presentation

Transcription

presentation

Non/minimally-invasive peripheral
neurostimulation in headache treatment:
results and mode of action.
Jean Schoenen. Headache Research Unit. Liège University.
Prof.Dr.Jean Schoenen
Dept. of Neurology.
Headache Research Unit.
University of Liège. Belgium.
Conflicts of interest:
Investigator/advisor for GSK, BMS,
Amgen, Allergan, Colucid,
Boehringer, Merck, Almirall, Pfizer,
Medtronic, Gammacore, ATI, STX-Med,
St Jude Medical, Chordate,
Biomedica 2014
1
University Dept of Neurology
CHR Citadelle - Liège
Part 1:
The primary headaches
1. Migraine
2. Tension-type headache
3. Cluster headache
and other trigeminal autonomic cephalalgias
4. Other primary headaches
ICHD-II. Cephalalgia 2004; 24 (Suppl 1)
©International Headache Society 2003/4
Migraines: the clinical phenotypes
ICHD-II (2004)
A:
4 - 72 h
B:
C:
Migraine
n  5
• hemicrania
1.
18%
in
the
general
population
•
throbbing/pulsating
2.
2/4
3.
++ / +++
• aggravated by physical activity
4.
D:
1.
1/2
2.
E:
• intense, reduces performances
• nausea/vomiting
 + 
 • sensoriphobia
normal
Chronic Migraine : ICHD-3 beta classification
1.3. Complications of Migraine
A1.5.1. Chronic Migraine
A. Headache (tension-type and/or migraine) on ≥ 15 days per month for >3
months & fulfilling criteria B and C
B. Occurring in a patient who has had at least 5 attacks fulfilling criteria for
1.1 Migraine without aura &/or 1.2 Migraine with aura
2% in the general population
C. On ≥ 8 days per month for >3 months headache fulfilling any of the
following:
1. typical criteria for migraine without aura
2. typical criteria for migraine with aura
3. believed by the patient to be migraine at onset and relieved by a
triptan or ergot derivative
D. Not better accounted for by another ICHD-3 diagnosis
Headache
Research
Unit
CLUSTER HEADACHE: natural history
0.25% in the general population
Cluster headache

Episodic (80%)

Chronic (20%)
- Cluster period lasts for
more than one year
without remission or
remission lasts less
than 1 month
Episodic
Chronic 13%
Chronic
Episodic 33%
(Manzoni)
Cluster-free intervals
1.1 yr  3.5 yr
(Igarashi)
Manzoni GC et al. Cephalalgia. 1991.
Igarashi H, Sakai F. Cephalalgia. 1996.
1-2% treatment-resistant ?
ICHD-II Cephalalgia. 2004.
(« suicidal headache »)
Why is there a place for neurostimulation
in primary headaches ?
1. Primary headaches are associated with central nervous system
dysfunctions on which neurostimulation may act
2. preventive drug treatments are ineffective in 1 patient out of 2,
and most of them have disabling side effects
3. acute treatments are ineffective in 1 migraineur out of 4,
but may have side effects and contraindications
4. the chronic forms of primary headaches (3%) become
resistant to preventive drug treatments
5. there are no new preventive drugs available in the near future,
and novel acute drugs may not be more effective
MEDICAL DEVICE TREATMENTS
FOR HEADACHE
Scribonius Largus, physician to Emperor Claudius, was
a staunch advocate of the remedy. He wrote in the 1st
century:
“ To immediately remove and permanently cure a
headache, …. a live black torpedo is put on the
place which is in pain, until the pain ceases and the
part grows numb.”
Jean Schoenen
NEUROSTIMULATION METHODS
FOR HEADACHES
Peripheral neurostimulation
- occipital nerve stimulation (ONS) _ Rp/ CH + ChMIG
Refractory
headaches
invasive
(percutaneous)
- sphenopalatine ganglion stimulation _ Rp/ CH (MIG)
(pergingival)
- vagus nerve stimulation (VNS) _ Rp/ pilot trials CH + EpMIG
(transcutaneous)
- supraorbital nerve stimulation (Cefaly®) _ Rp/ EpMIG
(transcutaneous)
Central neurostimulation
- transcranial magnetic (TMS) & direct current
stimulation (tDCS) _ Rp/ EpMIG + ChMIG
Jean Schoenen
nonAny
invasive
headache
Occipital nerve stimulation for drug-resistant chronic cluster
headache: a prospective pilot study
Delphine Magis, Marta Allena, Monica Bolla, Victor De Pasqua, Jean-Michel Remacle, Jean Schoenen
Lancet Neurology 2007
Oh MY, Ortega J, Bellotte JB, Whiting DM, Aló K. Peripheral
nerve stimulation for the treatment of occipital neuralgia
and transformed migraine using C1-2-3 subcutaneous
paddle style electrode : a technical report.
Neuromodulation 2004; 7: 103-112.
• A paddle style stimulation electrode
(Medtronic 3587A Resume II°) was
implanted on the CCH side
subcutaneously via a retromastoid C2–3
approach.
• The stimulator (Medtronic 7425 Itrel
3°) was switched on as soon as a typical
attack occurred.
Jean Schoenen
ONS in drCCH: long term outcome
(Magis et al. Headache 2011)
3,5
3
Mean intensity
Mean attack frequency/day
2,96
2,58
2,5
2,24
2
9 patients pain-free
(2 without preventive drug treatment)
3 patients ≥ 90% better
1,5
(1 without drugs)
2 patients without improvement
1
0,5
Stimulation parameters
• pulse width: 330-450 µsec
• frequency: 45-130 Hz
• voltage: 3.1-10.5 Hz
0,12 (p<0.001)
0
Before ONS
Follow-up
(n=14; 11-64mths)
Jean Schoenen
-94%
ONS trials in drug-resistant Chronic Cluster Headache
(Magis & Schoenen. Lancet Neurology 2012)
Authors
Number of
patients
Follow-up
(months)
Results :
number of patients
with ≥ 50%
improvement
Magis et al. 2007 & 2011
14
36.8
12
Empty battery
Burns et al. 2007& 2009
14
17.5
5
Empty battery
Electrode
migration
Infection
Proietti Cecchini et al. 2009
(A)
13
21
8
Empty battery
Lara Lara et al. 2009 (A)
6
6-15
4
De Quintana et al. 2010
4
6
4
Salomet al. 2010 (A)
14
?
7
Infection
Müller et al. 2010
10
12
9
Infection
Fontaine et al. 2011
13
14.6
10
Empty battery
Strand et al. 2011
3
12
2
TOTAL
91
Adverse effects
61
(67%)
1st sham-controlled trial (ICON) = ongoing (Wilbrink et al. Cephalalgia 2013)
Jean Schoenen
What is the rationale for ONS?
Neurovascular
headache
Pain control
centers
Meningeal
vessel
SP
CGRP
NO
V1
V1 som.
PAG
(front)
Nucleus
Tractus
solitarius
visc
stop
C2
ONS
Spinal
trigeminal
nucleus
Brain stem
The TRIGEMINOVASCULAR SYSTEM:
the major pain-signallingJean
system
of the brain
Schoenen
GIGA-NEUROSCIENCES
& NEUROLOGY DEPT
Headache Research Unit
ONS increases the nociceptive blink reflex (instead of reducing it)
and has no effect on pain tresholds,
p=0.001
p=0.005
BLINK AUC (microVxms)
0,8
0,7
0,6
Baseline
0,5
1 week
0,4
1 month
0,3
0,2
Stimulator
OFF
0,1
0
Cluster
side
Healthy
side
ONS: possible mechanisms?
