Chu Fort de France !!!

Manjit S Matharu

Headache Group, Institute of Neurology &
The National Hospital for Neurology and Neurosurgery
London
UK

St Jude Medical
Intractable Chronic Migraine Course
22nd February 2012

ICHD-‐II Diagnostic Criteria
Episodic attacks of headache lasting 4-‐72 hours with the following
features:

Headache has at least two of the following During headache at least one of the following:
characteristics:
Nausea and/or vomiting
Unilateral location
Photophobia and phonophobia
Pulsating quality
Moderate or severe pain intensity
Aggravation by routine physical activity

Further sub-‐classified on basis of frequency of headaches
Episodic migraine <15 days/month
Chronic migraine >15 days/month

Phases of Migraine

Time

Premonitory Aura Headache &
Resolution
Associated Features

Complex array of Aura symptoms occur with
symptoms reflecting focal headache:
cortical or brainstem – Always 18%
dysfunction – Sometimes 13%
– Never

Gradual evolution 69%
5-‐30minutes (<60minutes) Types of aura:
– Visual 99%
Usually before headache; – Sensory 31%
can be during or even – Language 18%
after headache – Motor 6%

Pain: • Unilateral or bilateral
• Throbbing, worsened by movement or
activity
• Cutaneous allodynia
• Neck stiffness/pain (80%)

Associated Sensory hyperexcitability
Symptoms: • Photophobia, phonophobia, osmophobia
• Motion sensitivity/vertigo

Gastrointestinal disturbance
• Nausea/Vomiting/Diarrhoea

MIGRAINE IS A FEATUREFUL HEADACHE

ICHD-‐IIR DIAGNOSTIC CRITERIA
Migraine headache occurring on
of medication overuse, not attributed to another disorder.

On During headache at least one
has at least two of the following characteristics: of the following:
Unilateral location Nausea and/or vomiting
Pulsating quality Photophobia and phonophobia
Moderate or severe pain intensity and/or treated and relieved by triptan(s) or
ergot before developing into a migraine
Aggravation by routine physical activity

1. ICHD 2006 Headache Classification Committee of the International Headache Society. Olesen J et al. Cephalalgia 2006;26:742

One-‐year prevalence of migraine is approximately 10%1
Migraine is more prevalent than common disorders such as
diabetes and asthma.2
In Europe and America, WHO estimates the prevalence of
migraine to be 6–8% in men and 15–18% in women.3
Chronic migraine affects 1.4-‐2.2% of people wordwide4
European Union

Migraine 50M Chronic Medically Refractory
Migraine Chronic Migraine
7.3M 1M?
1. Stovner LJ et al. Cephalalgia 2007;27:193–210. 2. World Health Organization. The Global Burden of Disease: 2004 update, Part 3, 28–37.
3. World Health Organization. Headache disorders, 2004. 4. Natoli JL, et al. Cephalagia 2010;30:599-‐609.

Migraine is one of the 20 most common causes of
years of life lived with disability1
WHO global burden of disease survey rates severe
migraine, along with quadriplegia, psychosis and
dementia, in a group as the most disabling chronic
disorders1
80% of migraine patients report severe or very severe
pain2
91% of migraine patients report disability2

1. Menken M,Munsat T, Toole J. Archives of Neurology 2000; 57:418-420.
2. Lipton RB et al. Headache. 2001.

91% of migraine patients report disability

Work/School Productivity 51%
Reduced by 50%

Unable to Do Chores/ 76%
Household Work

Household Work Productivity 67%
Reduced by 50%

Missed Family/Social 59%
Leisure Activity

0% 20% 40% 60% 80% 100%

Lipton RB et al. Headache. 2001.

Affects 1.4-‐2.2% of people wordwide1
Significantly more burdensome than episodic
migraine:2
80
70 71.7 * 67.2
61.4 *
60 56.5 *
Mean MSQ score

48.3
50 44.4
40 Chronic migraine
30 Episodic migraine

20
* P<0.0001
10
0
Unable to perform normal Difficult to perform Emotional effects
activities normal activities

1. Natoli JL, et al. Cephalagia 2010;30:599-‐609.
2. Blumenthal AM et al Lancet 2010

Migraine is an important public health problem
that is associated with substantial costs1–3
Direct costs Indirect costs
Medication Absence from work (absenteeism)
Reduced productivity at work
Consultation
(presenteeism)
Hospital admission Lost career opportunities
Diagnostic investigations Unemployment

In Europe, 41 million patients with migraine cost
the economy €27 billion overall in 20044

1. Steiner TJ et al. Cephalalgia 2003;23:519–527. 2. Hawkins K et al. Headache 2008;48:553 563. 3. Stewart WF et al. JAMA 2003;290:2443 2454. 4. Andlin-‐Sobocki
P et al. Eur J Neurol 2005;12(Suppl 1):1

Aura: Pathophysiological Hypotheses

Wolff’s vascular hypothesis Cortical spreading depression of Leao

Migraine aura secondary to cerebral Wave of excitation followed by inhibition that
hypoxia traverses the cortex at 3-‐6 mm/min

Hyperperfusion
Normal
CBF
Hypo-‐
perfusion

Aura Headache
2 4 6 8 10 12
Hours after angiography
Leao. J. Neurophysiol. 1944; Leao and Morison. J. Neurophysiol. 1945
Wolff. Headache and other head pain. 1963 Silberstein SD et al. Headache in Clinical Practice. 2nd ed. 2002

Xenon-‐133 Studies

Relative timing of CBF, Aura and
Headache

Hyperperfusion
Normal
CBF
Hypo-‐
perfusion

Aura Headache

2 4 6 8 10 12
Hours after angiography

Olesen et al, Ann Neurol 1990; Olesen, Migraine and other headaches: the vascular mechanisms. 1991; Olesen, The headaches. 1993

