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