Effect of 6-24m ONS on brain metabolism
(Magis et al. BMC Neurol 2011)
(May et al Nature Medicine 1999;5:836-838)
Ipsilateral side to pain and neurostimulation (n=10)
Areas hypermetabolic at baseline
compared to healthy controls
Areas hypermetabolic at baseline
which normalize after 6-24m ONS
Jean Schoenen
ONS: possible mechanisms?
Area hypermetabolic in responders
vs non-responders
Analyse
Rép > non
rép
Régions
cérébrales
CCA périgénual
Coordonnées
selon Talairach
Z score
x
y
z
du pic
P corrigé
-8
0.002*
28
-8
4.01
Ipsilateral perigenual
anterior cingulate cortex
Jean Schoenen
ONS in Chronic Migraine
(Medtronic° device)
ONSTIM
(Saper et al. 2010)
45%
40%
: - 95% CI
39%
40%
50% responders
35%
30%
25%
20%
15%
p=0032
10%
6%
5%
p=0.003
0%
0%
≥ 50% of headache days
≥ 3 pts in intensity on VAS 0-10
Preset ONS
(n=16)
% reduction in headache days/month
Active ONS
(n=28)
Medical Rp
(n=17)
GON block (n=5)
ONS in refractory Migraine
(Magis & Schoenen. Lancet Neurology 2012)
Number of
patients
Follow-up time
(months)
Popeney & Alo. 2003
25
18.3
Matharu et al. 2004
8
18
Schwedt et al. 2007
8
19
Lipton et al. 2009 (A)
(PRISM)
125
3
Marchioretto & Serra
2010 (A)
34
12
Saper et al. 2011
66
3
Silberstein et al. 2011 (A)
157
3
Reed et al.2009, 2011 (A)
ONS+SNS
44
13
Narouze et al. 2011 (A)
12
13
Linder & Reed 2011 (A)
ONS+SNS
13
?
Authors
Total
500
Results
Side effects
64% patients improved by at Lead migration
least 50%
Infection
100% of patients improved by Abdominal haematoma
at least 50%
Lead migration
50% of patients improved by at
Lead migration
least 50%
Infection
No
difference
negative
Site pain
vs. sham
Sensory symptoms
Overall 56% frequency
Light
reduction
39% of patients improved by at Lead migration
not powered for efficacy
least 50%
Infection
Reduction in headache days by
the 1° endpoint not Infection
36%
met
reduction
Slight lead migration
reduction
reduction
(60% pain free)
≈ 56%
improvement, but
much less in RCTs
Cluster Headache and
the Sphenopalatine ganglion
(New York Medical Journal)
JC DEVOGHEL.
Cluster headache and sphenopalatine block.
Acta Anaesthesiol Belg. 1981;32(1):101-7.
(N=120 patients; 85% with relief)
Neurovascular
HEADACHE
V1 som.
SPG
GSP
SSN
SP
pial / dural
vessel
NO
Nucleus
tractus
solitarius
CGRP
V1 visc
Ach
Trigeminal
nucleus
caudalis
VIP
C2 som
The trigemino-parasympathetic reflex circuit
BRAIN STEM
Lance & Goadsby 2005
Burstein & Jakubowski 2009
Study designed to investigate the safety and efficacy of the ATI Neurostimulation
SystemTM for SPG stimulation for the treatment of chronic cluster headache.
• On-demand, patient-controlled therapy via Remote Controller
2a
Investigational Use Only
Investigational Use Only
2d
Remote Controller
ATI Neurostimulation SystemTM
Pathway CH-I: RESPONDERS
Long term follow-up (n=14; 18 mths):
• moderate attacks (72%): 93% success
• mild attacks (12%): 83% success
• severe attacks (16%): 39% success
Adverse events:
Reversible sensory disturbances in
maxillary division of the trigeminal
nerve
(81% of patients)
FOR HEADACHES
(percutaneous)
(pergingival)
(transcutaneous)
(transcutaneous)
Jean Schoenen
invasive
Anecdotal reports on invasive
Vagus nerve stimulation in 1ary headaches
Cephalalgia 2005
Cephalalgia 2008
Neurol Sci 2009
Novel devices for TRANSCUTANEOUS VNS
CERBOMED
Gammacore°
Jean Schoenen
Nemos°
A randomized, multicentre study for the prevention and acute
treatment of chronic cluster headache using gammaCore ®,
versus standard of care (PREVA)
20
18
16
16,5
16,0
14,8
14
12
10
8,7
8
6
4
2
0
n= 41
n=33
GammaCore
n=44
run-in
treatment period
n=46
Standard of Care
Prevention of Migraine by supraorbital transcutaneous neurostimulation
using the Cefaly® device (PREMICE):
a multi-centre, randomised, sham-controlled trial.
Schoenen J, Vandersmissen B, Jeangette S, Herroelen L, Vandenheede M, Gérard P, Magis D.
(Neurology 2013; 80:697-704)
Multicenter – Belgian Headachs Society:
•
•
Cefaly°-STX-Med
•
•
•
HeadRun - Headache Research Unit, ULg (Prof. Schoenen)
CHU Erasme (ULB) & Cliniques de l’Europe, Bruxelles (Dr
Vandermissen)
CHU de Charleroi (Dr Jeangette)
AZ Gasthuisberg (KUL), Leuven (Dr Herroelen)
CHC de l’Espérance à Liège (Dr Vandenheede)
PROTOCOLE
• Episodic Migraine without/with aura: 2-8 attacks/month
• N= 5 centres (Belgian Headache Society)
• N= 34 effective stimulation daily stimulation square pulses:
- verum – 60 Hz, 250 μsec, 16 mA
for 20 minutes
• N= 33 sham stimulation
- sham – 1 Hz, 30 μsec, 1 mA
• Protocole: 1 prospective baseline
+ 3 month randomized, double blinded phase
Investigator-initiated trial; sponsored
by STX-Med
PREMICE
PREMICE: results – 1° outcome measures
Reduction of migraine days per month
Cephaly°-STX-Med
(square pulse, 60Hz, 300μsec,
max 16 mA, 20 min)
Percentage of 50% responders
Actif
50,00 %
38.1%
p=0.02
Placebo
*
40,00
30,00
12%
20,00
(*: p<0.03)
No adverse effect
10,00
(except for local paresthesias)
0,00
Responder
Jean Schoenen
Discussion: comparison with topiramate
60
%
Efficacy
Side effects
50
45
38,1
40
25
20
0
0
0
-20
-19
CEFALY VERUM
TOPIRAMATE
-25
-40
-44
-48
-60
Migraine days
Migraine attacks
50% responders
Adverse effects
Drop-outs
PREMICE: patients’ satisfaction & compliance
Patients’ satisfaction
Actif
17
18
Placebo
16
14
70.6%
13
Adherence
to the treatment
10
12
10
7
39.4% of treatment
• Optimal6 number
sessions:
6
90 (100%)
8
6
• Effective number - verum group:
4
4
4
55 (61.7%)
2
• Effective number – sham group:
49 (54.4%)
0
Very SatisfiedModeratly Satisfied Not Satisfied
N/A
Safety and efficiency of Transcutaneous Supraorbital Neurostimulation (tSNS)
with the Cefaly® device in headache treatment: a survey of 2,313 headache
sufferers in the general population.
