Headache Group, UCSF

Migraine Disclosure- by proportion*

2014
• Sandler Family Trust
Recent Advances in Neurology • Department of Defence
University of California, San Francisco
• Governments: California, China, Germany, Australia,
12th February 2012 Portugal, NINDS
Professor Peter J. Goadsby • Industry: Amgen/Allergan/eNeura
• Consulting: Allergan, Ajinomoto, Alder, Amgen, Arteaus, Avanir, Colucid, Gore,
eNeura, Ethicon, Heptares, Nupathe, Pfizer, DrReddy and Zosano
• Reviewing: Belgian Research Council, European Space Agency, Italian Telethon,
Medical Research Council UK, Migraine Research Foundation, Migraine Trust,
Netherlands Research Council, National Health and Medical Research Council,
Australia, Organisation for Understanding Cluster Headache- UK.

*Font scale for direct contributions in proportion to contribution Q1-13 to Q4-13

Department of Neurology
(Font ~ {Contribution/Total Group Income} * 100)

International Classification of Headache

Disorders-IIIβ Cases
I- Primary European
II Secondary
1. Migraine
2. Tension-type headache – infection
3. Trigeminal autonomic cephalalgias – hemorrhage
3.1 Cluster headache
3.2 Paroxsymal hemicrania – trauma
3.3 SUNCT/SUNA – tumour
3.4 Hemicrania continua
4. Other Primary Headaches – CSF pressure change
4.1 Cough headache
4.2 Exercise Headache III Cranial neuralgias/facial pain
4.3 Sexual activity headache
- trigeminal neuralgia
4.4 Thunderclap headache
4.5 Cold stimulus: external/ingestion - glossopharngeal neuralgia
4.6 External pressure: compression/traction - occipital neuralgia
4.7 Stabbing Headache
4.8 Nummular headache
4.9 Hypnic headache
4.10 New Daily Persistent Headache
Cephalalgia 2013;33:629

1
 Cases Nummular Headache
European
4.8 Pain in a small area without a lesion
A. Continuous pain fulfilling B-C
B. Felt in a round or elliptical shape 1-6 cm in
diameter
C. Lasting hours or days
D. Not better accounted for by another ICHD-III
diagnosis
United States
• Case series (Grosberg et al., 2009)
- Nine patients
- PHx- Migraine (6)
- Three had moderate to severe pain
- Five continuous, three episodic, one evolved
- Rx- amitriptyline

Migraine - Update Migraine

The Attacks & the Disorder
• Clinical Aspects Attacks Disorder
• Repeated attacks
• Premonitory symptoms
• Disorder mechanisms • Pain
– < 15 days/month: Episodic
– ≥ 15 days/month: Chronic
– unilateral
• Family history
• Treatment – throbbing
• Triggers (biology)
– movement worse
– Sleep: missing/excess
• Nausea
– Food: skipping meals
• Sensory sensitivity
– Chemical: alcohol or nitroglycerin
– photophobia – Weather
– phonophobia – Sensory: light, smells
– osmophobia – Hormonal
• Aura – Stress- relaxation

“The simple headaches have the same characters, and occur under the same causal
conditions of heredity &c, as those in which there are additional other sensory symptoms”
Gowers 1893

2
 Chronic Migraine Chronic Migraine
ICHD-I ICHD-II

A. Headache frequency ≥15 days for

≥ 3 months
B. Attacks fulfill criteria for migraine
without aura
C. Not attributed to another disorder

