1

Migraine 2015

Recent Advances in Neurology

12th February 2015

Peter J GoadsbyDirector, NIHR-Wellcome Trust King’s Clinical Research Facility

&Professor of Neurology, University of California, San Francisco

Department of Neurology

Headache Group, Kings/UCSFDisclosure- by proportion*

•National Institute for Health Research, UK

• Governments: European Union, Spain, Portugal, China, Department of Defence, Kyrgyzstan, Australia, NINDS

• Industry: Amgen/Allergan• Consulting/reviews : ATI, Belgian Research Council, BMS, B-I, Colucid, Eli-Lilly,

European Space Agency, Italian Telethon, Medical Research Council UK, Medtronic, Migraine Research Foundation, Migraine Trust, Netherlands Research Council, Neuralieve, Neuraxon, Electrocore, NHMRC, OUCH-UK, Pfizer, Teva

*Font scale for direct contributions in proportion to contribution Q4-13 to Q3-14(Font ~ {Contribution/Total Group Income} * 100)

International Classification of Headache Disorders-IIIββββ

I- Primary1. Migraine2. Tension-type headache3. Trigeminal autonomic cephalalgias

3.1 Cluster headache3.2 Paroxsymal hemicrania3.3 SUNCT/SUNA3.4 Hemicrania continua

4. Other Primary Headaches4.1 Cough headache4.2 Exercise Headache4.3 Sexual activity headache4.4 Thunderclap headache4.5 Cold stimulus: external/ingestion4.6 External pressure: compression/traction4.7 Stabbing Headache4.8 4.9 Hypnic headache4.10 New Daily Persistent Headache

II-Secondary5. Trauma or injury to the head6. Cranial or cervical vascular7. Intracranial non-vascular

8. Substances9. Infection10. Homoeostasis

11. Disorder head, neck, eyes…12. Psychiatric

Cephalalgia 2013;33:629

III-Cranial neuralgias/facial pain- trigeminal neuralgia- trigeminal neuropathy- glossopharngeal neuralgia-nervus intermedius neuralgia-occipital neuralgia- Tolosa-Hunt- Burning Mouth Syndrome

Case 1

2

Cough Headache4.1 Cough HeadacheHeadache precipitated by coughing or other Valsalva (straining) manoeuvre, but not by prolonged physical exercise, in the absence of any intracranial disorder.

A. At least two headache episodes fulfilling criteria BDB. Brought on by and occurring only in association with coughing, straining and/or other Valsalva manoeuvreC. Sudden onset

D. Lasting between 1 second and 2 hoursE. Not better accounted for by another ICHD-3 Dx

ICHD-III-beta Cephalalgia 2013;33:629

Cough Headache4.1 Cough HeadacheHeadache precipitated by coughing or other Valsalva (straining) manoeuvre, but not by prolonged physical exercise, in the absence of any intracranial disorder.

A. At least two headache episodes fulfilling criteria BDB. Brought on by and occurring only in association with coughing, straining and/or other Valsalva manoeuvreC. Sudden onset

D. Lasting between 1 second and 2 hoursE. Not better accounted for by another ICHD-3 Dx

Raskin Neurology 1995;45:1784ICHD-III-beta Cephalalgia 2013;33:629

Migraine - Update

• Clinical Aspects• Disorder mechanisms• Treatment

MigraineThe Attacks & the Disorder

• Premonitory symptoms• Pain

– unilateral– throbbing– movement worse

• Nausea• Sensory sensitivity

– photophobia– phonophobia– osmophobia

• Aura

• Repeated attacks– < 15 days/month: Episodic– ≥ 15 days/month: Chronic

• Family history• Triggers (biology)

– Sleep: missing/excess– Food: skipping meals– Chemical: alcohol or nitroglycerin– Weather– Sensory: light, smells– Hormonal– Stress- relaxation

Attacks Disorder

“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

3

PRDM16TRPM8LRP1ZNF555ADARB2GRM7HTR7MEF2DTGFBR2PHACTR1ASTN2

SUSCEPTIBILITY LOCI

FHM

FAMILIAL MIGRAINE

CACNA1AATP1A2SCN1A

TRESKCK1δ

When does migraine begin?