(Magis et al. JHP 2014)
Only 40% of the 46.6% non-satisfied patients
used the device for the recommended time
Con nues
46,6
53,4
Total duration of use in patients who discontinued
STNS (min)
Stops
45,00%
40,00%
35,00%
53.4% of subjects decided to
continue and purchase the device
after a test period of 2 months
(..though some abandoned
treatment afterwards !)
% of patients
30,00%
25,00%
20,00%
15,00%
10,00%
5,00%
0,00%
0
1 to 20
21 to 40
41 to 60
60 to 100
100 to 200
200 to 400
> 400
Combined supraorbital & suboccipital CEFALY°
thermonociceptive cortical evoked potentials (forehead) in MO patients (n=15)
BLOCK 1 N2-P2 M0
80
Amplitude µVolt
70
60
p=0.007
50
40
30
T0
52,76
20
T1
36,45
10
0
Block 1
Amplitude N2-P2 1ère stimulation
MO
Contact heat-evoked potentials (CHEPs)
Amplitude µVolt
120
100
p=0.01
80
60
40
20
T0
79,55
T1
56,81
0
Première Stimulation
NON/MINIMALLY INVASIVE NEUROSTIMULATION
in 1ary Headaches
1. Minimally invasive ONS is effective in refractory chronic cluster
headache, but a RCT is awaited
2. Available RCTs of ONS in chronic migraine are less convincing
3. Sphenopalatine ganglion neurostimulation can abort cluster
headache attacks, and possibly decrease attack frequency, but its
place in cluster headache management needs to be explored
4. Transcutaneous vagus nerve stimulation looks promising in
cluster headache and in migraine, but RCTs are needed
5. Transcutaneous supraorbital neurostimulation with the Cefaly°
device has a preventive effect in episodic migraine
6. The precise mod(s)e of action of the peripheral nerve
stimulations remain(s) to be determined; a modulatory effect on
central pain-control systems may be a common denominator
7. In the future the combination of several neurostimulation
modalities may be more effective
8. More research is needed to understand mode of action, identify
responders and define the most effective methods and
stimulation protocols
Jean Schoenen
I’m grateful to the patients and to those who did the work…
Clinical Research
Judit Áfra
Marta Allena
Anna Ambrosini
Roberta Baschi
Valentin Bohotin
Monica Bolla
Gianluca Coppola
Laura Di Clemente
Julien Cremers
Arnaud Fumal
Pierre-Yves Gérardy
Valeria La Salvia
Adolorata Mascia
Delphine Magis
Alberto Proietti-Cecchini
Peter Sándor
Tullia Sasso d’Elia
Simona Sava
Alessandro Vigàno
Wei Wang
Homo neuromodulandus
Collaborations
- S.Laureys. Cyclotron Research Centre. Liège University
- R. Hustinx, Nuclear Medicine Department, CHU Liège
- G. Coppola, C Di Lorenzo. Neurology Dept. Uni Roma 1. I
- L. Vecsei, A. Pardutz. Neurology Dept. Szeged University. H
- R. Dallel. INSERM U929.Clermont-Ferrand University. F
- M. Hamon. INSERM U677. Univ P&M Curie. Paris. F
- EU STREP EUROHEAD (LSHM- CT-2004-5044837)
MD Ferrari (Leiden), J Olesen (Copenhagen)
…and thank you for your attention
Preventive Anti-Migraine Drugs have
limited efficiency
Overall absolute efficacy rates
Valproate,
Topiramate, Betablockers,
Flunarizine,
Methysergide
55
Lamotrigine:
✚ in mig with aura
Riboflavin, Q10,
Petasites,
Candesartan
Much worse in CHRONIC MIGRAINE
- in mig without aura
50
(Steiner et al. 1997, Lampl et al. 2005,
Fumal & Schoenen 2006)
& Medication Overuse Headache !
Rare
adverse
effects
Lisinopril, Mg,
Pizotifen,
Cyclandelate
25
0
2. PREVENTIVE THERAPY
Frequent
adverse
effects
10
20
30
40
Jean Schoenen
50
60
70
80
90
100 %
The trigemino-parasympathetic reflex circuit
Neurovascular
HEADACHE
V1 som.
SPG
GSP
SSN
SP
pial / dural
vessel
NO
Nucleus
tractus
solitarius
CGRP
V1 visc
Ach
Trigeminal
nucleus
caudalis
VIP
C2 som
BRAIN STEM
Lance & Goadsby 2005
Jean Schoenen
GIGA-NEUROSCIENCES
& NEUROLOGY DEPT
ONS in Chronic Migraine
(St Jude Medical device)
Jean Schoenen
OBJECTIVES
what is the place for neurostimulation
methods in primary headaches?
what do we know about their mode of
action?
what is the future?
Acute Migraine Therapy
Overall absolute efficacy rates of triptans (%)
Injectable sumatriptan
Gain =
Efficacy &
speed of action
OT
Injectable sumatriptan
Oral triptans
Gain =
Safety &
tolerability
%
1. ACUTE THERAPY
Prof.Dr.Jean Schoenen
Dept. of Neurology.
Headache Research Unit.
University of Liège. Belgium.
University Dept of Neurology
CHR Citadelle - Liège
Non-invasive peripheral neurostimulation in
headache treatment:
results and mode of action.
rTMS
Supraorbital
TENS (Cefaly°)
Auricular
VNS
ONS
Conflicts of interest:
Investigator/advisor for GSK, BMS,
Amgen, Allergan, Colucid,
Boehringer, Merck, Almirall, Pfizer,
Medtronic, Gammacore, ATI, STX-Med,
St Jude Medical, Chordate,
SPG
stim
Cervical
VNS
« HOMO NEUROMODULANDUS »
A Neurophysiological Model of Chronic Migraine Pathogenesis
Cortical
sensitisation
Mitochondrial
ATP 
7
Limbic system
6
Metabolic strain
(insula, amygdala, ,
nucleus accumbens,
hippocampus..,)
3
Thalamic
sensitisation
8
4
Brain stem
(PAG, monoaminergic nuclei)
5
CSD
Ion channel/
pump
dysfunction
(FHM)
Trigeminovascular
sensitisation
2
Aura
1
Headache
Migraine
attack
Persistent
headache
The MIGRAINE- PAIN pathophysiological link
Structural & functional
changes in « pain matrix »
EM
(potentiation)
initial
amplitude
Tissue density VBM MRI
initial
amplitude
Chronic
pain
CM
(habituation)
EPISODIC
MIGRAINE
<
(Wang et al. Pain 2010)
<
(Magnetoencephalography)
5
20
Height threshold T = 3.551808 {p<0.001 (unc.)}
Extent threshold k = 0 voxels
- brain stem changes
Acute
pain
Medication overuse headache
Riederer et al. J Neurosci
2013
glucose metabolism MOH
35
40
5
(Weiller et al. 1995, Goadsby et al 2009, Riederer et al. 2013)
(Matharu et al. Brain 2005)
20
30
(Coppola & Schoenen
2012) .\opt_matching
SPMresults:
(Weiller et al Nature Neuroscience 1995)
15
25
- visual processing
Chronic migraine
CHRONIC
MIGRAINE
10
SPM{T }
Migraine-specific changes
<
Episodic migraine
contrast(s)
1
SPM mip
[-2.76652, -34.5, -7.35279]
Resp T1 > T1
(review by May. Brain 2009)
10
15 20
Design matrix
25
(Fumal & Schoenen Brain 2006)l )
NEUROSTIMULATION
PERIPHERAL
CENTRAL
SI
Circ.cingul.antér.
