Transcript MIGRAINE

MIGRAINE
臺北榮民總醫院 神經醫學中心
陳韋達
Outline
 Clinical
diagnosis and evaluation of
migraine
 Pathophysiology
 Treatment
of migraine
of migraine
Origin of Headache

Distention, traction, or dilatation of intracranail or
extracranial arteries

Traction or displacement of large intracranial veins or
their dural envelope

Compression, traction, or inflammation of cranial and
spinal nerves

Spasm, inflammation, and trauma to cranial and cervical
muscles

Meningeal irritation and raised intracranial pressure

Perturbation of intracerebral serotonergic projections 
impaired central inhibition?
Diagnosis of Headache Disorders

International Classification of Headache Disorders (ICHD)
– Conducted by the Headache Classification
Subcommittee of International Headache Society (IHS)
– ICHD-1, 1988 (中譯版：臺大 洪祖培等)
–
ICHD-2, 2004 (中譯版：臺灣神經學會頭痛學組)
國際頭痛疾病分類 ICHD-2
2003/9

1、偏頭痛

2、緊縮型頭痛

3、叢發性頭痛與其他三叉自律神經頭痛

4、其他原發性頭痛

5、歸因於頭部及頸部外傷之頭痛

6、歸因於顱部或頸部血管疾患之頭痛

7、歸因於非血管性顱內疾患之頭痛

8、歸因於與物質或物質戒斷之頭痛

9、歸因於感染之頭痛

10、歸因於與体內恒定疾患之頭痛

11、歸因於頭顱、頸、眼、耳、鼻、鼻竇、牙、口或其他面部或顱部結構疾
患之頭痛或顏面痛

12、歸因於精神疾患之頭痛

13、顱神經痛和中樞性顏面痛

14、其他頭痛、顱部神經痛、中樞或原發性顏面痛
有多少人頭痛

96% 以上的人畢生會發生一次以上頭痛

1997-1999 大臺北地區頭痛調查 (15歲以上)
 女性：14%
 男性：5%
偏頭痛，57% 其他頭痛，29% 無
偏頭痛，46% 其他頭痛，50% 無

全臺灣15歲以上成人約 9.7 % (150萬) 的人有偏頭痛 (
女115萬，男35萬，約3：1)

約4% (60萬) 的人其頭痛平均天數每個月超過15天，符合
慢性每日頭痛的診斷。其中三成濫用止痛藥。
Adjusted Age-specific Prevalence of Migraine
Women
Men
偏頭痛發作

前趨症狀 (premonitory symptoms)
 疲倦、注意力差、頸部僵硬、想吃東西、呵欠

預兆 (aura)
 視覺預兆:
閃光、星星、盲點、愛麗絲仙境
 感覺異常:
手指末端有針刺感
 運動障礙：半側偏癱
 語言障礙：失語症口齒不清

頭痛發作 (headache)

發作結束 (postdrome)
診斷標準
無預兆偏頭痛 (migraine without aura)