Episodic Syndromes that may be migraine• Recurrent GI disturbance

- Cyclical vomiting- Abdominal migraine

• Benign paroxysmal vertigo• Benign paroxsymal torticollis

Is Infantile Colic- Paroxysmal Fussing of Infancy1- the start ?• Definition: crying 3 hrs/day, 3 days/wk for 3 weeks• No evidence for gastrointestinal basis• Study2 (n = 154)

- Prevalence of colic: 14% - Prevalence of migraine in mothers of children with colic

(PR): 2.6 [1.2-5.5] 1. Wessel et al., Pediatrics 1954;14:4212. Gelfand et al., Neurology 2012;79:1392

From the GWAS…Transient Receptor Potential Channels

• TRPV (vanilloid)- Cation channel- Low pH (protons or acid)- Heat: >43oC- Capsaicin, endocannabinoids

• TRPA1 (ankyrin repeats)- Located in trigeminal ganglion- Colocalised with CGRP- Mustard oil, wasabi, cinnamon

• TRPM (melastatin)- Na+/Ca2+ channel- Cold: < 20oC- Menthol

Albrecht et al.,JHP 2013;1:P70

TRPA1 Umbellulone-California Bay

Laurel

Nassini et al., Brain 2012;135:376

Kayama et al., Cephalalgia 2013;33[Suppl 8]:224

%pa

tient

s

Substance P, PPE, TRPV1 & CGRP antagonists in Migraine• Double-blind randomized parallel group

single attack adult migraineurs

n = 32 31 12 /32 51 51 42 32

Connor et al.,Cephalalgia 1998;18:392

Olesen et al.,NEJM

2004;350:1104

Roon et al.,Ann Neurol

2000;47:238

Substance P Plasma Protein TRPV1 CGRP Extravasation (PPE)

Blocker

Dural Plasma Protein Extravasation

Buzzi et al., Brain Res 1999;583:137

Chizh et al.,EFIC2009

4

Genetics and Treatment Responses in Migraine

1. Freilinger et al. Nat Genet. 2012;44:7772. Christensen et al., J Head Pain 2014;15[Suppl 1]:M3

• Subjects from Danish Headache Center (n = 1806)- Semi-structured migraine interview- Blood samples- Twelve migraine SNPs1

- Logistics regression to look for association with drug responses

• Outcome- SNP rs2651899 in PRDM16 had OR of 2.6 for efficacy to a triptan2

Chronic MigraineICHD-I

Cephalalgia1988;8 (suppl 7):1-96

Chronic MigraineICHD-II

A. Headache frequency ≥15 days for ≥ 3 months

B. Attacks fulfill criteria for migraine without aura

C. Not attributed to another disorder

Cephalalgia 2004;24 (suppl 1):1-160

Chronic MigraineICHD-II-R

A. Headache frequency ≥15 days for ≥3 monthsB. Patient with at ≥5 attacks of migraine without

aura (MWoA) in the pastC. On ≥8 days per month for three months has

1. typical MWoA

2. attacks treated and relieved by triptans/ergots

D. Not attributed to another disorder, particularly no medication overuse

(Olesen et al., Cephalalgia 2006;26:742)

5

Chronic MigraineICHD-IIIββββ

A. Headache frequency ≥15 days for ≥3 monthsB. Patient with at ≥5 attacks of migraine with aura

(MwA) or without aura (MwoA) in the pastC. On ≥8 days per month for three months one of:

1. MwoA: C. pain characteristics AND D. nausea/sensitivity

2. MwA: typical aura (B & C)3. Attacks considered migraine by patient and relieved by

triptans/ergots

D. Not better accounted for by another ICHD-III diagnosis

ICHD-IIIβ Cephalalgia 2013;33:629-808

Tension-Type Headache (appendix)