Insula
Système
limbique
IL-3°
VMpo-3°
subst.grise périaqueducale
(opioïdes)
Nx.du raphé
Bulbe rostral
ventro-médial
Pericranial nerves
= peripheral nervous system
Brain structures
= central nervous system
(sérotonine,
noadrénaline)
GS-1°
I-2°
stl
sta
V-2°
Ascending sensory pathways
rp
INVASIVE NEUROSTIMULATION IN CLUSTER HEADACHE - HEADRUN
Safety and efficiency of Transcutaneous Supraorbital Neurostimulation (tSNS)
with the Cefaly® device in headache treatment: a survey of 2,313 headache
sufferers in the general population. Magis et al. (submitted)
Overall 4.3 % of subjects reported 1 or more side effects
Contact heat evoked potentials (CHEPS)
N2
N3
P2
____ N2-P2
____ P2-N3
PARAMETRES DE STIMULATION:
20 stimulations
Température Baseline: 42°C
Température peak: 53°C
Interstimulus: 10-25 sec
Enregistrement Cz-Fz
CHEPS N2-P2 WRIST vs FOREHEAD - Healthy Subjects (n=17) - Baseline
wrist
poignet
60
forehead
front
50
p=0.007
Linear (poignet)
Linear (front)
Amplitude µVolt
40
30
p=0.03
20
10
0
1
2
3
Block
4
5
CHEPS N2-P2 WRIST vs FOREHEAD – Migraineurs (n=16) - Baseline
wrist
60
poignet
p<0.001
forehead
front
50
Linear (poignet)
Amplitude µVolt
Linear (front)
40
30
20
p=0.007
10
0
1
2
3
4
5
CHEPS HABITUATION HV vs MO baseline
p=0.03
Combined Supraorbital & Suboccipital CEFALY°
effect on CHEPS
Combined tSNS-tONS Cefaly stimulation:
• 60Hz – 16 mA
• for 20 minutes
• MO:n=15; HV:n=15
Contact heat-evoked potential (CHEP)
CHEPS (forehead) in MO patients (n=15)
before (T0) and after (T1) combined CEFALY°
BLOCK 1 N2-P2 M0
80
Amplitude µVolt
70
60
p=0.007
50
SLOPE N2-P2 stimulations 1-10 MO
40
30
T0
52,76
20
T1
36,45
10
0,0
-0,5
0
-1,0
Block 1
-1,5
-2,0
Amplitude N2-P2 1ère stimulation
MO
Amplitude µVolt
-3,0
-3,5
120
-4,0
100
p=0.01
80
60
40
20
-2,5
T0
79,55
T1
56,81
0
Première Stimulation
p=0.08
MO
CHEPS (forehead) before and after
combined Supraorbital & Suboccipital CEFALY°
HV (n=15): CHEPS N2-P2 FRONT T0 vs T1
50
T0
Amplitude µVolt
40
T1
30
20
10
0
1
2
3
4
5
MO (n=15): CHEPS N2-P2 FRONT T0 vs T1
60
T0
T1
Linear (T0)
Linear (T1)
Amplitude µVolt
50
p=0.007
40
30
p=0.08
20
10
0
1
2
3
4
5
Conclusion: CHEPS studies
• both in HV and MO patients CHEPS amplitude and
habituation are greater at the forehead than at the
wrist
• compared to HV, MO patients have greater
habituation of forehead CHEPS and tend to have a
higher amplitude
• in MO patients, but not in HV, the combined
supraorbital-suboccipital Cefaly° is able to decrease
forehead CHEPS amplitude and habituation
FOR HEADACHES
Refractory
headaches
invasive
(percutaneous)
(pergingival)
(transcutaneous)
(transcutaneous)
Jean Schoenen
nonAny
invasive
headache
The rationale for neuromodulation in headaches
1. What is the pathophysiology of the disorder ?
• Interictal
• Pre-ictal & ictal
• Migraine with aura subtypes
• Chronic migraine
• Disease duration
2. What is the target for neurostimulation/-modulation ?
3. Which method(s) are optimal for the pre-defined objective ?
4. What is the risk/benefit ratio ?
5. Which patients should be selected ?
(responders, disease state,
acceptability, tolerance, …)
repetition of attacks
What are the pathophysiological targets for neurostimulation in migraines ?
Transcranial
neurostimulation
thalamo-cortical
dysrhythmia
mitochondrial
ATP 
cortical
hyperresponsivity
metabolic strain
abnormal limbic
& pain control
?
CSD
Trigeminovascular
system activation
attack
FDG-PET before and after ONS
in chronic cluster headache
Peripheral
neurostimulation
Headache
Aura
Migraine
attack
Model of migraine pathogenesis
Areas withvs
persistent
hypermetabolism
non-responders
after
effective
(Magis
et al.ONS
2011)
Transcranial magnetic stimulation (TMS)
Single
pulse
TMS
• transiently interferes
with cortical function
N=164 (82 sham)
TMS 2 pulses over occiput
Within 1h after aura onset
Jean Schoenen
Repetitive transcranial magnetic stimulation (rTMS)
& direct current transcranial stimulation (dTCS)
rTMS
dTCS
anode
• high frequency
ACTIVATION
Effect of 1 Hz rTMS (5daily sessions) on VEP habituation
In a healthy subject
• low frequency
20
0
-20
-40
-60
-80
1 week
9 weeks
-100
days
(Fumal et al 2007)
Jean Schoenen
70
63
56
49
42
35
28
21
14
7
2
1
re
-120
befo
INHIBITION
%habituation
cathode
INHIBITORY rTMS or tDCS in migraine prevention
1Hz rTMS (=inhibitory)
Cathodal tDCS(=inhibitory)
N=26 (13 sham)
Target region:
visual cortex
Both studies = negative
Stimulation
What went wrong ? Intensity:
1mA - 15 min.
Sessions:
3/week for 8
weeks
N=27 (13 sham)
Target region: vertex
Total amount pulses: 500.
Session: 1/day per 5 days
Teepker et al. 2010
Antal et al. 2011
The cycling pathophysiology of migraine
Premonitory
symptoms
Between
attacks
Headache
Between
attacks
BRAIN RESPONSIVITY & METABOLIC STRAIN
Interictal
habituation
habituation
habituation
energy demand
energy demand
energy demand
thalamo-cortical
activity
thalamic
control
monoaminergic
disposition
thalamo-cortical
activity
thalamic
control
monoaminergic
disposition
Habituation increases
habituation
thalamo-cortical
activity
thalamic
control
monoaminergic
disposition
Deficit of habituation
Premon.MIGRAINE
& Ictal
CHRONIC
Habituation normalises
Pre-ictal
Habituation decreases further
Deficient habituation
Interictal
energy demand
thalamo-cortical
activity
thalamic control
monoaminergic
disposition
(Coppola & Schoenen 2013)
Cortical responsivity: EPISODIC vs. CHRONIC Migraine.
