Migraine

By : Dr. Adel Misk

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 Contents

Introduction to Migraine

Epidemiology

Pathophysiology of Migraine

Stages of Migraine

Diagnosis

Differential diagnosis of migraine

Treatment & the role of Erenumab

Conclusions
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 Introduction

o Migraine is characterized by moderate to severe

throbbing and pulsating pain, often with increased
sensitivity to light and sound, usually confined to one
side of the head.

o Aura is the complex of neurological symptoms that

occurs just before or at the onset of migraine
headache.

o The IHS has classified two major subtypes4

o Migraine without aura ~70% of attacks
o Migraine with aura ~30% of attacks

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June 2016 1. Stovner et al. Cephalgia 2007, 27 193-210; 2. Headache Classification Subcommittee of the International Headache Society.
Cephalalgia 2013;33:629–808; 3. Katsarava Z, et al. Cephalalgia 2011;31:520–529; 4. Lipton RB, et al. Neurology 2002;58:885–894
 Migraine may occur with or without aura (International
Headache Society Diagnostic Criteria ICHD-3b)
 Migraine is a debilitating condition characterized by recurrent head pain
accompanied by various focal disturbances of the nervous system
Migraine without aura ( ̴ 70% of
attacks1) at least five attacks fulfilling Migraine with aura ( ̴ 30% of
following criteria2: attacks1) at least two attacks2:

Headache attacks lasting 4-72 hours

(untreated or unsuccessfully treated) ... Meeting criteria listed for
migraine without aura
Unilateral location
Aura symptoms include:
Throbbing/pulsating sensititivity to light, smells,
Any two sound, nausea/vomiting
characteristics
Worsened by movement Aura is a complex of neurological symptoms
that occur before or at the onset of
migraine headache but it may occur after the
pain phase has initiated or continue into the
Moderate or severe intensity
headache phase2

•Blind spots
Nausea/vomiting
•Colored spots
Any one
•Flashes of light
symptom
Phonophobia/photophobia •Sparkles and stars

•Tunnel vision

•Zigzags

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1. Lipton et al. 2002;58:885–894; 2. The International Classification of Headache Disorders, 3rd edition (beta version) Cephalalgia
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June 2016 2013;33(9):629–808
 Prevalence of migraine is highest in Europe and North
America
 The global prevalence in the last year for headache was reported 47% and for
migraine 10%1
 Life-time prevalence, as expected, is higher: 66% for headache, 14% for
migraine1
 Migraine is most prevalent in Europe, and least prevalent in Africa 1

According to World
Health Organization’s
North
ranking of causes of America
Europe 15%
disability, headache 13%
Asia 9%
disorders are1:
Africa 5%
 One of the 10 most
disabling conditions Central/South
for either gender America 9%
 One of the 5 most
disabling for
women

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GLNS/AMG/0013 1. Stovner LJ, et al. Cephalalgia 2007;27:193–210
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 Migraine is most prevalent among adults

Prevalence of different headaches in different age

 Migraine and categories1
tension-type
Children/adolescents Adults Elderly All ages
headache is most
prevalent among 60
adults1
50

 Chronic daily

% of population
40
headache is less
prevalent among 30
children and
adolescents1 20

10

0
Headache Migraine TTH CDH

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 Migraine overview
Pathophysiology

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 The brain lacks sensory receptors

 The brain lacks sensory receptors 1  Activation of meningeal receptors is

 However, pain receptors
(nociceptors) are present in the dura
and pia of the meninges2
thought to underlie the distinctive
throbbing pain of migraine1
 These receptors originate in the
trigeminal ganglion2

Skull bone
Cerebrum Subarachnoid
Skull bone
Space (contains Dura mater
cerebrospinal fluid)
Arachnoid Cranial
mater meninges

Pia mater

Blood vessel
Cerebrum

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 Meningeal nociceptors signal pain
though the trigeminovascular system (TGVS)

 The trigeminal is the fifth cranial

nerve, which innervates the head1 Activation of the TGVS
leads to the pain of migraine3
 Neurons in the trigeminal ganglion
receive afferent signals from
nociceptors in the meninges and
cerebral blood vessels, as well as
other areas of the head
 Ascending axonal projections
transmit these signals to secondary
neurons in the spinal trigeminal
nucleus
 From the trigeminal nucleus, tertiary
connections are made to the
thalamus, hypothalamus, and cortex2
 These connections are thought to
underlie the characteristic features of
migraine pain2 Figure with permission from Russo AF2