A. 至少有五次以上頭痛發作符合 B, C 和 D 項

B. 頭痛過程持續 4-72小時[沒治療或治療沒成功]

C. 至少有以下四項中的兩項
 一側的頭痛
 搏動性的頭痛
 頭痛中度到嚴重[會影響工作生活]
 日常活動如走路或爬樓梯等會使頭痛加劇

D. 至少有以下兩項中的一項
 噁心或嘔吐
 畏光及怕吵

E. 非歸因於其他疾患
診斷標準
預兆偏頭痛 (Migraine with aura)

A. 至少有兩次以上頭痛發作符合 B 項

B. 預兆至少包括下列一項
– 完全可逆視覺症狀
– 完全可逆感覺症狀
– 完全可逆失語性語言障礙

C. 至少具下列兩項
– 同名側的視覺症狀及/或單側感覺症狀
– 至少一種預兆在≥5分鐘逐漸產生，及/或不同預兆在
≥5分鐘相繼發生
– 每一種狀持續 ≥5分鐘及 ≤60分鐘

D. 符合無預兆偏頭痛基準 B-D 的頭痛，在預兆同時或預
兆之後的60分鐘內發生

E. 非歸因於其他疾患
偏頭痛的診斷工具
頭痛日誌
記錄重點
1、疼痛程度
2、疼痛時段
3、相關症狀及預兆
4、持續時間
5、服用葯物及其有效程度
6、月經日期
頭痛疾患的診斷工具
 頭痛日誌
–
頭痛位置、性質、伴隨症狀、時間與頻率因素、預兆、
誘發原因、月經日期
 神經放射線檢查
–
Frishberg BM 1994: CT or MRI for migraineurs with
normal NE shows positive findings in 4/987(0.4%) : 3
with tumor, 1 with AVM
 實驗室檢查
–
腦血管攝影、腰椎穿刺、腦波、腦血管超音波、眼底及
眼壓檢查、耳鼻喉科檢查
Diagnostic flow chart of headache
Headache?
thunderclap headache
hyper-acute onset
intracranial HTN
Posture-related
One-sided pain+
cranial autonomic s/s
Associated w/ recent event
medication overuse
Trigeminal-autonomic
cephalalgia
Secondary headache
Medication-overuse
headache
Migraine or other
primary headaches
偏頭痛的後遺症
 慢性偏頭痛 (chronic migraine)
 偏頭痛重積狀態 (status Migrainosus)
– 定義：偏頭痛發作時間超過三天，無頭痛時間
少於4小時 (不含睡眠)
 無梗塞之持續性預兆 (persistent aura without infarction)
 偏頭痛梗塞 (migrainous Infarction)
– 預兆持續一小時以上併影像學之腦梗塞証據
 偏頭痛引發之癲癇發作 (migraine-triggered seizure)
偏頭痛的後遺症
Deep White Matter Lesions
Kruit MC, et al. JAMA 2004; 291: 427-34
Risk Factors for Chronic Daily Headache
(CDH)
 A history
of migraine
 Medication
overuse
 Caffeine
consumption
- Dietary and medications
 Obesity（OR=5.3）
 Snoring（OR=3.3）
 Stressful
Life Events
Wang SJ. et al. Neurology 2000;54:31 4-9
Scher AJ et al. Neurology 2002；58(S3):A332
Scher AJ et al. Neurology Pain 2003;106:81-9
Lu SR et al.Cephalalgia 2001;21:980-6
Juang KD,et al. Cephalalgia 2004;24:54-9
Katsarava Z et al. Neurology 2004;62:788-90
Migraine Comorbid and Co-occurring
Disorders
Cardiovascular
Psychiatric
Hypertension
Mitral valve prolapse
Patent foramen ovale
Raynaud’s phenomenon
Stroke
Depression
Anxiety
Bipolar disorder
Eating disorders
．Anorexia / bulimia
．Obesity
Neurologic
Gastrointestinal
Pulmonary
Seizure disorder
Gastric ulcers
Irritable bowel syndrome
Smoking
Asthma
Allergies
Endocrine
Chronic pain
Menstrual abnormalities
Hypothyroidism
Fibromyalgia
Chronic fatigue syndrome
Migraine with aura is associated with
cerebrovascular disease

Myocardial infarction (MI) (OR 2.08)

Coronary revascularisation (1.74)

Angina (1.71)

Death from ischemic cardiovascular disease (2.33)

Patent foramen ovale (PFO)

Other associated CV risks
– Unfavourable cholesterol profile
– High blood pressure
– Parental history of early MI
Kurth T, 2008; kurth T, 2007; Scher AI 2005
Outline
 Clinical
diagnosis and evaluation of
migraine
 Pathophysiology
 Treatment
of migraine
of migraine
“The concept of migraine is a state of central
neuronal hyperexcitability.”
Welch KMA 1990
Hypersensitivity to external stimuli
in Migraine