Persistent ictal-like visual cortical reactivity in chronic migraine
(Magnetoencephalography)
EM=episodic migraine
CM=chronic migraine
↑ relative amplitude
= potentiation
↓ relative amplitude
= habituation
Episodic Mig: potentiation
Remitted CM: potentiation
Chronic Migraine: habituation
Chen WT, Wang SJ et al., Cephalalgia 2009;29:1202-11
Chen WT, Wang SJ et al., Pain 2011; 52:254-8
Chen WT, Lin YY, Fuh JL, MS Hamalainen, YC Ko, Wang SJ. Brain
2011;134(Pt 8):2387-95
Chen WT, Wang SJ et al., Cephalalgia 2012;32:537-43
EXCITATORY tDCS of the visual cortex in EPISODIC migraine
Transcranial Direct Current Stimulation (tDCS) of the visual cortex: a proof-of-concept study based on interictal electrophysiological abnormalities in migraine Vigano A,
Sasso d’Elia T, Sava SL, Auvé M, De Pasqua V, Colosimo A, Di Piero V, Schoenen J, Magis D Journal of Headache and Pain 2013.
Proof-of-concept study
Anodal tDCS (1mA, 15 min)
N =13 patients (tDCS 2/wk for 8wks;
Baseline= 2 months; Treatment= 2 months
VEP N1P1 habituation – HV (n=11)
0,1
12,00
p=0.024
0
slope value
Migraine attacks
Increase in habituation
0,05
-0,1
8,00
FIRST BLOCK N1P1
-0,15
7
6,00
5
4,00
-0,2
-0,25
-0,3
t0
t1
3
2,00
t2T0
T1
T2
0,00
BASELINE
VEP N1P1 habituation–MO (n=13)
0,10
20
18
16
14
12
10
8
6
4
2
0
0,00
p=0.04
-0,05
-0,10
-0,15
-0,20
-0,25
-0,30
t0
(before tDCS)
t1
(immed post-tDCS)
t2
(after 3 hrs)
TREATMENT
Migraine days
0,05
slope value
39%,
p=0.02
10,00
-0,05
47%
p= 0.03
BASELINE
TREATMENT
N=11: 5=sham (placebo) parallel
20 Hz rTMS DLPFC
400 pulses, 12 sessions/2d
Jean Schoenen
EXCITATORY quadripulse rTMS of visual cortex V1
using primer QP rTMS over V2 in healthy volunteers (n=10)
Quadripulse rTMS with primer = excitatory (Hamada et al. 2009)
1° PRIMER V2 (N=4; ISI: 50ms; 20Hz; 10 min)
5 sec
5 sec
0
10 minutes
5 sec
5 sec
30 minutes
SLOPE OF AMPLITUDE CHANGES VEP P1N2
-0,05
Mean slope value
2° SECOND V1 (N=4; ISI: 30ms; 20Hz; 30 min)
p<0.05
-0,1
-0,15
-0,2
-0,25
-0,3
-0,35
T0
T1
T2
QP inhibitory rTMS in healthy volunteers(n=10)
80% threshold
N=4; ISI: 50ms; 20Hz
Quadripulse « long ISI » = inhibitory
5 sec
Mean slope value
0,2
5 sec
5 sec
30 minutes
SLOPE OF AMPLITUDE CHANGES VEP P1N2
p=0.04
0,1
0
-0,1
-0,2
-0,3
T0
T1
T2
INHIBITORY quadripulse rTMS of visual cortex in CHRONIC migraine
80% threshold
5 sec
30
5 sec
5 sec
N° of migraine days/month
25
(n=16; 2 sess/week;1 month
Sasso d’Elia et al. submitted)
30 minutes
250
Migraine hours /month
p=0.04
p<0.001
200
15
10
-41%
5
0
10
150
100
-23%
-36%
50
0
p=0.03
Severe attacks /month
60
50
6
4
-33%
2
-48%
40
30
20
-36%
10
0
T8w
T4w
T0
QPI rTMS – 2x/wk
Acute medication
intake/month
p=0.005
p=0.01
8
Days (mean SD)
-45%
N° Drugs (mean ± SD)
Days (mean
SD)
20
N of hours (mean SD)
p=0.001
Follow-up 4wks
0
-56%
T8w
T4w
T0
QPI rTMS – 2x/wk
Follow-up 4wks
NEUROMODULATION in MIGRAINES:
conclusions & perspectives
1. There is evidence that supraorbital neurostimulation with the Cefaly° device is efficient
in the preventive treatment of EPISODIC migraine
2. There is evidence that 2 pulses of transcranial magnetic stimulation over the visual cortex
can prevent the headache during attacks of migraine WITH AURA
3. There is some indication that percutaneous occipital nerve stimulation (ONS) is effective
in CHRONIC migraine
1. There is pilot proof-of-concept data suggesting that excitatory anodal tDCS over the
visual cortex has a preventive effect in EPISODIC migraine (RCT in progress)
2. There is pilot proof-of-concept data suggesting that cathodal tDCS over the visual cortex
& anodal tDCS over DLPFC has a preventive effect in CHRONIC migraine (RCT finished)
3. There is pilot proof-of-concept data suggesting that inhibitory rTMS over the visual cortex
has a preventive effect in CHRONIC migraine (RCT in progress)
4. First studies are awaited for
- transcutaneous vagus nerve stimulation in EM & CM
- combined cathodal tDCS over visual cortex and anodal tDCS over left DLPFC in CM
- combined transcutaneous supraorbital-suboccipital neurostimulation in EM & CM
Avoid risk factors
Use prophylactic treatment
in high frequency migraine
(excess cafeine, stress, estrogens..)
Manage comorbid disorders
Restrict acute drug consumption
& prefer NSAIDs to analgesics
(depression, anxiety, chronic pains..)
Prevention
CHRONIC MIGRAINE
Medication overuse
Preventive pharmacotherapy
icld. topiramate & valproate.....
Detoxification
_
+
OnabotulinumtoxinA
(≥ 2 cycles)
+
_
Integrated multimodal
treatment program
Transcranial
neuromodulation
Invasive
neuromodulation
Diagnosis, pathophysiology and
management of Chronic Migraine:
a proposal of the Belgian
Headache Society
+
_
EPISODIC MIGRAINE
+
+
Day Clinic for Multimodal Headache Treatment (ULg)
Neurostimulation
Aerobic
exercise
Relaxation
therapy
PsychoEducation
Recruitment by
Headache Clinic,
& network of GPs
+ Neurologists
Chronic
Migraine
patient
Sustained
internet-based
follow-up
Drug
treatment
Follow-up by
Headache Clinic,
GPs + Neurologists
INHIBITORY quadripulse rTMS of visual cortex in CHRONIC migraine
80% threshold
5 sec
5 sec
5 sec
30 minutes
N=15; Baseline (T0)= 2 months; Treatment (T1)= 2 months; Follow-up(T2) = 2 months (Sasso D’Elia et al. submitted.