• Episodic– lasts 30 mins to 7 days– Two of

• pressing/tight pain

• mild/moderate severity• bilateral• no aggravation by

activity

– Both of• No nausea• Photophobia or

phonophobia, not both

• Chronic– ≥15 days/month– Two of

• pressing/tight pain

• mild/moderate severity• bilateral• no aggravation by

activity

– Both of• No vomiting• Only one of mild

nausea, photophobia or phonophobia

ICHD-III-beta Cephalalgia 2013;33:629

Relationship ofMigraine and Tension-type headache

• throbbing• movement worse• associations

– nausea– photophobia– phonophobia

• Aura

• Family history• Triggers

– Sleep: missing/excess– Eating: including alcohol– Weather– Hormonal– Stress- relaxation

• Non-throbbing• no effect of movement• associations

– No nausea– No photophobia– No phonophobia

• ? aura

Attacks

Patient

(*P < 0.05)

% p

atie

nts

Botulinum Toxin A (Botox-A) in the preventive management of chronic migraine

50% & 75% responder rates

*

n = 696 688 358 347 153 153

Headache 2010;50:921 Cephalalgia 2011;31:87 Headache 2006;46:838

*

50% 75%

6

Possible Mechanism(s) of Action of Botulinum Toxin in Chronic Migraine

• Peripheral sensory effect – Blocks release of neurotransmitters associated with

peripheral sensitization of sensory afferents, such as glutamate and CGRP

– Reduced muscle afferent (1a) input• Trans-cranial afferent effect

– Inhibits transmission in sensory nerves that traverse the cranium and have collateral dural branches

• Trigeminal-autonomic reflex effect– Inhibition of sphenopalatine ganglion activatiomn

Shaari et al., Otolaryngol Head & Neck Surg 1995;112:556

Burstein et al.,Cephalalgia 2014;34:853

Paterson et al. Ann Neurol. 2014;75:591

Migraine - Update

• Clinical Aspects• Disease mechanisms

�Premonitory symptoms

• Treatment

Case 2 Migraine: The Premonitory Phase

0

20

40

60

80

100

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yawn

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emotio

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Giffin et al.Neurology 2003;60:935

Time (hours)

-100 -50 0 50 100

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0

20

40

60

80

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headache

premonitory

*

* Premonitory- somnolence- Gowers, 1883

Afridi et al.,Arch Neuro 2005;62:1270

7

Dopamine, the A11 and its trigeminocervical effects

MMA: middle meningeal artery

Charbit et al. J Neurosci 2009

Baseline response

A11 A11 5-40 mins 5-40 mins post i.v. post iv D2 antagonist D2 antagonist

*

* **

Per

cent

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asel

ine

firin

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0

20

40

60

80

100

120

MMANoxious pinchInnocuous brush

Baselineresponse

*

*

n =

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n =

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n =

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n =

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n =

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20

40

60

80

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120

140

160 M M Anoxious pinchinnocuous brush

Baseline

response

5-40m ins post lesion A 11

o r con tro lLe

sion

A11

(n

= 8

)

Sha

m

(n =

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*

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(n =

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m

(n =

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Lesi

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(n =

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Lesi

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(n =

8)

Bergerot et al. Ann Neurol 2007;61:251

Premonitory Phase of MigraineH2

15O PET• Patients with premonitory symptoms, such as yawning and thirst, and no headache• First premonitory scan vs baseline

Maniyar et al., Brain 2014;137:232

Hypothalamus PAG Dorsal pons

Premonitory phase of migraineH2

15O PET- Nausea & Photophobia• Patients with GTN-triggered premonitory symptoms, such as yawning and no headache• Comparison: Photophobia or Nausea with symptom absent during premonitory phase