Cephalalgia
1988;8 (suppl 7):1-96 Cephalalgia 2004;24 (suppl 1):1-160

Chronic Migraine Chronic Migraine

ICHD-II-R ICHD-IIIβ
A. Headache frequency ≥15 days for ≥3 months
A. Headache frequency ≥15 days for ≥3 months
B. Patient with at ≥5 attacks of migraine with aura
B. Patient with at ≥5 attacks of migraine without
(MwA) or without aura (MwoA) in the past
aura (MWoA) in the past
C. On ≥8 days per month for three months one of:
C. On ≥8 days per month for three months has
1. MwoA: C. pain characteristics AND D. nausea/sensitivity
1. typical MWoA
2. MwA: typical aura (B & C)
2. attacks treated and relieved by triptans/ergots
3. Attacks considered migraine by patient and relieved by
D. Not attributed to another disorder, particularly triptans/ergots
no medication overuse D. Not better accounted for by another ICHD-III
diagnosis
(Olesen et al., Cephalalgia 2006;26:742) ICHD-IIIβ Cephalalgia 2013;33:629-808

3
 Botulinum Toxin A (Botox-A) in the preventive Botulinum Toxin A (Botox-A) in the preventive
management of chronic migraine… in context management of chronic migraine
50% & 75% responder rates
• 18-65 yrs, baseline one month/ 50% days migraine/probable migraine
• Primary endpoint: headache episodes baseline vs last four weeks (20-24)
• Result: I- NS, II- significant; I/II Headache days/migraine days- significant

Baseline, n = 12.7 11.5 19 19 17 17

0
Reduction in migraine/probable migraine days

% patients
n = 338 341 358 347 153 153
-2 *
-4
*
-4.7 +
-6
-6.1 -6.3
* -6.4
n = 696 688 358 347 153 153
-8 -7.6 **
-8.7 Placebo Botox-A Topiramate
-10
Aurora et al Diener et al Silberstein et al. Headache 2010;50:921 Cephalalgia 2011;31:87 Headache 2006;46:838
Cephalalgia 2010;40:793 2010;40:804 Headache 2007;47:170 50% 75%
Headache episode- Four hours headache bounded by no pain; * P = 0.002; ** P = 0.001; +P = 0.01 (*P < 0.05)

Levetiracetam in Chronic Daily Headache Lacosamide is ineffective in Episodic Migraine

Prevention
• Double-blind randomised placebo-controlled crossover trial • Double-blind randomized placebo-controlled, parallel group
• CDH: migraine (74%) and tension-type headache (37%) • Migraine: 2-8 attacks/month AND ≤ 15 days headache/month
• Issues: drop-out and ordering effects • Stable acute treatment
50 • Primary endpoint- reduction in migraine rates in days
Placebo Levetiracetam 3g Placebo: -1.4, Lacosamide 100mg: -1.4, 300mg: -1.6
40
(% patients)

% patients
30

19
•Adverse event:
20 18
15.5 - fatigue

10 8

N= 83 82 n= 71 70 74
0
Headache free rate Loss of CDH criteria

Beran & Spira Cephalalgia 2011;41:530 (NCT00440518)

4
 Case 1 Landmark Study
Migraine in Primary Care Offices

• Prospective, open-label study

• Patients tracked for three months or six attacks
• Assigned ICHD diagnoses by experts

100
Migraine Migrainous
80 76

% Patients
60

40
18
20

(Tepper et al., Headache 2004;44:856-864)

Tension-Type Headache Relationship of

(appendix) Migraine and Tension-type headache
Attacks
• Episodic • Chronic
• throbbing • Non-throbbing
– lasts 30 mins to 7 days – ≥15 days/month • movement worse • no effect of movement
– Two of – Two of • associations • associations
• pressing/tight pain • pressing/tight pain – nausea – No nausea
• mild/moderate severity • mild/moderate severity – photophobia – No photophobia
– phonophobia – No phonophobia
• bilateral • bilateral
• Aura • ? aura
• no aggravation by • no aggravation by
activity activity Patient
• Family history
– Both of – Both of • Triggers
• No nausea • No vomiting – Sleep: missing/excess
• Photophobia or • Only one of mild – Eating: including alcohol
phonophobia, not both nausea, photophobia or – Weather
phonophobia – Hormonal
ICHD-III-beta Cephalalgia 2013;33:629 – Stress- relaxation