Viganò, Sasso d’Elia et al.EHMTIC 2012)
Migraine attacks
35
10
89
78
67
56
45
34
23
12
01
0
56%,
p = 0.03
30
25
20
15
10
5
0
T0
T1
T2
Attack duration - hours
160
140
120
100
80
60
40
20
0
42%,
p=0.05
Pain intensity
Beck Depression Inventory
 73%,
p=0.01
T0
T3
T0
60
50
50
40
40
T1
T2
State-Trait Anxiety InventoryDrug intake
Y2
 30%,
ns.
3030
2020
10
10
0
0
T0
T1
T2
T0
T0
T3
T1
T2
QP inhibitory rTMS in Chronic Migraine (n=16)
30
N° of migraine days/month
25
p<0.001
Days (mean  SD)
20
p=0.001
15
10
5
0
T8w
T4w
T0
QPI rTMS – 2x/wk
Follow-up 4wks
10
Migraine severe attacks days/month
9
p=0.03
Days (mean SD)
8
7
p=0.01
6
5
4
3
2
1
0
T8w
T4w
T0
QPI rTMS – 2x/wk
Follow-up 4wks
60
Acute medication intake/month
p=0.005
N° Drugs (mean ± SD)
50
40
30
20
10
0
T8w
T4w
T0
QPI rTMS – 2x/wk
Follow-up 4wks
250
Hours with migraine/month
p=0.04
N of hours (mean  SD)
200
150
100
50
0
T8w
T4w
T0
QPI rTMS – 2x/wk
Follow-up 4wks
A Neurophysiological Model of Chronic Migraine Pathogenesis
Cortical
sensitisation
Mitochondrial
ATP 
Limbic system
Metabolic strain
(insula, amygdala, ,
nucleus accumbens,
hippocampus..,)
Thalamic
sensitisation
Brain stem
CSD
Ion channel/
pump
dysfunction
(FHM)
Trigeminovascular
sensitisation
Aura
Headache
Migraine
attack
Persistent
headache
What is refractory cluster headache ?
(Towards a deﬁnition of intractable headache for use in clinical practice and trials
PJ Goadsby, J Schoenen, MD Ferrari, SD Silberstein, D Dodick. Cephalalgia 2006)
+ suboccipital injection
of Diprophos°-lidocaïne
(Ambrosini et al. Pain 2005)
Jean Schoenen
Hypothalamic DBS in CCH :
Adverse events
Patients
1 to 4
Oculomotor disturbances was the limiting factor
for voltage increase in all patients;
otherwise no side effects
5 (CM)
• Had panic attack & respiratory distress during
implantation which had to be interrupted.
• Had no attacks for 2 weeks, thereafter daily
attacks recurred.
• After unremarkable implantation except for
occurrence of an attack treated by DHE iv and
moderate hypertension, became comatous
• Remained in deep coma with bilateral mydriasis
and articial ventilation for 3 days, then died
• CT scan : intracerebral hemorrhage along
electrode tract
6 (BV)
Jean Schoenen
GIGA-NEUROSCIENCES
& NEUROLOGY DEPT
CLUSTER HEADACHE: management
Medical
Treatment
Acute
Therapy
Preventive
Therapy
Surgical
Treatment
Occipital nerve
Hypothalamic
DBS
Spheno-palatine ganglion stimulation
stimulation
ONS: possible mode of action in CCH ?
(Magis et al. BMC Neurology 2011)
Analyse
Rép > non
rép
Régions
cérébrales
CCA
périgénual
FDG-PET before and after ONS
Coordonnées
selon
Talairach
x
y
z
Z
score
du pic
P corrigé
-8
4.01
0.002*
28
-8
Nociceptive blink reflex
p=0.001
p=0.005
0,8
Baseline
1 week
1 month
0,7
BLINK AUC (microVxms)
0,6
vs non-responders
0,5
0,4
0,3
0,2
0,1
0
Cluster
side
Healthy
side
Stimulator
OFF
Areas with persistent hypermetabolism
after effective ONS
Jean Schoenen
Prevention of Migraine by supraorbital transcutaneous neurostimulation
using the Cefaly® device (PREMICE):
a multi-centre, randomised, sham-controlled trial.
(Schoenen et al. Neurology 2013)
Mean number of migraine days
9,00
Cephaly°-STX-Med
•
•
•
•
•
•
(square pulse, 60Hz, 300μsec,
max 14.99 mA, 20 min)
8,00
7,00
Migraine without aura: 2-8 attacks/mth
N= 5 centres (Belgian Headache Society)
N= 34 active stimulation
N= 33 sham stimulation
Duration: 1 month baseline
+3 months Cefaly°
Sponsored by STX-Med
6,00
5,00
4,00
50,00
%
*
2,00
Actifs
0,00
1
Actif
p=0.02
Placebo
1,00
Percentage of 50% responders
38.1%
3,00
Placebo
40,00
30,00
12%
20,00
10,00
0,00
Responder
Jean Schoenen
2
3
4
NEUROMODULATION in Chronic Migraine: summary
1. Non- or minimally invasive neurostimulation methods
rTMS
are effective in migraine (& cluster headache) prevention
2. Multi-site neurostimulation might be more effective
Supraorbital
TENS (Cefaly°)
3. Pathophysiology-based approaches may be more effective
Auricular
VNS
4. Double-blinded RCTs must are needed to prove efficacy
ONS
SPG
stim
5. More research is needed to understand mode of action,
identify responders and define the most effective methods
and stimulation protocols
Cervical
VNS
Jean Schoenen
Excitatory stimulations of the visual cortex
Excitatory intermittent theta burst rTMS (n=13 HV)
FIRST BLOCK N1P1
μV
7
6,5
p=0.03
6
Increase in VEP 1st block
amplitude
5,5
5
4,5
4
3,5
3
T0
T1
(before- rTMS)
T2
(immed post-rTMS)
(after 3 hrs)
SLOPE OF N1P1
0
-0,05
-0,1
P<0.05
-0,15
-0,2
-0,25
p<0.05
-0,3
-0,35
T0
(before- rTMS)
T1
(immed post-rTMS)
T2
(after 3 hrs)
(Viganò et al. EHMTIC 2012)
Inhibitory rTMS of the visual cortex
80% threshold
5 sec
Healthy
volunteers
(n=14)
7,5
7
5 sec
5 sec
30 minutes
FIRST BLOCK P1N2
μV
p=0.02
6,5
6
Decrease in VEP 1st block
amplitude
p=0.03
5,5
5
4,5
4
3,5
3
T0 rTMS)
(before-
0,2
(immedT1
post-rTMS)
(afterT23 hrs)
HABITUATION SLOPE OF P1N2
0,1
p=0.04
0
Decrease in habituation
-0,1
-0,2
-0,3
T0
(before- rTMS)
T1
T2
(immed post-rTMS)
(after 3 hrs)
Inhibitory rTMS or tDCS in migraine prevention
1Hz rTMS
Cathodal tDCS
N=26 (13 sham)
Target region:
visual cortex
Stimulation
Intensity:
1mA - 15 min.
N=27 (13 sham)
Target region: vertex
Total amount pulses: 500.