BOLD fMRI
(i) Initial cortical gray hyperemia,
with
(ii) Characteristic duration, and
(iii) Characteristic velocity, which is
(iv) Followed by hypoperfusion, and
shows
(v) Attenuated response to visual
activation, and
(vi) Recovery to baseline mean level,
and
(vii) Concurrent recovery of the
stimulus driven activation
(viii) Spreading phenomenon did not
cross prominent sulci

Hadjikhani et al, PNAS 2001

Cortical spreading depression rather than vasoconstriction is the basis of aura

Specific dorsal rostral pontine activation in migraine

Spontaneous Spontaneous Chronic
Episodic Migraine Episodic Migraine Migraine

Weiller et al, Nature 1995 Afridi et al, Arch Neurol 2005 Matharu et al, Brain 2004

CSD-‐triggered Trigeminovascular Activation?
Visually-‐triggered Migraine

BOLD-‐fMRI Study

Meninges

Trigeminal
nerve
Sphenopalatin
e ganglion Trigeminal
ganglion

Pain
Cao et al, Arch Neurol 1999; Cao et al, Neurology 2002
Superior salivatory
nucleus

Trigeminal BOLD signal changes in brainstem
nucleus
before occipital cortex signal changes
Adapted from (consistent with CSD) or onset of visual
Iadecola C. Nat Med 2002; Bolay H et al. Nat Med. 2002.
symptoms

Abnormal cortical Abnormal brain stem
activity function
Hyperexcitable brain Excitation of brain
( Ca++, Glu, Mg++) stem, PAG, etc.

Cortical Spreading Depression

Activation/Sensitization of TGVS Headache
Pain

Vasodilation Central Sensitization
Neurogenic
Inflammation

TGVS=trigemino-‐vascular system.
Adapted from Pietrobon D, Striessnig J. Nat Rev Neurosci. 2003;4:386-‐398.

Pharmacological
Treatments
Lifestyle
modification Psychological
and trigger and behavioural
management treatments

Education and Headache Surgical
Support Management treatments

• A high percentage of migraine patients report triggers
• 76% to 95% of patients report triggers1
• The mean number of triggers per patient is 6.71
90
80
70
Percentage of patients

60
50
40
30
20
10
0
Stress Hormones Missed Weather Sleep Perfume Neck Lights Alcohol Smoke Sleeping Heat Food
meals disturbance /odours pain late

Triggers

1. Kelman L. Cephalalgia 2007;27:394–402.

Non-‐specific Treatments Specific Treatments
• Paracetamol 1g • Triptans:
• NSAIDs (high-‐dose & soluble): Sumatriptan
Aspirin 600-‐900mgs Rizatriptan
Ibuprofen 600-‐800mgs Zolmitriptan
Naproxen 500-‐1000mgs Almotriptan
Tolfenamic acid 200mgs Eletriptan
Diclofenac 50-‐75mgs Naratriptan
• Opioids Frovatriptan
• Use concurrently with Prokinetics: • Ergot derivatives:
Domperidone 10-‐20mgs Ergotamine 1-‐2mg tablet or
Metoclopramide 10mgs suppository

Acute medications are used to provide relief of pain and associated symptoms1
Overuse of acute medication is common in individuals with chronic migraine1–3
20-‐30% in population; 50%–80% in headache clinics
Avoid opioids and ergots if possible in patients with frequent attacks4,6
Limit the use of acute medication to <3 days/week4,5

1. Silberstein SD et al. eds. Headache in Clinical Practice. 2nd ed. London: Martin Dunitz; 2002:69–146. 2. Lipton RB et al. Neurology 2003;61;154–155. 3. Wang SJ et
al. Pain 2001;89:285–292. 4. Diener HC et al. Lancet Neurol 2004;3:475–483. 5. Silberstein SD et al. eds. Headache in Clinical Practice. 2nd ed. London: Martin
Dunitz; 2002:69–111. 6. Bigal ME et al. Headache 2008;48:1157–1168

Develops through chronic overuse of acute medication taken to treat
headache or other pain1
Defined in the 2006 ICHD-‐IIR guideline as:2
– Headache on
– Regular overuse for >3 months of acute symptomatic treatment drugs,
during which time headaches have developed or worsened markedly

Overuse of all headache medication taken on an ad hoc basis to relieve pain
may result in medication overuse headache3
Most commonly associated with regular use of:
– Simple analgesics or NSAIDs on
– Opioids, ergots, combination analgesics or triptans on 3

Preventives less effective with concurrent medication (analgesic) overuse

1. Manack A et al. Headache 2009;49:1206
2. ICHD 2006 Headache Classification Committee of the International Headache Society. Olesen J et al. Cephalalgia 2006;26:742
3. World Health Organization (WHO) in collaboration with the European Headache Federation (EHF). J Headache Pain 2007;8:S1 .

Very common
Worldwide prevalence estimated to be 2%
60–85% patients seen in tertiary referral centres with
chronic daily headache have medication overuse
headache
Greater impact on daily functioning than episodic
migraine
In one study significant impairment or reduction in
function in 71% of days

Medication overuse1,2*

Preventative therapy Detoxification

FAIL

* 15 days/month: simple analgesics, combinations of drugs; or 10 days/month: combination analgesics, ergotamines, triptans, opioids, barbiturates.