Sensitivity to light, sound, and odors
– Interictal
–
ictal

Attacks triggered by light or other sensory stimuli

Visual discomfort and intense
illusion to grating patterns
Deficient habituation in migraine
Check size=8 min, reversal rate =3.1 hz
Schoenen J et al, Eur J Neurol 1995;2:115-122
Deficient habituation in migraine
Check size=8 min, reversal rate =3.1 hz
Afra J et al., Brain 1998; 121:233-241
Serotonin may be involved in
presynaptic depression
Principles of Neural Science, 4/e
Habituation Depends on
Subcortical-cortical Aminergic Projections
Sensory cortex
Thalamocortical loops
Thalamus
Ach
DA
NE
5-HT
Brain
stem
His
Basal
Basal
forebrain
forebrain
State-setting
State-setting
chemically
chemicallyaddressed
addressed
connections
connections
Repeated Stimuli
Cephalalgia 2007; 27:1429-1439
Migraine: a neurochemical disorder with
low serotonergic disposition
 Interictal
– Plasma
5HT↓; HIAA↑
 Ictal
– Urine
5-HIAA↑
– Plasma
5HT↑; HIAA↓
Int Arch Allergy Appl Immunol 1961;19:55-8
Cephalalgia 2007;27:1296-1300
Ictal Serotonin Change in Migraine
Acute headache Sumatriptan
Neurology 2008;70:431-9
Interictal
Fluoxetine reverses VEP dishabituation
in migraine
Headache 2002;42:582-7
Fluoxetine 20mg/d
x 1 mo
-9.3%
-10.1%
Headache 2002;42:582-7
Homeostatic Changes and
Altered Excitability in Migraine
 Dysfunction
 Disordered
 Deficiency
 Abnormal
of aminergic subcortical projections
mitochondrial energy metabolism
of systemic and brain Mg++
glutamate metabolism
Proposed Mechanisms of Migraine
Abnormal cortical
Activity:
Hyperexcitable brain
(5HT↓, Ca ↑, Glu ↑, Mg ↓)
Abnormal brainstem
Function:
Excitation of brain
stem, PAG, etc
Cortical Spreading Depression
?
Activation/Sensitization of TGVS
Vasodilation;
Neurogenic Inflammation
Central Sensitization
TGVS=tngemunal vascular
sensitization.Adopted from Pietrobon D.
Striessing J. Nat Neurosci.2003;4:386-398.
Headache
Pain
Cortical Spreading Depression (CSD)
Leão AAP, 1914-1993
J Neurophysiol 1944;7:359-390
Cortical Spreading Depression
Leão (1944):
Olesen (1990):
Lashley (1941):
Cortical Spreading Spreading Oligemia
Spreading aura
Depression (CSD)
2 – 3 mm / min
Milner PM (1958)
偏頭痛的腦部血流變化-- Spreading Oligemia
Olesen J et al. Ann Neurol. 1990.
Migraine is primarily of neural, not vascular origin.
Cortical Spreading Depression
in human brain
PNAS 2001 (April); 98: 4687-4692
Ann Neurol 2001;50:582-587
Proposed Mechanisms of Migraine
Abnormal cortical
Activity:
Hyperexcitable brain
(5HT↓, Ca ↑, Glu ↑, Mg ↓)
Abnormal brainstem
Function:
Excitation of brain
stem, PAG, etc
Cortical Spreading Depression
?
Activation/Sensitization of TGVS
Vasodilation
Neurogenic Inflammation
peripheral sensitization
Central Sensitization
TGVS=tngemunal vascular
sensitization.Adopted from Pietrobon D.
Striessing J. Nat Neurosci.2003;4:386-398.
Headache
Pain
Trigeminal Vascular Activation
NEJM 2002;346:257-270
Proposed Model of Migraine
Genetic
Dysfunctioned aminergic
Channelopathy or transmission (5HT etc.)
Ca ↑, Glu ↑, Mg ↓
& cortical hyperexcitability
↑5HT
transmission
Reduced mitochondrial
energy reserve
Excessive
metabolic strain
Genetic
abnormality?
Migraine aura
Biochemical shifts
Spreading depression
Endogenous
Pain
Control system
Modified from Biomed & Pharmacother 1996;50:71-78
Trigeminal
Vascular
activation
Migraine attack
偏頭痛與遺傳

偏頭痛患者有70%以上亦有家屬罹病

父母有一人偏頭痛，則小孩罹病率 46%

父母雙方均偏頭痛，則小孩罹病率 66%

預兆型偏頭痛比無預兆型更易遺傳

一般常見之偏頭痛則為多重基因遺傳

能表現遺傳性偏頭痛之特定基因病變
– FHM-1, FHM-2, FHM-3 家族性偏癱性偏頭痛 (Familial
hemiplegic migraine, FHM)
–
–
NOTCH 3 gene  CADASIL (cerebral autosomal dominant
arteriopathy with subcortical infarcts and leukoencephalopathy)
SLC1A3  EAAT1 (excitatory amino acid transporter 1)
glutamate transporter
Vande Ven RCG. Arch Neurol 2007
Familial Hemiplegic Migraine
Animal Models of Migraine
in the past three decades
Outline
 Clinical
diagnosis and evaluation of
migraine
 Pathophysiology
 Treatment
of migraine
of migraine
偏頭痛急性治療

Triptans (翠普登)
– Sumatriptan 50mg po
– Sumatriptan 20mg in
– Sumatriptan 50mg, 100mg FDT (fast-disintegrating
tablet)

Ergots (麥角胺)
– Ergotamine 1mg/caffeine 100mg (eg. Cafergot etc.)
2# po
– Dihydroergotamine 5-10 mg po

NSAIDs: ketorolac 2 mg im/iv, oral NSAIDs

Others
– Neuroleptics: prochlorperazine 5-10 mg iv
– Corticosteroids: dexamethasone 5 mg im
偏頭痛急性治療準則