5
 Infantile Colic Migraine - Update

A1.6.1.3 Infantile Colic • Clinical Aspects

Description: Recurrent infantile attacks of irritability that are not predictable
in duration or time occurring between birth and 4 months consistent with
Wessel’s criteria.
• Disease mechanisms
Diagnostic Criteria:

Premonitory symptoms
A. Recurrent episodes of irritability, fussing or crying from birth to 4 months
of age fulfilling criteria B and C
• Treatment
B. Episodes lasting 3 or more hours per day
C. Episodes occurring at least 3 days per week for at least 3 week.
D. Not better accounted for by another ICHD-III diagnosis

Gelfand et al., Neurology 2012;79:1392

Dose-dependent dopaminergic modulation of

Migraine: The Premonitory Phase trigeminocervical complex neurons
100 Giffin et al. MMA: middle meningeal artery Bergerot et al. Ann Neurol 2007;61:251
100 Neurology 2003;60:935
premonitory
80
80 headache
VAS rating of state of health

postdrome
60 60
premonitory

40
40

20
20

headache
0
0
-100 -50 0 50 100 *
wn

t
r ia

er
ck

l
s

irs

na
es

ng
ne

Time (hours)
yu
ya

th

io
n

hu

ot
l
ed

iff

po

em
st
tir

• Double-blind placebo controlled crossover

• Four period (n = 19 subjects; n = 76 attacks)
* Premonitory- somnolence- Gowers, 1883
• Symptoms reported 7-48 hrs prior to attack
% attacks aborted

• Migraine with aura

120

100
Firing (% baseline)

80

60
30 mg
40

20 saline
dopamine 20µ g/kg
0
baseline 5 10 15 20 25 30
Waelkens BMJ 1982;289:944 Time (min)

6
 Charbit et al.
A11 Modulation of J Neurosci 2009 Premonitory Phase of Migraine
Trigeminocervical Neurons H215O PET
• Patients with premonitory symptoms, such as yawning and thirst, and no
Stimulation Lesion headache
20
20 20
20 • First premonitory scan vs baseline
MMA MMA + A11 MMA MMA + A11
15 15 15 15
Hypothalamus PAG Dorsal pons

Total cells fired

Total cells fired

Total cells fired

Total cells fired

10 10
10 10

5 5
5 5

0 0
0.00 0.02 0.04 0.06 0.08 0.10 0.00 0.02 0.04 0.06 0.08 0.10
0 0
Time (sec) 0.00 0.02 0.04 0.06 0.08 0.10 0.00 0.02 0.04 0.06 0.08 0.10 Time (sec)
Time (sec) Time (sec)

MMA
160 M MA
Noxious pinch
n ox io u s p in ch
120 Innocuous brush * in n o cu o u s b ru s h
140
*
Baseline
100 response
Percentage of baseline firing

Percentage of baseline firing

120
*
Baseline response
B aseline
80 *
response
100
*
*
*
* 80
60

60

Lesion A11 (n = 8)

Lesion A11 (n = 8)
Lesion A11 (n = 8)
40

Sham (n = 5)
40

Sham (n = 5)
Sham (n = 5)
20
n = 13

n = 12
n = 14

20
n=5

n=5

n=5

n=5

n=6
n=5

n=5

n=6

n=6

0 0
A11 A11 5-40 mins 5-40 mins
post i.v. post iv 5 -40 m in s
D2 antagonist D2 antagonist p o st le sio n A 1 1
o r co n tro l
Maniyar et al., Brain 2014;137:232

Migraine - Update Trigeminovascular System & Migraine

• Clinical Aspects
• Disease mechanisms
– Premonitory symptoms
• Treatment

(Goadsby et al., NEJM 2002; 346:257-270)