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 Peripheral events are thought to play a key role in migraine

 Migraine pain involves peripheral

events outside the blood–brain barrier 1 Neurogenic inflammation
 Neurogenic inflammation is a ‘sterile’ in the dura
inflammation of meningeal vessels MC
HA
triggered by sensory nerve activation2
 Activation of meningeal nociceptors
leads to release of vasoactive,
proinflammatory peptides such as
substance P and CGRP3 CGRP

CGRP is a neuropeptide messenger

molecule associated with migraine AV

 CGRP-induced MC degranulation is CGRP

thought to maintain inflammation by
activating and sensitizing meningeal
nociceptors2
 Promotion of neurogenic inflammation
in meningeal vessels is a key
mechanism contributing to CGRP’s
effects in migraine2
CGRP released from primary afferents
causes mast cell degranulation leading to
release of a cocktail of proinflammatory
molecules, including HA, which can
activate primary afferents4
Figure adapted with permission from Messlinger K, et al.4

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 Migraine overview
Stages of Migraine

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 Migraine may develop in stages, evolving over hours
and lasting sometimes days

Proportion of migraine patients experiencing each stage (%)

~30%–40% ~30% 100% ~70%

Associated
Features

Prodrome Aura Headache Postdrome

(Pre-Headache) (Post-Headache)

Few hours Few hours to

>1 hour 1–72 hours
to few days few days

Time
Figure based on information from American Headache Society 2015, Burstein et al. 2015, Ng-Mak et al. 2011, Charles et al. 2015.

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 The prodromal phase is an early warning sign of
migraine
 Denoted as preheadache or premonitory phase1

 Experienced hours or even days before a migraine attack1,2

 Nearly 30%–40% of migraineurs experience prodrome1

 These symptoms before the headache can assist with migraine diagnosis1

Potential symptoms of prodrome include¹,²

Concentration problems Depression Aphasia Diarrhea
Fatigue Food cravings Hyperactivity Hyperactivity
Increased thirst Increased urination Nausea Phonophobia
Photophobia Repetitive yawning Sleep issues Stiff neck
Irritability Euphoria Constipation

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 Migraine may occur with or without aura (International
Headache Society Diagnostic Criteria ICHD-3b)
 Migraine is a debilitating condition characterized by recurrent head pain
accompanied by various focal disturbances of the nervous system
Migraine without aura ( ̴ 70% of
attacks1) at least five attacks fulfilling Migraine with aura ( ̴ 30% of
following criteria2: attacks1) at least two attacks2:

Headache attacks lasting 4-72 hours

(untreated or unsuccessfully treated) ... Meeting criteria listed for
migraine without aura
Unilateral location
Aura symptoms include: visual
Throbbing/pulsating disturbances, sensory
Any two disturbances, and speech
characteristics disturbances
Worsened by movement

Aura is a complex of neurological

Moderate or severe intensity
symptoms that occur before or at the
onset of migraine headache but it may
Nausea/vomiting occur after the pain phase has
Any one initiated or continue into the headache
symptom phase2
Phonophobia/photophobia

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 The aura phase precedes a migraine attack in some
patients1
Diagnostic Criteria1 Aura symptoms (visual)2,3
A. At least two attacks fulfilling criteria B • Partial loss of sight
and C • Blurred vision
B. One or more of the following fully • Flashing lights
reversible aura symptoms: • Wavy lines, spots
• Visual, sensory, speech and/or • Monocular blindness
language, motor, brainstem, retinal
C. At least two of the following four Aura symptoms (other)2,3
characteristics: • Allodynia
• At least one aura symptom spreads • Hemiplegia or motor weakness
gradually over ≥5 minutes, and/or
two or more symptoms occur in • Auditory hallucinations, olfactory hallucinations
succession • Paresthesia
• Each individual aura symptom lasts • Dizziness
5-60 minutes • Partial paralysis (in hemiplegic migraine)
• At least one aura symptom is • Reduced sensation
unilateral
• Decrease or loss in hearing
• The aura is accompanied, or
followed within 60 minutes, by • Neck stiffness/pain
headache • Confusion

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 Migraine overview
Symptoms of Migraine

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 Symptoms of the headache phase of migraine

 During the most debilitating phase of migraine attack, pain ranges from mild
to severe1
 Migraine can affect the entire body
Unilateral pain (may become bilateral)

Migraine pain may occur in eyes, sinuses, jaw

Pain lasts from 1 hour to 72 hours

Pain worsened by physical activity

Characteristics of the
headache phase1

Increased sensitivity to sound (phonophobia)