Maniyar et al.Eur J Neurol 2014;11:1178

Photophobia (photic sensitivity) Nausea

Maniyar et al. J Headache Pain 2014;15:84

Triggering migraine

• Identifying triggers is a popular subject amongst migraineurs

• Provocation in migraine with aura1

- Patients (n=27) reporting bright/flickering lights or exercise- Exercise: 4/12 triggered attack- Lights (VEP & stroboscope): 0/12 triggered attack

• Stress and migraine2

- Patients (n=22) with 30 days of eDiary- Perceived Stress Scale- Reduced stress associated with migraine 6, 12 & 18hr

later with OR 1.5 to 1.9- Increased stress not associated with migraine

1. Hougaard et al. Neurology 2013;80:4282. Lipton et al. Neurology 2014;82:1395

8

Migraine - Update

• Clinical Aspects• Disease mechanisms

– Premonitory symptoms

• Treatment

Trigeminovascular System & Migraine

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

Ergot Alkaloid (tetracylic ergolene)Family Tree

Dihydroergotamine

zolmitriptan eletriptan

rizatriptan almotriptan

naratriptan frovatriptan

donitriptan

triptans

CP122,288 4991w93

anti-PPEcompounds

COL-144

LY334370

5HT1F agonists

PNU142633

5HT1D agonists

non-triptans

Sumatriptan

Ergotamine

NH

NMe2MeNHSO2

NHO

O

NH

NMe2(4991W93)

CH3

H H

lasmiditan

(Goldstein et al., Headache 2012;52:1402)

% P

atie

nts

Transdermal sumatriptan for migraine

• Randomised double-blind placebo controlled study• Subjects: migraine with & without aura• Primary endpoint: 2 hr pain free

n = 228 226

*

9

34.5

19.610.1 6.7 5.9

25.2

58.7

43.7

28.423.1

17.7

31.2

0

20

40

60

80

100

Painresponse- 2

h

Sustainedresponse 2-

24h

Pain free 2h Sustainedpain free 2-

24h

Sustainedpain free 2-

48h

Any AE

placebo DHE- 0.5mg (actual)

(Aurora et al., Headache 2011;51:507)

% P

atie

nts

Dihydroergotamine by inhalation (MAP0004) in the treatment of acute migraine

• Randomised double-blind placebo controlled study• Primary endpoint: 2 hr pain relief

n = 397 395 401 404

*

**

**

AE Placebo DHE

Nausea

CoughTaste

2.0

1.21.7

4.5

2.56.4

Ergot Alkaloid (tetracylic ergolene)Family Tree

Dihydroergotamine

zolmitriptan eletriptan

rizatriptan almotriptan

naratriptan frovatriptan

donitriptan

triptans

CP122,288 4991w93

anti-PPEcompounds

COL-144

LY334370

5HT1F agonists

PNU142633

5HT1D agonists

non-triptans

Sumatriptan

Ergotamine

NH

NMe2MeNHSO2

NHO

O

NH

NMe2(4991W93)

CH3

H H

lasmiditan

Lasmiditan, 5-HT 1F receptor agonist, in acute migraine

(% p

atie

nts)

• Double-blind parallel group randomised• Placebo-controlled trial• Migraine with/without aura; no preventives

N = 81 79 81 69 68

Farkkila et al., Lancet Neurol 2012;11:405

Adverse events:• Dizziness• Fatigue• Vertigo• Somnolence

Bouchelet et al., Br J Pharmacol 2000;129:501

Trigeminovascular System & Migraine

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

5-HT1D CGRP

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

10

Trigeminal Activation & CGRP

Ann Neurol Neuropeptides Ann Neurol1988;23:193 1990;16:69 1990;28;183 1993;33:48

Cat Human Cat Human

(pm

ol/l)