儘早用藥，效果確實

分層治療
– 輕中度偏頭痛：以非類固醇抗發炎藥物為第一線
– 中重度偏頭痛：以翠普登或麥角胺為第一線

藥物併用，療效更佳，如翠普登併用NSAID，或多巴胺拮
抗劑併用其他急性用藥

特殊情形
– 孕婦或兒童，以單純止痛藥乙醯氨酚為第一線
–

偏頭痛重積狀態，優先使用類固醇
頻繁使用急性治療，可能導致「藥物過度使用頭痛」
Medication Overuse Headache, MOH
Triptans 翠普登

Agonists for 5-HT 1B/1D ± 5-HT 1F

1st triptan: sumatriptan

2nd triptan: zolmi-, nara-, *riza-, *almo-, frova-, *ele– Higher central penetrance
– *Highest 2h effectiveness with relief within 30-60 min
 Imigran® 英明格 (1 tab = sumatriptan 50 mg)
–
–
Onset ~ 40-60 min
Abolish pain ~ 2-4 hr
–
Responder rate ~ 70%
–
Also effective for nausea, vomiting photophobia and
phonophobia
Ergotamine
Non-selective Agonists for 5-HT 1B/1D ± 5-HT 1F

ergotamine 1mg/caffeine 100mg  Dihydroergotamine 5mg
加非葛Cafergot
治偏頭痛錠Antimigraine
克痛敏Cafegotamine
可伏痛Cafeton
痛安錠Ergocafe
易克痛Ergoton
麥角咖啡鹼錠Coffegot
豐醫痛錠Ergoffeine
益汝朗Ergodan
偏痛停Migratin
倍安達Baenta
優去痛敏Yuchitonmin
痛平定Tonpen
益可達Ergolar
益克偏Ergofen
麥咖因 Ergocaine
塞戈羅Seglor (5mg；其中
1.5mg為立即釋放劑型、3.5mg
為緩慢釋放劑型)
道得通Dihydergot (2.5mg)
樂又適Rayosu (1mg)
安得寧Antoxine (1.5mg)
Triptans/Ergots for Migraine Treatment
NEJM 2002;346:257-270
Key Differences Ergots vs. Triptans
Ergots
Triptans
5-HT
1A
++++
+
1B
1D
+++
+++
++
+++
2A
2C
+++
+++
–
–
Adrenergic
a1
a2
+++
+++
–
–
Dopamine
D2
+++
–
Dysphoria
Nausea / Emesis
Anti-migraine
Peripheral Vascular
Effects
Asthenia
Dizziness
GI / Nausea / Emesis
Triptan/Ergot
Contraindication and Adverse Events

Contraindication
– ischemic heart disease
– uncontrolled HTN
– basilar or hemiplegic migraine
– pregnancy
– MAO-I use

Adverse Events
– paresthesia, tingling
– flushing, burning, or warm/hot sensation
– dizzy, somnolence, fatigue, heaviness
偏頭痛預防療法

Anti-epileptic drugs (AED)
– topiramate、valproic acid、gabapentin

Beta-blockers
– propranolol、atenolol、nadolol、metoprolol

Calcium channel blockers
– flunarizine、verapamil

Anti-Depressants
– TCA, selective serotonin reuptake inhibitors
American Association of Neurology, 2000
Mechanism of Migrane Preventatives
Glutamate
GABA
Neurotransmission Neurotransmission
NE
5-HT
β-Blockers




TCAs




CCBs




VPA




GBP




TPM




CCBs=calcium channel blockers; VPA=valproate; GBP=gabapentin; TPM=topiramate.
Adapted from Silberstein SD et al. Wolff’s Headache and Other Head Pain. 2001:121-237.
偏頭痛預防療法
採行時機

每個月頭痛3-4次以上或慢性頭痛

急性藥物無法完全減輕頭痛，或有使用禁忌者

急性藥物每週使用超過兩次以上

發作時間超過48小時或發作程度過於嚴重影響生活品質

特殊形式偏頭痛，如併偏癱、過長預兆，或偏頭痛腦梗塞
施行方式

每天服藥，一般需持續4-6個月，並於2-3週逐漸減藥
預期效果

頭痛發生率降低50+%；急診求診頻次降低 82%

減少不必要之腦部造影檢查CT 75%，MRI 88%
TAKE HOME MESSAGES

Migraine is a prevalent, disabling neurological disease
more common in female and associated with
cardiovascular risks

Hyperexcitability of brain is the pivotal pathomechanism
of migraine, which may be linked to inherited
channelopathy, dysfunctioned amine transmission, and
reduced mitochondrial energy reserve

Triptans and ergots are migraine-specific acute
treatments, acting by 5HT1b/1d antagonism

Anticonvulsants can prevent migraine probably due to
the effect of neuro-stabilization after long-term use