1. Diener HC, Limmroth V. Lancet Neurol 2004;3:475–483.
2. Katsarava Z et al. Curr Neurol Neurosci Rep 2009;9:115–119.

Out-‐patient Setting Day Case or In-‐patient Setting
• Beta-‐blockers • Botox
– Propranolol • Greater occipital nerve blocks
• Antidepressants • Intravenous dihydroergotamine infusions
– Amitriptylline
• Serotonergic antagonist
Pizotifen
Methysergide
• Antiepileptic drugs (AEDs)
Topiramate
Valproate
Gabapentin
• Calcium channel antagonists
– Flunarizine
• Botox
• ACE inhibitors and ARBs
– Lisinopril
– Telmisartan
• Herbs, Vitamins and Minerals

Chronic Migraine is a relatively common primary headache
disorder
Migraine is a neurovascular disorder
Chronic Migraine is a very painful and highly disabling disorder
While there are numerous medical treatment options, a subset
of these patients is intractable to conventional medical
treatments.
There is a clear need for novel approaches for the management
of this highly disabled patient group

DEFINITION

• Headache on > 15 days/month for at least 3 months
• Affects 3-‐4% of the population
• Descriptive term
• Not diagnosis
• Encompasses heterogeneous group of primary and
secondary headache syndromes

CAUSES

After secondary
causes are ruled out

Primary headache
disorders

Chronic daily headache Episodic headache
Frequency Frequency <15 days/month

Short-‐duration chronic Long-‐duration chronic
daily headache daily headache With or without
Duration <4 hours or multiple Daily or near-‐daily headache medication overuse
discrete episodes lasting

Chronic tension-‐ New daily Hemicrania
Chronic migraine
type headache persistent headache continua

1. Silberstein SD et al. Neurology 1996;47:871

Migraine is typically most prevalent during the most productive
years of adulthood – between the ages of 20 and 50 years1
One study suggests that 75–90% of the total economic cost of
migraine is associated with absenteeism or reduced/lost
workplace productivity2
People with chronic migraine are less likely to be actively
working full-‐time, with an employment rate that is 81% of that
for patients with low-‐frequency headache3
For those patients with chronic migraine who can work, their
disorder results in a >50% reduction in productivity at work or
school4

1. Stovner LJ et al. Eur J Neurol 2006;13:333–345.
2. Brown JS et al. Headache 2005;45:1012
3. Stewart WF et al. Poster presented at the 14th International Headache Congress, September 10–13 2009, Philadelphia, PA, USA.
4. Munakata J et al. Headache 2009;49:498–508.

Primary diagnosis ICHD-‐II migraine or chronic migraine
Refractory Headaches cause signi quality of
life despite modi factors, and adequate
trials of acute and preventive medicines with established ef

1. Failed adequate trials of preventive medicines, alone or in
combination, from at least 2 of 4 drug classes:
a. Beta-‐blockers
b. Anticonvulsants
c. Tricyclics
d. Calcium channel blockers

2. Failed adequate trials of abortive medicines from the following
classes, unless contraindicated:
a. Both a triptan and DHE intranasal or injectable formulation
b. Either NSAID or combination analgesics
Disabling With signi disability
Schulman et al, Headache 2008;48:778-78

Weiner 1995
Started performing ONS in patients who responded to repeated greater occipital
nerve blocks

Weiner & Reed, 1999

Peripheral neurostimulation for control of intractable occipital neuralgia
Most of these patients were reported to had chronic migraine in subsequent

functional imaging study

Subsequently, numerous groups reported positive experiences in several primary and
secondary headache syndromes
Weiner R, Reed KL. Neuromodulation. 1999;2(3):217-21.

PRIMARY HEADACHES SECONDARY HEADACHES

Chronic migraine Occipital neuralgia
Chronic cluster headache Cervicogenic headache
Hemicrania continua Post-‐traumatic headache
SUNCT

• Open Label series
• ONSTIM Study
• PRISM Study
• St Jude Medical Study

OPEN LABEL CASE SERIES
Author Number Mean duration Number Follow up
of disorder improved (>50%) (yrs)
(yrs)
Popeney 25 10 22 1.5

Oh 10 12 10 0.5

Matharu 8 5.8 8 1.5

Schwedt 8 Not stated 3 1.5

TOTAL 51 43 (84%)

Medication overuse probably negatively affects outcome

Popeney& Alo Headache 2003; Oh et al. Neuromodulation 2004;
Schwedt et al Cephalalgia 2007; Matharu et al Brain 2004

Occipital Nerve Stimulation for the Treatment of Intractable
Chronic Migraine Headache

Multicentre, prospective, single blind, controlled feasibility
study
66 medically intractable chronic migraine
Failed at least 2 classes of preventives
Bilateral ONS
Randomised 2:1:1 to
– Adjustable stimulation (AS)
– Preset stimulation (PS)
– Medical Management (MM)
• Responder defined as:
– 50% reduction in headaches days/month
– 3-‐point drop (VRS 0-‐10) in pain intensity

Saper JR, et al Cephalalgia. 2011;31(3):271-285.

This prospective, randomized, double-blind, controlled study examined the efficacy and
safety of occipital nerve stimulation in adult chronic migraine patients.

Adjustable Stimulation (AS)
Patients
(Active, N=29 completed)
enrolled
who
responded to
an occipital
nerve block Preset Stimulation (PS)

2:1:1 ratio (Control, N=16 completed)

Medical Management (MM)
(Comparator, N=17 completed)

12 Weeks

Mean percent reduction (SD) Mean (SD) reductions in actual
in headache days per month headache days per month

Baseline 22.4+6.3 23.4+5.1 23.7+4.3
30% 8

27.0% 7
25%
(44.8) 6.7
6 (10.0)
20%
5

15% 4

3
10%
8.8% 2
(28.6)
5%
1 1.5
4.4% (4.6) 1
(19.1)
(4.2)
0% 0
Adjustable Preset Medical Adjustable Preset Medical
Stimulation (AS) Stimulation (PS) Management Stimulation (AS) Stimulation (PS) Management
(MM) (MM)

Reduction (SD) in Responder rates
overall pain intensity
2 50%

40%
1.5 1.6 39%

30%
1

20%

0.5 0.5
0.6 10%

6%
0%
0 0%
Adjustable Preset Medical Adjustable Preset Medical
Stimulation (AS) Stimulation (PS) Management Stimulation (AS) Stimulation (PS) Management
(MM) (MM)

Fifty-six device-related adverse events occurred in 36 out of 51 patients.