7
 Transdermal sumatriptan for migraine Needle-free sumatriptan injection

• Randomised double-blind placebo controlled study • Needle-free injection: powered by N2

• Subjects: migraine with & without aura • Bioequivalent: when injected onto abdomen/thigh not arm
• Primary endpoint: 2 hr pain free • Delivers: sumatriptan 6mg s/c not IMI

Abdomen

90

Plasma sumatriptan (ng/mL)

80
70
60
50
40
% Patients

30
20
Skin 10
0

* Muscle 0 1 2 3 4 5
Time (hours)
6 7 8 9 10

Arm
80
70

Injectate 80 60

Plasma sumatriptan (ng/mL)

50
70
40
60 30

n= 228 226 50
40
20
10
0
30 0 10 20 30 40 50 60
20 Tim e (m in)

10
0
0 1 2 3 4 5 6 7 8 9 10

(Goldstein et al., Headache 2012;52:1402) (Brandes et al., Headache 2009;49:1435) Time (hours)

Ergot Alkaloid (tetracylic ergolene) Dihydroergotamine by inhalation (MAP0004) in

Family Tree the treatment of acute migraine
• Randomised double-blind placebo controlled study
Ergotamine CH3 • Primary endpoint: 2 hr pain relief
Dihydroergotamine

NMe2
H H 100
MeNHSO2 Sumatriptan
N
H
80 placebo DHE- 0.5mg (actual)

% Patients
triptans non-triptans
*
58.7
60 *
43.7
zolmitriptan eletriptan
anti-PPE 5HT1F agonists 5HT1D agonists 40 34.5 *
28.4 * 31.2
compounds
19.6
23.1 * 25.2
rizatriptan almotriptan 17.7
20 10.1
CP122,288 4991w93 LY334370 PNU142633 6.7 5.9
n = 397 395 401 404
naratriptan frovatriptan 0
COL-144
Pain Sustained Pain free 2h Sustained Sustained Any AE
donitriptan response- 2 response 2- pain free 2- pain free 2-
O
h 24h 24h 48h
NH NH
O
AE Placebo DHE

Nausea 2.0 4.5

(Silberstein et al., Headache 2011;51:507) Cough 1.2 2.5
(4991W93) NMe2
Taste 1.7 6.4

8
 Ergot Alkaloid (tetracylic ergolene)
DHE Receptor Binding and Headache Recurrence Family Tree

• Kon/off determined with in vitro binding methods CH3

Ergotamine
• Dissociation t1/2 calculated (/hr)
Dihydroergotamine

5HT1B DHE Sumatriptan MeNHSO2

NMe2 H H
Sumatriptan
N
H

triptans non-triptans

zolmitriptan eletriptan
1.38 0.17 anti-PPE 5HT1F agonists 5HT1D agonists
compounds
rizatriptan almotriptan
5HT1D CP122,288 4991w93 LY334370 PNU142633
naratriptan frovatriptan
COL-144
donitriptan
O

NH NH

1.28 0.09 O

(4991W93) NMe2
Kori et al., Headache 2012;52:874

Bouchelet et al., Br J
Pharmacol 2000;129:501
Lasmiditan, 5-HT1F receptor Trigeminovascular System & Migraine
agonist, in acute migraine
5-HT1D CGRP
• Double-blind parallel group randomised
• Placebo-controlled trial
• Migraine with/without aura; no preventives

Hou et al., Brain Res 2001;909:112-120

(% patients)

Adverse events:
• Dizziness
• Fatigue
• Vertigo
• Somnolence
N= 81 79 81 69 68

Farkkila et al., Lancet Neurol 2012;11:405 (Goadsby et al., NEJM 2002; 346:257-270)

9
 Dural Plasma Protein Extravasation

Trigeminal Activation Substance P, PPE & CGRP

& CGRP antagonists in Migraine
• Double-blind randomized parallel group
Buzzi et al., Brain Res 1999;583:137 single attack adult migraineurs
50 Substance P Plasma Protein CGRP
Extravasation Blocker 44