Increased sensitivity to light (photophobia)

Increased sensitivity to odors (osmophobia)

Depression or severe anxiety

Nausea and vomiting

Hot flashes and chills

Dizziness and vertigo

Dehydration or fluid retention

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 The postdrome phase follows headache in a migraine
attack
 Sometimes denoted as postheadache, it immediately follows the headache
phase in a migraine attack1
• Commonly recognized by migraine patients as a period of ‘headache
hangover,’ ‘lingering effect,’ or feeling ‘wiped out’ 1
• The probable cause of postdrome phase is abnormal cerebral blood flow for
up to 24 hours after the end of the headache stage 2
• Postdrome may be observed in migraine cases even when headache is
absent2

Potential symptoms of postdrome include¹,²

• Altered mood, particularly depression
• Nausea, dizziness
• Fatigue, tiredness, weakness
• Poor concentration and comprehension

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 Migraine overview
Diagnosis

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 Dignosis of migraine

At least five attacks fulfilling

following criteria)1,2

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 Migraine overview
Differential diagnosis of migraine

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 Differential diagnosis of migraine

 There is no actual test to definitively diagnose migraine, as no biomarker is

currently available1

 Diagnosis is based on medical history and ruling out other causes for the
attacks1

 A thorough examination is carried out, including a complete neurological

assessment2

 CT or MRI scans may be performed to rule out other causes of headache

but they cannot be used to diagnose migraine

 Diagnosis of migraine with or without aura is conducted per the ICHD

criteria1,2

 Headache in migraine with aura starts during the aura or within 60 minutes
following onset of aura2

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 Differential diagnosis of migraine

Characteristic Migraine Tension Cluster

Moderate or severe Mild or moderate intensity, Severe or very

Pain type
intensity, throbbing1 pressing or tightening1 severe intensity1

Unilateral, typically
Headache Often unilateral,
Bilateral 1
around or behind one
location can be bilateral1
eye1

Headache
4-72 hours1 30 min to 1 week1 15-180 min1
duration

Headache Recurrent with variable One or more daily

Infrequent to daily1
frequency frequency1 during clusters1

Nausea, vomiting, sound

Other possible Pericranial tenderness, Nasal congestion, facial
symptoms or light sensitivity, pain sound or light sensitivity1 sweating, eyelid edema1
aggravated by activity1

Affects women 2-3 times Higher prevalence in Affects men 3 times more
Demographics
more often than men2 women than in men3 often than women1
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 Migraine overview
Treatment

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 Pharmacological treatment of migraine
Acute and prophylactic therapies

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 The Goals of Migraine Therapy

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 Migraine treatment guidelines

 Initial treatment is analgesics or Triptanes; if unsuccessful, addition of

prophylaxis is considered

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 Migraine overview
the role of Erenumab

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 Erenumab

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 Erenumab

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 Erenumab

• Therapeutic monoclonal antibodies are large polypeptides and those approved to

date are all of the IgG class; they bind to specific ligands or receptors to modulate
their function
• AMG 334 is a potent and selective CGRP receptor antagonist
• AMG 334 is a fully human antibody, which may result in lower immunogenicity than
do chimeric or humanised antibodies
• AMG 334 has a long serum half-life 21 days that facilitates convenient monthly
dosing
• AMG 334 appears to completely block the CGRP receptor in vivo
• Clinical efficacy appears to be mediated via peripheral sites of action (no need to
cross the BBB)
• Erenumab is not degraded by the liver or kidneys and is not expected to cause liver
or renal toxicity like with small-molecule CGRP receptor antagonists1
• Erenumab is not centrally penetrating (i.e. does not cross the blood–brain barrier)
and is therefore not expected to have CNS-related AEs such as somnolence and
cognitive dysfunction

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 Conclusions

 Migraine is a common disabling primary headache disorder

• Globally, the prevalence of current headache disorder is 47% and

current migraine is 10%1

 Based on frequency of attacks, migraine is classified as episodic (1–14

headache days/month) and chronic (≥15 headache days/month) for more
than 3 months, with features of migraine headache on at least 8
days/month2,3

 Migraine may be associated with variety of comorbidities, including

depression, anxiety, stroke, and cardiovascular disorders4

 Acute/prophylactic treatment mainly focuses on controlling the pain and

symptoms of acute attack; however, there is significant need for efficacious
and tolerable prophylactic migraine treatments5,6

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 Thank
you

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