Adverse Events % Adverse Events %

Lead migration/dislodgement 24% Implant site (IPG) hematoma 2%

Therapeutic product ineffective 16% Implant site (IPG) irritation 2%
Implant site (lead/extension tract) Implant site (lead/extension tract)
14% 2%
infection inflammation
Incision site complications 8% Lead fracture 2%

Implant site (IPG) infection 4% Migraine 2%

Implant site (IPG) pain 4% Post-procedural nausea 2%

Neck pain 4% Post-procedural pain 2%

Burning sensation 2% Rash 2%

Discomfort 2% Sensation of pressure 2%

Extension migration/dislodgement 2% Stitch abscess 2%

High impedance 2% Suture-related complications 2%

Hypotension 2% Tenderness 2%

Lipton RB, et al. PRISM study: Occipital nerve stimulation for treatment-refractory migraine. Presented at: 14th

Congress of the International Headache Society; September 10-13, 2009; Philadelphia, PA.

Multicentre, prospective, double blind, controlled study
132 migraine patients ( 6 days/month, 4 hrs each)
Failed at least 2 acute and 2 preventive treatments
Bilateral ONS
Trial stimulation for 5-‐10 days
Randomised in 1:1 ratio for 12 weeks
– Active stimulation (<12.7mA, 60 Hz, 250 sec)
– Sham stimulation (>1mA, 2Hz, 10 sec for 1sec/90 mins)
• All subjects has active stimulation from 12 weeks onwards
• Primary end-‐point: change in headache days/month at 12
weeks

This prospective, randomized, double-blind, controlled study examined the safety and
efficacy of occipital nerve stimulation for the preventive treatment of refractory migraine in
132 patients in 13 centres.

Patients
enrolled Active Stimulation

1:1 ratio
Trial stimulation to Two-year follow-up
assess its predictive conducted to assess
value safety.

Sham Stimulation
(Control)

5–10 days 12 Weeks

Primary efficacy measure: reduction in migraine days per month

Mean reduction (SD) in Mean percent reduction in
migraine days per month migraine days per month
6 100%

90%
5.5
5
(8.7) 80%

70%
4
3.9 60%

3 (8.2) 50%

40%
2
30%

20% 27%
1 20%
10%

0 0%
Active Stimulation Sham Stimulation Active Stimulation Sham Stimulation

A two-year follow-up was conducted to assess safety. Complications included the following:

Adverse Events Number of Cases

Non-‐targeted area sensory symptoms 18.0%

Implant site pain/discomfort 17.3%

Infection 15.0%

Incision site pain/discomfort 7.9%

Lead migration 6.8%

In this study, occipital nerve stimulation did not produce a
statistically significant benefit in the active vs. control group.
However, subgroup analysis identified several predictors of a
favourable response to stimulation, including the following:
Not overusing headache medications
Not using opiates
A positive response to a trial stimulation

Silberstein et al. The Safety and Efficacy of Occipital Nerve Stimulation for the Management of Chronic
Migraine. Presented at: 15th Congress of the International Headache Society; June 23-‐26, 2011; Berlin.

Multicentre, prospective, double blind, controlled study
157 chronic migraine patients, with VAS score > 6/10
Headache pain is posterior head pain or pain originating in
the cervical region
Failed at least 2 acute and 2 preventive treatments
Bilateral ONS
Randomised in 2:1 ratio for 12 weeks
• All subjects has active stimulation from 12 weeks onwards
• Primary end-‐point: 50% VAS with no increase in average
headache frequency or duration.
• Secondary end-‐points: MIDAS-‐disability days, Headache
Index, Zung Pain and Distress Scale, Patient Satisfaction,
Safety

Patient
Enrolled

Group A: Active

PNS
Implanted
2:1 Ratio
Randomize and
Device Activation Group B: Control (Blind)

80-‐ to 90-‐day roll in 4-‐week visit 12-‐week visit 24-‐week visit 52-‐week visit

Control pts were blinded using pt programmers that did not communicate with the IPG,
plus pts were also told that a range of settings were being tested.
Neither the patient nor the study investigator knew whether the patient was active or
control (“double-blind”) during the first 12 weeks.

Primary Outcome
50% VAS reduction with no increase in average headache frequency or duration

18
16
P=0.21
14
12
10
8
6
4
2
0
Active Sham

Continuous Proportion Responder Analysis Based on Mean Daily Average Pain Intensity
VAS Measurements With No Increase in Average Headache Frequency or Duration

met
Control Group Active Group
% reduction protocol
% responders % responders p-‐value1
Patients Achieving Various Levels of Pain Relief from baseline objective
(n=52) (n=105)
(>10% dif.)2

100% 0,0% 38,5% 69,5% <0,001 Yes
Percentage of Patients

10,0% 30,8% 58,1% 0,001 Yes
80%
20,0% 19,2% 41,9% 0,005 Yes
60%
30,0% 17,3% 37,1% 0,011 Yes

40% 40,0% 15,4% 25,7% 0,143 No

50,0% 13,5% 17,1% 0,553 No
20%
60,0% 9,6% 11,4% 0,731 No

0% 70,0% 1,9% 4,8% 0,664 No
0% 20% 40% 60% 80% 100%
80,0% 1,9% 3,8% 1 No
Percentage of Pain Reduction
90,0% 0,0% 1,0% 1 No

Control (n=52) Active (n=105) 100,0%
1 Two-sided test of no difference
2 One-sided lower 95% confidence bound

Significance demonstrated at 30% reduction in pain (p-value=0.011)

Patient diaries recorded whether or not patients had a headache each day, the
daily average headache intensity, and the daily headache duration, in hours.
Data was used to identify Headache Days, defined as a day with a headache
lasting four or more hours with at least moderate intensity.