40
(pmol/l)

Placebo Active

%patients
30

20 16 16
12
10
10
2
Cat Human Cat Human n= 32 31 42 32
0
Ann Neurol Neuropeptides Ann Neurol GR205171 CP122,288 Olcegepant 2.5mg
1988;23:193 1990;16:69 1990;28;183 Connor et al., Roon et al., Olesen et al.,
Cephalalgia 1998;18:392 Ann Neurol 2000;47:238 NEJM 2004;350:1104

Oral CGRP receptor antagonists are effective in the Biologic Approaches to Migraine
treatment of acute migraine
• Amgen1
• Double-blind parallel group randomised controlled trials – Human monoclonal IgG1 (AM338) receptor
• Two hour pain free – CLR/RAMP1
– Binding potency pM Labeling of smooth muscle and endothelial cells
– Inhibited CGRP-stim cAMP IC50s 1-20nM
– Fifty fold selectivity over other receptors in the class
– Phase II- Episodic and Chronic Migraine
• Alder Biopharmaceuticals2
Z E S – ALD403: α and β CGRP antibody
(% patients)

– Phase II: Episodic migraine prevention

Arteaus Therapeutics3
– CGRP antibody- LY2951742
– …”positive phase II data…”
• Labrys4
– LBR-101 (RN-307 Rinat Pharmaceuticals/Pfizer)
– CGRP antibody
N = 348 333 354 70 73 69 203 85 100 – T1/2: 40 days
– Phase II: to begin in (?) chronic migraine
1. Liu et al., Shi et al., Headache 2011;51[Suppl 1]:6,59
Lancet Cephalalgia Cephalalgia 2. Smith IHC Boston 28th June 2013
2008;372:2115 2011;31:573 2014;34:114 3. De Hoon et al., Cephalalgia 2013;33[Suppl 8]:247
Telcagepant BI-44370 BMS-92771 4. Garzone et al., Cephalalgia 2013;33:966

10
 Case Primary Sex Headache
4.3 Primary headache associated with sexual activity
A. At least two episodes of pain in the head and/or neck fulfilling criteria B-D
B. Brought on by and occurring only during sexual activity
C. Either or both of the following:
1. increasing in intensity with increasing sexual excitement
2. abrupt explosive intensity just before or with orgasm
D. Lasting from 1 minute to 24 hours with severe intensity and/or up to 72
hours with mild intensity
E. Not better accounted for by another ICHD-3 diagnosis.

Transcranial magnetic stimulation Transcranial magnetic

for Migraine stimulation blocks CSD not
• Randomised double-blind placebo controlled study TCC in rat
• Include: 30% aura episodes, aura leads to headache 90% Andreou et al., JHP 2010;5:58
• Exclude: Prolonged aura, MOH
• TMS- 0.9T for 180 µs; Sham- click and vibrate
• Primary endpoint: 2 hr pain free plus non-inferiority for nausea/photo/phono
• Blinding: Thought they got active, 67% Sham and 72% active

50 Sham Active
*
39
40
% Patients

29
30
22
20 16

10
n= 82 82
0
pain free 2 hr Sustained pain free 2-24 hr
Holland et al.,
(Lipton et al., Lancet Neurol 2010;9:973) Cephalalgia 2009;29:22

11
sTMS significantly modulates cortico-thalamic Migraine
activation following CSD A brain systems disorder with many manifestations
CSD sensitizes the Episodic Migraine Chronic migraine
Arch Neurol 2005;62,1270 Brain 2004;127:220-230
sensory thalamus

CSD

• 5-HT1B/1D: triptans
• CGRP: gepants
• 5-HT1F: ditans
• Orexin 1 & 2: rexants
• mGluR5: glurants
• ASICs: mambalgins
• nNOS: NXN
• TRP: ?
Andreou et al., JHP 2013;1:I6 • Neuromodulation
(after Goadsby et al., NEJM 2002; 346:257-270)

