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
tiredn
ess
stiff n
eck
yawn
polyu
riahu
nger
thirst
emotio
nal
premonitoryheadachepostdrome
Giffin et al.Neurology 2003;60:935
Time (hours)
-100 -50 0 50 100
VA
S r
atin
g of
sta
te o
f hea
lth
0
20
40
60
80
100
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
age
of b
asel
ine
firin
g
0
20
40
60
80
100
120
MMANoxious pinchInnocuous brush
Baselineresponse
*
*
n =
14
n =
13
n =
12
n =
5
n =
5
n =
5
n =
5
n =
5
n =
5
n =
6
n =
6
n =
6
Per
cent
age
of b
ase
line
firin
g
0
20
40
60
80
100
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 =
5)
*
*
Sha
m
(n =
5)
Sha
m
(n =
5)
Lesi
on A
11
(n =
8)
Lesi
on A
11
(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