Mean Baseline and Change From Baseline in Headache Days per month—Last Value Carried Forward

Visit Control Group (n=52) Active Group (n=105) P-Value

Baseline

Mean ( std) 17,1 ( 8.2) 20,5 ( 7,6) 0,011

Week 12

Mean Change1 -4,3 (25,1%) -7,3 (35,6%) 0,02

Difference (95% CI) -3,0 (-5,5, -0,5)

1 Adjusted for study center, prior use of alternative therapy, and baseline

Significant reduction -3.0 days in Headache Days (per month) between Active & Control
groups (p=0.02)

The patient-recorded average pain intensity in their electronic diary using a
VAS with a 100 mm line to indicate severity progression.
Patients were asked to record these measurements on each day that they
experienced headache.

Mean Baseline and Change From Baseline in Daily Average Pain Intensity VAS Measurements By Visit —Last Value Carried Forward


Baseline

Mean ( std) 56,0 ( 17,2) 59,5 ( 16,2) 0,221

Week 12

Mean Change1 -6,1 -13,6 0,006

Difference (95% CI) -7,5 (-12,8, -2,2)


The active group had significant reduction in relief in average pain intensity on days
with pain vs. the control group (P=0.006).

The Migraine Disability Assessment (MIDAS) is a questionnaire which
measures headache-related disability during the previous 90 days based on
five disability questions.

Mean Baseline and Change From Baseline in the MIDAS Headache Questionnaire Sum of Items 1 – 5—Last Value Carried Forward


Baseline

Mean ( std) 152,7 ( 77,1) 158,4 ( 76,8) 0,664

Week 12

Mean Change1 -20,4 -64,6 <0,001

Difference (95% CI) -44,1 (-65,4, -22,9)

The MIDAS questionnaire was completed at baseline and 12 weeks after the system was
implanted. The reduction in disability of 44.1 days between the groups is statistically
significant (p<0.001).

The differences reported between the Active and Control Groups for both measures were
statistically significant (p<0,001).

Percentage of Pain Relief Since Surgery Percentage of Patients Satisfied
With Headache Relief
100%
100%

80%
80%

60% 60%
51,4%
42,1%
40% 40%

17,2% 19,2%
20% 20%

0% 0%

Control Group (n=52) Active Group (n=105)
Control Group (n=52) Active Group (n=105)

Active group participants reported (on average) 42,1% pain relief and 51,4% of them
were satisfied with their level of pain relief.

A total of 76 patients experienced one or more anticipated adverse events during the first open label study phase (50 in the Active
group and 26 in the Control group).
A total of 114 adverse events occurred in these 78 patients. All events were reviewed and classified into the appropriate category.
According to this classification, 42 events were classified as hardware-related, 28 events were classified as biological-related, 28
events were classified as stimulation-related, and 16 events were classified as non-device/procedure-related.

Total Total
Adverse Event + (N=153) Adverse Event + (N=153)
n (%) n (%)

Lack of efficacy/return of symptoms 15 (9,8%) Nausea/vomiting 3 (2,0%)

Persistent pain and/or numbness at IPG/lead site 15 (9,8%) Expected post-‐op pain/numbness at IPG/lead
2 (1,3%)
site
Normal battery depletion 12 (7,8%) Skin erosion 2 (1,3%)
Unintended stimulation effects 10 (6,5%) Hematoma 1 (0,7%)
Lead migration 9 (5,9%) Seroma 1 (0,7%)
Battery failure 8 (5,2%) Wound site complications 1 (0,7%)
Lead breakage/fracture 5 (3,3%) Pain or swelling at IPG site–trauma-‐related 1 (0,7%)
Infection 4 (2,6%) Allergic reaction to surgical materials 1 (0,7%)
Battery passivation 3 (2,0%) Device malfunction–IPG 1 (0,7%)
Device malfunction–programmer 3 (2,0%) IPG migration 1 (0,7%)

MECHANISM OF ACTION

Anatomical Convergence of Trigeminal and Cervical input

MECHANISM OF ACTION

Functional Convergence of Trigeminal and Cervical input

Bartsch et al, Brain 2002

MECHANISM OF ACTION
1. Effect at Segmental level

Gate-Control Theory of Pain
Activation of somatosensory
afferent A- nerve fibres blocks
nociceptive transmission at a
segmental level

2. Involvement of Supraspinal
Structures

Gate control at supraspinal level

Activation of descending
antinociceptive pathways

3. Neuroplasticity

MECHANISM OF ACTION

Paraesthesia-related rCBF changes

Significant activation in the dorsal rostral pons, anterior
cingulate cortex and left pulvinar

Matharu et al, Brain 2004

Patients with chronic migraine are often left without effective treatment,
leading lives that are painful and compromised.1
Occipital nerve stimulation involves a minimally invasive surgical procedure.
While the body of evidence is still emerging, ONS appears to be promising in
managing the pain and disability of intractable chronic migraine.
Frequent causes of adverse events are related to lead migration.
Predictors of response and long-‐term outcome are largely unknown
Reserved for medically-‐intractable and highly disabled patients
Performed in experienced headache centres

1. Saper JR, Dodick DW, Silberstein SD, McCarville S, Sun M, Goadsby PJ; ONSTIM Investigators. Occipital nerve stimulation for the treatment

of intractable chronic migraine headache: ONSTIM feasibility study. Cephalalgia. 2011;31(3):271-285.

A total of 76 patients experienced one or more anticipated adverse events during the first open label study phase (50 in the
Active group and 26 in the Control group).
A total of 114 adverse events occurred in these 78 patients. All events were reviewed and classified into the appropriate
category. According to this classification, 42 events were classified as hardware-related, 28 events were classified as biological-
related, 28 events were classified as stimulation-related, and 16 events were classified as non-device/procedure-related.