Session: 1/day per 5 days
Teepker et al. 2010
Sessions:
3/week for 8
weeks
Antal et al. 2011
Gammacore°: 2 x 90 sec at 15 min interval
Moderate-severe attacks (n=19 patients)
Pain-free at 2h:
21%
• in 2 out of 3 attacks: 33%
Pain relief at 2h:
47%
Mild attacks (n=8 patients)
Pain-free at 2h:
63%
Noninvasive vagus nerve stimulation as treatment for trigeminal allodynia.
Oshinsky ML, Murphy AL, Hekierski H Jr, Cooper M, Simon BJ.
Pain. 2014 May;155(5):1037-42.
Transcutaneous VNS
(1ms 5kHz sine wave pulses, at 25Hz for 2 min)
Glutamate in TNC
Periorbital allodynic threshold
Available non/minimally-invasive
neurostimulation methods
TRANSCRANIAL
PERIPHERAL
• Supraorbital nerve stimulation (SNS)
•
Transcranial magnetic stimulation
(TMS)
• Vagus nerve stimulation (VNS)
•
• Occipital nerve stimulation (ONS)
Repetitive transcranial magnetic
stimulation (rTMS)
•
Trancranial direct current stimulation
(tDCS)
Mode of action: largely unknown
Mode of action: partly known
Neurovascular Headaches &
the Sphenopalatine Ganglion (SPG)
Neurovascular
HEADACHE
V1 som.
SPG
GSP
SSN
SP
pial / dural
vessel
NO
Nucleus
tractus
solitarius
CGRP
V1 visc
Ach
Trigeminal
nucleus
caudalis
VIP
C2 som
BRAIN STEM
The trigemino-parasympathetic Lance & Goadsby 2005
reflex circuit
Effect on comorbid migraine
of (implanted) VNS in epileptic patients
Cephalalgia 2008
Mauskop A. Cephalalgia 2008
VNS in 6 patients
• excellent outcome in 2/3 chronic migraine
• good outcome in 2/2 chronic cluster headache
Jean Schoenen
Hypothalamic DBS in CH: the « moving » target
Authors
Stereotactic coordinates (mm)
OFF
Midline (X)
Posterior to
Inferior to
AC-PC midpoint (Y) AC-PC line (Z)
Leone et al. 2001
Schoenen et al.
2005
2
6
8
Franzini et al. 2003
Bartsch et al. 2008
2
3
5
2.2
3.24
3.69
Fontaine et al.
2009
With time: less posterior, less deep
ONS trial in Chronic Migraine (Silberstein et al. 2012):
SHORTCOMINGS
•
Patient selection 1: « Only patients who underwent a successful trial to determine proper lead
placement of the PNS device received implantation of the permanent system (n=157). »
•
Patient selection 2: « ...patients were selected according to the posterior location of their
headache. »
•
Surgical procedure: «... wide variety in placement of the leads – some « caudally along the
nerve ( !), ..some perpendicular, ..some uni- others bilateral »
•
Blinding: in the « control » group patients had no stimulation at all and thus no perception.
However, before randomization they underwent a « trial of the PNS system » with effective
stimulation!
•
Very low placebo response: « ...response rate in the Control group was 15%. »
•
Adverse effects: 1 patient out of 5 had persistent pain or numbness.
•
Negative trial for the 1° endpoint: « ... pain reduction was largely chosen as the primary endpoint
based .. »
Nonetheless, the CE Mark was obtained
Jean Schoenen
abnormal limbic
& pain control
thalamo-cortical
dysrhythmia
mitochondrial
ATP 
cortical
hyperresponsivity
metabolic strain
?
CSD
Trigeminovascular
system activation
Aura
Headache
Migraine
attack
What are the pathophysiological targets for neurostimulation in migraines ?
Transcranial
neurostimulation
abnormal limbic
& pain control
Peripheral
neurostimulation
thalamo-cortical
dysrhythmia
mitochondrial
ATP 
cortical
hyperresponsivity
metabolic strain
?
CSD
Trigeminovascular
system activation
Aura
Headache
Migraine
attack
Pilot trial of excitatory anodal tDCS of visual cortex
in episodic migraine
Viganò et al.
N° of patients =13 (tDCS 1mA per 15 mins) 2/wk 8wks;
Baseline= 2 months; Treatment= 2 months
Attack duration - hours
Migraine attacks
12,00
39%,
p=0.02
10,00
8,00
160
22%,
p = 0.04
140
120
100
6,00
80
60
4,00
40
2,00
20
0,00
0
BASELINE
TREATMENT
BASELINE
Migraine days
20
18
16
14
12
10
8
6
4
2
0
Drug intake
47%
p= 0.03
BASELINE
TREATMENT
TREATMENT
20,00
18,00
16,00
14,00
12,00
10,00
8,00
6,00
4,00
2,00
0,00
24%,
p = 0.09
BASELINE
TREATMENT
What is refractory migraine ?
(Towards a deﬁnition of intractable headache for use in clinical practice and trials
PJ Goadsby, J Schoenen, MD Ferrari, SD Silberstein, D Dodick. Cephalalgia 2006)
 2-3% in the general population
Jean Schoenen
Headache
Research
Unit
ACUTE RESPONSE
POSSIBLE PREVENTIVE RESPONSE (?)
ADVERSE EVENTS
SAFETY
 Sensory disturbances in maxillary division of the trigeminal
nerve (81% of patients)


- Cranial nerve exams to proactively identify sensory disturbances
- Most ranked mild/moderate and resolved within 3 months
- Surgical adverse events similar in number, severity and duration to other
trans-oral, gingival buccal surgical procedures
2 infections, resolved with antibiotics, none required explant
2 incidences of mild paresis at nasolabial fold
- 3 lead revisions

- 2 leads originally placed within PPF but not proximate to SPG
- 1 lead tip placed within maxillary sinus
2 explants
- 1 lead migration within the PPF within hours of implant
- 1 implant completed with Neurostimulator that was too long for the
anatomy; lead migrated out of the PPF within weeks of implant
Migraine pathophysiology – targets for neurostimulation
(LF=low attack frequency; HF= high frequency/chronic migraine)
Neurostimulation
(- inhibitory; + excitatory)
Cortical preactivation
& habituation
(e.g. visual cortex)
Abnormal Pain Control
(DNIC, insula, ACC..)
LF 
+ visual
HF 
- visual
LF 
HF 
- prefrontal/
insula
+ prefrontal/
insula
LF 
+ S1
HF 
- S1/
Sensori-motor matrix
S1,Temporal gyrus ?
.
temporal gyrus
Transcranial direct current stimulation (tDCS)
Anode: activates cortex
Cathode: inhibits cortex
Cluster Headache and the Sphenopalatine ganglion
(New York Medical Journal)
JC DEVOGHEL.
Cluster headache and sphenopalatine block.
Acta Anaesthesiol Belg. 1981;32(1):101-7.
N=120 patients; 85% with relief (…but recurrence)
Targets for attack treatment
MIGRAINE-like
HEADACHE
P
A
G
V1 som.
