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1. 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
2. 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
3. Phases of Migraine
Time
Premonitory Aura Headache &
Resolution
Associated Features
4. 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%
5. 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
6. 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
7. 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.
8. 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.
9. 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.
10. 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
11. 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
12. 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
13. 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
14. 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
15. 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
16. 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
17.
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.
18. Pharmacological
Treatments
Lifestyle
modification Psychological
and trigger and behavioural
management treatments
Education and Headache Surgical
Support Management treatments
19. • 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.
20. Pharmacological
Treatments
Lifestyle
modification Psychological
and trigger and behavioural
management treatments
Education and Headache Surgical
Support Management treatments
21. 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
22. 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 .
23. 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
24. 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.
26. Pharmacological
Treatments
Lifestyle
modification Psychological
and trigger and behavioural
management treatments
Education and Headache Surgical
Support Management treatments
27. 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
28.
29. 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
30. 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
31. 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.
32. 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
33. 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
34.
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.
36.
• Open Label series
• ONSTIM Study
• PRISM Study
• St Jude Medical Study
37. 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
38. 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.
39. 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
40. 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)
42. 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%
43. 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
44. 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
45. 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
46. 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%
47. 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
48. 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
49. 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.
50.
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
51. 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)
52. 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)
53. 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
Visit Control Group (n=51) Active Group (n=99) P-Value
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)
1 Adjusted for study center, prior use of alternative therapy, and baseline
The active group had significant reduction in relief in average pain intensity on days
with pain vs. the control group (P=0.006).
54. 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
Visit Control Group (n=52) Active Group (n=105) P-Value
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)
1 Adjusted for study center, prior use of alternative therapy, and baseline
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).
55. 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.
56. 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%)
58. MECHANISM OF ACTION
Functional Convergence of Trigeminal and Cervical input
Bartsch et al, Brain 2002
59. 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
60. 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
61. 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.
62.
63. 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%)
64. 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%)
67. Chronic Headache
Chronic Headache = HA
The reasons to define chronic vs. episodic HA
Individual burden
Burden of social environment
Co-morbidities
Costs
69. 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. 70
CM = migraine on 15 days/month
CTTH = TTH on 15 days/month
73. 73
Migraine
With With
migraine migraine
Visual analogue scale
features features
Without
Without migraine
migraine fetures
features
Triptan
TTH?
Abortive Migraine? TTH
Abortive Migraine
time
74. 74
IHS 2004,
CM = migraine on 15 days/month
No medication overuse
Diary is needed
Rely on patients recall
Too restrictive
75. 75
IHS 2006,
CM =
Migraine
HA on
8 HA days is migraine
No medication overuse
76. 76
Allergan, PREEMPT,
CM =
Migraine
HA on
50% is migraine
77. 77
American way to do it, Silberstein-‐Lipton
CM =
Migraine
HA on
No diary is needed
82. 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. 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. 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
88. 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
89. 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.
91. 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.
95. 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. ………….
96. 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.
98. 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.
99. 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.
100. 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
104. 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
105. 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
106. 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
107. 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
108. 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
109. 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
110. 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
111. 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
115. 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
116.
117.
118.
119. 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”
126. 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)
127. 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.
129. “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
130. Extreme “Out” Migration
“Extreme” migration of occipital nerve stimulation electrode lead
The electrode lead has migrated all the way toward the generator pocket
131.
132.
133. “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
135. 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.