Total
Category Adverse Event + (N=153)
n (%)
Patients with one or more anticipated AE 76
Normal battery depletion 12 (7,8%)
Lead migration 9 (5,9%)
Battery failure 8 (5,2%)

Hardware-‐Related Lead breakage/fracture 5 (3,3%)
Battery passivation 3 (2,0%)
Device malfunction–programmer 3 (2,0%)
Device malfunction–IPG 1 (0,7%)
IPG migration 1 (0,7%)
Lack of efficacy/return of symptoms 15 (9,8%)
Stimulation-‐Related Unintended stimulation effects 10 (6,5%)
Nausea/vomiting 3 (2,0%)

A total of 76 patients experienced one or more anticipated adverse events during the first open label study phase (50 in the Active
group and 26 in the Control group).
A total of 114 adverse events occurred in these 78 patients. All events were reviewed and classified into the appropriate category.
According to this classification, 42 events were classified as hardware-related, 28 events were classified as biological-related, 28
events were classified as stimulation-related, and 16 events were classified as non-device/procedure-related.

Total
Category Adverse Event + (N=153)
n (%)

Patients with one or more anticipated AE 76

Persistent pain and/or numbness at IPG/lead site 15 (9,8%)

Infection 4 (2,6%)

Expected post-‐op pain/numbness at IPG/lead site 2 (1,3%)

Skin erosion 2 (1,3%)

Biological Hematoma 1 (0,7%)

Seroma 1 (0,7%)

Wound site complications 1 (0,7%)

Pain or swelling at IPG site–trauma-‐related 1 (0,7%)

Allergic reaction to surgical materials (sutures, antibiotic, anesthesia) 1 (0,7%)

Non-‐Device-‐Related Other 16 (10,5%)

65

Patient selection for
successful therapy

Zaza Katsarava

Headaches

Headache = 80%

Migraine = 15-18%

TTH = 30-70%

Chronic headache 3-4%

Chronic Headache

Chronic Headache = HA

The reasons to define chronic vs. episodic HA

Individual burden
Burden of social environment
Co-morbidities
Costs

Chronic Headache

The prevalence of chronic headache is about 3-4%
For systemic review see Stovner et al, 2006

69

After Secondary
Causes Are Ruled
Out Primary
Headache
Disorders

Chronic Headache Episodic Headache
Frequency Frequency <15
days/month days/month
Chronic Daily
Short-Duration Headache (Long
Chronic Daily With or Without
Headache Duration)
Medication
Duration <4 hours or Daily or near-‐daily Overuse
multiple discrete
episodes headache
lasting
Chronic
New Daily
Chronic Tension- Hemicrania
Persistent
Migraine Type Continua
Headache
Headache

Silberstein SD et al. Neurology. 1996;47:871-‐875.
Dodick D. N Engl J Med. 2006;354:158-‐165.

70

CM = migraine on 15 days/month

CTTH = TTH on 15 days/month

Visual analogue scale

71


72

73

Migraine
With With
migraine migraine

features features

Without
Without migraine
migraine fetures
features
Triptan
TTH?
Abortive Migraine? TTH
Abortive Migraine

time

74

IHS 2004,
CM = migraine on 15 days/month
No medication overuse

Diary is needed
Rely on patients recall
Too restrictive

75

IHS 2006,
CM =
Migraine
HA on
8 HA days is migraine
No medication overuse

76

Allergan, PREEMPT,
CM =
Migraine
HA on
50% is migraine

77

American way to do it, Silberstein-‐Lipton
CM =
Migraine
HA on

No diary is needed

78

Population-based sample
N = 18,000

Mail/phone interviews

9968 respondents
Response rate = 63.4%

Annual follow-ups

79

Chronic Migraine definition PREEMPT
( migrainous)

Chronic Migraine definition IHS, 2006
( migrainous)
ICHD-2 definition2
0.4%
Chronic Migraine definition S-L
0.5% ( migrainous)
1.9% Silberstein-Lipton Criteria3

Chronic Daily Headache
1. Katsarava et al. Cephalalgia, 2011.
2.8% (
2. Olesen J et al. Cephalalgia.
2006;26(6):742-746.
3. Silberstein SD et al. Headache.
1994;34:1-7.

CM according to S-L = 185

IHS MIG criteria
IHS CM = 45

The rest, 185 – 45 = 140

TTH criteria
IHS TTH = 40

What is the rest? N = 100

81

CM is NOT just more MIG

82

Low Medication
Definition Females Age BMI Education Overuse*
CM-‐I ( 70% 44 26.4 70% 27%

CM-‐II (
69% 45 26.5 73% 31%
migrainous, including overuse)

CM-‐III ( any migrainous) 71% 46 25.9 78% 11%

High-‐frequency EM (9-‐14 days/month) 70% 40 24.3 66% 13%

Low frequency EM (0-‐8 days/month) 66% 40 24.1 60% 16%

Katsarava et al. Migraine Trust
GHC = German Headache Consortium.
2008. Abstract.

83

70 *
60 Chronic migraine
Episodic migraine
* *
50
41
40 * * * * *
%

31 30
30 * 26 *
* 19
20 15
10

0
Allergies or Sinusitis Asthma Bronchitis Depression Chronic Anxiety High Blood High Obesity Arthritis
Hay Fever Pain Pressure Cholesterol

• Chronic migraine was defined as reported ICHD-2 diagnosis of migraine and
days/month
*p<0.05.
Data from the American Migraine Prevalence and Prevention (AMPP) study. Buse D et al. J Neurol Neurosurg Psychiatry. 2010; In press.

