh
LEV
Medication-overuse headache
- Behavior
Electronic von Frey
anesthesiometer
Osmotic minipump
Forehead withdrawal
threshold
Two-bottle choice test
Medication-overuse headache
- Immunohistochemistry
CGRP in TG
CGRP in dural afferents
C-fos in TNC