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MIGRAINE PATHOPHYSIOLOGY

Nada Šternić

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Primary headache is a big andcommon problem in neurology

The main disabling form of primaryheadache we’ve been facing with

Introduction

Headacheis migraine History

Aim

Migraine

Genetics

Anatomy

WE CARE

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Physiology

Pathogenesis

Summary

Headache caused by a life‐threatening disorder makes only 6% out of all headaches

The problem is: what is the Introduction

Headachepossibility to recognize these 6% in the jungle of the rest 94% and how to do it?

History

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Migraine

Genetics

Anatomy

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For example: Unilateral headache with miosis

Dg: Nasopharyngeal carcinoma Introduction

Headache

History

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Migraine

Genetics

Anatomy

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Physiology

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Summary

Generally speaking migraine is an inherited episodic disorder of the brain involving disfunction of subcortical structures that

d l i

Introduction

Headachemodulate sensory input History

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Migraine

Genetics

Anatomy

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Physiology

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20

25

30Females

Males

nce

(%)

Migraine: prevalence by age and gender ♦

Introduction

Headache

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5

10

15

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0 20 40 60 80

Mig

rain

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eval

en History

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Migraine

Genetics

Anatomy

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♦Neurology. 1993;43:S6-S10.Migraine in the United States: a review of epidemiology and health care use.Lipton RB, Stewart WFDepartment of Neurology, Albert Einstein Collage of Medicine, Bronx, NY.

0 20 40 60 80Age (years)

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Physiology

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Introduction

Headache

IS HEADACHE AN EVIL SPECIFIC FOR OUR AGE?

History

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Migraine

Genetics

Anatomy

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Physiology

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In the manuscripts from the ancient town Niniva, 7th century B.C, ‐ first written notes about headache, even about the features that could resemble to a modern concept of a

Introduction

Headacheresemble to a modern concept of a migraine AURA

History

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Migraine

Genetics

Anatomy

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Physiology

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Also, in the manuscripts having been found out in the area of ancient Egypt ‐ descriptions of a severe unilateral headache, the main Gods Chorus and Set had used

Introduction

Headachemain Gods Chorus and Set had used to suffer of

History

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Migraine

Genetics

Anatomy

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In classic stories from ancient Greece ‐ some notes about the principal God Zeus, suffering from a very bad head pain…

Introduction

Headache

History

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Migraine

Genetics

Anatomy

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Introduction

Headache

History

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Migraine

Genetics

Anatomy

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…but in the new era it is much better understood than has been case for the last four millennia

Our aim here will be to explore the anatomy and physiology relevant for

Introduction

Headacheanatomy and physiology relevant for migraine

Un understanding of the pathopsyiology of migraine will enable the clinician to give many explanations concerning this type of headache to

History

Aim

Migraine

Genetics

Anatomyconcerning this type of headache to patients

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Physiology

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Summary

Migraine: A Common Episodic Headache Disorder

Neurologic disorder:• strong genetic component

Introduction

Headache(up to 50%) History

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Migraine

Genetics

Anatomy

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Physiology

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Migraine: A Common Episodic Headache Disorder

Global prevalence in adults: >10%• women: 15%–17%

Introduction

Headache

• men: 6%–9%

2 major subtypes:• without aura (~75%)

• with aura (~25%)

History

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Migraine

Genetics

Anatomy

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Physiology

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Summary

Migraine: A Common Episodic Headache Disorder

Burden:• among the world’s 20 most

Introduction

Headachedisabling diseases (WHO)

• indirectly costs employers up to USD 13 billion per year

• direct medical costs exceed USD 1 billion per year

History

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Migraine

Genetics

Anatomy

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Physiology

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Definition of Migraine♦: Repeated episodes of headache (4 to 72 hours) with the following features:

Any two of:• unilateral

Introduction

Headache

• throbbing

• worsened by movement

• moderte to severe

Any one of:• nausea/vomiting

History

Aim

Migraine

Genetics

Anatomy• photophobia and phonophobia

WE CARE

♦Cephalalgia. 2004;24:9-160.The International Classification of Headache Disorders: 2nd editionHeadache Classification Subcommittee of the International Headache Society

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Summary

One of the most important aspects of the pathophysiology of migraine is the inherited nature of the disorder

h f b h d

Introduction

HeadacheThe first report about that derives from the 17th century

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Migraine

Genetics

Anatomy

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Physiology

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Both twin studies and population‐based epidemiological surveys strongly suggest that migraine without aura is a multifactorial disorder caused by a combination

Introduction

Headachedisorder, caused by a combination of genetic and environmental factors

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Migraine

Genetics

Anatomy

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In approximately 50% of the reported families, familial hemiplegic migraine (FHM) has been assigned to chromosome 19p13

Few clinical differences have been

Introduction

HeadacheFew clinical differences have been found between chromosome 19‐linked and chromosome 19 unlinkedFHM families

The clinical phenotype does not associate particularly with the known

History

Aim

Migraine

Genetics

Anatomyassociate particularly with the known mutations♦

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♦N Engl J Med 2001; 345(1):17-24The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channelDucros Aa, Denier C, Joutel A, et al.Faculte de Medicine, Laribosiere, Paris, France