Trigeminal Ganglion Superior Sagittal M igraineSinus

**

*

* *

*

*

Lars Edvinsson

June, 1985, Sweden

CGRP receptor antagonists are effective in the treatment of acute migraine

• Double-blind parallel group randomised controlled trials• Two hour pain free

NEJM Lancet Cephalalgia Cephalalgia Cephalalgia2002;346:257 2008;372:2115 2011;31:573 2014;34:114 2011;31:712olcegepant telcagepant BI-44370 BMS-92771 MK-3207

(% p

atie

nts)

O Z E S

N = 42 32 348 333 354 70 73 69 203 85 100 133 59

Monoclonal Antibodies for Migraine Prevention are Effective

• Amgen AMG 3341

– Human IgG1 receptor CLR/RAMP1 – Phase II- episodic & chronic Migraine

� Alder Biopharmaceuticals- ALD 4032

– Humanized CGRP peptide antibody– Phase II: episodic migraine

� Arteaus Therapeutics/Lilly- LY29517423

– Humanized CGRP peptide antibody

– Phase II: episodic migraine

• Labrys/Tev- LBR-1014

– Humanized CGRP peptide antibody

– Phase II: episodic & chronic migraine

1. Shi et al., Headache 2014;54:14172. Dodick et al., Lancet Neurol 2014;13:11003. Dodick et al., Lancet Neurol 2014;13:8854. Bigal et al., Cephalalgia 2014;34:968

FelgenhauerKlin Wochen 1974;24:1158

CasesEuropean

11

CasesEuropean

United States

CasesEuropean

United States

Nummular headache

4.8 Pain in a small area without a lesion1

A. Continuous pain fulfilling B-CB. Felt in a round or elliptical shape 1-6 cm in diameterC. Lasting hours or daysD. Not better accounted for by another ICHD-III diagnosis

1. Cephalalgia 2013;33;6292. Goldberg et al. Neurology 2014:P5.206

Case2

• Female – aged 52• History of nine focal areas on the head• Pain: sharp, severe continuous with alodynia• Rx: nortriptyline, pregabalin, topiramate, celecoxib

and onabotulinum toxin type A-> improved

22

16

39

29

0

10

20

30

40

50

pain free 2 hr Sustained pain free 2-24 hr

Sham Active

(Lipton et al., Lancet Neurol 2010;9:973)

% P

atie

nts

Transcranial magnetic stimulation for Migraine

• Randomised double-blind placebo controlled study• Include: 30% aura episodes, aura leads to headache 90%• 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

n = 82 82

*

12

Single pulse Transcranial Magnetic StimulationsTMS

• Transcranial magnetic stimulation first described as a method to stimulate corticospinal tracts

• Based on efforts by Marsden, Merton & Morton to unravel cortical influences on the motor reflexes

Barker et al. Lancet. 1985;1(8437):1106Merton et al. Lancet. 1982;2(8298):597

Transcranial magnetic stimulation blocks CSD not

TCC in ratAndreou et al., JHP 2010;5:58

Holland et al.,Cephalalgia 2009;29:22

sTMS significantly modulates cortico- thalamic activation following CSD

CSD sensitizes the sensory thalamus

CSD

Andreou et al., JHP 2013;1:I6

sTMS in the UK

Bhola et al., J Headache Pain 2014;15[Suppl 1]:M22 Plus

Migraine days reduced with duration of treatment

13

12

38

0

10

20

30

40

50

50% Responders

Sham Active

(Schoenen et al., Neurol 2013;80:697)

% P

atie

nts

Transcutaneous Supraorbital Nerve Stimulation

• Randomised double-blind, placebo-controlled study, 30 day baseline/90 day treatment• Thirty minutes stimulation (supratrochlear/supraorbital n. 60Hz/16 mA) versus sham (1Hz/1mA)• Include: migraine with and without aura, 2+/month; Exclude: failed ≥ 3 preventives; MOH• Primary endpoint: reduction in migraine days baseline versus month three: -30% vs +5%, p = 0.02

n = 33 34

*

MigraineA brain systems disorder with many manifestations

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

Episodic MigraineArch Neurol 2005;62,1270

Chronic migraineBrain 2004;127:220-230

• 5-HT1B/1D: triptans• CGRP: gepants• 5-HT1F: ditans• Orexin 1 & 2: rexants• mGluR5: glurants• ASICs: mambalgins• nNOS: NXN• TRP: ?• Neuromodulation