Case Hypnic Headache

4.9 Attacks of headache that awaken the patient from sleep
A. Headache develops only during sleep, and awakens patient
and fulfills criteria B-E
B. ≥10 days per month for at least 3 months
C. Lasting ≥ 15 minutes and < 4 hours after waking
D. No cranial autonomic symptoms or restlessness
E. Not better accounted for by another ICHD-III Dx

Raskin Headache 1988;28:534

ICHD-III-beta

12
 Trigeminal Autonomic Oxygen for Acute Cluster Headache
Cephalalgias (TACs)*
• Randomised, double-blind, placebo controlled, four attack
study
• Two period each with paired air/oxygen
3.1 Cluster Headache • n = 76 patients, reporting n = 278 attacks
a. Episodic 100 Placebo Oxygen 100%

% Response at 15 Mins
b. Chronic **
78
3.2 Paroxysmal Hemicrania 80
a. Episodic 66
b. Chronic 60
3.3 SUNCT (Short-lasting Unilateral Neuralgiform
headache attacks with Conjunctival injection and 40 31
Tearing)/SUNA 20
3.4 Hemicrania continua 20
3.4 TAC- not otherwise classified
0
Pain free Associated symptom free
*Goadsby & Lipton Brain 1997;120:193
Cephalalgia 2004; 24[Suppl 1]: 1-160
ICHD-III-beta
Cohen et al., JAMA 2009;302:2451; ** P < 0.001

Oxygen inhibits trigeminal neurons activated by Superior Trigeminal Autonomic Cephalalgias

Salivatory Nucleus (SuS) stimulation trigeminal-autonomic activation facilitated by the brain
y = -12
O2 inhibits lacrimal sac blood flow O2 inhibits SuS V neurons Cluster headache Paroxysmal hemicrania SUNCT Hemicrania continua

dura mater
Pain

V ganglion SSN

trigeminal
pterygopalatine nucleus
ganglion
C1

Akerman et al., Brain 2012;135:3664

C2

13
 Hemicrania continua Hemicrania Continua
The Placebo-Controlled Indomethacin Test
A. Headache occurring > three months with B-E
B. Unilateral headache with moderate or greater severity 10

C. Headache is accompanied by either one of

1. One or more cranial autonomic features 8 Placebo
a. Conjunctival injection, or lacrimation, or both
Indomethacin 100 mg
b. Nasal congestion, or rhinorrhoea, or both

Verbal Rating Scale

c. Eyelid oedema
6
d. Forehead or facial sweating

(pain)
e. Forehead and facial flushing
f. Sense of aural fullness
4
g. Miosis, or ptosis, or both
2. Sense of restlessness, or aggravation of pain with
movement, or both 2
D. Headache is prevented completely by indomethacin
E. Not better accounted for by another ICHD-III diagnosis
0

6 8 10 12 14 16 18 20 22
Time
injection
(Cittadini et al., Brain 2010;173:1973 and ICHD-III-beta) (hrs)

Indomethacin-sensitive headache Does indometacin work through Nitric

ventrolateral midbrain activation in PET studies Oxide?
Hemicrania continua Effect of NSAIDs on neurogenic Indometacin blocks SNP
dural vasodilation meningeal dilation
Matharu et al.,
Headache 2004;44:747

Paroxysmal hemicrania y = -12 z = -12

Matharu et al.,
Ann Neurol 2006;59:535

Summ et al., J Head Face Pain 2010;11:477

14
 Botulinum toxin and Botulinum toxin and vasomotor
the Sphenopalatine Ganglion
rhinitis
• Dogs (n = 4): botulinum toxin type A soaked gauze applied to nasal cavity
• SPG stimulation for ten minutes (50 Hz)
• Collected nasal secretion • Patients with vasomotor rhinitis
• Reduced in three of four
• Random: Control (n=5), BTX-A 10U (n=15), 20U (n=10)
• BTX-A or control injected into inferior and middle
turbinates
• Results
– Total symptom score reduced for 20U vs control
– Total symptom score no effect for 10U vs control