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The biological basis for the linkage to chromosome 19 is mutation, involving the Cav 2.1 (P/Q) type voltage‐gated calcium channelCACNA1A gene♦

Introduction

HeadacheCACNA1A gene♦

Now known a FHM‐I, this mutation is responsible for about 50% of identified families

History

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Migraine

Genetics

Anatomy

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♦Neuron 2000; 25(3):533-535Nomenclature of voltage-gated calcium channelsErtel EA, Campbell II KP, Harpold MM, et al.Department of Physiology and Biophysics, University of Washington, Seattle

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Mutations in the ATP1A2 gene have been identified to be responsible for about 20% of FHM families (FHM‐II) comprising

Introduction

Headacheepilepsy in terms of clinical presentation♦

History

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Migraine

Genetics

Anatomy

WE CARE

♦Nat Genet 2003;33(2):192-196.Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha 2 subunit associated with familial hemiplegic migraine type 2De Fusco M, Marconi R, Silvestri L, et al.Human Molecular Genetics Unit, Dibit-San Raffaele, Milan, Italy

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Most recently, mutations in the voltage‐gated sodium channel gene SCNA1 have been identified as the cause for FHM‐III♦

Introduction

Headache

History

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Migraine

Genetics

Anatomy

WE CARE

♦Lancet 2005; 366(9483):371-377Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraineDichgans M, Freillinger T, Eckstein G, et al..Department of Neurology, Klinikum Grosshadern, Ludwig-Maximmilians Universitat, Munchen, Germany

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Taken together, the known mutations in familial hemiplegic migraine suggest that migraine, or at least the neurological manifestations currently called the

Introduction

Headachemanifestations currently called the aura, are caused by an ionopathy

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Migraine

Genetics

Anatomy

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Trigeminal innervations and Pain producing Intracranial structures

Human dural nerves that innervate the cranial vessels largely consist of

ll d l d d

Introduction

Headachesmall‐diameter myelinated and unmyelinated fibers that almost certainly subserve a nociceptive function

History

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Migraine

Genetics

Anatomy

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They arise from the ophthalmic division of the trigeminal ganglion and in the posterior fossa from the upper cervical dorsal roots

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Introduction

HeadacheNeurons in trigeminal ganglion contain substance P and calcitonin‐gene‐related peptide (CGRP), both of which can be released when the trigeminal ganglion is stimulated

History

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Migraine

Genetics

Anatomy

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Physiology

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Preclinical studies suggest that cortically spreading depression may be a sufficient stimulus to activate trigeminal neurons,

Introduction

Headachealthough this is still controversial area

History

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Migraine

Genetics

Anatomy

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Just as dihydroergotamine can block trigeminovascular nocicpetive transmission, probably at least by a local effect

Introduction

Headachein the trigeminocervical complex, dihydroergotamine can block central sensitization associated with dural stimulation by an inflammatory soup

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Migraine

Genetics

Anatomyy p

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Trigeminovascular System

PAIN

Cortex

PAIN

Meningeal blood vessels

5‐HT1B

receptor

Autonomic activation

PhonophobiaPhotophobia

Trigeminalganglion

Thalamus

5‐HT1D

receptor

Autonomic activation

Nausea, emesis

Trigeminalnucleus caudalis

Electrical stimulation of the trigeminal ganglion in both humans and cats leads to increases in extracerebral blood flow and local release of both

Introduction

Headacheflow and local release of both CGRP and substance PCGRP is elevated in headache in humansAlso, nitric‐oxide‐donor‐triggered migraine also results in increase

History

Aim

Migraine

Genetics

Anatomymigraine, also results in increase of CGRPThat fact is very important from the therapeutical point of view

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Data sugest convergence of cervical and ophthalmic inputs at the level of the second‐order neuron (Thalamus)Human imaging studies have

Introduction

HeadacheHuman imaging studies have confirmed activation of thalamus contralateral to pain In migrenous attackThe role of posterior Hypothalamus? Can be both

History

Aim

Migraine

Genetics

AnatomyHypothalamus? Can be both pronociceptive and antinociceptiveNew therapeutic possibilities?

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Physiology

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Functional brain imaging (PET) has demonstrated activation of dorsal midbrain as well as periaqueductal gray and in the

Introduction

Headachedorsal pons, near the locus coeruleus in studies during migraine with aura

History

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Migraine

Genetics

Anatomy

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Dysfunction of brainstem pain and vascular control centers

Brainstem activation during a

Higher CNS Centers

PhotophobiaPhonophobiaThalamus

spontaneous migraine attackPain

Weiller, C. et al, Brain stem activation in spontaneoushuman migraine attacks, Nature Medicine 1(7):658‐660, July 1995

Dysfunction of brainstem pain and vascular control centers

Brainstem activation during a

Higher CNS Centers

PhotophobiaPhonophobiaThalamus

spontaneous migraine attackPain

dorsal pons

posteriorcingulate

Afridi SK.et al, A Positron Emission Tomographic Study in Spontaneous Migraine, Arch Neurol 62:1270‐75, Aug 2005

dorsal pons

temporal lobe

cerebellum

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Two different concepts:• vascular concept