84

9944 responders (of 18.000 = 55%)

Prevalences:
HA : cHA = 255, eHA = 5361, noHA = 4040, missing = 288
MIG : cMIG = 108, eMIG = 1601, noHA = 4030, 4205
excluded
TTH : cTTH = 50, eTTH = 1203, noHA = 4030, 5283 excluded
Combination of MIG and TTH and unclassifiable excluded

Chronic back pain = 1290

85

N cBP OR 95% CI
No HA 3259 316 (9.6%) Referent = 1

Episodic HA 4903 807 (16.5%) 2.3 2.0 – 2.7

Chronic HA 229 146 (63.7%) 14.5 10.7 – 20.0

Age (in years) 1.03 1.02 – 1.04

Males 3925 489 (12.5%) Referent = 1

Females 4466 801 (17.9%) 1.4 1.2 – 1.6

No daily drinking 7437 1125 (15.1%) Referent = 1

Daily drinking 954 143 (15.0%) 1.1 0.9 – 1.4

No smoking 5850 808 (13.8%) Referent = 1

Smoking 2541 466 (18.3%) 1.4 1.2 – 1.6

High education 2879 279 (9.7%) Referent = 1

Low education 5512 981 (17.8%) 1.6 1.3 – 1.8

BMI 4667 602 (12.9%) Referent = 1

BMI 25-‐30 2717 417 (15.3%) 1.1 1.0 – 1.3

BMI 1007 239 (23.7%) 1.8 1.5 – 2.1

86

N cBP OR 95% CI
No Headache 3238 314 (9.7%) Referent = 1
Episodic MIG 1462 279 (19.1%) 2.6 2.1 – 3.2
Chronic MIG 100 66 (66%) 15.8 10.2 – 24.5
Age (in years) 1.03 1.02 – 1.04
Males 2410 250 (10.4%) Referent = 1
Females 2390 409 (17.1%) 1.4 1.1 – 1.7
Daily driking 608 67 (11.0%) 0.97 0.7 – 1.3
Smoking 1471 243 (16.5%) 1.5 1.2 – 1.8
Low education 3327 520 (15.6%) 1.6 1.3 – 2.0
BMI 2556 304 (11.9%) Referent = 1
BMI 25-‐30 1622 214 (13.2%) 1.1 0.9 – 1.3
BMI 622 124 (19.9%) 1.6 1.2 – 2.0

87

N cBP OR 95% CI
No Headache 3238 314 (9.7%) Referent = 1

Episodic TTH 1104 170 (15.4%) 2.1 1.7 – 2.7

Chronic TTH 47 29 (61.7%) 13.7 7.4 – 25.3

Age (in years) 1.03 1.02 – 1.04

Males 2435 247 (10.1%) Referent = 1

Females 1954 266 (13.6%) 1.4 1.1 – 1.7


Daily driking 618 79 (12.8%) 1.2 0.9 – 1.6


Smoking 1295 176 (13.6%) 1.4 1.1 – 1.7


Low education 3013 397 (13.2%) 1.5 1.2 – 1.9

BMI 4923 207 (4.2%) Referent = 1

BMI 25-‐30 2857 188 (6.6%) 1.3 1.02 – 1.6

BMI 1067 102 (9.6%) 2.0 1.5 – 2.6

Central sensitization
Blink reflex and pain evoked
potentials in MOH
Transient increase, normalizing
again after withdrawal
(Ayzenberg et al. 2006)

50
45
40
35
30
25
20
15
10
Tr

A n

Tr

A n
C

Ep rols

na M

na M
on

ip

ip
m

ta

lg OH

ta

lg OH
t

ig

es

es
ra

ic

ic
in

s
M
e

M
O

O
H

H

1. Central disinhibition

2. Stimulation of 6. PAIN
meningeal sensory
nerve (trigeminal)

3. Release of Thalamus

pain-
Nerve enhancing TNC
Vessel
dilation neuropeptid
es, such as Spinothala 5. Activation of
Peptide
CGRPTrige mic cortical pain
release minal
Inflammation track centers via
TrigeminGangli
al Nerve on thalamus
4. Activation of trigeminal
nucleus caudalis can result
in central sensitization
1. Pietrobon D et al. Nat Rev Neurosci. 2003;4:386-
CGRP = calcitonin gene-related peptide; TNC = trigeminal nucleus 398.
candalis. 2. Pietrobon D. Neuroscientist. 2005;11:373-386.

Post-traumatischer Kopfschmerz
Reversible VBM changes in chronic posttraumatic
headache

91

Low- High-
frequency frequency Chronic
No migraine
episodic episodic migraine
migraine migraine

Transformation is often gradual and can evolve over several months or
years1,2
Transformation is neither inexorable nor irreversible; spontaneous or
induced remissions are possible and common1,2
Transformation happens in some but not all episodic patients (~3% of
episodic migraine sufferers)2

1. Lipton RB. Neurology. 2009;72:S3-S7.
2. Bigal ME, Lipton RB. Curr Opin Neurology
2008;21:301-308.

Right diagnosis
Multimodal approach
Patient education
Psychological co-morbidities
Physiotherapy
Stop medication overuse (if any)
Preventive medication
Topiramate, BOTOX
Betablockers, Valproate etc.

Right diagnosis

Do not miss secondary headache
Do not mix CM and CTTH
Do not miss MOH
Do consider psychiatric co-morbidities

Chronic headache with medication overuse

???
Medication overuse headache

Suggestion for IHS classification

17. Chronic migraine due to .....
17.1. divorce
17.2. hyperactive child
17.3. sick and bed fasted parent
17.4. ………….

Medication
Overuse1,2

Preventive
Therapy Detoxification

* 15 days/month: simple analgesics, combinations of drugs; or 10 days/month: 1. Diener HC, Limmroth V. Lancet Neurol. 2004;3:475-483.
combination analgesics, ergotamines, triptans, opioids, barbiturates. 2. Katsarava Z et al. Curr Neurol Neurosci Rep. 2009, 9:115-119.

Education
Withdrawal
Preventive medication
Psychological treatment
Follow up

Single analgesic Ergotamines
Triptans
Combination analgesics

3

Patients With Headache (%)
100
90
Headache Intensity

80
2 70
60
50
40
1
30
20
10
0 0
1 2 3 4 5 6 7 8 9 1011121314 1 2 3 4 5 6 7 8 9 1011121314
Days of Withdrawal Therapy Days of Withdrawal Therapy

Diener HC, Limmroth V. Lancet Neurol. 2004;3:475-483.