Ozcan et al., Am J Otolaryngol 2006;27:314

Shaari et al., Otolaryngology Head & Neck Surgery 1995;112:556

Intravenous Dihydroergotamine (DHE) Occipital nerve stimulation in migraine & chronic

and Migraine migraine- PRISM
• Intravenous DHE is effective in acute migraine • Double-blind randomized parallel group sham stimulation controlled study
(Winner et al., Arch Neurol 1996;53:180)
• Migraine ≥6 days/month or chronic migraine (ICHD-II)
• Repetitive intravenous DHE- 1g 8hrly prn
• Failed two preventives/two attack treatments
– Medically refractory chronic migraine (n = 326-> 114)
– Follow-up: 11± 2 months migraine days migraine days- no MOH migraine days- +MOH
– Efficacy 0
n= 62 63
• Headache free in hospital: 69%; at one month: 83%
• Comparable effect: females, migraine type, age, triptan or opioid overuse
-2
• Predictors of good outcome days
– Increase dose from 7 to 11mg
-2.6
– Absence of nausea
– Adverse events
-4
-3.9
• Nausea
-4.8 -5
• Leg cramps -6 -5.5
• IV site pain/discomfort NS -5.9
• Limb pain Sham- 1us, 10Hz, <1mA, 1s on 90min off
• Diarrhea/abdominal cramps/constipation -8
Active- 250usec/60Hz, 0-12mA
• Chest pain (n = 5): normal ECG
(Nagy et al., Neurology 2011; 77:1827) •Adverse event:
(Lipton et al., Cephalalgia 2009;29:30) non-target sensory symptoms

15
 Occipital nerve stimulation in chronic migraine Occipital nerve stimulation in chronic migraine
ONSTIM St Jude
• Double-blind randomized parallel group sham stimulation controlled study • Double-blind randomized parallel group sham stimulation controlled study
• Note- occipital pain, fail 2 preventives, exclude MOH • Chronic migraine or probable chronic migraine
• Occipital pain, failed two preventives; Successful trial ≥50% reduction in pain or paresthesia
50 Pre-set Adjustable Medically managed • Results: Implanted (n = 177); Primary endpoint- Failed

39
40 NS *

30 27
%

%
20
9 *
10 6
4 **
n= 16 29 17 0 n= 52 105
0
reduction in headache days 50 % responder rate
*P = 0.02
* Adverse event: lead migration in 24 % * Adverse event: lead migration in 14%

(Saper et al., Cephalalgia 2011;31:271) *P = 0.032; **P = 0.003 (Silberstein et al., Cephalalgia 2012;32:1165)

Genetics of Migraine
Acute Medication Overuse Familial Hemiplegic Migraine- an ionopathy

FHM-II ATP1A2:
Definition FHM-I CACNA1A:
Na+/K+ ATPase chr 1q23
• Headache ≥15 days/month for > three months P/Q voltage-gated Ca2+ channel chr 19
• Overuse of Ophoff et al. Cell 1996; 87:543
• Triptan ≥ 10 days/month
• Opioid ≥ 10 days/month
• Paracetamol or NSAID ≥ 15 days/month

Is this a receptor agonist problem?
De Fusco et al. Nat Gen 2003;33:192
Consequences
• General Medical issues: CVS, GI, Psychiatric
• Rebound headache: headache returns when medicine effect dissipates FHM-III SCN1A:
• Inhibition of effect of preventives Voltage-gated Na+ channel chr 2

Management
• Withdraw offending substance
• Offer symptomatic support
• Consider infusion center or in-patient approaches
• Start a preventive when appropriate
Dichgans et al., Lancet 2005;366:371 van den Maagdenberg et al., Neuron 2004;41:701-710