(referred pain
to face)
rTMS
5-HT1B/D
pial / dural
vessel
NO
V1 visc
NO
CGRP
+ glutamate
Trigeminal
nucleus
caudalis
Receptors
• serotonergic
BRAIN STEM
C2 som
• glutamatergic
(referred pain
• vanilloid
to neck)
• cannabinoid
• adenosine
• nociceptin
The TRIGEMINOVASCULAR SYSTEM :
• prostanoid
the main pain-signalling system of the viscera brain
• ..
Jean Schoenen
Theta burst (TB) and Quadripulse (QP) rTMS
Theta burst « intermittent » = excitatory
80% seuil
N=3
50Hz
2 sec
2 sec
10 sec
Huang et al Neuron 2005
x 19 = 190 sec = 600 pulses
80% seuil
N=4
ISI: 50ms; 20Hz
5 sec
Hamada et al J Physiol 2008
5 sec
5 sec
30 minutes
(Non-invasive) NEUROSTIMULATION methods
are promising in headaches, if…….
rTMS
Supraorbital
TENS (Cefaly°)
Auricular
VNS
ONS
SPG
stim
Cervical
VNS
« HOMO
NEUROMODULANDUS
» to prove their efficacy
1. Double-blinded
RCTs
2. Correct rationale
3. Research efforts to understand their mode of action
Jean Schoenen
Hypothalamus & cluster headache
Functional change
(PET-activity)
Volume 345:1428-1429
November 8, 2001
Number 19
(May et al Lancet 1998)
Structural change
(MRI voxel-based morphometry)
 6 mm posterior to
AC-PC midpoint
 2 mm left of midline
 8 mm below
commissural plane
Stereotactic Stimulation of Posterior
Hypothalamic Gray Matter in a Patient with
Intractable Cluster Headache
Massimo Leone, M.D.
Angelo Franzini, M.D.
Gennaro Bussone, M.D.
Carlo Besta Neurological Institute
20133 Milan, Italy
(May et al Nature Medicine 1999;5:836-838)
Jean Schoenen
Problème clinique
Functional change
(PET-activity)
Résultats Migraine
Résultats AVF
Perspectives
Hypothalamic DBS in CCH: synopsis of results
Auteur
Schoenen
D'Andrea
Leone
Benabid (A)
Starr
Owen
Nikkhah
Mateos (A)
Black (A)
Bartsch
Fontaine
Piacentino (A)
Total
Nb patients
6
3
16
1
4
1
2
2
2
6
11
4
58
Nb
rémission
2
2
10
1
0
1
0
1
0
2
3
3
25 (43%)
Nb
amélioration Durée de
>50%
suivi (ans)
1
4
0
2.5
0
4
0
1
2
1
0
0.7
0
2
1
1
2
2.6
1
1.4
3
1
1
>0.4
11 (19%)
= 62% améliorés
1.8
(Leone et al. NEJM 2001)
Hypothalamic DBS in CCH :
Adverse events
Patients
1 to 4
Oculomotor disturbances was the limiting factor
for voltage increase in all patients;
otherwise no side effects
5 (CM)
• Had panic attack & respiratory distress during
implantation which had to be interrupted.
• Had no attacks for 2 weeks, thereafter daily
attacks recurred.
• After unremarkable implantation except for
occurrence of an attack treated by DHE iv and
moderate hypertension, became comatous
• Remained in deep coma with bilateral mydriasis
and articial ventilation for 3 days, then died
• CT scan : intracerebral hemorrhage along
electrode tract
6 (BV)
Jean Schoenen
GIGA-NEUROSCIENCES
& NEUROLOGY DEPT
A Neurophysiological Model of Migraine Pathogenesis
Hyperresponsivity
of sensory cortices
Mitochondrial
ATP 
(EP habituation,
EEG synchronisation, connectivity)
Metabolic strain
3
Thalamo-cortical
Dysrhythmia
6
Limbic system
(amygdala, hypothalamus)
5
(EEG, HFO, MRI-DTI)
Upper brain stem
4
CSD
Ion channel/
pump
dysfunction
(FHM)
2
Trigeminovascular
system activation
Aura
1
Migraine
attack
Headache
Central sensitisation
of pain processing
7
(LEP, CHEPs, nBR,
temporal summation NWR)
8
amplifies & persists in
CHRONIC MIGRAINE
Hypothalamic DBS in CCH:
synopsis of results
Functional change
(PET-activity)
Authors
Schoenen
D'Andrea
Leone
Benabid (A)
Starr
Owen
Nikkhah
Mateos (A)
Black (A)
Bartsch
Fontaine
Piacentino (A)
Total
Nb patients
6
3
16
1
4
1
2
2
2
6
11
4
58
Nb
>50%
Nb
Follow-up
remissions improvement (years)
2
1
4
2
0
2.5
10
0
4
1
0
1
0
2
1
1
0
0.7
0
0
2
1
1
1
0
2
2.6
2
1
1.4
3
3
1
3
1
>0.4
25 (43%)
11 (19%)
= 62% improved
1.8
(Leone et al. NEJM 2001)
Lessons learnt from Hypothalamic DBS in drCCH
1. before starting the procedure, 12 patients were recruited:
while on the waiting list for 4 months, 10 went into remission !
→ « refractory » chronic cluster may
not be irreversibly refractory !!
2. The relevant target & mode of action are
not known
→ fiber tract stimulation ?
→ neuromodulatory effect
(Fontaine et al. Brain 2010)
3. hypothalamic DBS is an effective treatment for intractable
chronic cluster headache,
→ no controlled RCTs, but recurrence with stimulator OFF
→ but it is not a benign, riskless procedure
4.
Are there less invasive procedure ?
GIGA-NEUROSCIENCES
& NEUROLOGY DEPT
Jean Schoenen
Humanized Monoclonal anti-CGRP antibodies
ALD 403 (Alder Biopharamaceuticals)
• phase 1 completed April 2013
• phase 1B (or 2) « recruiting »: 1 dose IV, efficacy at 12 weeks
• objectif : >50% reduction of attacks with 1 subcut injection/month
LY2951742 (Arteaus Therapeutics)
• phase 1 completed
• phase 2 actively recruiting: RCT 150mg SC/ 2 weeks vs placebo
190 patients between June 2012 & October 2013
RN-307 (Pfizer-Rinat; sold to LABRY in January 2013 )
• phase 1 terminated January 2013
• phase 2 planned in 2013 (positioned for chronic migraine!)
PFO4427429: 2 phase 1 studies – development halted in August 2012
Monoclonal anti-CGRP receptor antibody
AMG-334 AA95 (AMGEN)
• prevents capsaïcine-induced cutaneous blood flow  in monkeys
• 2 phase 1 studies: tolerance, safety, effect on caps-ind blood flow
•
recruiting May 2013
Avoid risk factors
Use prophylactic treatment
in high frequency migraine
(excess cafeine, stress, estrogens..)
Manage comorbid disorders
Restrict acute drug consumption
& prefer NSAIDs to analgesics
(depression, anxiety, chronic pains..)
Prevention
CHRONIC MIGRAINE
Medication overuse
Preventive pharmacotherapy
icld. topiramate & valproate.....
-
Detoxification
+
OnabotulinumtoxinA
(≥ 2 cycles)
+
Integrated multimodal
treatment program
Transcranial
neuromodulation
Invasive
neuromodulation
EPISODIC MIGRAINE
+
+

presentation

Transcription

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