-3.9

-2.6

-4.8-5.5

-5.9

-5

-8

-6

-4

-2

0migraine days migraine days- no MOH migraine days- +MOH

Sham- 1us, 10Hz, <1mA, 1s on 90min off

Active- 250usec/60Hz, 0-12mA

(Lipton et al., Cephalalgia 2009;29:30)

days

Occipital nerve stimulation in migraine & chronic migraine- PRISM

• Double-blind randomized parallel group sham stimulation controlled study• Migraine ≥6 days/month or chronic migraine (ICHD-II)• Failed two preventives/two attack treatments

n = 62 63

NS

•Adverse event :non-target sensory symptoms

96

27

39

40

0

10

20

30

40

50

reduction in headache days 50 % responder rate

Pre-set Adjustable Medically managed

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

%

Occipital nerve stimulation in chronic migraineONSTIM

• Double-blind randomized parallel group sham stimulation controlled study• Note- occipital pain, fail 2 preventives, exclude MOH

***

n = 16 29 17

NS

* Adverse event : lead migration in 24 %

14

(Silberstein et al., Cephalalgia 2012;32:1165)

%Occipital nerve stimulation in chronic migraine

St Jude• Double-blind randomized parallel group sham stimulation controlled study• Chronic migraine or probable chronic migraine• Occipital pain, failed two preventives; Successful trial ≥50% reduction in pain or paresthesia

• Results: Implanted (n = 177); Primary endpoint- Failed

*

n = 52 105

* Adverse event : lead migration in 14%*P = 0.02

2.16

1.23

1.73

1.03 1.12

0

1

2

3

Stroke CVS disease MI

migraine with aura migraine without aura migraine

(Schurks et al., BMJ 2009;339:b3419)

Odd

s ra

tios

Migraine frequency and CVS risk in females

• Meta-analysis• Risk adjusted for BP, age, smoking, BMI, cholesterol, family history• Highest risk for stroke: females, migraine with aura, <45, smoke & O/C

Does Migraine “hurt” the brain?

(Palm-Meinders et al., JAMA 2012;308:1889)

EVA Study• French population based vascular risk study• Patients born between 1922-32• Interviewed/diagnosis probable migraine or non-migraine• Cohort n = 1170/migraine (166)/+aura (24)

• Results-Battery of ten cognitive tests showed no difference between migraine and non-migraine;-Average scores decline-No effect of migraine status on rate of decline-No effect of presence of brain changes on MRI on decline

(Kurth et al., BMJ 2010;341)

CAMERA-I

Kruit et al., Brain 2005;128:2068

CAMERA-II• Population-based, 9 year follow-up• Ctrl 83/140 and Migraine 203/295• Adjust: age, sex, BP, diabetes, education

• Results- Supratentorial:

- increased deep white matter hyperintensities by 0.11 [0.01-0.26] ml females with MwoA- new changes

- Not related to BP or diabetes- Infratentorial: no change in hyperintensities- Progression unrelated to headache frequency- No effect of hyperintensities on cognition

3

1.5

3

-0.05-1

0

1

2

3

4

5

midazolam ketamineC

hang

e

Is glutamate involved in human aura?

n = 9 9

Afridi et al., Neurology 2013; in press

*

* P = 0.032

• Randomized double-blind active control parallel group multiple attack crossover• Migraine with prolonged aura (ICHD-I)/hemiplegic migraine• Ketamine/placebo versus Midazolam/placebo (intranasal) (2 x 3 attacks/arm)• Primary Endpoint: reduced length or severity of attack

Length Severity