16
 Migraine Genes Transient Receptor Potential Channels
• Two GWAS’s • TRPV (vanilloid)
• Migraine without aura
• Findings
- Cation channel
- Transient receptor potential cation channel subfamily - Low pH (protons or acid)
M member 8: TRPM8, aka cold and menthol receptor - Heat: >43oC
- Lipoprotein receptor related protein 1: LRP1,
glutamate signaling - Capsaicin, endocannabinoids
• TRPA (ankyrin repeats)
- Located in trigeminal ganglion
- Colocalized with CGRP Albrecht et al.,
EHMTIC 2012
- Mustard oil, wasabi, cinnamon
• TRPM (melastatin)
- Na+/Ca2+ channel
- Cold: < 20oC
Chasman et al., Nat Gen 2011;43:695
Freilinger et al., Nat Gen 2012;42:869 - Menthol

Migraine frequency and CVS risk in females Does Migraine “hurt” the brain?
CAMERA-I
• Meta-analysis
• Risk adjusted for BP, age, smoking, BMI, cholesterol, family history
• Highest risk for stroke: females, migraine with aura, <45, smoke & O/C
migraine with aura migraine without aura migraine Kruit et al., Brain 2005;128:2068
3 CAMERA-II EVA Study
• Population-based, 9 year follow-up • French population based vascular risk study
2.16 • Ctrl 83/140 and Migraine 203/295 • Patients born between 1922-32
Odds ratios

• Adjust: age, sex, BP, diabetes, education • Interviewed/diagnosis probable migraine or

2 1.73
non-migraine
• Results • Cohort n = 1170/migraine (166)/+aura (24)
1.23 1.12 - Supratentorial:
1.03
1 - increased deep white matter • Results
hyperintensities by 0.11 [0.01-0.26] ml -Battery of ten cognitive tests showed no
females with MwoA- new changes difference between migraine and non-
- Not related to BP or diabetes migraine;
0 - Infratentorial: no change in hyperintensities -Average scores decline
Stroke CVS disease MI - Progression unrelated to headache frequency -No effect of migraine status on rate of
- No effect of hyperintensities on cognition decline
-No effect of presence of brain changes on
(Schurks et al., BMJ 2009;339:b3419) MRI on decline
(Palm-Meinders et al., JAMA 2012;308:1889) (Kurth et al., BMJ 2010;341)

17
 Glurants, allosteric modulators of
Is glutamate involved in human aura?
mGluR5 receptors
• Randomized double-blind active control parallel group multiple attack crossover • ADX10059, randomised, double-blind placebo-controlled parallel group
• Migraine with prolonged aura (ICHD-I)/hemiplegic migraine
• Migraine with or without aura (n = 129)
• Ketamine/placebo versus Midazolam/placebo (intranasal) (2 x 3 attacks/arm)
• Primary endpoint: pain free at two hours (p = 0.039)
• Primary Endpoint: reduced length or severity of attack

5 Length Severity
4 50 50
3 3 midazolam ketamine
40 40
3
Change

24 hr SPF
2 hr pain free
30 30
2 1.5

1
20
* 20
n= 9 9
0
* 10 10

-0.05 0 N= 66 62 0
-1 Placebo ADDx10059 Placebo ADX10059

* P = 0.032
Afridi et al., Neurology 2013; in press Goadsby & Keywood Cephalalgia 2009;29:7

CGRP is not necessary for plasma

protein extravasation (PPE)
CGRP knockout
900 • Dural PPE not present in NK1
800 CGRP knock-out knock-out mice
Area under curve

700 + SR140333

600 • Histamine not necessary for PPE

500 • CGRP does not produce PPE in
400 isolation
300
200 *
100
0
Parafin Mustard Oil

Grant et al., Eur J Pharmacol 2005;507:273-280

18