• neuro‐vascular concept

Different forms of MigrainesIntroduction

Headache

• Migraine with aura

• Migraine without aura

History

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Migraine

Genetics

Anatomy

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Vascular concept

Specific cause unknown

Key factors in migraine headache pain

Introduction

Headache

• Initial intracranial vascular constriction‐ reduced blood flow triggers aura

‐ intracranial extracerebral blood vessels dilatate

History

Aim

Migraine

Genetics

Anatomy‐ activates perivascular trigeminal

sensory nerves

‐ initiates “pain” transmission to the brain

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Vascular concept

Specific cause unknown

Key factors in migraine headache pain

Introduction

Headache

• Activated nerves release neuropeptides‐ exacerbates vessel swelling ‐

vicious cycle

‐ increases pain transmission

History

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Migraine

Genetics

Anatomy

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Physiology

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Vascular concept

Specific cause unknown

Key factors in migraine headache pain

Introduction

Headache

• Central pain transmission activates other CNS pathways‐ nausea, phonophobia, photophobia

History

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Migraine

Genetics

Anatomy

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Physiology

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Neuro‐vascular concept

Specific cause may be related to hypersensitivity of occipital, hypothalamic and limbic cortex

Introduction

Headache

History

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Migraine

Genetics

Anatomy

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Physiology

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Key factors in migraine headache pain• Activation of sensory neurons,

located in the trigeminal system d l f h l

Introduction

Headache‐ causing dilatation of the meningeal

blood vessels

‐ local release of neuropeptides –Substance P, nitric oxide, 5‐HT, Neurokinin A and CGRP

‐ plasma protein extravasation

History

Aim

Migraine

Genetics

Anatomyplasma protein extravasation

‐ initiation neurogenic inflammation

‐ Initiates “pain” transmission to the brain

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Key factors in migraine headache pain• Neurogenic inflammation in the

meninges causes reactive impulsesIntroduction

Headache• Central pain transmission activates

other CNS pathways‐ nausea, phonophobia, photophobia

History

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Migraine

Genetics

Anatomy

WE CARE

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Physiology

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Summary

THE ROLE OF 5HT

5HT1B

receptor

5HT1B

receptor

5HT1D

receptor

5HT1D

receptor

CGRP releaseCGRP release

Vasodilation, inflammationVasodilation, inflammation

Dilation

Pain

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1. Cortical spreading

Depression (Aura)

Vasokonstriction2. Vasodilation

MIGRAINE WITH AURA

VasokonstrictionNeurogenic inflammation

Pain

3. Activation of

brainstem centres

2. Vasodilation

MIGRAINE WITHOUT AURA

Neurogenic inflammation

Pain

1. Activation of

brainstem centres

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But…

...the fundamental problem in migraine is in the brain

MIGRAINE: INTEGRATED HYPOTHESIS

Vasodilation

Intracranial blood vessels

PAIN Nitric oxide

Neuropeptides

Trigeminalganglion

Thalamus

Cortex SerotonergicParasympathetic

Mi i t iSensory nerve activation

Pain transmission

Ferrari MD, The Lancet 1998;351:1043‐51

Migraine triggers

Generator ?

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Migraine is a primary episodic headache disorder characterised by various combinations of :• neurological

Introduction

Headache• gastrointestinal

• autonomic changesHistory

Aim

Migraine

Genetics

Anatomy

WE CARE

♦Lancet 2004; 363:381-391MigraineSilberstein SD.Jefferson Headache Centre, Philadelphia, PA, USA

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Migraine is best understood as a primary disorder of the brain♦

• genetic predisposition

• cortical, occipital, hypothalamic hypersensitivity

Introduction

Headachehypersensitivity

• temporarely disturbance of pain inhibiting systems of the brain stem (periaqueductal gray)

• release of vasoactive neuropeptides inducing neurogenic inflammation

History

Aim

Migraine

Genetics

Anatomy• central sensitation of the trigeminal

system

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Pathogenesis

Summary♦N Engl J Med 2002; 346(4):257-270.Migraine—current understanding and treatmentGoadsby PJ, Lipton RB, Ferrari MD.Insttitute of Neurology, National Hospital for Neurology and Neurosurgery, London, UK

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The best treatment for any disease comes from understanding its pathophysiology♦

• focused treatment of acute attacsIntroduction

Headache

• prophylaxis History

Aim

Migraine

Genetics

Anatomy

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♦Ther Clin Risk Manag 2007; 3(3):449-459.Acute migraine: Current treatment and emerging therapiesKalra AA, Elliot DDepartment of Neurology, LSU Health Sciences Center Shreveport, LA; USA

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THANK YOUTHANK YOU

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Nadežda Čovičković‐ŠternićNeurology Clinic, Clinical Center of Serbia Dr Subotica 6, 11000 Belgrade, SerbiaPhone:+381 11 3064 200Fax:+381 11 2684 577E mail: macasternic@yahoo.com

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