Controls
Abrupt withdrawal Controls
Abrupt withdrawal
Prophylaxis
only Prophylaxis
only
No. of Headache Days/Month

30
from the start from the start
60

Headache Days/Month
Patients Exhibiting a
P = 0.01
25

50% Reduction in
50

20 40

(%)
15 30

10 20

5 10

0 0
0 1 2 3 4 5 6 7 8 9 10 11 12 Month 3 Month 5 Month 12

Months Following Withdrawal Months Following Withdrawal

Hagen K et al. Cephalalgia. 2009;29:221-232.

1. Everything that is true for conservative
treatment is also true for ONS
1. Education
2. Realistic goals
3. Take your time
4. Give time to patients

Conservative treatment

1. Betablocker (Metoprolol 100-200mg)
2. Calcium channel antagonist (Flunarizine 5-10mg)
3. Valproic acid 600-900mg
4. Topiramate 50-200mg
5. BOTOX

Topiramate Efficacy
Mean Change in Headache
Days
Primary
2 Placebo Topiramate endpoint
0.7
1 0.5
0.1 0.2
0
-1 -0.6
-2
-3 -2.9
-3.0*
-4 -3.5*
-5 -4.7**
-6 * p < 0.05 vs placebo -5.4**
** p < 0.01 vs placebo
Wk 4 Wk 8 Wk 12 Wk 16 Last 4 wks
Patien
26 25 20 15 27
ts
32 30 25 24 32

BOTOX Efficacy
Mean Change in Headache Days

Peripheral Nerve Stimulation for
the Management of Intractable
Chronic Migraine
Implant Techniques

Laurence Watkins
Consultant Neurosurgeon

National Hospital for Neurology & Neurosurgery, London

Intractable Chronic Migraine Course, Leiden February 2012

Introducing a novel procedure

Theoretical background and peer support
Registered with NICE (on hold until CE mark awarded)
Likely to now “re-‐visit” guidance
Business case to Trust – novel procedures protocol
Support from Trust management, R&D, host PCT (Funding Body)
Cadaveric workshops
Developing a PCT “application pack” and a strict protocol for
Multidisciplinary assessment
Rigorous consent procedure so that patients are aware of relative novelty of the procedure
Documented audit of complications and outcome

First Meeting (with implanter)

Check have been fully assessed in Headache Neurology Clinic
(chronic, disabling, intractable)
General fitness & airway satisfactory; reflux?
MRI ? (because can’t have MRI once ONS is implanted)
Any major surgery planned ? (because restriction of monopolar
diathermy once ONS implanted)
Explaining procedure

Discussion with patient

Known risks:
may not help
infection requiring removal of implant
electrode migration
neck stiffness
breakage or failure of components
tethering to skin or muscle
skin erosion
Clearance from Funding Body/PCT

Hospital Stay

Typically 3-‐4 days, but could be reduced
if pre-‐op assessment, implant activation
and patient education all done in clinic

Postoperative programming of the
implant
Teaching patient to use the “handset
control” +/-‐ recharger

Follow up clinics

Typically 4 in first year
Joint assessment with Headache Neurologist
and Specialist Nurse, additional post-‐operative
appointments in Neurosurgery Clinic.
Sometimes all combined in day care unit
Gradually refine the settings to get best
response (headache diary), without patient
discomfort

Stages of the operation
Insertion of electrodes
LA + Sedation
Test stimulation of electrodes
Awake
Insertion of battery and tunnelling of leads
Asleep (GA with LMA)
Alternatively GA throughout
if difficult airway or reflux (or patient preference)
USA: 2 stage procedure

Occipital Nerve Anatomy
PNS electrode should overlay the course
of the occipital nerves
Epifascial plane
Direction of insertion
Medial to lateral
Lateral to medial
Fluoroscopic control
Anchoring

Lead Placement (Anchor Midline)

Main technical challenges

Placing electrodes to get paraesthesiae

Anchoring/looping the electrodes

Minimising infection risk

Not “instant” result so can’t really do “trial electrodes”

Technique first described for
Occipital Neuralgia

Then for Transformed (Chronic)
Migraine

Lead Placement (Anchor at
Mastoid)

Anchoring the Electrodes

Attach to the hard underlying fascia
Use non-‐absorbable sutures
Choice of anchor
long (tubular) anchor, butterfly
anchor
others commercially available
Anchor direction—no kinks
Loops at “every level” (cervical, chest and
behind IPG)

Lead Tunneling and IPG
Placement: Gluteal,
Infraclavicular, or Abdominal

CAUTION: It is important to place strain relief loops at the site of the lead-extension connection and at the
IPG connection.

Migraine Study Key Adverse
Events Summary

Adverse Event Controlled Phase Open-Label Phase

Persistent pain, numbness at implant site 23 (15%) 15 (10%)

Lead migration 20 (13%) 9 (6%)

Unintended stimulation effects (migration?) 7 (4%) 10 (7%)

Infection 7 (4%) 4 (3%)

Skin erosion 6 (4%) 2 (1%)

Lead breakage, fracture 2 (1%) 5 (3%)

“Out” Migration

Migration of occipital nerve stimulation electrode leads
Both left and right leads have migrated away from their original position
Try reprogramming prior to revision surgery

Extreme “Out” Migration

“Extreme” migration of occipital nerve stimulation electrode lead
The electrode lead has migrated all the way toward the generator pocket

“In” Migration

A. B.

“In” migration of the occipital nerve stimulation electrode lead.
A. Original electrode lead position, B. Electrode position 8 month after insertion
with “in” migration to the contralateral side of the neck

Insertion Plane
Too Deep Too Superficial

Skin Erosion

Erosion of occipital nerve stimulation electrode lead

PRECAUTION: Skin Erosion—Because PNS leads used to aid in the management of intractable chronic
migraine are placed under the skin, be careful to place the lead at the appropriate depth to avoid the risk
of skin erosion.

Minimizing the Possibility of
Erosion—Electrode Insertion
Plane

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